Randomized Controlled Early versus Late Ventricular Intervention Study in Posthemorrhagic Ventricular Dilatation: Outcome at 2 Years.

OBJECTIVE: To compare the effect of intervention at low vs high threshold of ventriculomegaly in preterm infants with posthemorrhagic ventricular dilatation on death or severe neurodevelopmental disability. STUDY DESIGN: This multicenter randomized controlled trial reviewed lumbar punctures initiated after either a low threshold (ventricular index of >p97 and anterior horn width of >6 mm) or high threshold (ventricular index of >p97 + 4 mm and anterior horn width of >10 mm). The composite adverse outcome was defined as death or cerebral palsy or Bayley composite cognitive/motor scores <-2 SDs at 24 months corrected age. RESULTS: Outcomes were assessed in 113 of 126 infants. The composite adverse outcome was seen in 20 of 58 infants (35%) in the low threshold group and 28 of 55 (51%) in the high threshold (P = .07). The low threshold intervention was associated with a decreased risk of an adverse outcome after correcting for gestational age, severity of intraventricular hemorrhage, and cerebellar hemorrhage (aOR, 0.24; 95% CI, 0.07-0.87; P = .03). Infants with a favorable outcome had a smaller fronto-occipital horn ratio (crude mean difference, -0.06; 95% CI, -0.09 to -0.03; P < .001) at term-equivalent age. Infants in the low threshold group with a ventriculoperitoneal shunt, had cognitive and motor scores similar to those without (P = .3 for both), whereas in the high threshold group those with a ventriculoperitoneal shunt had significantly lower scores than those without a ventriculoperitoneal shunt (P = .01 and P = .004, respectively). CONCLUSIONS: In a post hoc analysis, earlier intervention was associated with a lower odds of death or severe neurodevelopmental disability in preterm infants with progressive posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.

Increased Use of Therapeutic Hypothermia in Infants with Milder Neonatal Encephalopathy due to Presumed Perinatal Asphyxia.

INTRODUCTION: Adverse outcomes have been reported in infants with mild neonatal encephalopathy (NE). Increasing clinical experience with the application of therapeutic hypothermia (TH) may have resulted in the treatment of newborns with milder NE during recent years. OBJECTIVE: To determine whether infants treated with TH in the initial years following implementation had a higher degree of NE than infants treated during subsequent years. METHODS: Infants with NE treated with TH from February 2008 until July 2017 were included. Thompson and Sarnat scores, amplitude-integrated electroencephalography (aEEG) background patterns before the start of TH, and neurodevelopmental outcome at 2 years were compared between infants treated from February 2008 until October 2012 (period 1) and infants treated from November 2012 until July 2017 (period 2). RESULTS: 211 newborns with NE were treated with TH (period 1: n = 109, period 2: n = 102). Sarnat scores in period 1 and 2 were mild in 7.3 vs. 28.4%, moderate in 66.1 vs. 44.1%, and severe in 26.6 vs. 22.5%, respectively (p = 0.008). Thompson scores were lower in period 2 (median = 9, IQR 7-12) than in period 1 (median = 10, IQR 8.5-13.5, p = 0.018). The aEEGs and neurodevelopmental outcomes were comparable between the periods. CONCLUSIONS: Based on Thompson and Sarnat scores, but not aEEG background patterns, infants treated during the second period had milder NE than infants treated during the first years following implementation of TH. There was no difference in 2 years neurodevelopmental outcome. Further research is necessary to evaluate the value of TH for infants with clinically mild NE.

Periventricular Hemorrhagic Infarction in Very Preterm Infants: Characteristic Sonographic Findings and Association with Neurodevelopmental Outcome at Age 2 Years.

