Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood-brain barrier disruption.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

Critical congenital heart disease beyond HLHS and TGA: neonatal brain injury and early neurodevelopment.

BACKGROUND: Characterization of brain injury and neurodevelopmental (ND) outcomes in critical congenital heart disease (cCHD) has primarily focused on hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA). This study reports brain injury and ND outcomes among patients with heterogeneous cCHD diagnoses beyond HLHS and TGA. METHODS: This prospective cohort study included infants with HLHS, TGA, or heterogenous "Other cCHD" including left- or right-sided obstructive lesions, anomalous pulmonary venous return, and truncus arteriosus. Brain injury on perioperative brain MRI and ND outcomes on the Bayley-II at 30 months were compared. RESULTS: A total of 218 participants were included (HLHS = 60; TGA = 118; "Other cCHD" = 40, including 8 with genetic syndromes). Pre-operative (n = 209) and post-operative (n = 189) MRI showed similarly high brain injury rates across groups, regardless of cardiopulmonary bypass exposure. At 30 months, participants with "Other cCHD" had lower cognitive scores (p = 0.035) compared to those with HLHS and TGA, though worse ND outcome in this group was driven by those with genetic disorders. CONCLUSIONS: Frequency of brain injury and neurodevelopmental delay among patients with "Other cCHD" is similar to those with HLHS or TGA. Patients with all cCHD lesions are at risk for impaired outcomes; developmental and genetic screening is indicated. IMPACT: This study adds to literature on risk of brain injury in patients with critical congenital heart disease (cCHD) diagnoses other than hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), a heterogenous cohort of patients that has often been excluded from imaging studies. Children with cCHD beyond HLHS and TGA have similarly high rates of acquired brain injury. The high rate of neurodevelopmental impairment in this heterogenous group of cCHD diagnoses beyond HLHS and TGA is primarily driven by patients with comorbid genetic syndromes such as 22q11.2 deletion syndrome.

Brain age predicted using graph convolutional neural network explains neurodevelopmental trajectory in preterm neonates.

OBJECTIVES: Dramatic brain morphological changes occur throughout the third trimester of gestation. In this study, we investigated whether the predicted brain age (PBA) derived from graph convolutional network (GCN) that accounts for cortical morphometrics in third trimester is associated with postnatal abnormalities and neurodevelopmental outcome. METHODS: In total, 577 T1 MRI scans of preterm neonates from two different datasets were analyzed; the NEOCIVET pipeline generated cortical surfaces and morphological features, which were then fed to the GCN to predict brain age. The brain age index (BAI; PBA minus chronological age) was used to determine the relationships among preterm birth (i.e., birthweight and birth age), perinatal brain injuries, postnatal events/clinical conditions, BAI at postnatal scan, and neurodevelopmental scores at 30 months. RESULTS: Brain morphology and GCN-based age prediction of preterm neonates without brain lesions (mean absolute error [MAE]: 0.96 weeks) outperformed conventional machine learning methods using no topological information. Structural equation models (SEM) showed that BAI mediated the influence of preterm birth and postnatal clinical factors, but not perinatal brain injuries, on neurodevelopmental outcome at 30 months of age. CONCLUSIONS: Brain morphology may be clinically meaningful in measuring brain age, as it relates to postnatal factors, and predicting neurodevelopmental outcome. CLINICAL RELEVANCE STATEMENT: Understanding the neurodevelopmental trajectory of preterm neonates through the prediction of brain age using a graph convolutional neural network may allow for earlier detection of potential developmental abnormalities and improved interventions, consequently enhancing the prognosis and quality of life in this vulnerable population. KEY POINTS: •Brain age in preterm neonates predicted using a graph convolutional network with brain morphological changes mediates the pre-scan risk factors and post-scan neurodevelopmental outcomes. •Predicted brain age oriented from conventional deep learning approaches, which indicates the neurodevelopmental status in neonates, shows a lack of sensitivity to perinatal risk factors and predicting neurodevelopmental outcomes. •The new brain age index based on brain morphology and graph convolutional network enhances the accuracy and clinical interpretation of predicted brain age for neonates.

