Fecal microbiota and volatile metabolome pattern alterations precede late-onset meningitis in preterm neonates.

OBJECTIVE: The fecal microbiota and metabolome are hypothesized to be altered before late-onset neonatal meningitis (LOM), in analogy to late-onset sepsis (LOS). The present study aimed to identify fecal microbiota composition and volatile metabolomics preceding LOM. METHODS: Cases and gestational age-matched controls were selected from a prospective, longitudinal preterm cohort study (born <30 weeks' gestation) at nine neonatal intensive care units. The microbial composition (16S rRNA sequencing) and volatile metabolome (gas chromatography-ion mobility spectrometry (GC-IMS) and GC-time-of-flight-mass spectrometry (GC-TOF-MS)), were analyzed in fecal samples 1-10 days pre-LOM. RESULTS: Of 1397 included infants, 21 were diagnosed with LOM (1.5%), and 19 with concomitant LOS (90%). Random Forest classification and MaAsLin2 analysis found similar microbiota features contribute to the discrimination of fecal pre-LOM samples versus controls. A Random Forest model based on six microbiota features accurately predicts LOM 1-3 days before diagnosis with an area under the curve (AUC) of 0.88 (n=147). Pattern recognition analysis by GC-IMS revealed an AUC of 0.70-0.76 (P<0.05) in the three days pre-LOM (n=92). No single discriminative metabolites were identified by GC-TOF-MS (n=66). CONCLUSION: Infants with LOM could be accurately discriminated from controls based on preclinical microbiota composition, while alterations in the volatile metabolome were moderately associated with preclinical LOM.

The effect of preterm birth on thalamic development based on shape and structural covariance analysis.

Acting as a central hub in regulating brain functions, the thalamus plays a pivotal role in controlling high-order brain functions. Considering the impact of preterm birth on infant brain development, traditional studies focused on the overall development of thalamus other than its subregions. In this study, we compared the volumetric growth and shape development of the thalamic hemispheres between the infants born preterm and full-term (Left volume: P = 0.027, Left normalized volume: P < 0.0001; Right volume: P = 0.070, Right normalized volume: P < 0.0001). The ventral nucleus region, dorsomedial nucleus region, and posterior nucleus region of the thalamus exhibit higher vulnerability to alterations induced by preterm birth. The structural covariance (SC) between the thickness of thalamus and insula in preterm infants (Left: corrected P = 0.0091, Right: corrected P = 0.0119) showed significant increase as compared to full-term controls. Current findings suggest that preterm birth affects the development of the thalamus and has differential effects on its subregions. The ventral nucleus region, dorsomedial nucleus region, and posterior nucleus region of the thalamus are more susceptible to the impacts of preterm birth.

Umbilical Cord Blood as an Alternative to Neonatal Blood for Complete Blood Count: A Comparison Study.

OBJECTIVE: To assess concordance between umbilical cord blood (UCB) and neonatal blood (NB) laboratory test results at birth. STUDY DESIGN: This retrospective study considered very preterm neonates (<32 weeks' gestational age) admitted to a tertiary neonatal intensive care unit from 2012 to 2023. Inclusion criteria required neonates with a complete blood count measured in both UCB and NB drawn within 2 hours after birth. Median hemoglobin (Hb) and hematocrit (Hct) concentrations were compared between UCB (venous samples) and NB (venous, arterial, or capillary samples). RESULTS: A total of 432 neonates with paired UCB and NB values were included in the study. Hb concentration in UCB was 14.7 g/dL (IQR 13.5-16.1 g/dL) compared with 14.8 g/dL (IQR 12.6-19.3 g/dL) in venous NB samples, 13.9 g/dL (IQR 12.9-15.3 g/dL) in arterial NB and 18.7 g/dL (IQR 16.6-20.8 g/dL) in capillary NB. The regression equation showed a correction factor of 1.08 for converting Hb values from UCB to venous NB. Median Hct concentration in UCB was 0.45 L/L (IQR: 0.41-0.49 L/L) compared with 0.48 L/L (IQR 0.43-0.54 L/L) in venous NB, 0.42 L/L (IQR 0.38-0.45 L/L) in arterial NB and 0.57 L/L, (IQR 0.51-0.63 L/L) in capillary NB. CONCLUSIONS: Hb and Hct concentrations measured in UCB are similar to those measured in venous blood in very preterm infants and are valid alternatives for NB tests at birth. Hb and Hct concentrations in arterial and capillary NB are respectively lower and higher compared with UCB measurements.

