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Brain Research Jul 2024Periventricular leukomalacia (PVL) is a neurological condition observed in premature infants, characterized by hypomyelination and activation of microglia. Maternal...
Periventricular leukomalacia (PVL) is a neurological condition observed in premature infants, characterized by hypomyelination and activation of microglia. Maternal inflammation-induced brain injury in offspring significantly contributes to the development of PVL. Currently, there are no clinical pharmaceutical interventions available for pregnant women to prevent maternal inflammation-mediated brain injury in their offspring. Inosine has been shown to modulate the immune response in diverse stressful circumstances, such as injury, ischemia, and inflammation. The aim of this investigation was to examine the potential prophylactic impact of inosine on offspring PVL induced by maternal inflammation. This was accomplished by administering a 1 mg/ml inosine solution (40 ml daily) to pregnant Sprague-Dawley (SD) rats for 16 consecutive days prior to their intraperitoneal injection of lipopolysaccharide (350 µg/kg, once a day, for two days). The results showed that maternal inosine pretreatment significantly reversed the reduction in MBP and CNPase (myelin-related markers), CC-1 and Olig2 (oligodendrocyte-related markers) in their PVL pups (P7), suggesting that inosine administration during pregnancy could improve hypomyelination and enhance the differentiation of oligodendrocyte precursor cells (OPCs) in their PVL pups. Furthermore, the protective mechanism of inosine against PVL is closely associated with the activation and polarization of microglia. This is evidenced by a notable reduction in the quantity of IBA 1-positive microglia, a decrease in the level of CD86 (a marker for M1 microglia), an increase in the level of Arg 1 (a marker for M2 microglia), as well as a decrease in the level of pro-inflammatory factors TNF-α, IL-1β, and IL-6, and an increase in the level of anti-inflammatory factors IL-4 and IL-10 in the brain of PVL pups following maternal inosine pretreatment. Taken together, inosine pretreatment of pregnant rats can improve hypomyelination in their PVL offspring by triggering the M1/M2 switch of microglia.
Topics: Animals; Female; Pregnancy; Microglia; Rats, Sprague-Dawley; Rats; Inosine; Inflammation; Lipopolysaccharides; Leukomalacia, Periventricular; Myelin Sheath; Animals, Newborn; Prenatal Exposure Delayed Effects
PubMed: 38432260
DOI: 10.1016/j.brainres.2024.148844 -
Chinese Medical Journal Feb 2024Very low birth weight (VLBW) infants are the key populations in neonatology, wherein morbidity and mortality remain major challenges.
BACKGROUND
Very low birth weight (VLBW) infants are the key populations in neonatology, wherein morbidity and mortality remain major challenges.
METHODS
A retrospective cohort study conducted aiming to analyze the clinical characteristics of VLBW in our hospital between January 2016 and December 2021. Neonates with a birth weight of <1500 g were included. Mortality, care practices, and major morbidities were analyzed, and compared with that of previous 7 years (2009-2015).
RESULTS
Of the total 1750 VLBW, 1386 infants born with birth weight between 1000-1499 g and 364 were below 1000 g, 42.9% (751/1750) required delivery room resuscitation, 53.9% (943/1750) received non-invasive ventilation only, 38.2% (669/1750) received invasive ventilation; 1517 VLBW infants received complete treatment. Among them, 60.1% (912/1517) of neonates had neonatal respiratory distress syndrome (NRDS), 28.7% (436/1517) had bronchopulmonary dysplasia (BPD), 22.0% (334/1517) had apnea, 11.1% (169/1517) had culture-confirmed sepsis, 8.4% (128/1517) had pulmonary hemorrhage, 7.6% (116/1517) had severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL), 5.7% (87/1517) had necrotizing enterocolitis (NEC), 2.0% (31/1517) had severe retinopathy of prematurity. The total and in-hospital mortality rates were 9.7% (169/1750) and 3.0% (45/1517), respectively. The top three diagnoses of death among those who had received complete treatment were sepsis, NRDS, and NEC. In 2009-2015, 1146 VLBW were enrolled and 895 infants received complete treatment. The incidences of apnea, IVH, and IVH stage ≥3/PVL, were higher in 2009-2015 compared with those in 2016-2021, while the incidences of NRDS and BPD were characterized by significant increases in 2016-2021. The total and in-hospital mortality rates were 16.7% (191/1146) and 5.6% (50/895) respectively in 2009-2015.
