Preterm birth increases cerebral palsy hazards in children of mothers with chronic hypertension in pregnancy.

BACKGROUND: Children of mothers with chronic-hypertension in pregnancy have high rates of preterm-birth (<37 weeks of gestation) and small-for-gestational-age (SGA), both of which are risk factors of cerebral palsy (CP). This study investigated the cumulative risks of CP in children exposed to maternal chronic-hypertension vs. other types of hypertensive-disorders-of-pregnancy (HDP), and whether preterm-birth and SGA potentiate the antenatal impact of chronic-hypertension to increase CP hazards. METHODS: This population-based cohort study enrolled 1,417,373 mother-child pairs with singleton live births between 2004 and 2011 from the Taiwan Maternal and Child Health Database. A total of 19,457 pairs with HDP were identified and propensity-score-matched with 97,285 normotensive controls. Children were followed up for CP outcome until age 6-13 years. HDP were classified into chronic-hypertension, gestational-hypertension, preeclampsia, and preeclampsia-with-chronic-hypertension. Using the normotensive group as the reference, the associations between chronic-hypertension and CP hazard were assessed with adjusted hazard ratios (HR) and 95% confidence intervals (CI) in Cox proportional hazards regression models, and the effects of preterm-birth and SGA on the associations were examined. RESULTS: The HDP group had higher rates of CP (0.8%) than the normotensive group (0.5%), particularly the subgroup of preeclampsia-with-chronic-hypertension (1.0%), followed by preeclampsia (0.9%), chronic-hypertension (0.7%) and gestational-hypertension (0.6%). Preterm-birth, but not SGA, exerted moderating effects to increase CP risks in children exposed to maternal chronic-hypertension. Before adjustments, chronic-hypertension alone had no substantial contribution to CP hazard (HR 1.35, 95% CI 1.00-1.83), while preeclampsia alone (1.64, 1.28-2.11) or with superimposed-chronic-hypertension (1.83, 1.16-2.89) had significant effects. After including preterm-birth in the multivariable model, the CP hazard for chronic-hypertension alone rather than other types of HDP was raised and became significant (1.56, 1.15-2.12), and the significance remained after stepwise adjustments in the final model (1.74, 1.16-2.60). CONCLUSIONS: Preterm-birth might potentiate CP hazards in children of mothers with chronic-hypertension in pregnancy.

White and gray matter integrity evaluated by MRI-DTI can serve as noninvasive and reliable indicators of structural and functional alterations in chronic neurotrauma.

We aimed to evaluate whether white and gray matter microstructure changes observed with magnetic resonance imaging (MRI)-based diffusion tensor imaging (DTI) can be used to reflect the progression of chronic brain trauma. The MRI-DTI parameters, neuropathologic changes, and behavioral performance of adult male Wistar rats that underwent moderate (2.1 atm on day "0") or repeated mild (1.5 atm on days "0" and "2") traumatic brain injury (TBI or rmTBI) or sham operation were evaluated at 7 days, 14 days, and 1-9 months after surgery. Neurobehavioral tests showed that TBI causes long-term motor, cognitive and neurological deficits, whereas rmTBI results in more significant deficits in these paradigms. Both histology and MRI show that rmTBI causes more significant changes in brain lesion volumes than TBI. In vivo DTI further reveals that TBI and rmTBI cause persistent microstructural changes in white matter tracts (such as the body of the corpus callosum, splenium of corpus callus, internal capsule and/or angular bundle) of both two hemispheres. Luxol fast blue measurements reveal similar myelin loss (as well as reduction in white matter thickness) in ipsilateral and contralateral hemispheres as observed by DTI analysis in injured rats. These data indicate that the disintegration of microstructural changes in white and gray matter parameters analyzed by MRI-DTI can serve as noninvasive and reliable markers of structural and functional level alterations in chronic TBI.

Mesenchymal stem cells reduce long-term cognitive deficits and attenuate myelin disintegration and microglia activation following repetitive traumatic brain injury.