Survival without severe neonatal morbidity after antenatal betamethasone dose reduction: a post hoc analysis of a randomized non-inferiority trial.

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.

When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Cerebral oxygenation during immediate fetal-to-neonatal transition and fidgety movements between six to 20 weeks of corrected age: An ancillary study to the COSGOD III trial.

Fidgety movements provide early information about a potential development of cerebral palsy in preterm neonates. The aim was to assess differences in the combined outcome of mortality and fidgety movements defined as normal or pathological in very preterm neonates according to the group allocation in the randomised-controlled multicentre COSGOD III trial. Preterm neonates of two centres participating in the COSGOD III trial, whose fidgety movements were assessed as normal or pathological at six to 20 weeks of corrected age, were analysed. In the COSGOD III trial cerebral oxygen saturation (crSO2) was measured by near-infrared spectroscopy (NIRS) during postnatal transition and guided resuscitation in preterm neonates randomised to the NIRS-group, whereby medical support was according routine, as it was also in the control group. Fidgety movements were classified in normal or abnormal/absent at six to 20 weeks of corrected age. Mortality and fidgety movements of preterm neonates allocated to the NIRS-group were compared to the control-group. Normal outcome was defined as survival with normal fidgety movements. One-hundred-seventy-one preterm neonates were included (NIRS-group n = 82; control-group n = 89) with a median gestational age of 29.4 (27.4-30.4) and 28.7 (26.7-31.0) weeks in the NIRS-group and the control-group, respectively. There were no differences in the combined outcome between the two groups: 90.2% of the neonates in the NIRS-group and 89.9% in the control-group survived with normal outcome (relative risk [95% CI]; 0.96 [0.31-2.62]).Conclusions: In the present cohort of preterm neonates, monitoring of crSO2 and dedicated interventions in addition to routine care during transition period after birth did not show an impact on mortality and fidgety movements defined as normal or pathological at six to 20 weeks corrected age. What is Known • Fidgety movements display early spontaneous motoric pattern and may provide early information about a potential development of cerebral palsy in preterm neonates.  What is New  â€¢ This retrospective observational study of the randomised-controlled multicentre COSGOD III trial is the first study investigating the potential influence of cerebral oxygenation guided resuscitation during postnatal transition period on combined outcome of mortality and fidgety movements up to 20 weeks of corrected age in very preterm neonates. • This study adds to the growing interest of assessing cerebral oxygenation, that monitoring of cerebral oxygen saturation and dedicated interventions during postnatal transition period according to the COSGOD III trial has no significant influence on mortality and fidgety movements defined as normal or pathological in very preterm neonates.

Nomogram to predict risk of neonatal mortality among preterm neonates admitted with sepsis at University of Gondar Comprehensive Specialized Hospital: risk prediction model development and validation.