Relationship between social support and post-discharge mental health symptoms in mothers of preterm infants.

BACKGROUND: Social support is associated with decreased symptoms of postpartum mood and anxiety disorders (PMAD) in mothers of healthy infants, but less is known about social support and PMADs in mothers with preterm infants. The purpose of this study was to examine the relationship between social support and symptoms of PMADs reported by mothers in the months following hospital discharge of their preterm infant. METHODS: Mothers of infants less than 33 weeks gestational age were enrolled from neonatal intensive care units (NICU) at 6 sites. Mothers completed PMAD measures of depression, anxiety and post-traumatic stress approximately 3 months following their infant's discharge. Multivariable regression was used to evaluate relationships between social support and PMAD measures. RESULTS: Of 129 mothers, 1 in 5 reported clinically significant PMAD symptoms of: depression (24%), anxiety (19%), and post-traumatic stress (20%). Social support was strongly inversely associated with all 3 PMADs. Social support explained between 21% and 26% of the variance in depression, anxiety and post-traumatic stress symptoms. CONCLUSION: Increased social support may buffer PMAD symptoms in mothers of preterm infants after discharge. Research is needed to determine effective screening and interventions aimed at promoting social support for all parents during and following their infant's hospitalisation.

Long-term cognitive outcomes in term newborns with watershed injury caused by neonatal encephalopathy.

BACKGROUND: We previously reported that increasing severity of watershed (WS) injury in neonatal magnetic resonance imaging (MRI) is associated with worse language outcomes in early childhood. In the present study, we investigated the relationship between neonatal injury patterns and cognitive profile in adolescents with neonatal encephalopathy. METHODS: Term neonates with encephalopathy were prospectively enrolled and imaged using brain MRI from 1999 to 2008. Neonatal brain injury was scored according to the degree of injury in WS and basal ganglia/thalamus (BG/T) areas. The children underwent a neurocognitive assessment and follow-up brain MRI at the age of 10-16 years. The relationship between neonatal brain injury patterns and adolescent cognitive outcomes was assessed. RESULTS: In a cohort of 16 children, neonatal MRI showed WS injury in 7, BG/T injury in 2, and normal imaging in 7. Children with WS injury had lower estimated overall cognitive ability than those with normal imaging. Increasing WS injury score was associated with decreasing estimated overall cognitive ability, Perceptual Reasoning Index, and digit span score. CONCLUSIONS: Children with the WS injury are at an increased risk of having problems in long-term intellectual ability. These cognitive outcomes may underlie early language difficulties seen in children with neonatal WS injury. IMPACT: Adolescents with a history of neonatal encephalopathy and watershed pattern of injury on neonatal brain magnetic resonance imaging (MRI) had lower overall cognitive ability, perceptual reasoning skills, and auditory working memory than those with normal neonatal imaging. Children with post-neonatal epilepsy and cerebral palsy had the worst cognitive outcomes. Watershed pattern of injury confers high long-term differences in intellectual ability.

Rate of head ultrasound abnormalities at one month in very premature and extremely premature infants with normal initial screening ultrasound.

BACKGROUND: Premature infants are at risk for multiple types of intracranial injury with potentially significant long-term neurological impact. The number of screening head ultrasounds needed to detect such injuries remains controversial. OBJECTIVE: To determine the rate of abnormal findings on routine follow-up head ultrasound (US) performed in infants born at ≤ 32 weeks' gestational age (GA) after initial normal screening US. MATERIALS AND METHODS: A retrospective study was performed on infants born at ≤ 32 weeks' GA with a head US at 3-5 weeks following a normal US at 3-10 days at a tertiary care pediatric hospital from 2014 to 2020. Exclusion criteria included significant congenital anomalies, such as congenital cardiac defects necessitating surgery, congenital diaphragmatic hernia or spinal dysraphism, and clinical indications for US other than routine screening, such as sepsis, other risk factors for intracranial injury besides prematurity, or clinical neurological abnormalities. Ultrasounds were classified as normal or abnormal based on original radiology reports. Images from initial examinations with abnormal follow-up were reviewed. RESULTS: Thirty-three (14.2%) of 233 infants had 34 total abnormal findings on follow-up head US after normal initial US. Twenty-seven infants had grade 1 germinal matrix hemorrhage, and four had grade 2 intraventricular hemorrhage. Two had periventricular echogenicity and one had a focus of cerebellar echogenicity that resolved and was determined to be artifactual. CONCLUSION: When initial screening head ultrasounds in premature infants are normal, follow-up screening ultrasounds are typically also normal. Abnormal findings are usually limited to grade 1 germinal matrix hemorrhage.

