Endovascular treatment of patients with stroke caused by anterior cerebral artery occlusions.

BACKGROUND: Occlusion of the anterior cerebral artery (ACA) is uncommon but may lead to significant disability. The benefit of endovascular treatment (EVT) for ACA occlusions remains uncertain. METHODS: We included patients treated with EVT and compared patients with ACA occlusions with patients who had internal carotid artery (ICA) or proximal (M1/M2) middle cerebral artery (MCA) occlusions from the MR CLEAN Registry. Primary outcome was the modified Rankin Scale score (mRS). Secondary outcomes were functional independence (mRS 0-2), National Institutes of Health Stroke Scale (NIHSS) score, delta-NIHSS (baseline minus NIHSS score at 24-48 h), and successful recanalization (expanded thrombolysis in cerebral infarction (eTICI) score 2b-3). Safety outcomes were symptomatic intracranial hemorrhage (sICH), periprocedural complications, and mortality. RESULTS: Of 5193 patients, 11 (0.2%) had primary ACA occlusions. Median NIHSS at baseline was lower in patients with ACA versus ICA/MCA occlusions (11, IQR 9-14; versus 15, IQR 11-19). Functional outcome did not differ from patients with ICA/MCA occlusions. Functional independence was 4/11 (36%) in patients with ACA versus 1949/4815 (41%) in ICA/MCA occlusions; median delta-NIHSS was - 1 (IQR - 7 to 2) and - 4 (IQR - 9 to 0), respectively. Successful recanalization was 4/9 (44%), versus 3083/4787 (64%) in ICA/MCA occlusions. Mortality was 3/11 (27%) versus 1263/4815 (26%). One patient with ACA occlusion had sICH; no other complications occurred. CONCLUSION: In this cohort ACA occlusions were uncommon. Functional outcome did not differ between patients with ACA occlusions and ICA/MCA occlusions. Prospective research is needed to determine feasibility, safety, and outcomes of EVT for ACA occlusions.

Efficacy of Levetiracetam as Add-On Therapy in the Treatment of Seizures in Neonates.

INTRODUCTION: There is no consensus regarding the efficacy of add-on therapy with levetiracetam (LEV) in the treatment of seizures in neonates. The aim of this study was to evaluate the efficacy of add-on therapy with LEV for achieving >80% seizure reduction after phenobarbital (PB) treatment. METHODS: Retrospective cohort study of near term neonates admitted to the neonatal intensive care unit with EEG-confirmed seizures despite treatment with PB as first-line therapy and using LEV as 2nd-, 3rd- or 4th-line treatment. Antiseizure medication was administered according to national guidelines. All neonates were monitored with 2-channel amplitude-integrated electroencephalography. The total seizure burden in minutes, 2 h before and 4 h after administration of LEV, was calculated using raw EEG. Primary outcome was the efficacy of LEV in achieving >80% seizure reduction. The efficacy of additional midazolam (MDZ) and lidocaine (LDC) was also calculated. RESULTS: A total of 47 full-term neonates were included. The mean total loading dose of LEV was 40 mg/kg (36-44 mg/kg). Seizure etiology consisted of hypoxic-ischemic encephalopathy (n = 11), hemorrhagic or ischemic stroke (n = 16), central nervous system infection (n = 8), genetic (n = 8), metabolic disorders (n = 3), and unknown (n = 1). Following LEV administration, >80% seizure reduction was observed in 17% (8/47) of neonates, whereas it was 23% (6/26) after MDZ and 92% (23/25) after LDC administration. DISCUSSION: Although the cumulative loading dose of LEV was low and the group of infants studied was heterogeneous, the efficacy of LEV as add-on therapy for the treatment of seizures in neonates was limited. The highest seizure reduction rate was seen after LDC administration.

Clinical phenotype of FOXP1 syndrome: parent-reported medical signs and symptoms in 40 individuals.