The underlying mechanisms for the beneficial effects exerted by bone marrow-mesenchymal stem cells (BM-MSCs) in treating repetitive traumatic brain injury (rTBI)-induced long-term sensorimotor/cognitive impairments are not fully elucidated. Herein, we aimed to explore whether BM-MSCs therapy protects against rTBI-induced long-term neurobehavioral disorders in rats via normalizing white matter integrity and gray matter microglial response. Rats were subjected to repeated mild lateral fluid percussion on day 0 and day 3. On the fourth day post-surgery, MSCs groups received MSCs (4 × 106 cells/ml/kg, intravenously) and were assessed by the radial maze, Y maze, passive avoidance tests, and modified neurological severity scores. Hematoxylin & eosin, and Luxol fast blue stainings were used to examine the histopathology and white matter thickness. At the same time, immunofluorescence staining was used to investigate the numbers of tumor necrosis factor-alpha (TNF-α)-containing microglia in gray matter. Three to nine months after neurotrauma, rats displayed sensorimotor and cognitive impairments, reduced thickness in white matter, and over-accumulation of TNF-α-containing microglia and cellular damage in gray matter. Therapy with BM-MSCs significantly attenuated the rTBI-induced sensorimotor and cognitive impairments and all their complications. Mesenchymal stem cell therapy might accelerate the recovery of sensorimotor and cognitive impairments in rats with rTBI via normalizing myelin integrity and microglia response.

Maternal hypertensive pregnancy disorders increase childhood intellectual disability hazards independently from preterm birth and small for gestational age.

BACKGROUND: Children of mothers with hypertensive-disorders-of-pregnancy (HDP) have high rates of preterm-birth (<37 weeks' gestation) and small-for-gestational-age (SGA), both of which are risk factors of intellectual disability (ID). AIMS: To test the multiple-hit hypothesis that preterm-birth and SGA in the neonatal period might potentiate the antenatal impact of HDP to increase childhood ID hazards, and HDP might not have independent effects. METHODS: This population-based cohort study enrolled 1,417,373 mother-child pairs between 2004 and 2011. A total of 19,457 pairs with HDP were identified and propensity-score-matched with 97,285 normotensive controls. Children were followed up for ID outcome until 6-13 years of age. HDP were classified into chronic-hypertension, gestational-hypertension, preeclampsia, and preeclampsia-with-chronic-hypertension. Using the normotensive group as the reference, the associations between HDP subgroups and ID hazards were assessed with adjusted hazard ratios (aHR) and 95 % confidence intervals (CI), and the effects of preterm-birth and SGA on the associations were examined. RESULTS: The HDP group had higher cumulative rates of ID (1.6 %) than the normotensive group (0.9 %), particularly the subgroup of preeclampsia-with-chronic-hypertension (2.4 %), followed by preeclampsia (1.7 %), chronic-hypertension (1.5 %) and gestational hypertension (1.0 %). Preterm-birth and SGA exerted aggravating effects on ID hazards in children exposed to any HDP. After adjustments, maternal chronic-hypertension (aHR 1.59, 95 % CI 1.28-1.97), preeclampsia (1.52, 1.26-1.83), and preeclampsia-with-chronic-hypertension (1.86, 1.38-2.51) independently contributed to ID outcome. CONCLUSIONS: Maternal HDP other than gestational hypertension increased offspring's ID hazards independently from the potentiating hits of preterm-birth and SGA, implicating long-lasting influence of in-utero HDP exposure on children's cognitive development.

Preterm birth and small for gestational age potentiate the association between maternal hypertensive pregnancy and childhood autism spectrum disorder.

Children of mothers with hypertensive disorders of pregnancy (HDP) have high rates of preterm-birth (gestational age < 37 weeks) and small-for-gestational-age (SGA), both of which are risk factors of autism spectrum disorder (ASD). This study tested the multiple-hit hypothesis that preterm-birth and SGA in the neonatal period might potentiate the antenatal impact of HDP to increase childhood ASD hazards, and HDP might not be a major contributor. The propensity-score-matched cohort enrolled 18,131 mother-child pairs with HDP and 90,655 normotensive controls between 2004 and 2011. Children with siblings born to the same mothers were excluded for analysis to reduce the potential familial-genetic influence. HDP were classified into chronic-hypertension, gestational-hypertension, preeclampsia, and preeclampsia-with-chronic-hypertension. Using the normotensive group as the reference, the associations between HDP subgroups and the cumulative ASD risks were assessed with hazard ratios, and the effects of preterm-birth and SGA on the associations were examined. The HDP group had a higher cumulative rate of ASD (1.5%) than the normotensive group (1.2%). Preterm-birth and SGA exerted moderating effects to aggravate ASD hazards in children exposed to chronic-hypertension or gestational-hypertension. None of HDP types significantly contributed to ASD after adjustments. In conclusion, antenatal HDP exposure might predispose to ASD outcome through susceptibility to the impact of preterm-birth and SGA.

