Cortical Surface Matching of the Fetal Brain Pre and Post Fetal Surgery for Open Spina Bifida

Introduction: Fetal surgery has become a clinical reality, even for non-lethal conditions such as open spina bifidayelomeningocele, the spinal cord extrudes into a cereberospinal fluid (CSF) filled sac 1, 2. It is associated with brain anomalies such as hindbrain herniation and variable degrees of ventriculomegaly. Prenatalrepair yields better outcomes compared to postnatal surgery3. Nonetheless, mechanical tissue damage of brain parenchyma due to ventriculomegaly and damage to the neural tracts lead to abnormal white matter development, as demonstrated by diffusion weighted imaging studies4-9. This may lead to altered gyrification patterns in MMC patients. Gyrification, measured by magnetic resonance imaging (MRI), correlates with motor and cognitive function in infants, children and adolescents with who have undergone postnatal closure 6. Evaluation of cognitiveand motor function in fetuses who have had prenatal surgery, is performed only after birth, with deficits becoming more evident with increasing age. Clinicians therefore urgently need early fetal brain imaging methods that can predict the cognitive and motor challenges that fetuses may encounter after birth. We aim to demonstrate that longitudinal quantitative MRI measurement of cortical gyrification is possible, before and after repair. We will also demonstrate the curvature (curvedness and shape index) of cerebellum and ventricles before and after surgery. Methods: T2-weighted single-shot fast spin-echo (SSFSE) was performed of the fetal brain in multiple containing an axial, coronal and sagittal planewith 3mm slice thicknesson women with , both before surgery (n=12, 23+6 1+7 weeks, (22+1–25+6)) and after surgery (n=12, 26+1 1+3 weeks, (24+1– 29+4))acquisition time thirty-forty minutes. Initial diagnosis of open spina bifida was made on mid-trimester ultrasound. Fetuses affected by aneuploidy or with structural anomalies outside the CNS were excluded. A novel automated super resolution reconstruction (SRR) algorithm10, 11 was used to build 3D volumes of the fetal brain based on the 2D stacks that were acquired in different directions. Rigid slice-to-volume registration correcting for fetal motion was used to generate an SRR image in standard anatomical orientation, from which we automatically segmented white matter, ventricles, and cerebellum using template brain segmentations12, 13. 14make us of 12Brain masks for pre-operative SRR volumes were resampled from their corresponding post-operative MMC masks after affine and non-rigid alignment. All masks where manually corrected and meshes were generated using ITK-Snap14. A rigid coherent point drift algorithm was applied to find an initial correspondence for the intrasubject cortical, cerebellar and ventricle regions before and after surgery. Joint spectral matching (JSM) was then used to find the correspondence for the intrasubject at those two different time points. In JSM a dual layered graph was produced whereby layers correspond to the surface of the white matter, cerebellum or ventricles of each subject. The correspondence links from the initial intrasubject matching, connecting both layers to produce a set of shared eigenmodes of the surfaces. After mapping the post-operative surface to the pre-operative surface using JSM, we computed the change in parameters at the vertex of each mesh to explore longitudinal cortical gyrification, and curvature (curvedness and shape index) of the 12. Results: Figure 1 illustrates five spectral modes for the white matter, ventricles and cerebellum of a fetus before surgery (24 weeks), and therafter (26 weeks). Although the meshes are quite different in the three-dimensional space, with respect to different levels of folding, variation in shape, surface area and volume, they have similar representations in the spectral domain. Figure 2 shows the curvedness and shape index in the white matter, cerebellum and ventricles before and after fetal surgery. JSM allows us to map the mean curvatures of each mesh to compute changes in the mean and to generate the shape index.Figure 3 shows maps of mean curvature of a fetus pre and post-surgery. Positive values are depicted in red/yellow and represent gyri (convex structures), and negative values in blue represent sulci (concave) structures. JSM allows mapping of mean curvatures from the post-op to the pre-op space, computing the changes in mean curvature between these two time points in the pre-op space.Figure 4 illustrates the shape index histogram for white matter, showing the differences in gyri and sulci between the pre and post-operative MMC brain.Discussion: Surface-based matching provides additional information about changes in growth and gyrification of the fetal brain compared to measurement of total volume and shape change. This may be useful in evaluating changes in cerebral growth of MMC fetuses before and after fetal surgery. Spectral graph matching is a promising tool for matching shapes with significant differences in cortical folding, surface area, and volume, but with similar representations in the spectral domain such as depicted with fetuses before and after surgery12, 15. Future work may be able to better explore the physiological and mechanical properties contributing to the differences observed in brain growth and development in the context of fetal surgery. Conclusion: Novel analysis of fetal longitudinal correspondence of white matter, and development of specific regions of the brain as secondary gyri emerges, in the context of fetal surgery is demonstrated. This tool allows the measurement of the shape and growth of the white matter surface may help establish longitudinal growth trajectories. References: 1. Rethmann, C., et al., Evolution of posterior fossa and brain morphology after in utero repair of open neural tube defects assessed by MRI. Eur Radiol, 2017. 27(11): p. 4571-4580. 2. Zarutskie, A., et al., Prenatal brain imaging for predicting need for postnatal hydrocephalus treatment in fetuses that had neural tube defect repair in utero. Ultrasound Obstet Gynecol, 2019. 53(3): p. 324-334. 3. Adzick, N.S.T., E.A.; Spong, C. Y.; Brock III, J. W.; Burrows, P. K.; Johnson, M. P.; Howell, R. N.; Farrell, J. N.; Dabrowiak, M.E.; Sutton, L.N.; Gupta, N.; Tulipan, N.B.; D’Alton, M.E.; Farmer, D.L., A Randomised Trial of Prenatal versus Postnatal Repair of Myelomeningocele. N Engl J Med, 2011. 364: p. 993-1004. 4. Juranek, J., et al., Neocortical reorganization in spina bifida. Neuroimage, 2008. 40(4): p. 1516-22. 5. Juranek, J. and M.S. Salman, Anomalous development of brain structure and function in spina bifida myelomeningocele. Developmental Disabilities Research Reviews, 2010. 16(1): p. 23-30. 6. Treble, A., et al., Functional significance of atypical cortical organization in spina bifida myelomeningocele: relations of cortical thickness and gyrification with IQ and fine motor dexterity. Cereb Cortex, 2013. 23(10): p. 2357-69. 7. Hasan, K.M., et al., White matter microstructural abnormalities in children with spina bifida myelomeningocele and hydrocephalus: a diffusion tensor tractography study of the association pathways. J Magn Reson Imaging, 2008. 27(4): p. 700-9. 8. Mignone Philpott, C., et al., Diffusion-weighted imaging of the cerebellum in the fetus with Chiari II malformation. AJNR Am J Neuroradiol, 2013. 34(8): p. 1656-60. 9. Woitek, R., et al., Fetal diffusion tensor quantification of brainstem pathology in Chiari II malformation. Eur Radiol, 2016. 26(5): p. 1274-83. 10. Ebner, M., et al., An Automated Localization, Segmentation and Reconstruction Framework for Fetal Brain MRI, in Medical Image Computing and Computer Assisted Intervention – MICCAI 2018. 2018. p. 313-320. 11. Ebner, M., et al., An automated framework for localization, segmentation and super-resolution reconstruction of fetal brain MRI. NeuroImage, 2019. 12. Orasanu, E., et al., Cortical folding of the preterm brain: a longitudinal analysis of extremely preterm born neonates using spectral matching. Brain Behav, 2016. 6(8): p. e00488. 13. Kuklisova-Murgasova, M., et al., A dynamic 4D probabilistic atlas of the developing brain. Neuroimage, 2011. 54(4): p. 2750-63. 14. Yushkevich, P.A., et al., User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage, 2006. 31(3): p. 1116-28. 15. Lomabert, H., Spopring J., and Siddiqi K., Diffeomorphic spectral matching of cortical surafaces. Inf Process Med Imaging, 2013. 7917: p. 376-289

