The Association of Dexamethasone and Hydrocortisone with Cerebellar Growth in Premature Infants.

OBJECTIVES: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This study aimed to compare cerebellar growth in premature infants who received dexamethasone or hydrocortisone to premature infants who did not receive postnatal corticosteroids. STUDY DESIGN: Retrospective case-control study in infants born at a gestational age of <29 weeks and admitted to two level 3 neonatal intensive care units. Exclusion criteria were severe congenital anomalies and cerebellar or severe supratentorial lesions. Infants were treated with dexamethasone (unit 1) or hydrocortisone (unit 2) for chronic lung disease. Controls (unit 1) did not receive postnatal corticosteroids. Sequential head circumference (HC) and ultrasound measurements of transcerebellar diameter (TCD), biparietal diameter (BPD), and corpus callosum-fastigium length (CCFL) were performed until 40 weeks' postmenstrual age (PMA). Growth was assessed using linear mixed models correcting for PMA at measurement, sex, HC z-score at birth, and a propensity score indicating illness severity. Group differences before treatment were assessed using linear regression. RESULTS: 346 infants were included (68 dexamethasone, 37 hydrocortisone, 241 controls). Before starting corticosteroids, TCD, BPD, and HC measurements did not differ between patients and controls at a comparable PMA. After starting treatment, both types of corticosteroid had a negative association with TCD growth. BPD, CCFL, and HC growth were not negatively affected. CONCLUSION: Administration of dexamethasone and hydrocortisone are both associated with impaired cerebellar growth in premature infants without evident negative associations with cerebral growth.

Neurological Surveillance in Moderate-Late Preterm Infants-Results from a Dutch-Canadian Survey.

Preterm birth remains an important cause of abnormal neurodevelopment. While the majority of preterm infants are born moderate-late preterm (MLPT; 32-36 weeks), international and national recommendations on neurological surveillance in this population are lacking. We conducted an observational quantitative survey among Dutch and Canadian neonatal level I-III centres (June 2020-August 2021) to gain insight into local clinical practices on neurological surveillance in MLPT infants. All centres caring for MLPT infants designated one paediatrician/neonatologist to complete the survey. A total of 85 out of 174 (49%) qualifying neonatal centres completed the survey (60 level I-II and 25 level III centres). Admission of MLPT infants was based on infant-related criteria in 78/85 (92%) centres. Cranial ultrasonography to screen the infant's brain for abnormalities was routinely performed in 16/85 (19%) centres, while only on indication in 39/85 (46%). In 57/85 (67%) centres, neurological examination was performed at least once during admission. Of 85 centres, 51 (60%) followed the infants' development post-discharge, with follow-up duration ranging from 1-52 months of age. The survey showed a wide variety in neurological surveillance in MLPT infants among Dutch and Canadian neonatal centres. Given the risk for short-term morbidity and long-term neurodevelopmental disabilities, future studies are required to investigate best practices for in-hospital care and follow-up of MLPT infants.

Improved neonatal brain MRI segmentation by interpolation of motion corrupted slices.

BACKGROUND AND PURPOSE: To apply and evaluate an intensity-based interpolation technique, enabling segmentation of motion-affected neonatal brain MRI. METHODS: Moderate-late preterm infants were enrolled in a prospective cohort study (Brain Imaging in Moderate-late Preterm infants "BIMP-study") between August 2017 and November 2019. T2-weighted MRI was performed around term equivalent age on a 3T MRI. Scans without motion (n = 27 [24%], control group) and with moderate-severe motion (n = 33 [29%]) were included. Motion-affected slices were re-estimated using intensity-based shape-preserving cubic spline interpolation, and automatically segmented in eight structures. Quality of interpolation and segmentation was visually assessed for errors after interpolation. Reliability was tested using interpolated control group scans (18/54 axial slices). Structural similarity index (SSIM) was used to compare T2-weighted scans, and Sørensen-Dice was used to compare segmentation before and after interpolation. Finally, volumes of brain structures of the control group were used assessing sensitivity (absolute mean fraction difference) and bias (confidence interval of mean difference). RESULTS: Visually, segmentation of 25 scans (22%) with motion artifacts improved with interpolation, while segmentation of eight scans (7%) with adjacent motion-affected slices did not improve. Average SSIM was .895 and Sørensen-Dice coefficients ranged between .87 and .97. Absolute mean fraction difference was ≤0.17 for less than or equal to five interpolated slices. Confidence intervals revealed a small bias for cortical gray matter (0.14-3.07 cm3 ), cerebrospinal fluid (0.39-1.65 cm3 ), deep gray matter (0.74-1.01 cm3 ), and brainstem volumes (0.07-0.28 cm3 ) and a negative bias in white matter volumes (-4.47 to -1.65 cm3 ). CONCLUSION: According to qualitative and quantitative assessment, intensity-based interpolation reduced the percentage of discarded scans from 29% to 7%.