BACKGROUND: The first studies on patients with forkhead-box protein P1 (FOXP1) syndrome reported associated global neurodevelopmental delay, autism symptomatology, dysmorphic features and cardiac and urogenital malformations. The aim of this study was to assess the prevalence of congenital abnormalities in an unbiased cohort of patients with FOXP1 syndrome and to document rare complications. METHODS: Patients with FOXP1 syndrome were included, mostly diagnosed via whole-exome sequencing for neurodevelopmental delay. A parent-report questionnaire was used to assess medical signs and symptoms, including questions about features rated as most burdensome by patients and their family. RESULTS: Forty individuals were included, 20 females and 20 males. The mean age at assessment was 13.2 years (median 8.5 years; range 2-54 years; ≥18 years n = 7). Seven adults were included. All patients had developmental problems, including cognitive, communication, social-emotional and motor delays. The most prevalent medical signs and symptoms include delayed bladder control, sleeping problems, hypermetropia, strabismus, sacral dimple, undescended testes, abnormal muscle tone and airway infections. The most burdensome complaints for patients with FOXP1 syndrome, as perceived by parents, include intellectual disability, impaired communication, behaviour problems, lack of age-appropriate self-reliance, attention problems and anxiety. According to parents, patients have quite similar reported symptoms, although incontinence, obsessions and a complex sensory profile have a higher ranking. CONCLUSION: The results of this study may be used to further guide medical management and identify patient priorities for future research targeted on those features of FOXP1 syndrome that most impair quality of life of patients and their families.

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in SCN2A and KCNQ3-related epilepsy in neonates.

PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

Recurrent Intracranial Hypertension in a Toddler with Graves' Disease.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure without an evident cause. Obesity and the female sex have been recognized as risk factors for the development of this syndrome. Until now, Graves' disease has only been described in the literature as the probable cause of IIH in 7 patients. This report describes the case of a young girl with Graves' disease presenting with symptoms of intracranial hypertension (IH). CASE PRESENTATION: A 21-month-old girl presented with progressive symptoms of poor weight gain and bilateral exophthalmos. She also experienced difficulty sleeping, diarrhea multiple times per day, irritability, and heat intolerance. Laboratory investigation showed elevated free T4, fully suppressed TSH, and elevated anti-TSH antibodies, consistent with a diagnosis of new-onset Graves' disease. She was successfully treated with monotherapy thiamazole, titrated to the lowest possible dose of 1.25 mg once daily with normalization of thyroid function tests within 3 months of treatment initiation. After 18 months of treatment, her condition unexpectedly deteriorated as papilledema and slight esotropia were found at a routine checkup. An MRI and lumbar puncture showed increased intracranial pressure, but no underlying anatomical cause for the IH was found. Acetazolamide therapy was started, and papilledema in both eyes resolved within weeks. Unfortunately, papilledema has recurred several times over the following 2 years when attempts were made to decrease the acetazolamide dose. DISCUSSION/CONCLUSION: This case report is the first to describe a very young patient who developed significant IIH in the chronic stage of Graves' disease. IIH development seemed to be related to the progression of the Graves' ophthalmopathy, rather than initiation of thiamazole therapy or fluctuations in serum fT4 levels.

Combining advanced MRI and EEG techniques better explains long-term motor outcome after very preterm birth.

BACKGROUND: Preterm born children are at high risk for adverse motor neurodevelopment. The aim of this study was to establish the relationship between motor outcome and advanced magnetic resonance imaging (MRI) and electroencephalography (EEG) measures. METHODS: In a prospective cohort study of 64 very preterm born children, the motor outcome was assessed at 9.83 (SD 0.70) years. Volumetric MRI, diffusion tensor imaging (DTI), and EEG were acquired at 10.85 (SD 0.49) years. We investigated associations between motor outcome and brain volumes (white matter, deep gray matter, cerebellum, and ventricles), white matter integrity (fractional anisotropy and mean, axial and radial diffusivity), and brain activity (upper alpha (A2) functional connectivity and relative A2 power). The independence of associations with motor outcome was investigated with a final model. For each technique, the measure with the strongest association was selected to avoid multicollinearity. RESULTS: Ventricular volume, radial diffusivity, mean diffusivity, relative A2 power, and A2 functional connectivity were significantly correlated to motor outcome. The final model showed that ventricular volume and relative A2 power were independently associated with motor outcome (B = -9.42 × 10-5, p = 0.027 and B = 28.9, p = 0.007, respectively). CONCLUSIONS: This study suggests that a lasting interplay exists between brain structure and function that might underlie motor outcome at school age. IMPACT: This is the first study that investigates the relationships between motor outcome and brain volumes, DTI, and brain function in preterm born children at school age. Ventricular volume and relative upper alpha power on EEG have an independent relation with motor outcome in preterm born children at school age. This suggests that there is a lasting interplay between structure and function that underlies adverse motor outcome.

Prenatal exome sequencing: A useful tool for the fetal neurologist.