Early Magnetic Resonance Imaging Predicts 30-Month Outcomes after Therapeutic Hypothermia for Neonatal Encephalopathy.

OBJECTIVE: To evaluate the association of therapeutic hypothermia with magnetic resonance imaging (MRI) findings and 30-month neurodevelopment in term neonatal encephalopathy. STUDY DESIGN: Cross-sectional analysis of 30-month neurodevelopment (IQR 19.0-31.4) in a prospective cohort of mild-to-severe neonatal encephalopathy imaged on day 4 (1993-2017 with institutional implementation of therapeutic hypothermia in 2007). MRI injury was classified as normal, watershed, or basal ganglia/thalamus. Abnormal motor outcome was defined as Bayley-II psychomotor developmental index <70, Bayley-III motor score <85 or functional motor deficit. Abnormal cognitive outcome was defined as Bayley-II mental developmental index <70 or Bayley-III cognitive score <85. Abnormal composite outcome was defined as abnormal motor and/or cognitive outcome, or death. The association of therapeutic hypothermia with MRI and outcomes was evaluated with multivariable logistic regression adjusted for propensity to receive therapeutic hypothermia. RESULTS: Follow-up was available in 317 (78%) surviving children, of whom 155 (49%) received therapeutic hypothermia. Adjusting for propensity, therapeutic hypothermia was independently associated with decreased odds of abnormal motor (OR 0.15, 95% CI 0.06-0.40, P < .001) and cognitive (OR 0.11, 95% CI 0.04-0.33, P < .001) outcomes. This association remained statistically significant after adjustment for injury pattern. The predictive accuracy of MRI pattern for abnormal composite outcome was unchanged between therapeutic hypothermia-treated (area under the receiver operating curve 0.76; 95% CI 0.61-0.91) and untreated (area under the receiver operating curve 0.74; 95% CI 0.67-0.81) infants. The negative predictive value of normal MRI was high in therapeutic hypothermia-treated and untreated infants (motor 96% vs 90%; cognitive 99% vs 95%). CONCLUSIONS: Therapeutic hypothermia is associated with lower rates of brain injury and adverse 30-month outcomes after neonatal encephalopathy. The predictive accuracy of MRI in the first week of life is unchanged by therapeutic hypothermia. Normal MRI remains reassuring for normal 30-month outcome after therapeutic hypothermia.

Bronchopulmonary dysplasia precursors influence risk of white matter injury and adverse neurodevelopmental outcome in preterm infants.

