Federico Prefumo

Objectives: Fetal ventriculomegaly (VM) is a common prenatal finding with heterogeneous etiology and unpredictable outcome, yet its management remains among the least standardized in fetal medicine. This study aimed to establish expert consensus on key decision points in the prenatal management of fetal VM, and to systematically map the domains of persistent uncertainty as a structured framework for future research priorities. Methods: A two‐round modified Delphi study was conducted with an international panel of experts in fetal medicine, selected through a systematic review of publications that included more than 50 cases of VM over the preceding decade. Round 1 comprised 39 multiple‐choice questions, with consensus achieved when ≥ 75% of panelists selected a single answer option; items that did not reach consensus were reformulated into Likert‐scale statements for Round 2, which comprised 60 statements rated on a 9‐point Likert scale. In Round 2, consensus was defined by two simultaneous criteria: ≥ 75% of valid respondents scoring in the agreement (score, 7–9) or disagreement (score, 1–3) zone, with an interquartile range of ≤ 2. Non‐consensus domains were classified using a post ‐ hoc taxonomic framework into three categories: absent evidence (Type 1), divergent clinical frameworks (Type 2) and undefined construct (Type 3), which could occur independently or in combination. Results: Of 56 experts who completed Round 1, 45 (80%) also completed Round 2. In Round 1, consensus was reached on 20/39 (51%) questions. In Round 2, 6/60 (10%) statements reached positive consensus and four (7%) reached negative consensus; 50 (83%) did not reach consensus. Over the two rounds, consensus was achieved on standardized measurement technique, three‐tier grading, comprehensive neurosonographic and investigative work‐up, individualization of the timing of fetal magnetic resonance imaging, stepwise neurosurgical referral and delivery management of fetal VM. Classification of non‐consensus domains identified 15/50 (30%) items as Type 1, 16/50 (32%) as Type 2, 4/50 (8%) as Type 3 and 15/50 (30%) as Type 1+3. Ventricular asymmetry, the largest non‐consensus cluster with 12 items, was classified as Type 1+3 in 11/12 (92%) statements, reflecting the simultaneous absence of prospective outcome data and of a universally accepted operational definition. Conclusions: This Delphi study provides structured expert‐derived guidance, primarily applicable to specialist and referral settings, on the prenatal management of fetal VM across key clinical domains. Beyond consensus recommendations, we propose that the original contribution of this study is a hypothesis‐generating taxonomic map of persistent uncertainty, classifying unresolved domains by the nature of the underlying evidence gap and identifying the specific prerequisites (definitional, methodological or empirical) required before consensus can be achieved. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.

Introduction: Antenatal corticosteroids (ACS) are widely used to improve outcomes in preterm infants, with known benefits on respiratory morbidity and intraventricular hemorrhage (IVH). However, the effect of ACS timing on brain injury and development remains unclear. We aimed to evaluate the impact of a complete course of ACS (ccACS), with particular attention to timing, on brain lesions, growth, and neurodevelopment in very low birth weight (VLBW) infants using magnetic resonance imaging (MRI). Material and Methods: In this historical cohort study, all VLBW infants admitted to a tertiary neonatal intensive care unit between January 2019 and December 2021 were included. Clinical data, including timing of ACS administration, were collected. The primary outcome was the occurrence of brain injury on MRI at term‐equivalent age, including IVH, white matter lesions (WML), and cerebellar hemorrhage (CBH). Secondary outcomes were brain growth and maturation on MRI and neurodevelopment at 2 years assessed using the Griffiths Mental Development Scales. Outcomes were compared between infants with and without ccACS and according to different administration‐to‐birth intervals. Results: A total of 189 infants were included, of whom 139 (73.5%) received ccACS. Infants exposed to ccACS had a lower incidence of WML ( p = 0.02) and moderate/severe IVH ( p = 0.04). In extremely preterm infants (p = 0.006). No significant differences were observed in brain growth, maturation, or neurodevelopmental outcomes at 2 years. Conclusions: A complete course of ACS was associated with unadjusted lower rates of brain injury in VLBW infants, particularly when administered within 7 days before birth in extremely preterm infants, without adverse effects on brain growth, maturation, or neurodevelopment at 2 years.