BACKGROUND: Mortality in premature neonates is a global public health problem. In developing countries, nearly 50% of preterm births ends with death. Sepsis is one of the major causes of death in preterm neonates. Risk prediction model for mortality in preterm septic neonates helps for directing the decision making process made by clinicians. OBJECTIVE: We aimed to develop and validate nomogram for the prediction of neonatal mortality. Nomograms are tools which assist the clinical decision making process through early estimation of risks prompting early interventions. METHODS: A three year retrospective follow up study was conducted at University of Gondar Comprehensive Specialized Hospital and a total of 603 preterm neonates with sepsis were included. Data was collected using KoboCollect and analyzed using STATA version 16 and R version 4.2.1. Lasso regression was used to select the most potent predictors and to minimize the problem of overfitting. Nomogram was developed using multivariable binary logistic regression analysis. Model performance was evaluated using discrimination and calibration. Internal model validation was done using bootstrapping. Net benefit of the nomogram was assessed through decision curve analysis (DCA) to assess the clinical relevance of the model. RESULT: The nomogram was developed using nine predictors: gestational age, maternal history of premature rupture of membrane, hypoglycemia, respiratory distress syndrome, perinatal asphyxia, necrotizing enterocolitis, total bilirubin, platelet count and kangaroo-mother care. The model had discriminatory power of 96.7% (95% CI: 95.6, 97.9) and P-value of 0.165 in the calibration test before and after internal validation with brier score of 0.07. Based on the net benefit analysis the nomogram was found better than treat all and treat none conditions. CONCLUSION: The developed nomogram can be used for individualized mortality risk prediction with excellent performance, better net benefit and have been found to be useful in clinical practice with contribution in preterm neonatal mortality reduction by giving better emphasis for those at high risk.

Length of hospital stay and factors associated with very-low-birth-weight preterm neonates surviving to discharge a cross-sectional study, 2022.

BACKGROUND: The length of hospital stay of very-low-birth-weight neonates (birth weight < 1500 g) depends on multiple factors. Numerous factors have been reported to influence the length of hospital stay (LOS). The objective of this study was to identify the length of hospital stay and associated factors among very-low-birth-weight preterm neonates. METHOD: A hospital-based, cross-sectional study was conducted. Data was collected using a pretested, structured questionnaire from April 1 to November 30, 2022. The data was entered using Epidata and Stata version 15.1. The frequencies, mean, median, and interquartile range were used to describe the study population about relevant variables. A linear regression model was used to see the effect of independent variables on dependent variables. RESULT: About 110 very low-birth-weight preterm neonates who survived to discharge were included in the study. The median birth weight was 1370 g, with an IQR of 1250-1430. The mean gestational age was 32.30 ± 1.79 weeks. The median length of hospital stay was 24 days, with an IQR of 13.5-40. The gestational age, type of initial management given, and presence of complications had a significant association with the length of hospital stay for VLBW preterm neonates. CONCLUSION: The median hospital stay was 24 days. The gestational age, presence of complications, and type of initial management given were associated with LOS for VLBW preterm neonates. The length of the hospital stay of the VLBW preterm neonates can be reduced by applying the standards of care of very-low-birth-weight preterm neonates.

Precision and normal values of cerebral blood volume in preterm neonates using time-resolved near-infrared spectroscopy.

AIM: To investigate cerebral blood volume (CBV) in preterm neonates using time-resolved near-infrared spectroscopy. METHODS: In this prospective observational study, time-resolved near-infrared spectroscopy measurements of CBV using tNIRS-1 were performed in 70 preterm neonates. For measurements, a sensor was placed for a duration of 1 min, followed by four further reapplications of the sensor, overall five measurements. RESULTS: In this study, 70 preterm neonates with a mean ± SD gestational age of 33.4 ± 1.7 weeks and a birthweight of 1931 ± 398 g were included with a postnatal age of 4.7 ± 2.0 days. Altogether, 2383 CBV values were obtained with an overall mean of 1.85 ± 0.30 mL/100 g brain. A total of 95% of the measured CBV values varied in a range from -0.31 to 0.33 from the overall individual mean. Taking the deviation of the mean of each single application for each patient, this range reduced from -0.07 to 0.07. The precision of the measurement defined as within-variation in CBV was 0.24 mL/100 g brain. CONCLUSION: The overall mean CBV in stable preterm neonates was 1.85 ± 0.30 mL/100 g brain. The within-variation in CBV was 0.24 mL/100 g brain. Based on the precision obtained by our data, CBV of 1.85 ± 0.30 mL/100 g brain may be assumed as normal value for this cohort.