BACKGROUND: Cumulative supplemental oxygen (CSO) and cumulative mean airway pressure (CMAP) are associated with bronchopulmonary dysplasia (BPD) in preterm infants, but their relationships to white matter injury (WMI) and neurodevelopment have not been evaluated. METHODS: Preterm infants <32 weeks' gestation were prospectively imaged with 3 T MRI near term. CSO and CMAP were retrospectively summed over the first 14 and 28 days. Neurodevelopment was assessed at 30 months adjusted using the Bayley-III. ROC and linear regression were used to evaluate the relationship between CSO, CMAP, and BPD with WMI and neurodevelopmental performance, respectively. RESULTS: Of the 87 infants, 30 (34.5%) had moderate-severe BPD, which was associated with WMI (OR 5.5, 95% CI 1.1-34.9, p = 0.012). CSO and CMAP predicted WMI as well as BPD (AUC 0.68-0.77). CSO was independently associated with decreased language and cognitive performance (mean difference at 14 days: -11.0, 95% CI -19.8 to -2.2, p = 0.015 and -9.8, 95% CI -18.9 to -0.7, p = 0.035, respectively) at 30 months adjusted. CONCLUSIONS: BPD precursors predict WMI as well as BPD. Cumulative supplemental oxygen over the first 14 days of life is independently associated with lower language and cognitive performances. These data suggest that early respiratory status influences the risk of adverse neurodevelopment in preterm infants. IMPACT: Respiratory precursors to bronchopulmonary dysplasia (BPD), cumulative supplemental oxygen and mean airway pressure, over the first 14-28 days performed as well as BPD for the prediction of white matter injury on MRI in preterm infants. Cumulative supplemental oxygen was independently associated with lower language and cognitive performance on the Bayley-III at 30 months adjusted. These data suggest that early respiratory status may help explain why BPD is independently associated with adverse neurodevelopmental outcomes in the preterm population and highlights the importance of interventions targeting respiratory status as a potential avenue to improve neurodevelopmental outcomes.

Hindbrain regional growth in preterm newborns and its impairment in relation to brain injury.

Premature birth globally affects about 11.1% of all newborns and is a risk factor for neurodevelopmental disability in surviving infants. Histology has suggested that hindbrain subdivisions grow differentially, especially in the third trimester. Prematurity-related brain injuries occurring in this period may selectively affect more rapidly developing areas of hindbrain, thus accompanying region-specific impairments in growth and ultimately neurodevelopmental deficits. The current study aimed to quantify regional growth of the cerebellum and the brainstem in preterm neonates (n = 65 with individually multiple scans). We probed associations of the regional volumes with severity of brain injury. In neonates with no imaging evidence of injury, our analysis using a mixed-effect linear model showed faster growth in the pons and the lateral convexity of anterior/posterior cerebellar lobes. Different patterns of growth impairment were found in relation to early cerebral intraventricular hemorrhage and cerebellar hemorrhage (P < 0.05), likely explaining different mechanisms through which neurogenesis is disrupted. The pattern of cerebellar growth identified in our study agreed excellently with details of cerebellar morphogenesis in perinatal development, which has only been observed in histological data. Our proposed analytic framework may provide predictive imaging biomarkers for neurodevelopmental outcome, enabling early identification and treatment of high-risk patients. Hum Brain Mapp 37:678-688, 2016. © 2015 Wiley Periodicals, Inc.

Antenatal Exposure to Magnesium Sulfate Is Associated with Reduced Cerebellar Hemorrhage in Preterm Newborns.

OBJECTIVE: To determine the association of antenatal magnesium sulfate with cerebellar hemorrhage in a prospective cohort of premature newborns evaluated by magnetic resonance imaging (MRI). STUDY DESIGN: Cross-sectional analysis of baseline characteristics from a prospective cohort of preterm newborns (<33 weeks gestation) evaluated with 3T-MRI shortly after birth. Exclusion criteria were clinical evidence of a congenital syndrome, congenital infection, or clinical status too unstable for transport to MRI. Antenatal magnesium sulfate exposure was abstracted from the medical records and the indication was classified as obstetric or neuroprotection. Two pediatric neuroradiologists, blinded to the clinical history, scored axial T2-weighted and iron susceptibility MRI sequences for cerebellar hemorrhage. The association of antenatal magnesium sulfate with cerebellar hemorrhage was evaluated using multivariable logistic regression, adjusting for postmenstrual age at MRI and known predictors of cerebellar hemorrhage. RESULTS: Cerebellar hemorrhage was present in 27 of 73 newborns (37%) imaged at a mean ± SD postmenstrual age of 32.4 ± 2 weeks. Antenatal magnesium sulfate exposure was associated with a significantly reduced risk of cerebellar hemorrhage. Adjusting for postmenstrual age at MRI, and predictors of cerebellar hemorrhage, antenatal magnesium sulfate was independently associated in our cohort with decreased cerebellar hemorrhage (OR, 0.18; 95% CI, 0.049-0.65; P = .009). CONCLUSION: Antenatal magnesium sulfate exposure is independently associated with a decreased risk of MRI-detected cerebellar hemorrhage in premature newborns, which could explain some of the reported neuroprotective effects of magnesium sulfate.