Trends in Gestational Age-Related Intelligence Outcomes of School-Age Children Born Very Preterm from 2001 to 2015 in Taiwan.

OBJECTIVE: To investigate whether gestational age (GA)-related intelligence outcomes of children born very preterm improved over time. STUDY DESIGN: A multicenter cohort study recruited 4717 infants born at GA <31 weeks and admitted to neonatal intensive care units between 2001 and 2015 in Taiwan. Intelligence outcomes at age 5.5 years were classified by intelligent quotient (IQ) into no cognitive impairment (IQ > -1 SD), mild cognitive impairment (IQ = -1∼-2 SD), and moderate/severe cognitive impairment (IQ < -2 SD). Trends were assessed for neonatal morbidities, mortality, and intelligence outcomes by birth epoch (2001-2003, 2004-2006, 2007-2009, 2010-2012, 2013-2015) and GA (23-24, 25-26, 27-28, 29-30 weeks). RESULTS: Maternal education levels increased and rates of brain injury and mortality decreased over time. Among the 2606 children who received IQ tests, the rates of no, mild, and moderate/severe cognitive impairment were 54.5%, 30.5%, and 15.0%, respectively. There were significant trends in the increasing rates of no cognitive impairment and declining rates of mild and moderate/severe cognitive impairment in all GA groups across the 5 birth epochs. Relative to the occurrence in 2001-2003, the odds were significantly reduced for moderate/severe cognitive impairment from 2007-2009 (aOR 0.49, 95% CI 0.30-0.81) to 2013-2015 (0.35, 0.21-0.56) and for mild cognitive impairment from 2010-2012 (0.54, 0.36-0.79) to 2013-2015 (0.36, 0.24-0.53). CONCLUSIONS: For children born very preterm between 2001 and 2015 in Taiwan, the improvement of maternal education levels and improvements in neonatal brain injury and mortality were temporally associated with trends of decreasing intellectual impairment at school age across all GA groups.

Evaluation of feeding difficulties using videofluoroscopic swallow study and swallowing therapy in infants and children.

BACKGROUND: Infants and children with feeding difficulties have swallowing dysfunction and high risk of aspiration, which could be silent without choking, resulting in recurrent pneumonia and long-term respiratory morbidity. Videofluoroscopic swallow study (VFSS) is a useful tool for real-time visualization of the swallowing process and airway aspiration. This study reported a single-institutional 10-year experience of VFSS in pediatric patients with feeding difficulties and the efficacy of swallowing therapy. METHODS: From 2011 to 2020, 30 infants and children with feeding difficulties received VFSS examinations in a medical center at a median age of 19 months (range 7 days-8 years). The images of the swallowing process (oral phase, triggering of pharyngeal swallowing, and pharyngeal phase) under videofluoroscopy were analyzed by a radiologist and a speech-language pathologist. Aspiration severity was assessed from VFSS observations and rated by an eight-point Penetration-Aspiration-Scale (PAS), with higher scores indicating increased severity. Swallowing therapy was performed by experienced speech-language therapists, and follow-up of oral feeding tolerance and risk of aspiration pneumonia was done. RESULTS: Of the 30 patients, 24 (80%) had neurological deficits. High PAS scores (6-8) were observed in 25 (83.4%) patients, and 22 had a PAS score of 8, indicating silent aspiration. Of the 25 patients with high PAS scores, 19 (76%) had neurological deficits, and 18 (72%) depended on tube feeding at a median age of 20 months. Swallowing problems occurred most frequently during the pharyngeal phase in the patients with high PAS scores. VFSS-based swallowing therapy improved oral feeding ability and reduced aspiration episodes. CONCLUSION: Infants and children with swallowing dysfunction and neurological deficits had high risk of severe aspiration. Swallowing problems in the pharyngeal phase were the most common VFSS findings in patients with severe aspiration. VFSS may help guide problem-oriented swallowing therapy to reduce the risk of recurrent aspiration.

The interrelationships between neuronal viability, synaptic integrity, microglial responses, and amyloid-beta formation in an in vitro neurotrauma model.