Mild brain lesions do not affect brain volumes in moderate-late preterm infants.

PURPOSE: It is unknown whether frequently occurring mild brain lesions affect brain volumes in moderate (MP2; 32+0-33+6 weeks' gestation) and late (LP3; 34+0-35+6 weeks' gestation) preterm infants. Therefore, we aimed to investigate the effect of mild brain lesions on brain volumes in moderate-late preterm (MLPT4) infants and to compare brain volumes between MP and LP infants. METHODS: From August 2017 to November 2019, eligible MLPT infants born at Isala Women and Children's Hospital were enrolled in a prospective cohort study (Brain Imaging in Moderate-late Preterm infants 'BIMP-study'). MRI was performed around term equivalent age (TEA5). MRI scans were assessed for (mild) brain lesions. T2-weighted images were used for automatic segmentation of eight brain structures. Linear regression analysis was performed to compare absolute and relative brain volumes between infants with and without mild brain lesions and between MP and LP infants. RESULTS: 36 MP and 68 LP infants were included. In infants with mild brain lesions, intracranial volume (B = 27.4 cm3, p = 0.02), cerebrospinal fluid (B = 8.78 cm3, p = 0.01) and cerebellar volumes (B = 1.70 cm3, p = 0.03) were significantly larger compared to infants without mild brain lesions. After correction for weight and postmenstrual age at MRI, these volumes were no longer significantly different. LP infants had larger brain volumes than MP infants, but differences were not significant. Relative brain volumes showed no significant differences in both analyses. CONCLUSION: Neither having mild brain lesions, nor being born moderate prematurely affected brain volumes at TEA in MLPT infants.

Ultrasound measurements of brain structures differ between moderate-late preterm and full-term infants at term equivalent age.

BACKGROUND: Brain growth in moderate preterm (MP; gestational age (GA) 32+0-33+6 weeks) and late preterm infants (LP; GA 34+0-36+6 weeks) may be impaired, even in the absence of brain injury. AIMS: The aims of this study were to assess brain measurements of MP and LP infants, and to compare these with full-term infants (GA > 37 weeks) using linear cranial ultrasound (cUS) at term equivalent age (TEA). STUDY DESIGN: cUS data from two prospective cohorts were combined. Two investigators performed offline measurements on standard cUS planes. Eleven brain structures were compared between MP, LP and full-term infants using uni- and multivariable linear regression. Results were adjusted for postmenstrual age at cUS and corrected for multiple testing. RESULTS: Brain measurements of 44 MP, 54 LP and 52 full-term infants were determined on cUS scans at TEA. Biparietal diameter and basal ganglia-insula width were smaller in MP (-9.1 mm and - 1.7 mm, p < 0.001) and LP infants (-7.0 mm and - 1.7 mm, p < 0.001) compared to full-term infants. Corpus callosum - fastigium length was larger in MP (+2.2 mm, p < 0.001) than in full-term infants. No significant differences were found between MP and LP infants. CONCLUSIONS: These findings suggest that brain growth in MP and LP infants differs from full-term infants. Whether these differences have clinical implications remains to be investigated.

Consensus Approach for Standardizing the Screening and Classification of Preterm Brain Injury Diagnosed With Cranial Ultrasound: A Canadian Perspective.