CONCLUSION
Among VLBW infants born in 2016-2021, the total and in-hospital mortality rates were lower than those of neonates born in 2009-2015. Incidences of NRDS and BPD increased in 2016-2021, which affected the survival rates and long-term prognosis of VLBW.
PubMed: 38404117
DOI: 10.1097/CM9.0000000000002923 -
American Journal of Obstetrics and... Feb 2024Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was...
BACKGROUND
Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was proposed to decrease the potential dose-related long-term neurodevelopmental side effects, including psychological development, sleep, and emotional disorders. Because noninferiority of the half dose in terms of the need for exogenous surfactant was not shown in the primary analysis, its impact on survival without major neonatal morbidity needs to be investigated.
OBJECTIVE
This study aimed to investigate the impact of antenatal betamethasone dose reduction on survival of very preterm infants without severe neonatal morbidity, a factor known to have a strong correlation with long-term outcomes.
STUDY DESIGN
We performed a post hoc secondary analysis of a randomized, multicenter, double-blind, placebo-controlled, noninferiority trial, testing half (11.4 mg once; n=1620) vs full (11.4 mg twice, 24 hours apart; n=1624) antenatal betamethasone doses in women at risk of preterm delivery. To measure survival without severe neonatal morbidity at hospital discharge among neonates born before 32 weeks of gestation, we used the definition of the French national prospective study on preterm children, EPIPAGE 2, comprising 1 of the following morbidities: grade 3 to 4 intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis stage ≥2, retinopathy of prematurity requiring anti-vascular endothelial growth factor therapy or laser, and moderate-to-severe bronchopulmonary dysplasia.
RESULTS
After exclusion of women who withdrew consent or had pregnancy termination and of participants lost to follow-up (8 in the half-dose and 10 in the full-dose group), the rate of survival without severe neonatal morbidity among neonates born before 32 weeks of gestation was 300 of 451 (66.5%) and 304 of 462 (65.8%) in the half-dose and full-dose group, respectively (risk difference, +0.7%; 95% confidence interval, -5.6 to +7.1). There were no significant between-group differences in the cumulative number of neonatal morbidities. Results were similar when using 2 other internationally recognized definitions of severe neonatal morbidity and when considering the overall population recruited in the trial.
CONCLUSION
In the BETADOSE trial, severe morbidity at discharge of newborns delivered before 32 weeks of gestation was found to be similar among those exposed to 11.4-mg and 22.8-mg antenatal betamethasone. Additional studies are needed to confirm these findings.
PubMed: 38341166
DOI: 10.1016/j.ajog.2024.02.002 -
Journal of Integrative Neuroscience Jan 2024Cerebral visual impairment (CVI) is a common sequala of early brain injury, damage, or malformation and is one of the leading individual causes of visual dysfunction in...
BACKGROUND
Cerebral visual impairment (CVI) is a common sequala of early brain injury, damage, or malformation and is one of the leading individual causes of visual dysfunction in pediatric populations worldwide. Although patients with CVI are heterogeneous both in terms of underlying etiology and visual behavioural manifestations, there may be underlying similarities in terms of which white matter pathways are potentially altered. This exploratory study used diffusion tractography to examine potential differences in volume, quantitative anisotropy (QA), as well as mean, axial, and radial diffusivities (mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD), respectively) focusing on the dorsal and ventral visual stream pathways in a cohort of young adults with CVI compared to typically sighted and developing controls.
METHODS
High angular resolution diffusion imaging (HARDI) data were acquired in a sample of 10 individuals with a diagnosis of CVI (mean age = 17.3 years, 2.97 standard deviation (SD), range 14-22 years) and 17 controls (mean age = 19.82 years, 3.34 SD, range 15-25 years). The inferior longitudinal fasciculus (ILF), inferior fronto-occipital fasciculus (IFOF), vertical occipital fasciculus (VOF), and the three divisions of the superior longitudinal fasciculus (SLF I, II, and III) were virtually reconstructed and average tract volume (adjusted for intracranial volume), MD, AD, and RD were compared between CVI and control groups. As a secondary analysis, an analysis of variance (ANOVA) was carried out to investigate potential differences based on etiology (i.e., CVI due to periventricular leukomalacia (CVI-PVL) and CVI due to other causes (CVI-nonPVL)).