Physiological-based cord clamping stabilised cardiorespiratory parameters in very low birth weight infants.

AIM: We investigated the influence of physiological-based cord clamping (PBCC) on cardiorespiratory stability in very low birth weight (VLBW) infants during the first 72 h of life. METHODS: This retrospective study comprised VLBW infants born at <32 + 0 weeks of gestation and admitted to the neonatal intensive care unit of the Medical University of Graz, Austria, from December 2014 to April 2021. VLBW infants delivered with PBCC were matched by gestational age and birth weight to delayed cord clamping controls. The PBCC group was stabilised after birth with an intact cord. Routine monitoring parameters were compared between the groups. RESULTS: We included 54 VLBW infants. The mean gestational ages of the PBCC group and controls were 27.4 ± 1.9 versus 27.4 ± 1.8 weeks (p = 0.87), and the mean birth weights were 912 ± 288 versus 915 ± 285 g (p = 0.96), respectively. The mean cord clamping time was 191 ± 78 s in the PBCC group. Heart rate was lower in the PBCC group during the first 3 days after birth, reaching significance by 10 h. Other monitoring parameters did not reveal any differences between the two groups. CONCLUSION: PBCC stabilised cardiorespiratory parameters in VLBW infants. The lower heart rate in the PBCC group suggested higher blood volume following intact cord resuscitation.

Evaluation of the effect of intraventricular haemorrhage on cerebral perfusion in preterm neonates using three-dimensional pseudo-continuous arterial spin labelling.

BACKGROUND: Intraventricular haemorrhage (IVH) often arises as a cerebral complication directly related to preterm birth. The impaired autoregulation of cerebral blood flow is closely associated with IVH in preterm neonates. Three-dimensional pseudo-continuous arterial spin labelling (3D-pCASL) is a noninvasive magnetic resonance imaging (MRI) technique used for evaluating cerebral perfusion. OBJECTIVE: This study aimed to compare cerebral blood flow values among three distinct groups using 3D-pCASL: preterm neonates with and without IVH and preterm neonates at term-equivalent age. MATERIALS AND METHODS: A total of 101 preterm neonates who underwent conventional MRI and 3D-pCASL were included in this study. These neonates were categorised into three groups: 12 preterm neonates with IVH, 52 preterm neonates without IVH, and 37 healthy neonates at term-equivalent age. Cerebral blood flow measurements were obtained from six brain regions of interest (ROIs)-the frontal lobe, temporal lobe, parietal lobe, occipital lobe, basal ganglia, and thalamus-in the right and left hemispheres. RESULTS: The cerebral blood flow values measured in all ROIs of preterm neonates with IVH were significantly lower than those of neonates at term-equivalent age (all P<0.05). Additionally, the cerebral blood flow in the temporal lobe was lower in preterm neonates without IVH than in neonates at term-equivalent age (16.87±5.01 vs. 19.76±5.47 ml/100 g/min, P=0.012). Furthermore, a noteworthy positive correlation was observed between post-menstrual age and cerebral blood flow in the temporal lobe (P=0.037), basal ganglia (P=0.010), and thalamus (P=0.010). CONCLUSION: The quantitative cerebral blood flow values, as measured by 3D-pCASL, highlighted that preterm neonates with IVH had decreased cerebral perfusion. This finding underscores the potential of 3D-pCASL as a technique for evaluating the developmental aspects of the brain in preterm neonates.

Hemodynamic effects of noradrenaline in neonatal septic shock: a prospective cohort study.