Acquired brain injury remains common in very preterm infants and is associated with significant risks for short- and long-term morbidities. Cranial ultrasound has been widely adopted as the first-line neuroimaging modality to study the neonatal brain. It can reliably detect clinically significant abnormalities that include germinal matrix and intraventricular hemorrhage, periventricular hemorrhagic infarction, post-hemorrhagic ventricular dilatation, cerebellar hemorrhage, and white matter injury. The purpose of this article is to provide a consensus approach for detecting and classifying preterm brain injury to reduce variability in diagnosis and classification between neonatologists and radiologists. Our overarching goal with this work was to achieve homogeneity between different neonatal intensive care units across a large country (Canada) with regards to classification, timing of brain injury screening and frequency of follow up imaging. We propose an algorithmic approach that can help stratify different grades of germinal matrix-intraventricular hemorrhage, white matter injury, and ventricular dilatation in very preterm infants.

Incidence of brain lesions in moderate-late preterm infants assessed by cranial ultrasound and MRI: The BIMP-study.

PURPOSE: To evaluate the incidence and characteristics of brain lesions in moderate-late preterm (MLPT) infants, born at 32-36 weeks' gestation using cranial ultrasound (cUS) and magnetic resonance imaging (MRI). METHODS: Prospective cohort study carried out at Isala Women and Children's Hospital between August 2017 and November 2019. cUS was performed at postnatal day 3-4 (early-cUS), before discharge and repeated at term equivalent age (TEA) in MLPT infants born between 32+0 and 35+6 weeks' gestation. At TEA, MRI was also performed. Several brain lesions were assessed e.g. hemorrhages, white matter and deep gray matter injury. Brain maturation was visually evaluated. Lesions were classified as mild or moderate-severe. Incidences and confidence intervals were calculated. RESULTS: 166 MLPT infants were included of whom 127 underwent MRI. One or more mild lesions were present in 119/166 (71.7 %) and moderate-severe lesions in 6/166 (3.6 %) infants on cUS and/or MRI. The most frequent lesions were signs suggestive of white matter injury: inhomogeneous echogenicity in 50/164 infants (30.5 %) at early-cUS, in 12/148 infants (8.1 %) at TEA-cUS and diffuse white matter signal changes (MRI) in 27/127 (23.5 %) infants. Cerebellar hemorrhage (MRI) was observed in 16/127 infants (12.6 %). Delayed maturation (MRI) was seen in 17/117 (13.4 %) infants. Small hemorrhages and punctate white matter lesions were more frequently detected on MRI than on cUS. CONCLUSIONS: In MLPT infants mild brain lesions were frequently encountered, especially signs suggestive of white matter injury and small hemorrhages. Moderate-severe lesions were less frequently seen.

A systematic review on brain injury and altered brain development in moderate-late preterm infants.

OBJECTIVES: To provide a systematic review of brain injury and altered brain development in moderate-late preterm (MLPT) infants as compared to very preterm and term infants. STUDY DESIGN: A systematic search in five databases was performed in January 2020. Original research papers on incidence of brain injury and papers using quantitative data on brain development in MLPT infants were selected. The Johanna Briggs Institute 'Critical Appraisal Checklist for Studies Reporting Prevalence Data' was used for quality appraisal. Data extraction included: imaging modality, incidences of brain injury, brain volumes, 2D-measurements and diffusivity values. RESULTS: In total, 24 studies were eligible. Most studies had a moderate quality. Twenty studies reported on the incidence of brain injury in MLPT infants. The incidence of intraventricular hemorrhage (IVH) ranged from 0.0% to 23.5% and of white matter injury (WMI) from 0.5% to 10.8%. One study reported the incidence of arterial infarction (0.3%) and none of cerebellar hemorrhage. Eleven studies compared incidences of brain injury between MLPT infants and very preterm or term infants. Five studies reported signs of altered brain development in MLPT infants. CONCLUSIONS: The incidences of IVH and WMI in MLPT infants varied widely between studies. Other abnormalities were sparsely reported. Evidence regarding a higher or lower incidence of brain injury in MLPT infants compared to very preterm or term infants is weak due to moderate methodological quality of reported studies. There is limited evidence suggesting a difference in brain development between MLPT and term infants.