RESULTS
We observed a large degree of variation within the CVI group, which minimized the overall group differences in tractography outcomes when examining the CVI sample as a unitary group. In our secondary analysis, we observed significant reductions in tract volume in the CVI-PVL group compared to both controls and individuals with CVI due to other causes. We also observed widespread significant increases in QA, MD, and AD in CVI-PVL compared to the control group, with mixed effects in the CVI-nonPVL group.
CONCLUSIONS
These data provide preliminary evidence for aberrant development of key white matter fasciculi implicated in visual perceptual processing skills, which are often impaired to varying degrees in individuals with CVI. The results also indicate that the severity and extent of the white matter changes may be due in part to the underlying cause of the cerebral visual impairments. Additional analyses will need to be done in a larger sample alongside behavioural testing to fully appreciate the relationships between white matter integrity, visual dysfunction, and associated causes in individuals with CVI.
Topics: Child; Young Adult; Humans; Adolescent; Adult; White Matter; Neural Pathways; Diffusion Magnetic Resonance Imaging; Brain Injuries; Vision Disorders; Brain
PubMed: 38287851
DOI: 10.31083/j.jin2301001 -
European Radiology Jan 2024Cerebral magnetic resonance imaging (cMRI) at term-equivalent age (TEA) can detect brain injury (BI) associated with adverse neurological outcomes in preterm infants....
Incidence of brain injuries in a large cohort of very preterm and extremely preterm infants at term-equivalent age: results of a single tertiary neonatal care center over 10 years.
OBJECTIVES
Cerebral magnetic resonance imaging (cMRI) at term-equivalent age (TEA) can detect brain injury (BI) associated with adverse neurological outcomes in preterm infants. This study aimed to assess BI incidences in a large, consecutive cohort of preterm infants born < 32 weeks of gestation, the comparison between very (VPT, ≥ 28 + 0 to < 32 + 0 weeks of gestation) and extremely preterm infants (EPT, < 28 + 0 weeks of gestation) and across weeks of gestation.
METHODS
We retrospectively analyzed cMRIs at TEA of VPT and EPT infants born at a large tertiary center (2009-2018). We recorded and compared the incidences of BI, severe BI, intraventricular hemorrhage (IVH), periventricular hemorrhagic infarction (PVHI), cerebellar hemorrhage (CBH), cystic periventricular leukomalacia (cPVL), and punctate white matter lesions (PWML) between VPTs, EPTs, and across weeks of gestation.
RESULTS
We included 507 preterm infants (VPT, 335/507 (66.1%); EPT, 172/507 (33.9%); mean gestational age (GA), 28 + 2 weeks (SD 2 + 2 weeks); male, 52.1%). BIs were found in 48.3% of the preterm infants (severe BI, 12.0%) and increased with decreasing GA. IVH, PVHI, CBH, cPVL, and PWML were seen in 16.8%, 0.8%, 10.5%, 3.4%, and 18.1%, respectively. EPT vs. VPT infants suffered more frequently from BI (59.3% vs. 42.7%, p < 0.001), severe BI (18.6% vs. 8.7%, p = 0.001), IVH (31.9% vs. 9.0%, p < 0.001), and CBH (18.0% vs. 6.6%, p < 0.001).
CONCLUSION
Brain injuries are common cMRI findings among preterm infants with a higher incidence of EPT compared to VPT infants. These results may serve as reference values for clinical management and research.
CLINICAL RELEVANCE STATEMENT
Our results with regard to gestational age might provide valuable clinical insights, serving as a key reference for parental advice, structured follow-up planning, and enhancing research and management within the Neonatal Intensive Care Unit.
KEY POINTS
• Brain injury is a common cMRI finding in preterm infants seen in 48.3% individuals. • Extremely preterm compared to very preterm infants have higher brain injury incidences driven by brain injuries such as intraventricular and cerebellar hemorrhage. • Reference incidence values are crucial for parental advice and structured follow-up planning.