The interrelationships between neuronal viability, synaptic integrity, and microglial responses remain in infancy. In dealing with the question, we induced a stretch injury to evaluate the mechanical effects of trauma on rat primary cortical neurons and BV2 microglial cells in a transwell culture system. The viability of primary neurons and BV2 cells was determined by MTT. Synaptic integrity was evaluated by determining the expression of beta-secretase 1 (BACE1), amyloid-beta (Aß), microtubule-associated protein 2 (MAP2), and synaptophysin (vehicle protein). Both CD16/32-positive (CD16/32+) and CD206-positive (CD206+) microglia cells were detected by immunofluorescence staining. The phagocytic ability of the BV2 cells was determined using pHrodo E. coli BioParticles conjugates and flow cytometry. We found that stretch injury BV2 cells caused reduced viability and synaptic abnormalities characterized by Aß accumulation and reductions of BACE1, MAP2, and synaptophysin in primary neurons. Intact BV2 cells exhibited normal phagocytic ability and were predominantly CD206+ microglia cells, whereas the injured BV2 cells exhibited reduced phagocytic ability and were predominantly CD16/32+ microglial cells. Like a stretch injury, the injured BV2 cells can cause both reduced viability and synaptic abnormalities in primary neurons; intact BV2 cells, when cocultured with primary neurons, can protect against the stretch-injured-induced reduced viability and synaptic abnormalities in primary neurons. We conclude that CD206+ and CD16/32+ BV-2 cells can produce neuroprotective and cytotoxic effects on primary cortical neurons.

Early Mental Trajectories Predict Different Cognitive Levels at School Age in Very Preterm Children.

INTRODUCTION: Early identification of preterm children at high risk of intellectual disability (intelligence quotient [IQ] <70) or borderline intelligence (IQ = 70-84) is critical for different early intervention. We investigated whether early-life mental trajectories predict intellectual disability and borderline intelligence, respectively, among school-age preterm children. METHODS: A multicenter study recruited preterm infants born at <32 weeks' gestation between 2001 and 2014 in Taiwan who underwent mental assessments (Bayley Scales of Infant Development) at corrected ages 6, 12, and 24 months and IQs at age 5.5 years. Mental trajectories from ages 6 to 24 months determined using group-based trajectory modeling were employed to predict intellectual disability and borderline intelligence, respectively. Model fit was assessed using the area under the receiver operating characteristic curve (AUROC) and Akaike information criterion (AIC). RESULTS: Among the 1,680 children enrolled, three mental trajectories were identified: high-stable (59.7%), high-declining (35.3%), and low-declining (5.0%), in which the borderline-intelligence/intellectual-disability rate was 14.1%/1.5%, 36.1%/13.7%, and 10.7%/82.1%, respectively. Compared with children with normal intelligence, the low-declining trajectory had 37.7-fold higher odds (95% confidence interval [CI], 26.3-48.1) for intellectual disability, and the high-declining trajectory had 4.4-fold higher odds (95% CI, 3.1-6.1) for borderline intelligence. Compared to the models with risk factors alone (AIC 1,791.2), the models that included both risk factors and trajectory groups had better overall performance (AIC 1,419.8) and increased prediction power for intelligence outcomes: low-declining trajectory for intellectual disability (AUROC increased from 0.81 to 0.92) and high-declining trajectory for borderline intelligence (AUROC increased from 0.68 to 0.75). CONCLUSIONS: Early-life mental trajectories help identify preterm children at risk of intellectual disability and borderline intelligence, respectively, at school age for timely intervention.

Atypical Sensory Processing and Its Correlation with Behavioral Problems in Late Preterm Children at Age Two.

This study aimed to compare the prevalence rate of atypical sensory processing in late preterm (LP) and term children at two years of age and to further investigate the co-occurrence of atypical sensory processing and behavioral problems (internalizing/externalizing) in both groups of children. A total of 104 children (52 LP and 52 sex- and birth order-matched term children) were included. The primary caregivers were asked to complete the Infant/Toddler Sensory Profile-Chinese version and the Child Behavior Checklist 1.5-5Y-Chinese version (CBCL-C/1.5-5). We found that the LP group had a similar prevalence rate of atypical sensory processing to the term group. However, neonatal intensive care unit experience (r = -0.356, p = 0.013, with visual processing) and days of ventilation and supplementary oxygen (r = -0.392, p = 0.004, with low registration) after birth were significantly correlated with the atypical sensory processing of LP children. Both LP and term children with behavioral problems seemed to have a higher prevalence rate of atypical sensory processing than their peers without behavioral problems. However, when Bonferroni correction was used to control for the statistical errors of multiple comparisons, only in the LP group did the co-occurrence of atypical sensory processing (auditory and oral sensory processing and sensation avoiding) and behavioral problems reach significance. In conclusion, the influence of late preterm birth on sensory processing may become subtle at age two, with the exception of those LP children experiencing complicated medical management after birth. A high level of co-occurrence of atypical sensory processing and behavioral problems suggests that the administration of a sensory processing assessment may be helpful to clarify the cause of problematic behavior and to recommend an appropriate intervention for LP children with behavioral problems.