BACKGROUND: The incidence of neonatal septic shock in low-income countries is 26.8% with a mortality rate of 35.4%. The evidence of the hemodynamic effects of noradrenaline in neonates remains sparse. This study was carried out to evaluate the effects of noradrenaline in neonates with septic shock. METHODS: This was a single-center prospective cohort study in a tertiary care hospital's level III neonatal intensive care unit. Neonates with septic shock and those who received noradrenaline as a first-line vasoactive agent were included. Clinical and hemodynamic parameters were recorded before and after one hour of noradrenaline infusion. The primary outcomes were: response at the end of one hour after starting noradrenaline infusion and mortality rate. RESULTS: A total of 21 babies were analyzed. The cohort comprised 17 preterm neonates. The mean age of presentation with septic shock was 74.3 h. Resolution of shock at one hour after starting noradrenaline was achieved in 76.2% of cases. The median duration of hospital stay was 14 days. The mean blood pressure improved after the initiation of noradrenaline from 30.6 mm of Hg [standard deviation (SD) 6.1] to 37.8 mm of Hg (SD 8.22, p < 0.001). Fractional shortening improved after noradrenaline initiation from 29% (SD 13.5) to 45.1% (SD 21.1, p < 0.001). The mortality rate was 28.6% in our study. CONCLUSION: Noradrenaline is a potential drug for use in neonatal septic shock, with improvement in mean blood pressure and fractional shortening; however, further studies with larger sample sizes are needed to confirm our findings before it can be recommended as first-line therapy in neonatal septic shock.

Neonatal sepsis is one of the leading causes of neonatal mortality. In neonates with septic shock, mortality is high at 35.4% in low- and middle-income countries. The evidence of the hemodynamic effects of noradrenaline in neonates is still sparse, so we carried out a study in our tertiary care neonatal intensive care unit to evaluate the effects of noradrenaline in neonates with septic shock. Neonates with septic shock and those who received noradrenaline as a first-line vasoactive agent were included. Clinical and hemodynamic parameters were recorded before and after one hour of noradrenaline infusion. The primary outcomes were: response at the end of one hour after starting noradrenaline infusion and mortality rate. A total of 21 babies were analyzed. We found that there was a statistically significant improvement in the mean blood pressure and fractional shortening after noradrenaline initiation. The mortality rate was 28.6% in our study. We conclude that noradrenaline is a relatively safe and effective drug for the treatment of neonatal septic shock. However, further studies with larger sample sizes are needed to confirm our findings before it can be recommended as first-line therapy in neonatal septic shock.

Bacillus cereus Invasive Infections in Preterm Neonates: an Up-to-Date Review of the Literature.

Bacillus cereus group species are widespread, Gram-positive, spore-forming environmental bacteria. B. cereus sensu stricto is one of the major causes of food poisoning worldwide. In high-risk individuals, such as preterm neonates, B. cereus infections can cause fatal infections. It is important to note that the phenotypic identification methods commonly used in clinical microbiology laboratories make no distinction between B. cereus sensu stricto and the other members of the group (Bacillus anthracis excluded). As a result, all the invasive infections attributed to B. cereus are not necessarily due to B. cereus sensu stricto but likely to other closely related species of the B. cereus group. Next-generation sequencing (NGS) should be used to characterize the whole genome of the strains belonging to the B. cereus group. This could confirm whether the strains involved in previously reported B. cereus invasive infections preferentially belong to formerly known or emerging individual species. Moreover, infections related to B. cereus group species have probably been overlooked, since their isolation in human bacteriological samples has for a long time been regarded as an environmental contaminant of the cultures. Recent studies have questioned the emergence or reemergence of B. cereus invasive infections in preterm infants. This review reports our current understanding of B. cereus infections in neonates, including taxonomical updates, microbiological characteristics, bacterial identification, clinical features, host-pathogen interactions, environmental sources of contamination, and antimicrobial resistance.

Influence of Timing of Maternal Pertussis Immunization on the Avidity of Transferred Antibodies in Term and Preterm Neonates.

The timing of maternal pertussis vaccination influences the titers of cord-blood anti-pertussis antibodies. Whether it affects their avidity is unknown. We demonstrate in 298 term and 72 preterm neonates that antibody avidity is independent of the timing of maternal vaccination, whether comparing second with third trimester or intervals before birth.

Assessing the effects of head modelling errors and measurement noise on EEG source localization accuracy in preterm newborns: A single-subject study.