PubMed: 38279057
DOI: 10.1007/s00330-024-10592-z -
Children (Basel, Switzerland) Dec 2023Improvements in perinatal care have substantially decreased mortality rates among preterm infants, yet their neurodevelopmental outcomes and quality of life persist as a...
BACKGROUND
Improvements in perinatal care have substantially decreased mortality rates among preterm infants, yet their neurodevelopmental outcomes and quality of life persist as a pertinent public health concern. Family-centered care has emerged as a holistic philosophy that promotes effective alliances among patients, families, and healthcare providers to improve the quality of care.
AIMS
This longitudinal prospective study aims to evaluate the neurodevelopmental outcomes and brain MRI findings in a cohort of preterm newborns admitted to a neonatal intensive care unit (NICU) adopting a family-centered care model.
METHODS
Very low birth weight (VLBW) infants admitted to the NICU of Modena between 2015 and 2020 were enrolled. Infants who underwent conventional brain magnetic resonance imaging (MRI) at term-equivalent age were included. Neurodevelopmental follow-up was performed until the age of 24 months by a multidisciplinary team using the Amiel-Tison neurological assessment and the Griffiths Mental Developmental Scales (GMDS-R). Neurodevelopmental outcomes were classified as major sequelae (cerebral palsy, DQ ≤ 70, severe sensory impairment), minor sequelae (minor neurological signs such as clumsiness or DQ between 71 and 85), and normal outcomes (no neurological signs and DQ > 85). Risk factors for severe outcomes were assessed.
RESULTS
In total, 49 of the 356 infants (13.8%) died before hospital discharge, and 2 were excluded because of congenital disorders. Of the remaining 305 infants, 222 (72.8%) completed the 24 month follow-up and were included in the study. Neurodevelopmental outcomes were classified as normal ( = 173, 77.9%), minor ( = 34, 15.3%), and major sequelae ( = 15, 6.8%). Among 221 infants undergoing brain MRI, 76 (34.4%) had major lesions (intraventricular hemorrhage, hemorrhagic parenchymal infarction, periventricular leukomalacia, and large cerebellar hemorrhage). In the multivariate regression model, the retinopathy of prematurity (OR 1.8; value 0.016) and periventricular-intraventricular hemorrhage (OR 5.6; value < 0.004) were associated with major sequelae.
CONCLUSIONS
We reported low rates of severe neurodevelopmental outcomes in VLBW infants born in an Italian NICU with FCC. Identifying the risk factors for severe outcomes can assist in tailoring and optimizing early interventions on an individual basis, both within the NICU and after discharge.
PubMed: 38275433
DOI: 10.3390/children11010012 -
Frontiers in Pharmacology 2023The effect of inhaled nitric oxide (iNO) in neonates >34 weeks on improving respiration is well documented. However, the efficacy of iNO in preterm infants ≤34 weeks... (Review)
Review
The effect of inhaled nitric oxide (iNO) in neonates >34 weeks on improving respiration is well documented. However, the efficacy of iNO in preterm infants ≤34 weeks remains controversial. The main purpose of this review is to assess the effectiveness and safety of iNO treatment in preterm infants ≤34 weeks. We systematically searched PubMed, Embase and Cochrane Libraries from their inception to 1 June 2023. We also reviewed the reference lists of retrieved studies. Our study involved randomized controlled trials on preterm infants ≤34 weeks, especially those receiving iNO treatment, and mainly assessed outcomes such as bronchopulmonary dysplasia (BPD) and mortality. Two authors independently reviewed these trials, extracted data, and evaluated study biases. Disagreements were resolved by consensus. We used the GRADE method to assess evidence quality. Our research included a total of 17 studies involving 4,080 neonates and 7 follow-up studies. The synthesis of results showed that in neonates, iNO treatment reduced the incidence of BPD (RR: 0.92; 95% CI: 0.86-0.98). It also decreased the composite outcome of death or BPD (RR: 0.94; 95% CI: 0.90-0.98), without increasing the risk of short-term (such as intraventricular hemorrhage, periventricular leukomalacia) and long-term neurological outcomes (including Bayley mental developmental index <70, cerebral palsy and neurodevelopmental impairment). Furthermore, iNO did not significantly affect other neonatal complications like sepsis, pulmonary hemorrhage, necrotizing enterocolitis, and symptomatic patent ductus arteriosus. Subgroup analysis revealed that iNO significantly reduced BPD incidence in neonates at 36 weeks under specific intervention conditions, including age less than 3 days, birth weight over 1,000 g, iNO dose of 10 ppm or higher, or treatment duration exceeding 7 days ( < 0.05). Inhaled NO reduced the incidence of BPD in neonates at 36 weeks of gestation, and the effect of the treatment depended on neonatal age, birth weight, duration and dose of iNO. Therefore, iNO can be considered a promising treatment for the potential prevention of BPD in premature infants. More data, however, would be needed to support nitric oxide registration in this specific patient population, to minimize its off-label use.