Streptococcus gallolyticus - A potentially neglected pathogen causing neonatal sepsis not covered by routine group B streptococcus screening.

We report 4 cases of neonatal sepsis caused by Streptococcus gallolyticus. The clinical course was quite similar to early-and late-onset group B streptococcus disease. None of the mothers had group B streptococcus (GBS) colonization on prenatal screening nor received intrapartum antibiotics. We proposed the sporadic distribution of S. gallolyticus sepsis among neonates was partly due to relatively low colonization rate in adults compared with GBS. Species determination of S. gallolyticus may not be available using conventional microbiological methods and may contribute to underestimation or misclassification. In our series, we highlighted the importance of S. gallolyticus as an important pathogen in neonatal sepsis deserving further surveillance.

Trends in survival, neonatal morbidity and neurodevelopmental outcome of very preterm infants in Tainan, Southern Taiwan, 1995-2016.

BACKGROUND: Using regression modeling analysis to investigate the breakpoints of the trends in survival-without-major-neonatal-morbidities (MNM) or -without-neurodevelopmental- impairment (NDI) by year and gestational age (GA) in preterm infants. METHODS: We enrolled 2237 preterm infants (GA < 32 weeks) in Tainan, Taiwan. The trends in survival-without-MNM or -without-NDI by year (1995-2016) and GA (23-31 weeks), and the epochs and GA ranges with distinct changes were examined. Adjusted rate ratios (aRR) (95% confidence interval [CI]) were calculated using the rates in infants born at 23 weeks in 1995 as the reference. RESULTS: For yearly trend, there were three epochs (1995-2000, 2001-2006, 2007-2016) with distinct changes in the rates of survival-without-MNM (aRR [95% CI] 1.07 [1.02-1.12], 1.04 [1.02-1.07], 1.02 [1.01-1.04]) and -without-NDI (1.03 [1.02-1.07], 1.02 [1.01-1.04], 1.01 [0.98-1.04]). For GA trend, the three GA ranges with different increases in the rates of survival-without-MNM were 23+0-26+6 (1.60 [1.31-1.94]), 27+0-28+6 (1.24 [1.14-1.34]) and 29+0-31+6 weeks (1.17 [1.02-1.34]), while those in the rates of survival-without-NDI were 23+0-25+6 (1.14 [1.03-1.25]), 26+0-28+6 (1.06 [1.02-1.12]) and 29+0-31+6 weeks (1.04 [1.02-1.07]). The trends in survival-without-MNM and -without-NDI increased over years in infants with GA 25-31 but not < 25 weeks. CONCLUSION: The yearly trends in survival-without-MNM and -without-NDI had steady increases from 1995 to 2016 with distinct changes in three epochs, and the GA trends also increased with different rates per week in three GA ranges. Infants with GA < 25 weeks did not improve on the rates of survival-without-MNM or -without-NDI per year from 1995 to 2016.

Early Neurodevelopmental Trajectories for Autism Spectrum Disorder in Children Born Very Preterm.

BACKGROUND: Children born preterm are at high risk for autism spectrum disorder (ASD). However, there is still a lack of appropriate developmental markers. In this study, we aim to examine whether early mental performance trajectory is related to ASD outcome in the preterm population. METHODS: The population-based cohort included 414 very preterm survivors born between 2008 and 2014. After excluding children with severe neurosensory impairment, 319 children with available records of developmental quotients before age 2 years were enrolled. The trajectory of mental performance evaluated by using the Bayley Scales of Infant Development across 6, 12, and 24 months of age was analyzed with group-based trajectory modeling. At 5 years of age, the ASD diagnosis was established by using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. RESULTS: There were 29 children with ASD and 290 children without ASD. The mental performances from age 6 to 24 months could be classified into 3 trajectory patterns: low declining, high declining, and high stable, which corresponded to ASD prevalence at age 5 years of 35%, 9%, and 3%, respectively. ASD odds was 15 times higher in the low-declining group than in the high-stable group (odds ratio 15; 95% confidence interval 3.8-59; P < .001). Through the analysis of multinomial logistic regression, we found that male infants with longer exposure to oxygen therapy whose mothers had lower maternal education levels tended to follow the low-declining trajectory. CONCLUSIONS: The early-life mental trajectory patterns, by using the Bayley Scales of Infant Development, may lead to identification of vulnerable children born preterm for early ASD diagnosis and targeted intervention.