The accuracy of electroencephalogram (EEG) source localization is compromised because of head modelling errors. In this study, we investigated the effect of inaccuracy in the conductivity of head tissues and head model structural deficiencies on the accuracy of EEG source analysis in premature neonates. A series of EEG forward and inverse simulations was performed by introducing structural deficiencies into the reference head models to generate test models, which were then used to investigate head modelling errors caused by cerebrospinal fluid (CSF) exclusion, lack of grey matter (GM)-white matter (WM) distinction, fontanel exclusion and inaccuracy in skull conductivity. The modelling errors were computed between forward and inverse solutions obtained using the reference and test models generated for each deficiency. Our results showed that the exclusion of CSF from the head model had a strong widespread effect on the accuracy of the EEG source localization with position errors lower than 4.17 mm. The GM and WM distinction also caused strong localization errors (up to 3.5 mm). The exclusion of fontanels from the head model also strongly affected the accuracy of the EEG source localization for sources located beneath the fontanels with a maximum localization error of 4.37 mm. Similarly, inaccuracies in the skull conductivity caused errors in EEG forward and inverse modelling in sources beneath cranial bones. Our results indicate that the accuracy of EEG source imaging in premature neonates can be largely improved by using head models, which include not only the brain, skull and scalp but also the CSF, GM, WM and fontanels.

Cord blood granulocyte Colony-Stimulating factor level as an optimal predictor of umbilical cord arteritis associated with brain injury at term equivalent age in preterm neonates.

OBJECTIVE: The study aimed 1) to evaluate the association between the presence or absence of umbilical cord arteritis (UCA) and the cord blood cytokine levels, and 2) morbidity and mortality of preterm neonates; and 3) to identify predictive markers for UCA of preterm neonates. STUDY DESIGN: In this single-center retrospective observational cohort study, preterm neonates born at gestational age (GA) < 36 weeks were categorized pathologically according to the severity of intrauterine inflammation; those without UCA as Group 1, those with UCA as Group 2, and those without any intrauterine inflammation as Group 3 (control), and subgroup analyses classified by their GA were performed. We compared morbidity and mortality, and eight representative cytokine levels in cord blood samples between the groups. Subsequently, receiver operating characteristics (ROC) curves for UCA diagnosis for each cytokine were created, and values of areas under the curve (AUC) were calculated to determine the optimal predictive markers. RESULTS: In total, 105 patients (36, 58, and 11 in Groups 1, 2, and 3, respectively) were included. Multivariate logistic analysis revealed that patients with UCA had higher incidence of brain injury (Odds Ratio [OR] = 8.53, P = 0.0049, 95% Confidence Interval [CI]: 1.91 - 38.0), at term equivalent age in the subgroup analysis with GA < 32 weeks. Although the median value of cord blood granulocyte colony-stimulating factor (G-CSF) was significantly higher in Group 2 than in Group 1 or 3, only the G-CSF level was found to be high in the subgroup analysis with GA < 32 weeks. For UCA diagnosis, the AUC values of G-CSF were the highest among eight cytokines including interleukin 6 (IL-6). These findings were similar in the subgroup analysis with GA < 32 weeks. CONCLUSIONS: Preterm neonates, especially born at GA < 32 week, had higher morbidity from　brain injury in the group with UCA. The cord blood G-CSF level was highly accurate for predicting UCA and could thus be used as an optimal biomarker.

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

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

Hippocampal asymmetry of regional development and structural covariance in preterm neonates.

Premature birth is associated with a high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, yet the putative effects of hippocampal dysfunction remain poorly understood in preterm neonates. In particular, while asymmetry of the hippocampus has been well noted both structurally and functionally, how preterm birth impairs hippocampal development and to what extent the hippocampus is asymmetrically impaired by preterm birth have not been well delineated. In this study, we compared volumetric growth and shape development in the hippocampal hemispheres and structural covariance (SC) between hippocampal vertices and cortical thickness in cerebral cortex regions between two groups. We found that premature infants had smaller volumes of the right hippocampi only. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared with full-term peers, though preterm neonates exhibited an accelerated age-related change of hippocampal thickness in the left hippocampi. The SC between the left hippocampi and the limbic lobe of the premature infants was severely impaired compared with the term-born neonates. These findings suggested that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure with a high degree of asymmetry.