White Matter Injury in Premature Newborns.

Preterm newborns are highly susceptible to brain injury. White matter injury is among the dominant patterns of brain injury in preterm newborns. the purpose of this review is to discuss the pathogenesis, diagnosis, management, and prevention of white matter injury in premature newborns. the long-term outcome of white matter injury in children born prematurely is also addressed.

Diminished white matter injury over time in a cohort of premature newborns.

OBJECTIVES: To determine the rate of magnetic resonance imaging (MRI)-detected noncystic white matter injury (WMI) in a prospective cohort of premature newborns, and to evaluate its associations with changes in clinical predictors of WMI over the study period. STUDY DESIGN: A prospective cohort of premature newborns (<33 weeks gestational age) was studied with MRI within 4 weeks of birth and near term-equivalent age. A pediatric neuroradiologist scored the severity of WMI on T1-weighted MRI according to published criteria. WMI was classified as none/mild or moderate/severe. Subjects with severe cystic WMI, periventricular hemorrhagic infarction, or motion artifact on MRI were excluded. Changes in clinical characteristics and predictors of WMI over the study period (1998-2011) were evaluated. Predictors of moderate/severe WMI, including birth year, were evaluated using multivariate logistic regression. RESULTS: Among 267 newborns, 45 (17%) had moderate/severe WMI. The rate of moderate/severe WMI decreased over the study period (P = .002, χ(2) test for trends). On multivariate logistic regression, the odds of moderate/severe WMI decreased by 11% for each birth year of the cohort (OR, 0.89; 95% CI, 0.81-0.98; P = .02). Prolonged exposure to indomethacin also was independently associated with reduced odds of moderate/severe WMI. CONCLUSION: The decreasing burden of MRI-detected moderate/severe noncystic WMI in our cohort of premature newborns is independent over time of changes in the known clinical predictors of WMI. Prolonged exposure to indomethacin is associated with reduced WMI.

Impaired cognitive performance in premature newborns with two or more surgeries prior to term-equivalent age.

BACKGROUND: Anesthesia in early childhood is associated with adverse neurodevelopmental outcome; however, it is not known if age at exposure affects the risk of adverse outcome. Our objective was to evaluate the association of the number and timing of anesthetic exposures for surgery with cognitive outcome in a cohort of premature newborns. METHODS: A cohort study of exposure to anesthesia for surgery in premature newborns (<33 wk gestation) prospectively evaluated with neonatal magnetic resonance imaging (MRI) and neurodevelopmental testing at 3-6 y was employed. Exposure to anesthesia for surgery was classified as before term-equivalent age (TEA, <42 wk postmenstrual age) or after (≥42 wk). Multivariate regression was performed to analyze the association of composite IQ scores with the number of surgeries before and after TEA. RESULTS: Among 137 newborns, 25 (18.2%) had one surgery before TEA and 18 (13.1%) had ≥2 surgeries. Two or more surgeries before TEA were associated with significantly reduced composite IQ scores at 4.6 ± 0.6 y after adjusting for gestational age and illness severity. Neither the number of surgeries after TEA nor sedation for MRI was associated with cognitive outcome. CONCLUSIONS: More than one surgery prior to TEA is independently associated with impaired cognitive performance in premature newborns.

Diverse childhood neurologic disorders and outcomes following fetal neurologic consultation.

Fetal neurology encompasses the full spectrum of neonatal and child neurology presentations, with complex additional layers of diagnostic and prognostic challenges unique to the specific prenatal consultation. Diverse genetic and acquired etiologies with a range of potential outcomes may be encountered. Three clinical case presentations are discussed that highlight how postnatal phenotyping and longitudinal follow-up are essential to address the uncertainties that arise in utero, after birth, and in childhood, as well as to provide continuity of care.