Neonatal care bundles are associated with a reduction in the incidence of intraventricular haemorrhage in preterm infants: a multicentre cohort study.

OBJECTIVE: To investigate the effect of a nursing intervention bundle, applied during the first 72 hours of life, on the incidence of germinal matrix-intraventricular haemorrhage (GMH-IVH) in very preterm infants. DESIGN: Multicentre cohort study. SETTING: Two Dutch tertiary neonatal intensive care units. PATIENTS: The intervention group consisted of 281 neonates, whereas 280 infants served as historical controls (gestational age for both groups <30 weeks). INTERVENTIONS: After a training period, the nursing intervention bundle was implemented and applied during the first 72 hours after birth. The bundle consisted of maintaining the head in the midline, tilting the head of the incubator and avoidance of flushing/rapid withdrawal of blood and sudden elevation of the legs. MAIN OUTCOME MEASURES: The incidence of GMH-IVH occurring and/or increasing after the first ultrasound (but within 72 hours), cystic periventricular leukomalacia and/or in-hospital death was the primary composite outcome measure. Logistic regression analysis was used to explore differences between groups. RESULTS: The nursing intervention bundle was associated with a lower risk of developing a GMH-IVH (any degree), cystic periventricular leukomalacia and/or mortality (adjusted OR 0.42, 95% CI 0.27 to 0.65). In the group receiving the bundle, also severe GMH-IVH, cystic periventricular leukomalacia and/or death were less often observed (adjusted OR 0.54, 95% CI 0.33 to 0.91). CONCLUSIONS: The application of a bundle of nursing interventions is associated with reduced risk of developing a new/progressive (severe) GMH-IVH, cystic periventricular leukomalacia and/or mortality in very preterm infants when applied during the first 72 hours postnatally.

Assessment of Brain Injury and Brain Volumes after Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled ELVIS Trial.

OBJECTIVE: To compare the effect of early and late intervention for posthemorrhagic ventricular dilatation on additional brain injury and ventricular volume using term-equivalent age-MRI. STUDY DESIGN: In the Early vs Late Ventricular Intervention Study (ELVIS) trial, 126 preterm infants ≤34 weeks of gestation with posthemorrhagic ventricular dilatation were randomized to low-threshold (ventricular index >p97 and anterior horn width >6 mm) or high-threshold (ventricular index >p97 + 4 mm and anterior horn width >10 mm) groups. In 88 of those (80%) with a term-equivalent age-MRI, the Kidokoro Global Brain Abnormality Score and the frontal and occipital horn ratio were measured. Automatic segmentation was used for volumetric analysis. RESULTS: The total Kidokoro score of the infants in the low-threshold group (n = 44) was lower than in the high-threshold group (n = 44; median, 8 [IQR, 5-12] vs median 12 [IQR, 9-17], respectively; P < .001). More infants in the low-threshold group had a normal or mildly increased score vs more infants in the high-threshold group with a moderately or severely increased score (46% vs 11% and 89% vs 54%, respectively; P = .002). The frontal and occipital horn ratio was lower in the low-threshold group (median, 0.42 [IQR, 0.34-0.63]) than the high-threshold group (median 0.48 [IQR, 0.37-0.68], respectively; P = .001). Ventricular cerebrospinal fluid volumes could be calculated in 47 infants and were smaller in the low-threshold group (P = .03). CONCLUSIONS: More brain injury and larger ventricular volumes were demonstrated in the high vs the low-threshold group. These results support the positive effects of early intervention for posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.

Punctate white-matter lesions in the full-term newborn: Underlying aetiology and outcome.