OBJECTIVE: To describe the sonographic characteristics of periventricular hemorrhagic infarction (PVHI) and their association with mortality and neurodevelopmental disability in very preterm infants born in 2008-2013. STUDY DESIGN: Retrospective multicenter observational cohort study. Diagonal PVHI size was measured and severity score assessed. PVHI characteristics were scored and temporal trends were assessed. Neurodevelopmental outcome at 2 years of corrected age was assessed using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales. Multigroup analyses were applied as appropriate. RESULTS: We enrolled 160 infants with median gestational age of 26.6 weeks. PVHI was mostly unilateral (90%), associated with an ipsilateral grade III intraventricular hemorrhage (84%), and located in the parietal lobe (51%). Sixty-four (40%) infants with PVHI died in the neonatal period. Of the survivors assessed at 2 years of corrected age, 65% had normal cognitive and 69% had normal motor outcomes. The cerebral palsy rate was 42%. The composite outcome of death or severe neurodevelopmental disability was observed in 58%, with no trends over the study period (P = .6). Increasing PVHI severity score was associated with death (P < .001). Increasing PVHI size and severity score were negatively associated with gross motor scores (P = .01 and .03, respectively). Trigone involvement was associated with cerebral palsy (41% vs 14%; P = .004). Associated posthemorrhagic ventricular dilation (36%) was an independent risk factor for poorer cognitive and motor outcomes (P < .001 for both). CONCLUSIONS: Increasing PVHI size and severity score were predictive of less optimal gross motor outcome and death in very preterm infants.

Neurodevelopmental Outcomes in Preterm Infants with White Matter Injury Using a New MRI Classification.

OBJECTIVE: The aim of this study was to evaluate whether a new MRI scoring system for preterm non-haemorrhagic white matter injury (WMI), derived from the analysis of the natural evolution of WMI throughout the neonatal period until term-equivalent age, can be used for outcome prediction. METHODS: Eighty-two infants <36 weeks gestation with WMI diagnosed from sequential cranial ultrasound and confirmed on neonatal MRI were retrospectively included. WMI was classified in four grades of severity. Neurodevelopmental data at a median age of 24 months were analysed. RESULTS: In 74 surviving children WMI severity was strongly associated with the presence and severity of cerebral palsy (CP) and other neurodevelopmental impairments (Spearman's rank correlation 0.88, p < 0.001). Only 3 children with grade I WMI (9%) developed CP (all ambulant) and their developmental scores were not different to those from the controls, although they started walking significantly later (p = 0.036). Of the 6 children with grade II, 83% developed CP (mild in most), whereas 91% of the 34 children with grade III had CP (moderate-severe in 76%) and all had some degree of neurodevelopmental impairment. Three children with grade III WMI did not develop CP; their imaging showed, in contrast to children who developed CP, that the cysts did not affect the corticospinal tracts; also, myelin in the posterior limb of the internal capsule appeared normal in 2 children and suboptimal in 1. CONCLUSIONS: This MRI scoring system for preterm WMI can be used to predict neurodevelopmental outcomes. Individualized assessment of the site of lesions and the progression of myelination improves prognostic accuracy.

Low Cerebral Oxygenation in Preterm Infants Is Associated with Adverse Neurodevelopmental Outcome.

OBJECTIVE: To assess whether high and low levels of cerebral oxygenation (regional cerebral oxygenation [rScO2]) in infants born at <32 weeks of gestation were associated with adverse long-term outcome. STUDY DESIGN: Observational cohort study including preterm infants born at <32 weeks of gestation at the Wilhelmina Children's Hospital, The Netherlands, between April 2006 and April 2013. The rScO2 was continuously monitored for 72 hours after birth using near-infrared spectroscopy. Outcome was assessed at 15 and 24 months of corrected age by certified investigators. An unfavorable composite outcome was defined as an outcome score below -1 SD or death. Various rScO2 thresholds were explored. RESULTS: In total, 734 infants were eligible for analysis, 60 of whom died. Associations with an unfavorable cognitive outcome in multivariable analysis were comparable for time spent with a rScO2 below 55% and -1.5 SD (according to published reference values), with an OR of 1.4 (CI 1.1-1.7) for 20% of time below either threshold. Results at 15 months were comparable with results at 24 months. Results were not statistically significant for thresholds defining high values of rScO2. The composite motor outcome was not significantly related to either low or high values or rScO2. CONCLUSIONS: Low, but not high, rScO2 was associated with an unfavorable cognitive outcome. This suggests the use of a threshold of rScO2 <55% for future clinical studies when using adult near-infrared sensors (rScO2 <65% for neonatal sensors, approximately).