Fetal Cerebral Ventriculomegaly: A Narrative Review and Practical Recommendations for Pediatric Neurologists.

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists.

Evolution of pattern of injury and quantitative MRI on days 1 and 3 in term newborns with hypoxic-ischemic encephalopathy.

BACKGROUND: Brain injury in term neonatal hypoxic-ischemic encephalopathy (HIE) emerges on magnetic resonance imaging (MRI) by day 3. This study aimed to address the relationship of MRI, diffusion tensor imaging (DTI), and MR spectroscopic imaging (MRSI) findings on days 1 and 3 in a prospective cohort of term newborns with HIE. METHODS: A total of 24 term newborns with HIE were prospectively studied with MRI on days 1 and 3; 19 were imaged with DTI and MRSI on days 1 and 3. MRI was assessed using validated scores. The relationship between MRI, DTI, and MRSI values on days 1 and 3 was determined using linear regression for repeated measures. RESULTS: Conventional MRI showed a complex variation of findings from day 1 to 3. In gray matter, mean diffusivity (Dav) and metabolite ratios measured on day 1 were predictive of values on day 3 (all P ≤ 0.04). In white matter, Dav, fractional anisotropy (FA), and N-acetylaspartate (NAA)/choline on days 1 and 3 were strongly related (all P ≤ 0.003). Hypothermia appeared to attenuate the severity and progression of brain injury in the six treated newborns. CONCLUSION: In term newborns with HIE, quantitative MR values on days 1 and 3 are strongly associated, providing an objective measure of injury before qualitative images.

Advancing the Field of Fetal Neurology: A Call for Global Collaborations.

Fetal Neurology continues to grow as a distinct subspecialty informed by evolving precision diagnosis with advancements in prenatal neuroimaging, genetic and infectious testing. While there are inherent limitations and challenges in prenatal diagnostic testing and prognostic counseling, the interdisciplinary approach allows comprehensive guidance for perinatal and postnatal management of neurological disorders detected early in development. The current practice of fetal neurology is heterogenous and variable across centers. In low- and middle-income countries (LMICs), fetal neurology practice is under the umbrella of neonatal and perinatal medicine. Since infrastructure and capacity for prenatal diagnostic and prognostic counseling may be variable, the practice approach may have to be modified regionally based on resources, education, and setting. There is a need for collaborative development of educational opportunities, training, guidelines, and research exploring short- and long-term outcome of prenatally identified neurological conditions. Interdisciplinary collaborations and global professional networks are crucial to advance this unique subspecialty.

Spectrum of Fetal Intraparenchymal Hemorrhage in COL4A1/A2-Related Disorders.

BACKGROUND: COL4A1/A2 variants affecting the alpha 1 and 2 chains of type IV collagen are increasingly recognized as a cause of fetal and neonatal intracranial hemorrhage, porencephaly, and schizencephaly. Fetal magnetic resonance imaging (MRI) findings in COL4A1/A2-related disorders are not well characterized. METHODS: This is a retrospective case series of fetal MRI findings in eight patients with intraparenchymal hemorrhage (IPH) and COL4A1/A2 variants, five of whom have postnatal imaging and clinical follow-up. RESULTS: IPH was multifocal and bilateral in four of eight patients. IPH involved the frontal lobes in all cases and basal ganglia in six of eight. The median maximum diameter of IPH was 16 mm (range 6 to 65 mm). All patients had ventriculomegaly, and four of eight had intraventricular hemorrhage. Prenatal IPH size correlated clinically with motor outcomes, and none had clinically symptomatic recurrent hemorrhage. CONCLUSION: COL4A1/A2 variants can present with a spectrum of IPH prenatally, including small and/or unifocal IPH, as well as multifocal and bilateral IPH, involving the frontal lobes and basal ganglia. Given the wide spectrum of IPH severity seen on fetal brain MRI, genetic testing for COL4A1/A2 variants should be considered in all cases of fetal IPH.