Behavioral characteristics of autism spectrum disorder in very preterm birth children.

Background: Lower gestational age may increase autism spectrum disorder (ASD) vulnerability; however, the incidence of ASD diagnosis through a direct assessment on every very preterm birth child on the population base remains unclear. Moreover, the behavioral characteristics of preterm birth ASD are unknown. Methods: Every very preterm birth child (gestational age < 32 weeks; birth weight < 1500 g) who was discharged from neonatal intensive care units in Southern Taiwan and prospectively followed to 5 years of age was evaluated using the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R). The term birth (gestational age > 37 weeks) ASD children characterized by ADOS and ADI-R were group matched to the preterm birth ASD by age at examination for comparison. ADOS severity scores were calculated by the Mann-Whitney U test and ADI-R by multivariate analysis of variance and canonical discriminant analysis. Results: Two hundred forty-six (87%) of the 283 very preterm survivors were followed prospectively to 5 years of age. Nineteen (7.7%) of the 246 children fulfilled the diagnostic criteria of ASD. After excluding 1 patient with cerebral palsy and profound mental disability, 18 preterm ASD children were compared with 44 term birth ASD children. The two ASD groups were comparable for age at examination, gender, and intelligence quotient. The two groups showed comparable ADOS severity scores in social affect deficits, restricted repetitive behaviors, and total score, but had differences in qualitative abnormalities in reciprocal social interaction (Wilks lambda F value = 6.2, P < 0.001) of ADI-R. Compared to term birth ASD children, preterm birth ASD children exhibited worse nonverbal behaviors that regulate social interaction (OR 2.59, 95% CI 1.41-4.73, P = 0.002) but more favorable peer relationships (OR 0.58, 95% CI 0.38-0.90, P = 0.01) and socioemotional reciprocity (OR 0.55, 95% CI 0.33-0.92, P = 0.02). In contrast to the heterogeneous severity of social reciprocity in the term ASD group, the behavioral characteristics of the preterm ASD group showed a homogeneous reciprocal social interaction pattern. Conclusions: The 5-year incidence rate of ASD was high in very preterm birth children. Preterm birth ASD exhibited a specific behavioral phenotype of reciprocal social interaction.

Identifying Risk Factors Shared by Bronchopulmonary Dysplasia, Severe Retinopathy, and Cystic Periventricular Leukomalacia in Very Preterm Infants for Targeted Intervention.

BACKGROUND: Bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (sROP), and cystic periventricular leukomalacia (cPVL) are 3 major morbidities with long-term neurodevelopmental impairments in preterm infants. OBJECTIVE: To investigate the strength of associations and identify key risk factors shared by BPD, sROP, and cPVL for targeted intervention. METHODS: We studied the Taiwanese very-preterm-infant registry data on 3,507 infants admitted to neonatal intensive care units and discharged at postmenstrual age ≥36 weeks between 2008 and 2013. RESULTS: Of 3,507 infants, 1,497 presented with at least 1 morbidity (26 [1.7%], 386 [25.8%], and 1,085 [72.5%] exhibited 3, 2, and 1 morbidities, respectively). BPD was strongly associated with sROP (odds ratio 5.93; 95% confidence interval 5.02-7.03), followed by cPVL (2.08; 1.63-2.64), but sROP and cPVL were weakly associated (1.59; 1.17-2.13). Most risk factors contributed to BPD, which shared risk factors with sROP and cPVL. A birth weight of < 1,000 g, male sex, and prolonged mechanical ventilation (MV) were shared by BPD and sROP, and chorioamnionitis, severe respiratory distress syndrome, and prolonged MV specifically contributed to BPD and cPVL. Prolonged MV was the single risk factor common to BPD, sROP, and cPVL. Avoiding prolonged MV reduced the risk of having at least 1 of the 3 morbidities by 37%. CONCLUSIONS: BPD and sROP were most strongly associated. Most risk factors contributed to BPD, with differentially shared effects on sROP and cPVL. Prolonged MV was the only risk factor shared by all 3 morbidities, and avoiding it potentially reduced the risk of having at least 1 of them.

Isolated Cystic Periventricular Leukomalacia Differs from Cystic Periventricular Leukomalacia with Intraventricular Hemorrhage in Prevalence, Risk Factors and Outcomes in Preterm Infants.