Neurodevelopment After Perinatal Arterial Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Perinatal arterial ischemic stroke (PAIS) leads to cerebral palsy in ∼30% of affected children and has other neurologic sequelae. Authors of most outcome studies focus on middle cerebral artery (MCA) stroke without differentiating between site and extent of affected tissue. Our aim with this study was to report outcomes after different PAIS subtypes. METHODS: Between 1990 and 2015, 188 term infants from 2 centers (London [n = 79] and Utrecht [n = 109]) had PAIS on their neonatal MRI. Scans were reevaluated to classify stroke territory and determine specific tissue involvement. At 18 to 93 (median 41.7) months, adverse neurodevelopmental outcomes were recorded as 1 or more of cerebral palsy, cognitive deficit, language delay, epilepsy, behavioral problems, or visual field defect. RESULTS: The MCA territory was most often involved (90%), with posterior or anterior cerebral artery territory strokes occurring in 9% and 1%, respectively. Three infants died, and 24 had scans unavailable for reevaluation or were lost to follow-up. Of 161 infants seen, 54% had an adverse outcome. Outcomes were the same between centers. Main branch MCA stroke resulted in 100% adverse outcome, whereas other stroke subtypes had adverse outcomes in only 29% to 57%. The most important outcome predictors were involvement of the corticospinal tracts and basal ganglia. CONCLUSIONS: Although neurodevelopmental outcome was adverse in at least 1 domain with main branch MCA stroke, in other PAIS subtypes outcome was favorable in 43% to 71% of children. Site and tissue involvement is most important in determining the outcome in PAIS.

MRI Changes in the Thalamus and Basal Ganglia of Full-Term Neonates with Perinatal Asphyxia.

BACKGROUND: Magnetic resonance imaging (MRI) is the standard neuroimaging technique to assess perinatal asphyxia-associated brain injury in full-term infants. Diffusion-weighted imaging (DWI) is most informative when assessed during the first week after the insult. OBJECTIVES: To study the DWI abnormalities of the thalamus and basal ganglia in full-term infants with perinatal asphyxia. METHODS: Fifty-five (near) term infants (normothermia n = 23; hypothermia n = 32) with thalamus and/or basal ganglia injury were included. MRI findings were assessed visually and quantitatively calculating apparent diffusion coefficient (ADC) values. Thalamus/basal ganglia ADC ratios were calculated to analyze the differences between these areas. Infants with an early MRI (days 1-3) or later MRI (days 4-7) were compared. RESULTS: Isolated extensive thalamic injury was seen early, and focal thalamic and basal ganglia injury was seen later. On the early MRI, visual assessment underestimated abnormalities in the basal ganglia (59% abnormal vs. 90% abnormal on quantitative assessment; p = 0.015), suggesting the need for quantitative assessment. In infants treated with hypothermia, the thalamus/basal ganglia ADC ratio was lower. CONCLUSIONS: Both visual analysis and quantitative evaluation of cerebral MRI after perinatal asphyxia are needed, especially during the first few days after birth. Timing of ADC changes is influenced by therapeutic hypothermia.

Outcome of Preterm Infants With Postnatal Cytomegalovirus Infection.

OBJECTIVES: To assess whether preterm infants with postnatal cytomegalovirus infection develop neurologic sequelae in early childhood. METHODS: Infants <32 weeks' gestation were prospectively screened for cytomegalovirus (CMV) at term-equivalent age. Neurodevelopment was compared between CMV-positive and CMV-negative infants by using the Griffiths Mental Development Scales (GMDS) at 16 months' corrected age (CA); the Bayley Scales of Infant and Toddler Development, Third Edition or the GMDS at 24 to 30 months' CA; and the Wechsler Preschool and Primary Scale of Intelligence, Third Edition and Movement Assessment Battery for Children, Second Edition at 6 years of age. At 6 years old, hearing was assessed in CMV-positive children. RESULTS: Neurodevelopment was assessed in 356 infants at 16 months' CA, of whom 49 (14%) were infected and 307 (86%) were noninfected. Infected infants performed significantly better on the GMDS locomotor scale. There were no differences at 24 to 30 months' CA on the Bayley Scales of Infant and Toddler Development, Third Edition or GMDS. At 6 years of age, infected children scored lower on the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, but mean scores were within normal range, reaching significance only in verbal IQ (96 [SD 17] vs 103 [SD 15] points; P = .046). Multiple regression indicated no impact of CMV status but significant influence of maternal education and ethnicity on verbal IQ. No significant differences in motor development were found and none of the infected children developed sensorineural hearing loss. CONCLUSIONS: In this cohort study, postnatal cytomegalovirus infection in preterm children did not have an adverse effect on neurodevelopment within the first 6 years of life.