Background: Nutrition is one of the most modifiable determinants of brain development in preterm infants. Although increasing evidence supports associations between early nutritional exposures and neurodevelopment, studies remain heterogeneous regarding nutritional interventions, imaging biomarkers, and long-term outcomes. This systematic review aimed to summarize contemporary evidence on the relationship between nutrition and brain development in preterm infants using neuroimaging as the primary assessment tool while proposing an integrated translational framework to guide future research. Methods: Following a PECO framework, a systematic literature search was conducted in PubMed, Scopus, and CINAHL: population, infants born before 37 completed weeks of gestation; exposure, any enteral or parenteral nutritional exposure, supplementation strategy, fortification approach, or individualized nutritional intervention; comparator, an alternative nutritional strategy, lower or absent exposure, standard care or, when relevant, a term-born reference group; outcomes, MRI- or CUS-based measures of brain growth, maturation, connectivity, or injury. Studies reporting volumetric, morphometric, diffusion, connectivity, spectroscopy, or quantitative ultrasound outcomes were eligible. The methodology was adapted from the PROSPERO-registered review by Ottolini et al. Original studies published between 2020 and 2026 (1 January 2020–4 September 2026) evaluating nutritional exposures or interventions in preterm infants with magnetic resonance imaging (MRI) and/or cranial ultrasound (CUS) outcomes were included. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS), ROBINS-I and RoB 2 according to study design. Quantitative imaging studies were screened for eligibility for ATLAS assessment. Given the substantial heterogeneity in nutritional exposures, imaging protocols, timing of assessments, and neurodevelopmental outcomes, meta-analysis was not performed. Certainty of evidence was assessed at the level of each causal question and neuroimaging outcome domain using the GRADE framework. Randomized intervention evidence and observational exposure evidence were evaluated according to the design and target contrast contributing to each body of evidence. Judgments considered risk of bias, inconsistency, indirectness, imprecision, publication bias, and, where applicable, factors that could increase certainty. Statistical significance was not used to determine certainty, and studies arising from shared or partially overlapping parent populations were not counted as independent replication. Results: We found 33 reports that met the inclusion criteria: 4 evaluated randomized treatment contrasts, 5 non-randomized intervention comparisons, and 24 observational nutritional exposure analyses. Greater exposure to human milk and selected strategies involving early protein and lipid provision, docosahexaenoic acid, omega-3 fatty acids, and individualized nutritional support were associated in several studies with favorable MRI measurements, including larger total or regional brain volumes, more advanced white-matter maturation, and differences in structural or functional connectivity. Some studies also reported associations with later neurodevelopment. However, findings were not uniform, and GRADE certainty across outcome-specific nutrition–neuroimaging questions ranged from very low to low, principally because of risk of bias, imprecision, heterogeneous exposure and imaging definitions, and limited independent replication. Although causal inference cannot be directly drawn, neuroimaging may provide quantitative measures of brain development that can be investigated alongside long-term neurodevelopmental outcomes. We propose the Roadmap for Imaging-Guided Enhancement of Neurodevelopment (RIGEL), an integrative research framework combining imaging, molecular biomarkers, standardized neurodevelopmental assessment, and epidemiological evidence across developmental stages. RIGEL should be regarded as a hypothesis-generating research framework that requires prospective validation before any clinical implementation.

Neonatal hypoxic–ischemic encephalopathy (HIE) remains one of the leading causes of neonatal mortality and long-term neurodevelopmental disability despite therapeutic hypothermia, which provides only partial neuroprotection. Among adjunctive therapies, magnesium sulfate (MgSO₄) has emerged as one of the most biologically plausible neuroprotective agents because of its ability to modulate glutamate-mediated excitotoxicity, intracellular calcium influx, oxidative stress, neuroinflammation, and apoptotic pathways. Nevertheless, encouraging molecular and preclinical findings have not translated into consistent clinical benefit. This narrative review critically examines the translational gap between the molecular mechanisms of magnesium sulfate and its clinical performance in neonatal HIE. Evidence from experimental models, clinical studies and recent meta-analyses was integrated to identify the biological and methodological factors potentially responsible for this discrepancy. We discuss the evolving pathophysiology of HIE across the primary, latent, secondary and tertiary phases of brain injury and analyze how the timing of intervention, lesion heterogeneity and inadequate biological stratification may influence therapeutic responsiveness. Current clinical research has largely evaluated broad neurological outcomes, particularly cerebral palsy, despite the heterogeneous neuropathological substrates underlying neonatal brain injury. We argue that this strategy may dilute genuine treatment effects by grouping together distinct lesion phenotypes with different biological mechanisms. Accordingly, we propose the “Neuroprotection per Effective Therapy (NET)” framework, a conceptual translational model integrating molecular targets, experimental evidence, MRI-defined lesion phenotypes, methodological quality, and advanced statistical approaches to improve patient stratification and outcome selection. Rather than questioning the biological efficacy of magnesium sulfate itself, this review suggests that future progress will depend on aligning molecular mechanisms with clinically meaningful phenotypes. Precision-based translational strategies may ultimately allow magnesium sulfate and other neuroprotective therapies to better reveal their therapeutic effects in biologically appropriate patient subgroups.