Pulmonary hypertension in congenital diaphragmatic hernia: Antenatal prediction and impact on neonatal mortality

Objective: To determine the prevalence of pulmonary hypertension (PAH) in left-sided congenital diaphragmatic hernia (CDH); how we could predict it; and how PAH contributed to the model for mortality prediction. Study Design: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day (d) 1, 7, and at discharge. Studied predictors of PAH were: observed/expected-lung/head-ratio (o/e LHR), liver-herniation, fetoscopic endoluminal tracheal occlusion (FETO), and gestational age (GA) at delivery. The combined effect of pre- and postnatal variables on mortality was modeled by Cox regression. Results: Of the 197 neonates, 56 (28.4%) died. At d1, 67.5% (133/197) had PAH and 61.9% (101/163) by d7. Overall, 6.4% (9/141) had PAH at discharge. At d1, o/e LHR (odds ratio (OR) 0.96) and FETO (OR 2.99) independently correlated to PAH (areas under the curve [AUC]: 0.74). At d7, PAH significantly correlated only with the use of FETO (OR 3.9; AUC: 0.65). None were significant for PAH at discharge. Combining the occurrence of PAH with antenatal biomarkers improved mortality prediction (p = 0.02), in a model including o/e LHR (HR: 0.94), FETO (HR: 0.35), liver herniation (HR: 16.78), and PAH (HR: 15.95). Conclusions: Antenatal prediction of PAH was only moderate. The postnatal occurrence of PAH further increases the risk of death. Whereas this may be used to counsel parents in the postnatal period, our study demonstrates there is a need to find more accurate antenatal predictors for PAH

The ANTENATAL multicentre study to predict postnatal renal outcome in fetuses with posterior urethral valves: objectives and design

Abstract Background Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Methods Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1–β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. Results In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Conclusions Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV

Obstetric outcome after fetal reduction to singleton pregnancies

Objective To study the outcome after fetal reduction or selective termination to singleton pregnancies for various indications.status: publishe

Can fetal ultrasound result in prenatal diagnosis of Prader-Willi syndrome?