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.

A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia.

OBJECTIVE: To assess the predictive value of a novel magnetic resonance imaging (MRI) score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum, for neurodevelopmental outcome at 2 years and school age among term infants with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. STUDY DESIGN: This retrospective cohort study (cohort 1, The Netherlands 2008-2014; cohort 2, Sweden 2007-2012) including infants born at >36 weeks of gestational age treated with therapeutic hypothermia who had an MRI in the first weeks of life. The MRI score consisted of 3 subscores: deep grey matter, white matter/cortex, and cerebellum. Primary adverse outcome was defined as death, cerebral palsy, Bayley Scales of Infant and Toddler Development, third edition, motor or cognitive composite scores at 2 years of <85, or IQ at school age of <85. RESULTS: In cohort 1 (n = 97) and cohort 2 (n = 76) the grey matter subscore was an independent predictor of adverse outcome at 2 years (cohort 1, OR, 1.6; 95% CI, 1.3-1.9; cohort 2, OR, 1.4; 95% CI, 1.2-1.6), and school age (cohort 1, OR, 1.3; 95% CI, 1.2-1.5; cohort 2, OR, 1.3; 95% CI, 1.1-1.6). The white matter and cerebellum subscore did not add to the predictive value. The positive predictive value, negative predictive value, and area under the curve for the grey matter subscore were all >0.83 in both cohorts, whereas the specificity was >0.91 with variable sensitivity. CONCLUSION: A novel MRI score, which includes diffusion-weighted imaging and assesses all brain areas of importance in infants with therapeutic hypothermia after perinatal asphyxia, has predictive value for outcome at 2 years of age and at school age, for which the grey matter subscore can be used independently.

Rhythmic EEG patterns in extremely preterm infants: Classification and association with brain injury and outcome.

OBJECTIVE: Classify rhythmic EEG patterns in extremely preterm infants and relate these to brain injury and outcome. METHODS: Retrospective analysis of 77 infants born <28 weeks gestational age (GA) who had a 2-channel EEG during the first 72 h after birth. Patterns detected by the BrainZ seizure detection algorithm were categorized: ictal discharges, periodic epileptiform discharges (PEDs) and other waveforms. Brain injury was assessed with sequential cranial ultrasound (cUS) and MRI at term-equivalent age. Neurodevelopmental outcome was assessed with the BSITD-III (2 years) and WPPSI-III-NL (5 years). RESULTS: Rhythmic patterns were observed in 62.3% (ictal 1.3%, PEDs 44%, other waveforms 86.3%) with multiple patterns in 36.4%. Ictal discharges were only observed in one and excluded from further analyses. The EEG location of the other waveforms (p<0.05), but not PEDs (p=0.238), was significantly associated with head position. No relation was found between the median total duration of each pattern and injury on cUS and MRI or cognition at 2 and 5 years. CONCLUSIONS: Clear ictal discharges are rare in extremely preterm infants. PEDs are common but their significance is unclear. Rhythmic waveforms related to head position are likely artefacts. SIGNIFICANCE: Rhythmic EEG patterns may have a different significance in extremely preterm infants.

The Impact of Low-Grade Germinal Matrix-Intraventricular Hemorrhage on Neurodevelopmental Outcome of Very Preterm Infants.