BACKGROUND: Cystic periventricular leukomalacia (cPVL) is the most severe white matter injury and is often associated with intraventricular hemorrhage (IVH) in preterm infants. OBJECTIVE: The aim of this study was to investigate the prevalence, risk factors and neurodevelopmental outcomes of isolated cPVL and cPVL with low-grade and high-grade IVH in premature infants. METHODS: From 2001 to 2012, 9,964 infants with <31 weeks' gestational age (GA) admitted to Taiwan hospitals were enrolled. cPVL was classified into three groups: isolated cPVL, cPVL with low-grade (I/II) IVH, and cPVL with high-grade (III) IVH. RESULTS: Of 7,805 infants with complete ultrasound data, 286 (3.7%) had cPVL. Among the cPVL infants, 93 (32.5%) were isolated, 118 (41.3%) had low-grade IVH and 75 (26.2%) had high-grade IVH. The risk of cPVL with IVH was significantly higher among infants with <27 weeks' GA than those with ≥27 weeks' GA, in contrast to that of isolated cPVL. Using infants without cPVL and IVH as the reference group, the most significant predictor of isolated cPVL was neonatal sepsis (odds ratio 2.39; 95% confidence interval 1.52-3.77), while 5-min Apgar score <5 (2.50; 1.48-4.21) and prolonged mechanical ventilation (2.19; 1.42-3.42) were associated with cPVL with low-grade IVH, and GA <27 weeks (2.63; 1.56-4.42), pneumothorax (3.04; 1.40-6.65) and prolonged mechanical ventilation (3.36; 1.88-6.01) contributed to cPVL with high-grade IVH. cPVL infants with low-grade and high-grade IVH had a higher risk of abnormal neurodevelopmental outcomes than infants with isolated cPVL at the age of 24 months. CONCLUSIONS: Isolated cPVL, cPVL with low-grade IVH and cPVL with high-grade IVH had different risk factors and neurodevelopmental outcomes, suggestive of different causal pathways.

Postnatal Steroids and Febrile Seizure Susceptibility in Preterm Children.

OBJECTIVE: To investigate risk factors, seizure characteristics, and outcomes of febrile seizure (FS) in children born very preterm. METHODS: This study used a prospective registry data set of 844 preterm infants (birth weight <1500 g and gestational age <32 weeks) admitted to NICUs from 2001 to 2009 in southern Taiwan. We investigated the prevalence, risks, seizure patterns, and outcomes of FS in children aged 5 years. RESULTS: Among 575 children (follow-up rate, 85.8%) followed up for 5 years, 35 (6.1%) developed FS. The FS and non-FS groups were comparable regarding their mean gestational age, birth weight, 5-minute Apgar score <6, and prenatal and postnatal complications. No difference was observed in the use of prenatal corticosteroids between the 2 groups. The FS group had a significantly higher rate of postnatal corticosteroid treatment than the non-FS group, even after adjusting for confounding factors (odds ratio, 5.4 [95% confidence interval, 1.9-15.8]; P = .006). No differences were observed in IQs or subsequent epilepsy rates between the 2 groups. Although no difference was observed in the age of FS onset or neurodevelopmental outcomes between the 2 groups, children with FS who received postnatal corticosteroid treatment had a significantly lower mean body temperature during the first FS attack compared with those who did not receive postnatal corticosteroid treatment (38.6 ± 0.4°C vs 39.2 ± 0.6°C; P = .034). CONCLUSIONS: Children born very preterm have a higher rate of FS, and postnatal corticosteroid treatment was associated with FS susceptibility in these children.

Predicting neurodevelopmental outcomes at preschool age for children with very low birth weight.

The purpose of this study was to examine predictors of neurodevelopmental outcome in very low birth weight children without major impairment at 5 years of age, as well as to identify the contribution of early neurodevelopmental assessment to preterm children's later developmental outcomes. The participants in this study included 126 children who were prematurely born with very low birth weight. Outcomes of the childrens' later development were measured in tests that factored cognitive function, motor performance, and adaptive behavior. The results indicated that more than 50% of full-scale intelligence and 30% of both motor performance and adaptive behavior at the age of 5 can be explained by four predictors. The four predictors include preterm children's medical complications at birth, maternal education, early motor assessments, and cognitive assessments. Adding each test score obtained in early ages provides additional information to predict children's cognitive, motor, and adaptive behavior at 5 years of age. Manifold assessments conducted in multiple time periods strengthen the predictive values of later developmental outcomes. In addition, the findings of this study indicate that very low birth weight children tend to have lower adaptive behavior at 5 years old. With regard to our findings, we believe that having adaptive function is a reflection of a child's overall integrated abilities. Further study is warranted to increase understanding of this topic, as well as to be able to predict adaptive strengths and weakness and pinpoint limiting factors that may be useful for targeting behaviors in intervention.