Background/Objectives: Isolated Left Ventricular Apical Hypoplasia (ILVAH) is a rare congenital anomaly characterized by a truncated, spherical left ventricle (LV) with fibro-fatty apical replacement. Historically considered a benign condition of asymptomatic adults, its hemodynamic behavior under physiological stress remains poorly characterized. We present two distinct cases and a comprehensive literature review (n = 59) to redefine the clinical spectrum of ILVAH. Methods: To contextualize our findings, a comprehensive review of the literature was performed up to February 2026. We searched the PubMed/MEDLINE database using the terms “Isolated Left Ventricular Apical Hypoplasia”, “ILVAH”, “truncated left ventricle”, and “left ventricular apical hypoplasia”. The literature search and study selection were conducted in accordance with the PRISMA guidelines. Case presentations: Case 1 describes a male infant with ILVAH and muscular ventricular septal defects who unexpectedly developed transient systolic heart failure at one month of life, requiring prompt medical therapy (ACE inhibitors and diuretics) for functional recovery. Case 2 describes a 33-year-old woman with a known diagnosis of ILVAH. Serial echocardiography during her first pregnancy revealed progressive left atrial dilation and the onset of mild post-capillary pulmonary hypertension. Immediately following an elective cesarean section at 37 weeks, she experienced acute heart failure. She was successfully managed with pre-emptive volume offloading. Conclusions: ILVAH is not a universally benign anomaly. The morphologically deficient and rigid ventricle is vulnerable to afterload shifts in infancy and rapid volume expansion in adulthood. A review of all previously reported pregnancies in ILVAH reveals a consistent pattern of severe, unrecognized postpartum pulmonary edema. Proactive, multidisciplinary management is suggested to prevent clinical decompensation. Our findings suggest that ILVAH may act as a stress-sensitive restrictive congenital left ventricle disease rather than a universally benign anatomical variant, a hypothesis that warrants further investigation.

Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of neonatal mortality and long-term neurodevelopmental disability despite therapeutic hypothermia, which provides only partial neuroprotection. Among adjunctive therapies, magnesium sulphate (MgSO4) has emerged as one of the most biologically plausible neuroprotective agents because of its ability to modulate glutamate-mediated excitotox-icity, intracellular calcium influx, oxidative stress, neuroinflammation and apoptotic pathways. Nevertheless, encouraging molecular and preclinical findings have not translated into consistent clinical benefit. This narrative review critically examines the translational gap between the molecular mechanisms of magnesium sulphate and its clinical performance in neonatal HIE. Evi-dence from experimental models, clinical studies and recent meta-analyses was integrated to identify the biological and methodological factors potentially responsible for this dis-crepancy. We discuss the evolving pathophysiology of HIE across the primary, latent, secondary and tertiary phases of brain injury and analyse how the timing of intervention, lesion heterogeneity and inadequate biological stratification may influence therapeutic responsiveness. Current clinical research has largely evaluated broad neurological outcomes, particularly cerebral palsy, despite the heterogeneous neuropathological substrates underlying ne-onatal brain injury. We argue that this strategy may dilute genuine treatment effects by grouping together distinct lesion phenotypes with different biological mechanisms. Accordingly, we propose the **Neuroprotection per Effective Therapy (NET)** framework, a conceptual translational model integrating molecular targets, experimental evidence, MRI-defined lesion phenotypes, methodological quality and advanced statistical ap-proaches to improve patient stratification and outcome selection. Rather than questioning the biological efficacy of magnesium sulphate itself, this review suggests that future progress will depend on aligning molecular mechanisms with clinically meaningful phenotypes. Precision-based translational strategies may ultimately allow magnesium sulphate and other neuroprotective therapies to demonstrate their true therapeutic potential in neonatal HIE.

Objectives: To compare cardiac function in fetuses with and without fetal growth restriction (FGR). Methods: Medline and Embase databases were searched. Inclusion criteria were pregnancies complicated compared to those non‐complicated by FGR, defined according to the Delphi criteria. The following cardiovascular parameters were assessed. Markers of cardiac geometry and morphology, including the left and right sphericity index (SI). Markers primarily affecting the systolic function, including right (TAPSE) and left (MAPSE) cardiac output (CO), atrioventricular plane displacement, and peak systolic velocity of the aorta and pulmonary arteries. Markers primarily affecting the diastolic function, including the mitral and tricuspid E/A ratio. Markers of global cardiac function, including left and right isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) ejection time (ET), and myocardial performance index (MPI). Random‐effect meta‐analyses were used to analyze the data. Results: Fifteen studies were included. Fetuses affected by FGR had a smaller right SI (MD −0.23, 95% CI 0.44 to −0.01; p : 0.04) and left (MD: −0.20, 95% CI −0.33 to −0.05) compared to those not affected. There was no difference in left ( p = 0.179) and right ( p = 0.068) CO between fetuses affected and those not affected by FGR. Fetuses with FGR had shorter MAPSE (MD: −0.91 mm, 95% CI: −1.25 to −0.57; p < 0.001) and TAPSE (MD: −1.09 mm, 95% CI: −1.23 to −0.96; p < 0.001), while there was no difference in mitral ( p = 0.832) and tricuspid ( p = 0.504) E/A ratio. Left MPI was higher (MD: 0.09, 95% CI 0.04 to 0.14; p < 0.001) in fetuses with FGR compared with controls. Conclusion: FGR is associated with significant changes in fetal cardiac geometry and function.

1. Childbirth is a complex, still not fully understood, process which involves two main maternal components, myometrium, and cervix, characterized by substantial differences in tissue composition. ...