OBJECTIVE: To define fetal ultrasound characteristics triggering an antenatal diagnosis of Prader Willi syndrome (PWS). METHODS: Retrospective analysis of sonographic characteristics retrieved from obstetric ultrasound records. All children (n=11) had a postnatal genetically confirmed diagnosis of PWS. RESULTS: All patients (n=11) showed at least one aspecific abnormality on prenatal ultrasound. Ten out of eleven (90.9 %) had decreased fetal movements, 7 (63.6%) presented in breech position, 7 (63.6%) had severe intra-uterine growth restriction (<5th centile) and 4 (36.4%) showed a polyhydramnios. Immobile flexed limbs and clenched hands were seen in one patient (9.1%). Severe growth restriction combined with polyhydramnios favors the diagnosis in 3/11 cases. CONCLUSION: Prenatal sonographic phenotype of PWS includes decreased fetal movements, fetal malpresentation, severe intra-uterine growth restriction and polyhydramnios. These findings are not specific to PWS, but the combination of some of them (especially severe intra-uterine growth restriction and polyhydramnios) can prompt clinicians to perform invasive testing leading to a molecular cytogenomic diagnosis prenatally.status: publishe

Prenatal diagnosis of absent pulmonary valve syndrome in association with 22q11 deletion

Objective. To describe the prenatal sonographic appearances in cases of absent pulmonary valve syndrome and the importance of investigating the presence of 22q11 deletion. Methods. We describe 2 cases, which were referred because of a suspicion of a cardiac malformation. In both cases, a large anechoic mass emerging from the right ventricle was visualized and identified as an aneurysmal dilatation of the pulmonary trunk with hypertrophy of the right ventricle. The diagnosis of tetralogy of Fallot with absent pulmonary valve syndrome and a secondary diverticular dilatation of the pulmonary artery was made. A review of the literature revealed another 18 cases of prenatal diagnosis of absent pulmonary valve syndrome with or without knowledge of chromosomal abnormalities. Results. Pathologic examinations confirmed the diagnosis of absent pulmonary valve syndrome in both cases. Final results of fetal karyotyping revealed a 22q11 deletion in the first case. Conclusions. An abnormal 4-chamber view with an aneurysmal dilatation of the pulmonary trunk should suggest the diagnosis of this rare congenital anomaly. Perinatal death occurs in more than 60% of cases and is usually associated with hydrops fetalis, the presence of other malformations, or both. Even in the absence of extracardiac malformations, investigation for 22q11 deletion in cases of conotruncal cardiac abnormalities is recommended.status: publishe

Prenatal diagnosis of isolated ventricular noncompaction of the myocardium

Isolated ventricular noncompaction (IVNC), also known as spongy ventricular myocardium, is a rare cardiomyopathy characterized by numerous ventricular trabeculations and deep intertrabecular recesses, thought to be due to an arrest in cardiac embryogenesis. The clinical spectrum varies from asymptomatic patients to cardiac failure with neonatal death. Prenatal diagnosis has been reported sporadically. We report a case of IVNC diagnosed prenatally at 31.5 weeks' gestation. First-trimester screening revealed increased nuchal translucency, but the parents declined invasive prenatal diagnosis. Routine sonography at 31.5 weeks showed marked cardiomegaly with no other anomalies. Fetal echocardiography revealed numerous trabeculations and deep intertrabecular recesses within the cardiac ventricular myocardium. Diagnosis of ventricular noncompaction was made. Postnatal echocardiography confirmed the diagnosis and showed suboptimal left ventricular function. Isolated ventricular noncompaction is rare but needs to be considered in the differential diagnosis of left ventricular hypertrophy. Isolated ventricular noncompaction can be associated with other cardiac and extracardiac disorders, particularly neuromuscular. Diagnosis is made by echocardiography and color Doppler sonography, showing direct blood flow from the ventricular cavity into deep intertrabecular recesses.status: publishe

Late termination of pregnancy practice in two tertiary case centres in Flanders, Belgium

status: publishe

Persistent right umbilical vein in trisomy 18: Sonographic observation

Persistent right umbilical vein is a rare entity, with a prevalence of about 0.22%.(1) The intrahepatic variant is observed most frequently, and 72% of the fetuses are normal.(2,3) In a very limited number of cases, the persistent right umbilical vein terminates directly into the right atrium, without passage into the liver. The majority of fetuses with this variety have multiple congenital malformations.(2)status: publishe