Prenatal exome sequencing (pES) is a promising tool for diagnosing genetic disorders when structural anomalies are detected on prenatal ultrasound. The aim of this study was to investigate the diagnostic yield and clinical impact of pES as an additional modality for fetal neurologists who counsel parents in case of congenital anomalies of the central nervous system (CNS). We assessed 20 pregnancies of 19 couples who were consecutively referred to the fetal neurologist for CNS anomalies. pES had a diagnostic yield of 53% (10/19) with most diagnosed pregnancies having agenesis or hypoplasia of the corpus callosum (7/10). Overall clinical impact was 63% (12/19), of which the pES result aided parental decision making in 55% of cases (6/11), guided perinatal management in 75% of cases (3/4), and was helpful in approving a late termination of pregnancy request in 75% of cases (3/4). Our data suggest that pES had a high diagnostic yield when CNS anomalies are present, although this study is limited by its small sample size. Moreover, pES had substantial clinical impact, which warrants implementation of pES in the routine care of the fetal neurologist in close collaboration with gynecologists and clinical geneticists.

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.

PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Longitudinal Follow-Up of Children Born Preterm: Neurodevelopment From 2 to 10 Years of Age.

Objective: To investigate the rate and stability of impairments in children born preterm by assessing (1) early and school-age outcome in four developmental domains and (2) individual changes in outcome at both timepoints. Design: Prospective, longitudinal cohort study in children born in 2006-2007, <32 weeks' gestation. Follow-up at 2 and 10 years of age included standardized neurological, motor, cognitive and behavioral assessments. Children were categorized as having no, mild or moderate-severe impairment in these four domains. A composite impairment score was composed and the number of domains with impairments counted. For each child, individual outcomes at both timepoints were compared. Results: Follow-up at both time-points was available in 71/113(63%) children. At group level, there were no significant changes in the severity of impairments per domain. However, at individual level, there were less children with a mild abnormal composite score at 10 years of age (44 vs. 20%; p = 0.006), and more with a moderate-severe abnormal composite score (12 vs. 35%; p = 0.001). Especially children with normal/mild outcome at 2 years were likely to shift to other outcome categories over time. Conclusions: Children with early severe impairment are likely experiencing impairments later on, but early normal/mild abnormal outcomes should be interpreted with care, considering the large individual shifts over time. Long-term follow-up in all children born very preterm should therefore be continued to at least school-age.

Associations between Neonatal Magnetic Resonance Imaging and Short- and Long-Term Neurodevelopmental Outcomes in a Longitudinal Cohort of Very Preterm Children.

OBJECTIVE: To assess associations between neonatal brain injury assessed by magnetic resonance imaging and cognitive, motor, and behavioral outcomes at 2 and 10 years of age, in a longitudinal cohort of children born very preterm. STUDY DESIGN: There were 112 children born at <32 weeks of gestation who participated in a longitudinal prospective study on brain injury and neurodevelopmental outcome. Using the Kidokoro score, neonatal brain injury and altered brain growth in white matter, cortical and deep gray matter, and the cerebellum were assessed. Cognitive, motor, and behavioral outcomes were assessed during follow-up visits at both 2 (corrected) and 10 years of age. RESULTS: After adjusting for perinatal factors and level of maternal education, the global brain abnormality score was associated with cognition (B = -1.306; P = .005), motor skills (B = -3.176; P < .001), and behavior (B = 0.666; P = .005) at 2 years of age, but was not associated with cognition at 10 years of age. In the subgroup of children with a moderate-severe global brain abnormality score, magnetic resonance imaging was independently associated with cognitive impairment at 10 years of age. For children with milder forms of brain injury, only birth weight and level of maternal education were associated with cognitive outcomes. CONCLUSIONS: Neonatal brain injury, assessed by a standardized scoring system, was associated with short-term neurodevelopmental outcomes, but only with motor skills and behavior in childhood. Environmental factors, such as level of maternal education, become more important for cognitive development as children grow older, especially for children with relatively mild neonatal brain injury.

Intracerebral hemorrhage in a neonate with an intragenic COL4A2 duplication.

Intracerebral hemorrhage is rare in term born neonates. Besides several non-genetic risk factors, pathogenic variants in COL4A1 and COL4A2 have been described to play a role in the pathophysiology of neonatal intracerebral hemorrhage. To the best of our knowledge, no intragenic COL4A2 duplications have been reported in humans to date. We report a neonate with intracerebral hemorrhage and a de novo intragenic COL4A2 duplication. Although it is not clear yet whether this genetic factor fully explains the clinical phenotype, it may have contributed at least as a risk factor for cerebral hemorrhage. Screening for intragenic COL4A1 and COL4A2 duplications as part of collagen IV diagnostics should be considered as part of the fetal and neonatal work-up for unexplained cerebral hemorrhages and to collect more evidence of the pathogenicity of this genetic mechanism.