Age-dependent vulnerability of cyclosporine-associated encephalopathy in children.

INTRODUCTION: Cyclosporine (CsA) is an immunosuppressant known for its neurotoxicity, which presents with acute encephalopathy and seizures in the most severe form. However, whether there is age-related neurological susceptibility in pediatric population is poorly defined. The study aims to examine the vulnerability of CsA neurotoxicity among different age groups of pediatric patients in terms of occurrence rate, acute presentations, long-term outcomes, and neuroimaging findings. METHODS: Pediatric patients (age <18 years) who received CsA in a tertiary referral center between July 1, 1988 and August 31, 2011 were retrospectively reviewed for CsA-related encephalopathy. The clinical presentations, demographic data, and laboratory examinations were analyzed through t-test for numerical and Fisher's exact test for categorical variables. Exact logistic regression was used to examine the effect of each variables. RESULTS: Twelve (8%) of the enrolled 146 patients developed CsA-induced encephalopathy. Compared to the non-neurotoxicity group, the neurotoxicity group was significantly younger upon starting CsA (p = 0.008) and had higher percentages of hypertension after CsA treatment (p = 0.01). Regression analysis showed that age <6 years (OR 7.6, 95% CI 1.6-51.5; p = 0.007) and hypertension after CsA (OR 6.3, 95% CI 1.4-35.4; p = 0.016) were significantly associated with CsA encephalopathy. Younger children were prone to have more severe seizures in the acute stage and more epilepsy and neuropsychiatric disorders in the future. Follow-up neuroimaging showed parietal cerebral atrophy in all examined children <6 years of age. CONCLUSIONS: Age-dependent susceptibility of CsA neurotoxicity occurs in children, with severe acute presentations and long-term sequelae in children below 6 years old.

TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain.

BACKGROUND: Hypoxic-ischemia (HI) and inflammation are the two major pathogenic mechanisms of brain injury in very preterm infants. The neurovascular unit is the major target of HI injury in the immature brain. Systemic inflammation may worsen HI by up-regulating neuroinflammation and disrupting the blood-brain barrier (BBB). Since neurons and oligodendrocytes, microvascular endothelial cells, and microglia may closely interact with each other, there may be a common signaling pathway leading to neuroinflammation and neurovascular damage after injury in the immature brain. TNF-α is a key pro-inflammatory cytokine that acts through the TNF receptor (TNFR), and c-Jun N-terminal kinases (JNK) are important stress-responsive kinases. OBJECTIVE: To determine if TNFR1-JNK signaling is a shared pathway underlying neuroinflammation and neurovascular injury after lipopolysaccharide (LPS)-sensitized HI in the immature brain. METHODS: Postpartum (P) day-5 mice received LPS or normal saline (NS) injection before HI. Immunohistochemistry, immunoblotting and TNFR1- and TNFR2-knockout mouse pups were used to determine neuroinflammation, BBB damage, TNF-α expression, JNK activation, and cell apoptosis. The cellular distribution of p-JNK, TNFR1/TNFR2 and cleaved caspase-3 were examined using immunofluorescent staining. RESULTS: The LPS + HI group had significantly greater up-regulation of activated microglia, TNF-α and TNFR1 expression, and increases of BBB disruption and cleaved caspase-3 levels at 24 hours post-insult, and showed more cortical and white matter injury on P17 than the control and NS + HI groups. Cleaved caspase-3 was highly expressed in microvascular endothelial cells, neurons, and oligodendroglial precursor cells. LPS-sensitized HI also induced JNK activation and up-regulation of TNFR1 but not TNFR2 expression in the microglia, endothelial cells, neurons, and oligodendrocyte progenitors, and most of the TNFR1-positive cells co-expressed p-JNK. Etanercept (a TNF-α inhibitor) and AS601245 (a JNK inhibitor) protected against LPS-sensitized HI brain injury. The TNFR1-knockout but not TNFR2-knockout pups had significant reduction in JNK activation, attenuation of microglial activation, BBB breakdown and cleaved caspase-3 expression, and showed markedly less cortical and white matter injury than the wild-type pups after LPS-sensitized HI. CONCLUSION: TNFR1-JNK signaling is the shared pathway leading to neuroinflammation and neurovascular damage after LPS-sensitized HI in the immature brain.