BACKGROUND: Punctate white matter lesions (PWMLs) are small focal patches of increased signal intensity (SI) on T1- and decreased SI on T2-weighted magnetic resonance imaging (MRI). To date, there have been few reports of PWMLs in term born infants. OBJECTIVE: To identify associated diagnoses and factors predictive of clinical outcome in (near) term infants with PWMLs. METHODS: MRI studies and clinical records of (near) term infants, with PWMLs on MRI scans performed in two institutions in the first 28 postnatal days were reviewed. The PWMLs were classified according to their number, pattern and distribution. The medical records were examined to assess the associated diagnoses and determine the neurodevelopmental outcome at >12 months of age. Infants with congenital heart defect(s), those who had neonatal surgery, or those with perinatal arterial ischemic stroke were not eligible for the study. RESULTS: Forty-two (near) term infants with PWMLs were included. The major clinical association was perinatal asphyxia, present in 19/42 (45%). Ten (24%) had a history of seizures unrelated to asphyxia or a genetic diagnosis. Eleven (26%) had pathological genetic mutations. Other diagnoses, without seizures were identified in 2 (5%). The lesion load of PWMLs was high (>6) in 30/42 (71%). Evidence of irreversible white matter injury was present in 5 infants who had follow-up MRI performed between 18 and 24 months of age, because of clinical concerns. Five infants died and 37 had follow-up at a median age of 24 months. Neurodevelopmental outcome was poorest amongst 6 infants (16%) whose PWMLs occurred in the setting of a genetic disorder. CONCLUSION: PWMLs in (near) term infants represent white matter injury that may evolve into gliosis and/or white matter loss. Infants with PWMLs in the setting of a genetic disorder appeared at most risk of a poor outcome.

Treatment thresholds for intervention in posthaemorrhagic ventricular dilation: a randomised controlled trial.

OBJECTIVE: To compare a low versus a higher threshold for intervention in preterm infants with posthaemorrhagic ventricular dilatation. DESIGN: Multicentre randomised controlled trial (ISRCTN43171322). SETTING: 14 neonatal intensive care units in six countries. PATIENTS: 126 preterm infants ≤34 weeks gestation with ventricular dilatation after grade III-IV haemorrhage were randomised to low threshold (LT) (ventricular index (VI) >p97 and anterior horn width (AHW) >6 mm) or higher threshold (HT) (VI>p97+4 mm and AHW >10 mm). INTERVENTION: Cerebrospinal fluid tapping by lumbar punctures (LPs) (max 3), followed by taps from a ventricular reservoir, to reduce VI, and eventually a ventriculoperitoneal (VP) shunt if stabilisation of the VI below the p97+4 mm did not occur. COMPOSITE MAIN OUTCOME MEASURE: VP shunt or death. RESULTS: 19 of 64 (30%) LT infants and 23 of 62 (37%) HT infants were shunted or died (P=0.45). A VP shunt was inserted in 12/64 (19%) in the LT and 14/62 (23%) infants in the HT group. 7/12 (58%) LT infants and 1/14 (7%) HT infants required shunt revision (P<0.01). 62 of 64 (97%) LT infants and 36 of 62 (58%) HT infants had LPs (P<0.001). Reservoirs were inserted in 40 of 64 (62%) LT infants and 27 of 62 (43%) HT infants (P<0.05). CONCLUSIONS: There was no significant difference in the primary composite outcome of VP shunt placement or death in infants with posthaemorrhagic ventricular dilatation who were treated at a lower versus a higher threshold for intervention. Infants treated at the lower threshold received more invasive procedures. Assessment of neurodevelopmental outcomes will provide further important information in assessing the risks and benefits of the two treatment approaches.

Posthemorrhagic ventricular dilatation in preterm infants: When best to intervene?