BACKGROUND: Very preterm infants often show germinal matrix-intraventricular hemorrhage (GMH-IVH) on cranial ultrasound (cUS). AIM: To determine the impact of low-grade GMH-IVH on early neurodevelopmental outcome in very preterm infants. METHODS: A retrospective case-control study in very preterm infants with and without low-grade GMH-IVH on cUS. Additional magnetic resonance imaging (MRI) was available in all infants with a gestational age (GA) <28 weeks and high-risk infants >28 weeks. Infants were seen at 2 years' corrected age to assess neurodevelopment. RESULTS: In total, 136 infants (GA 24-32 weeks) with low-grade GMH-IVH on cUS were matched with 255 controls. Outcome data was available for 342 (87%) infants. Adverse outcome (i.e., cerebral palsy [CP], neurodevelopmental delay) was present in 11 (9%) cases and 20 (9%) controls. No statistically significant differences in outcome were found between cases and controls. Additional MRI was performed in 165/391 infants (42%) and showed additional lesions in 73 (44%) infants that could explain subsequent development of CP in 2 out of 5 infants and epilepsy in 1 of 2 infants. CONCLUSION: Very preterm infants with low-grade GMH-IVH on cUS have a similar early neurodevelopmental outcome compared with controls. Additional MRI showed mostly subtle abnormalities that were missed with cUS, but these could not explain subsequent development of CP and developmental delay in all infants.

Prediction of cognitive and motor outcome of preterm infants based on automatic quantitative descriptors from neonatal MR brain images.

This study investigates the predictive ability of automatic quantitative brain MRI descriptors for the identification of infants with low cognitive and/or motor outcome at 2-3 years chronological age. MR brain images of 173 patients were acquired at 30 weeks postmenstrual age (PMA) (n = 86) and 40 weeks PMA (n = 153) between 2008 and 2013. Eight tissue volumes and measures of cortical morphology were automatically computed. A support vector machine classifier was employed to identify infants who exhibit low cognitive and/or motor outcome (<85) at 2-3 years chronological age as assessed by the Bayley scales. Based on the images acquired at 30 weeks PMA, the automatic identification resulted in an area under the receiver operation characteristic curve (AUC) of 0.78 for low cognitive outcome, and an AUC of 0.80 for low motor outcome. Identification based on the change of the descriptors between 30 and 40 weeks PMA (n = 66) resulted in an AUC of 0.80 for low cognitive outcome and an AUC of 0.85 for low motor outcome. This study provides evidence of the feasibility of identification of preterm infants at risk of cognitive and motor impairments based on descriptors automatically computed from images acquired at 30 and 40 weeks PMA.

Preterm brain injury on term-equivalent age MRI in relation to perinatal factors and neurodevelopmental outcome at two years.

OBJECTIVES: First, to apply a recently extended scoring system for preterm brain injury at term-equivalent age (TEA-)MRI in a regional extremely preterm cohort; second, to identify independent perinatal factors associated with this score; and third, to assess the prognostic value of this TEA-MRI score with respect to early neurodevelopmental outcome. STUDY DESIGN: 239 extremely preterm infants (median gestational age [range] in weeks: 26.6 [24.3-27.9]), admitted to the Wilhelmina Children's Hospital between 2006 and 2012 were included. Brain abnormalities in white matter, cortical and deep grey matter and cerebellum and brain growth were scored on T1- and T2-weighted TEA-MRI using the Kidokoro scoring system. Neurodevelopmental outcome was assessed at two years corrected age using the Bayley Scales of Infant and Toddler Development, third edition. The association between TEA-MRI and perinatal factors as well as neurodevelopmental outcome was evaluated using multivariable regression analysis. RESULTS: The distribution of brain abnormalities and brain metrics in the Utrecht cohort differed from the original St. Louis cohort (p < .05). Mechanical ventilation >7 days (ß [95% confidence interval, CI]: 1.3 [.5; 2.0]) and parenteral nutrition >21 days (2.2 [1.2; 3.2]) were independently associated with higher global brain abnormality scores (p < .001). Global brain abnormality scores were inversely associated with cognitive (ß in composite scores [95% CI]: -.7 [-1.2; -.2], p = .004), fine motor (ß in scaled scores [95% CI]: -.1 [-.3; -.0], p = .007) and gross motor outcome (ß in scaled scores [95% CI]: -.2 [-.3; -.1], p < .001) at two years corrected age, although the explained variances were low (R2 ≤.219). CONCLUSION: Patterns of brain injury differed between cohorts. Prolonged mechanical ventilation and parenteral nutrition were identified as independent perinatal risk factors. The prognostic value of the TEA-MRI score was rather limited in this well-performing cohort.

Concurrent Validity Between Live and Home Video Observations Using the Alberta Infant Motor Scale.