The degree of prematurity affects functional brain activity in preterm born children at school-age: An EEG study.

Prematurely born children are at higher risk for long-term adverse motor and cognitive outcomes. The aim of this paper was to compare quantitative measures derived from electroencephalography (EEG) between extremely (EP) and very prematurely (VP) born children at 9-10 years of age. Fifty-five children born <32 weeks' of gestation underwent EEG at 9-10 years of age and were assessed for motor development and cognitive outcome. Relative frequency power and functional connectivity, as measured by the Phase Lag Index (PLI), were calculated for all frequency bands. Per subject, power spectrum and functional connectivity results were averaged over all channels and pairwise PLI values to explore differences in global frequency power and functional connectivity between EP and VP children. Brain networks were constructed for the upper alpha frequency band using the Minimum Spanning Tree method and were compared between EP and VP children. In addition, the relationships between upper alpha quantitative EEG results and cognitive and motor outcomes were investigated. Relative power and functional connectivity were significantly higher in VP than EP children in the upper alpha frequency band, and VP children had more integrated networks. A strong positive correlation was found between relative upper alpha power and motor outcome whilst controlling for gestational age, age during EEG recording, and gender (ρ = 0.493, p = 0.004). These results suggest that 9-10 years after birth, the effects of the degree of prematurity can be observed in terms of alterations in functional brain activity and that motor deficits are associated with decreases in relative upper alpha power.

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics and - Preliminary Dynamics of Neuroprotectant 2-Iminobiotin in Healthy Subjects.

BACKGROUND: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia. OBJECTIVE: The present first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without Captisol® as a solubilizing agent. METHODS: This randomized, double-blind, placebo-controlled, dose-escalation study was executed in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or placebo were infused every 4 h for 6 administrations in total. RESULTS: Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol® were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not to be affected by the presence of Captisol®. CONCLUSION: Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile with a small volume of distribution, with time-independent PK. Preliminary PD characterization of repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in the currently pursued indication of cerebral hypoxia-ischemia.

Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia.

BACKGROUND: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising neuroprotective agent additional to therapeutic hypothermia to improve the outcome of these neonates. METHODS: In an open-label study, pharmacokinetics and short-term safety of 2-iminobiotin were investigated in neonates treated with therapeutic hypothermia. Group A (n = 6) received four doses of 0.16 mg/kg intravenously q6h. Blood sampling for pharmacokinetic analysis and monitoring of vital signs for short-term safety analysis were performed. Data from group A was used to determine the dose for group B, aiming at an AUC0-48 h of 4800 ng*h/mL. RESULTS: Exposure in group A was higher than targeted (median AUC0-48 h 9522 ng*h/mL); subsequently, group B (n = 6) received eight doses of 0.08 mg/kg q6h (median AUC0-48 h 4465 ng*h/mL). No changes in vital signs were observed and no adverse events related to 2-iminobiotin occurred. CONCLUSION: This study indicates that 2-iminobiotin is well tolerated and not associated with any adverse events in neonates treated with therapeutic hypothermia after perinatal asphyxia. Target exposure was achieved with eight doses of 0.08 mg/kg q6h. Optimal duration of therapy for clinical efficacy needs to be determined in future clinical trials.

From diagnostic yield to clinical impact: a pilot study on the implementation of prenatal exome sequencing in routine care.

PURPOSE: Exome sequencing (ES) is an efficient tool to diagnose genetic disorders postnatally. Recent studies show that it may have a considerable diagnostic yield in fetuses with structural anomalies on ultrasound. We report on the clinical impact of the implementation of prenatal ES (pES) for ongoing pregnancies in routine care. METHODS: We retrospectively analyzed the impact of pES on pregnancy outcome and pre- or perinatal management in the first 22 patients counseled for pES because of one or more structural anomalies on fetal ultrasound. RESULTS: In two cases, a diagnosis was made by chromosomal microarray analysis after ES counseling. The remaining 20 cases were divided in three groups: (1) pES to aid parental decision making (n = 12), (2) pES in the context of late pregnancy termination requests (n = 5), and (3) pES to guide pre- or perinatal management (n = 3). pES had a clinical impact in 75% (9/12), 40% (2/5), and 100% (3/3) respectively, showing an overall clinical impact of pES of 70% (14/20). CONCLUSION: We show that clinical implementation of pES is feasible and affects parental decision making or pre- and perinatal management supporting further implementation of ES in the prenatal setting.