OBJECTIVE: To compare neurodevelopmental outcomes of preterm infants with and without intervention for posthemorrhagic ventricular dilatation (PHVD) managed with an "early approach" (EA), based on ventricular measurements exceeding normal (ventricular index [VI] <+2 SD/anterior horn width <6 mm) with initial temporizing procedures, followed, if needed, by permanent shunt placement, and a "late approach" (LA), based on signs of increased intracranial pressure with mostly immediate permanent intervention. METHODS: Observational cohort study of 127 preterm infants (gestation <30 weeks) with PHVD managed with EA (n = 78) or LA (n = 49). Ventricular size was measured on cranial ultrasound. Outcome was assessed at 18-24 months. RESULTS: Forty-nine of 78 (63%) EA and 24 of 49 (49%) LA infants received intervention. LA infants were slightly younger at birth, but did not differ from EA infants for other clinical measures. Initial intervention in the EA group occurred at younger age (29.4/33.1 week postmenstrual age; p < 0.001) with smaller ventricles (VI 2.4/14 mm >+2 SD; p < 0.01), and consisted predominantly of lumbar punctures or reservoir taps. Maximum VI in infants with/without intervention was similar in EA (3/1.5 mm >+2 SD; p = 0.3) but differed in the LA group (14/2.1 mm >+2 SD; p < 0.001). Shunt rate (20/92%; p < 0.001) and complications were lower in EA than LA group. Most EA infants had normal outcomes (>-1 SD), despite intervention. LA infants with intervention had poorer outcomes than those without (p < 0.003), with scores <-2 SD in 81%. CONCLUSION: In preterm infants with PHVD, those with early intervention, even when eventually requiring a shunt, had outcomes indistinguishable from those without intervention, all being within the normal range. In contrast, in infants managed with LA, need for intervention predicted worse outcomes. Benefits of EA appear to outweigh potential risks. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for preterm infants with PHVD, an EA to management results in better neurodevelopmental outcomes than a LA.

The Effect of Head Positioning and Head Tilting on the Incidence of Intraventricular Hemorrhage in Very Preterm Infants: A Systematic Review.

BACKGROUND: Despite advances in neonatal intensive care, germinal matrix-intraventricular hemorrhage (GMH-IVH) remains a frequent, serious complication of premature birth. Neutral head position and head tilting have been suggested to reduce the risk of GMH-IVH in preterm infants during the first 72 h of life. OBJECTIVE: The aim of this study was to provide a systematic review of the effect of neutral head positioning and head tilting on the incidence of GMH-IVH in very preterm infants (gestational age ≤30 weeks). In addition, we reviewed their effect on cerebral hemodynamics and oxygenation. METHODS: Literature was searched (June 2016) in the following electronic databases: CINAHL, Embase, Medline, SCOPUS, and several trial registers. RESULTS: One underpowered trial studied the effect of head positioning on the incidence of GMH-IVH. This randomized controlled trial enrolled 48 preterm infants and found no effect on the occurrence of GMH-IVH. Three observational studies investigated the effect of head rotation and/or tilting on cerebral oxygenation in 68 preterm infants in total. Their results suggest that cerebral oxygenation is not significantly affected by changes in head positioning. The effect of head positioning and/or tilting on cerebral hemodynamics was described in 2 observational studies of 28 preterm infants and found no significant effect. CONCLUSIONS: There is insufficient evidence regarding the effect of head positioning and tilting on the incidence of GMH-IVH and cerebral hemodynamics and oxygenation in preterm infants. We recommend further research in this field, especially in extremely preterm and clinically unstable infants during the first postnatal days.

Congenital Amegakaryocytic Thrombocytopenia Type II Presenting with Multiple Central Nervous System Anomalies.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive bone marrow failure, caused by MPL gene mutations. The combination of CAMT and central nervous system abnormalities is uncommon. We describe a case with a homozygous missense MPL gene mutation and polymicrogyria, underdevelopment of the cerebellum, and multiple intracranial hemorrhages.

Cranial ultrasound - optimizing utility in the NICU.

Cranial ultrasonography (cUS) is a reliable tool to detect the most frequently occurring congenital and acquired brain abnormalities in full-term and preterm neonates. Appropriate equipment, including a dedicated ultrasound machine and appropriately sized transducers with special settings for cUS of the newborn brain, and ample experience of the ultrasonographist are required to obtain optimal image quality. When, in addition, supplemental acoustic windows are used whenever indicated and cUS imaging is performed from admission throughout the neonatal period, the majority of the lesions will be diagnosed with information on timing and evolution of brain injury and on ongoing brain maturation. For exact determination of site and extent of lesions, for detection of lesions that (largely or partially) remain beyond the scope of cUS and for depiction of myelination, a single, well timed MRI examination is invaluable in many high risk neonates. However, as cUS enables bedside, serial imaging it should be used as the primary brain imaging modality in high risk neonates.