PURPOSE: Serial assessment of gross motor development of infants at risk is an established procedure in neonatal follow-up clinics. Assessments based on home video recordings could be a relevant addition. METHODS: In 48 infants (1.5-19 months), the concurrent validity of 2 applications was examined using the Alberta Infant Motor Scale: (1) a home video made by parents and (2) simultaneous observation on-site by a pediatric physical therapist. Parents' experiences were explored using a questionnaire. RESULTS: The intraclass correlation coefficient agreement between live and home video assessment was 0.99, with a standard error of measurement of 1.41 items. Intra- and interrater reliability: intraclass correlation coefficients were more than 0.99. According to 94% of the parents, recording their infant's movement repertoire was easy to perform. CONCLUSION: Assessing the Alberta Infant Motor Scale based on home video recordings is comparable to assessment by live observation. The video method is a promising application that can be used with low burden for parents and infants.

A Comparison of the Thompson Encephalopathy Score and Amplitude-Integrated Electroencephalography in Infants with Perinatal Asphyxia and Therapeutic Hypothermia.

BACKGROUND: In previous studies clinical signs or amplitude-integrated electroencephalography (aEEG)-based signs of encephalopathy were used to select infants with perinatal asphyxia for treatment with hypothermia. AIM: The objective of this study was to compare Thompson encephalopathy scores and aEEG, and relate both to outcome. SUBJECTS AND METHODS: Thompson scores, aEEG, and outcome were compared in 122 infants with perinatal asphyxia and therapeutic hypothermia. Of these 122 infants, 41 died and 7 had an adverse neurodevelopmental outcome. A receiver operating characteristics (ROC) analysis was also performed. RESULTS: Thompson scores were higher in infants with more abnormal aEEG background patterns (ANOVA, p < 0.001). The ROC analysis demonstrated that a Thompson score of 11 or higher or an aEEG background pattern of continuous low voltage or worse was associated with an adverse outcome (AUC 0.84 for both). CONCLUSIONS: High Thompson scores and a suppressed aEEG background pattern are associated with an adverse outcome after perinatal asphyxia and therapeutic hypothermia. Further studies are needed to identify the best technique with which to select patients for therapeutic hypothermia.

MRI and spectroscopy in (near) term neonates with perinatal asphyxia and therapeutic hypothermia.

BACKGROUND: Previous studies have demonstrated the association of abnormalities on diffusion-weighted MRI (DW-MRI) and proton magnetic resonance spectroscopy (1H-MRS) in infants with perinatal asphyxia. The use of therapeutic hypothermia might change this association. AIM: To study the association between DW-MRI and 1H-MRS and outcome after perinatal asphyxia and therapeutic hypothermia in infants with a gestational age of ≥36 weeks. PATIENTS AND METHODS: Infants with perinatal asphyxia and therapeutic hypothermia (n=88) were included when an MR examination was performed within 7 days after birth. Apparent diffusion coefficient (ADC) values of the basal ganglia and thalamus were calculated, as were lactate/N-acetylaspartate (LAC/NAA) and N-acetylaspartate/choline (NAA/Cho) ratios. Death or an abnormal neurodevelopment at ≥24 months was considered an adverse outcome. Receiver operating characteristic analysis was performed to determine cut-off levels. RESULTS: Of the 88 infants, 22 died and 7 had an adverse neurodevelopmental outcome. In infants with an adverse outcome, ADC values of the basal ganglia and thalamus were significantly lower, and Lac/NAA ratios were significantly higher than in infants with a normal outcome. Areas under the curve of ADC of the basal ganglia, thalami and Lac/NAA ratio were 0.89, 0.88 and 0.87, respectively. NAA/Cho ratios were in this cohort not associated with outcome. CONCLUSIONS: During and after therapeutic hypothermia, low ADC values and high Lac/NAA ratios of the basal ganglia and thalamus are associated with an adverse outcome in infants with perinatal asphyxia.

Does the development of executive functioning in infants born preterm benefit from maternal directiveness?