PubMed: 38273818
DOI: 10.3389/fphar.2023.1268795 -
Developmental Medicine and Child... Jan 2024To determine the significant risk factors of cerebral palsy (CP) in Taiwanese children and the associations between infant-related and parent-related factors.
AIM
To determine the significant risk factors of cerebral palsy (CP) in Taiwanese children and the associations between infant-related and parent-related factors.
METHOD
Data from 1 459 093 infants and their parents in Taiwan's national databases collected between 2009 and 2016 were used. The cohort with CP included children diagnosed with CP between birth and age 3 years; a total of 3254 children with CP were included in the final analysis. Hierarchical logistic regression models were used to estimate the odds ratio for the risk factors of CP.
RESULTS
The hierarchical logistic regression models indicated that significant risk factors associated with CP are suburban location, low income, maternal and paternal diabetes mellitus, paternal substance abuse, paternal seizure disorder, male sex, birth by Cesarean section, singleton birth, low birthweight, being born extremely and very preterm, intraventricular hemorrhage, and periventricular leukomalacia, as well as tube feeding, ventilator use, and dopamine administration within 6 months of age.
INTERPRETATION
In addition to common maternal and infant risk factors, we identified significant paternal risk factors associated with CP, including diabetes mellitus, seizure disorder, and substance abuse. The combination of maternal, paternal, and infant risk factors in CP holds great promise for early identification and intervention.
PubMed: 38263613
DOI: 10.1111/dmcn.15846 -
The Journal of Pediatrics Jan 2024To assess the rate and risk factors for reactivation of retinopathy of prematurity (ROP) after intravitreal injection (IVI) of antivascular endothelial growth factor...
OBJECTIVE
To assess the rate and risk factors for reactivation of retinopathy of prematurity (ROP) after intravitreal injection (IVI) of antivascular endothelial growth factor (VEGF) agents.
STUDY DESIGN
Infants who received IVI therapy between 2017 and 2022 were enrolled and divided into 2 groups: those with and without ROP reactivation. Information on ROP variables and patient variables were analyzed using multivariable logistic regression.
RESULTS
A total of 114 infants with 223 eyes were enrolled in the study. The ROP reactivation rate was 11.4% of infants (9.9% of eyes). The mean duration of reactivation was 84 ± 45 days. Among the 223 eyes treated with IVI, reactivation rates were 6% for bevacizumab, 13.9% for aflibercept, and 22.2% for ranibizumab. A multivariable regression model showed that ranibizumab was an independent risk factor (OR 11.4, P = .008) for reactivation. Other risk factors included infants with periventricular leukomalacia (OR 13.8, P = .003), patent ductus arteriosus ligation (OR 10.7, P = .032), and infants who still required invasive mechanical ventilation on the day of IVI therapy (OR 7.0, P = .018).
CONCLUSIONS
All anti-VEGF agents carry a risk of ROP reactivation, with the risk being greater with ranibizumab 0.25 mg than with bevacizumab 0.625 mg. Reactivation of ROP should be assessed vigilantly, especially in those infants with increased risks. Future research to determine the optimal anti-VEGF selection and dosage in high-risk infants is warranted.
PubMed: 38218371
DOI: 10.1016/j.jpeds.2024.113913 -
Cold Spring Harbor Molecular Case... Dec 2023Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of Patients with DHP deficiency exhibit a... (Review)
Review
Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in , has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.
Topics: Humans; Metabolism, Inborn Errors; Genetic Testing; Phenotype; Diphosphonates
PubMed: 38199782
DOI: 10.1101/mcs.a006319