Cyto/myeloarchitecture of cortical gray matter and superficial white matter in early neurodevelopment: multimodal MRI study in preterm neonates.

The cerebral cortex undergoes rapid microstructural changes throughout the third trimester. Recently, there has been growing interest on imaging features that represent cyto/myeloarchitecture underlying intracortical myelination, cortical gray matter (GM), and its adjacent superficial whitematter (sWM). Using 92 magnetic resonance imaging scans from 78 preterm neonates, the current study used combined T1-weighted/T2-weighted (T1w/T2w) intensity ratio and diffusion tensor imaging (DTI) measurements, including fractional anisotropy (FA) and mean diffusivity (MD), to characterize the developing cyto/myeloarchitectural architecture. DTI metrics showed a linear trajectory: FA decreased in GM but increased in sWM with time; and MD decreased in both GM and sWM. Conversely, T1w/T2w measurements showed a distinctive parabolic trajectory, revealing additional cyto/myeloarchitectural signature inferred. Furthermore, the spatiotemporal courses were regionally heterogeneous: central, ventral, and temporal regions of GM and sWM exhibited faster T1w/T2w changes; anterior sWM areas exhibited faster FA increases; and central and cingulate areas in GM and sWM exhibited faster MD decreases. These results may explain cyto/myeloarchitectural processes, including dendritic arborization, synaptogenesis, glial proliferation, and radial glial cell organization and apoptosis. Finally, T1w/T2w values were significantly associated with 1-year language and cognitive outcome scores, while MD significantly decreased with intraventricular hemorrhage.

Postnatal corticosteroid response in neonates < 32 weeks and relation with placental pathology.

Acute chorioamnionitis and maternal vascular malperfusion are associated with an increased risk of bronchopulmonary dysplasia. To prevent bronchopulmonary dysplasia, postnatal corticosteroids are given to preterm neonates. Clinical observations indicate not all neonates respond to corticosteroids, the so-called non-responders. This study aimed to investigate the association between placental pathology and short-term response to postnatal corticosteroids in neonates < 32 weeks postconceptional age at risk for bronchopulmonary dysplasia. All neonates < 32 weeks born between 2009 and 2016, receiving corticosteroids in the course of BPD, were included. The preterm neonates were divided into three groups depending on placental histology: acute chorioamnionitis, maternal vascular malperfusion, or no placental pathology. Respiratory support was assessed prior to treatment and at days 4 and 7. A responder was defined as extubation within 7 days after starting corticosteroid treatment. In total, 52% of the chorioamnionitis neonates, 67% of the maternal vascular malperfusion neonates, and 58% of neonates in the no pathology group were responders. The odds ratio for extubation was 0.53 (0.18-1.55) at day 4 and 0.66 (0.23-1.97) at day 7, in the chorioamnionitis group compared to the maternal vascular malperfusion. CONCLUSION: Short-term response to postnatal corticosteroids did not significantly differ between premature neonates born after acute chorioamnionitis, maternal vascular malperfusion, or no placenta pathology. However, a trend of better corticosteroid response in maternal vascular malperfusion neonates was found, potentially due to differences in prenatal pulmonary development and postnatal cortisol. WHAT IS KNOWN: • Bronchopulmonary dysplasia is related to chorioamnionitis and maternal vascular malperfusion. • Corticosteroids remain an important treatment in the course of bronchopulmonary dysplasia despite conflicting results and non-responsiveness in some preterm neonates. WHAT IS NEW: • Non-responsiveness might be related to differences in pulmonary inflammation and systemic cortisol due to predispositions triggered by chorioamnionitis or maternal vascular malperfusion. • Neonates born after maternal vascular malperfusion seem to respond better to postnatal corticosteroid treatment.