OBJECTIVE: Problems in early development of executive functioning may underlie the vulnerability and individual variability of infants born preterm for behavioral and learning problems. Parenting behaviors may aggravate or temper this increased risk for dysfunction. This study assessed how maternal parenting behaviors predict individual differences in early development of executive functioning in infants born preterm, and whether this varies with infant temperament, i.e., self-regulation. METHODS: Participants were 76 infants born preterm (≤36weeks' gestation and <2500g birth weight) and their mothers. Maternal sensitive responsiveness and directiveness were observed during a mother-infant interaction situation at 7, 10 and 14months corrected age. At the same ages, executive functioning was measured using the A-not-B task. An infant self-regulation questionnaire (IBQ-R) was completed by mothers at 7months. RESULTS: After controlling for perinatal risk factors, Multivariate Latent Growth Modeling showed that consistently higher levels of maternal directiveness predicted a stronger increase in A-not-B performance, which did not vary with infant self-regulation. No relationship between maternal sensitive responsiveness and development in A-not-B performance in infants born preterm was found. CONCLUSIONS: These results suggest that preterm infants' early executive functioning development in the first year of life may benefit from a more and consistent directive approach by their mothers. These findings have important implications for early intervention programs aimed at facilitating preterm infants' development.

Relation between clinical risk factors, early cortical changes, and neurodevelopmental outcome in preterm infants.

Cortical folding mainly takes place in the third trimester of pregnancy and may therefore be influenced by preterm birth. The aim of this study was to evaluate the development of specific cortical structures between early age (around 30weeks postmenstrual age) and term-equivalent age (TEA, around 40weeks postmenstrual age) in 71 extremely preterm infants, and to associate this to clinical characteristics and neurodevelopmental outcome at two years of age. First, analysis showed that the central sulcus (CS), lateral fissure (LF) and insula (INS) were present at early MRI in all infants, whereas the other sulci (post-central sulcus [PCS], superior temporal sulcus [STS], superior [SFS] and inferior [IFS] frontal sulcus) were only seen in part of the infants. Relative growth from early to TEA examination was largest in the SFS. A rightward asymmetry of the surface area was seen in development between both examinations except for the LF, which showed a leftward asymmetry at both time points. Second, lower birth weight z-score, multiple pregnancy and prolonged mechanical ventilation showed negative effects on cortical folding of the CS, LF, INS, STS and PCS, mainly on the first examination, suggesting that sulci developing the earliest were the most affected by clinical factors. Finally, in this cohort, a clear association between cortical folding and neurodevelopmental outcome at two years corrected age was found, particularly for receptive language.

Brain Volumes at Term-Equivalent Age in Preterm Infants: Imaging Biomarkers for Neurodevelopmental Outcome through Early School Age.

OBJECTIVE: To evaluate the relationship between brain volumes at term and neurodevelopmental outcome through early school age in preterm infants. STUDY DESIGN: One hundred twelve preterm infants (born mean gestational age 28.6 ± 1.7 weeks) were studied prospectively with magnetic resonance imaging (imaged at mean 41.6 ± 1.0 weeks). T2- and T1-weighted images were automatically segmented, and volumes of 6 tissue types were related to neurodevelopmental outcome assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (cognitive, fine, and gross motor scores) at 24 months corrected age (n = 112), Griffiths Mental Development Scales (developmental quotient) at age 3.5 years (n = 98), Movement Assessment Battery for Children, Second Edition (n = 85), and Wechsler Preschool and Primary Scale of Intelligence, Third Edition at age 5.5 years (n = 44). Corrections were made for intracranial volume, maternal education, and severe brain lesions. RESULTS: Ventricular volumes were negatively related to neurodevelopmental outcome at age 24 months and 3.5 years, as well as processing speed at age 5.5 years. Unmyelinated white matter (UWM) volume was positively associated with motor outcome at 24 months and with processing speed at age 5.5 years. Cortical gray matter (CGM) volume demonstrated a negative association with motor performance and cognition at 24 months and with developmental quotient at age 3.5 years. Cerebellar volume was positively related to cognition at these time points. Adjustment for brain lesions attenuated the relations between cerebellar and CGM volumes and cognition. CONCLUSIONS: Brain volumes of ventricles, UWM, CGM, and cerebellum may serve as biomarkers for neurodevelopmental outcome in preterm infants. The relationship between larger CGM volumes and adverse neurodevelopment may reflect disturbances in neuronal and/or axonal migration at the UWM-CGM boundary and warrants further investigation.