Trends in Amplitude-Integrated Electroencephalography in the Smallest Preterm Neonates.

BACKGROUND: Amplitude-integrated electroencephalography is increasingly used for the neuromonitoring of premature infants. However, it is still not clear how bioelectrical activity changes in the smallest gestational age newborns. The aim of our study was to evaluate the bioelectrical activity of amplitude-integrated electroencephalograms in premature newborns of different gestational age to assess how gestational age and postnatal age influence patterns of amplitude-integrated electroencephalograms and to test the hypothesis of whether the bioelectrical activity of the brain matures faster after the birth of premature newborns than in utero. METHODS: We prospectively included infants born before 32 weeks of gestational age between June 2020 and July 2022. Serial recordings of amplitude-integrated electroencephalograms were performed at three time points of age (days 1-3, 13-15, and 27-29). Recordings were analyzed for background patterns, the onset and appearance of cyclicity, and lower amplitude border and bandwidth, which were used to derive a composite Burdjalov score. RESULTS: In total, 140 premature neonates were included in the study, and 112 of them completed the study. The median gestational age of the newborns enrolled in the study was 29 (27-30) weeks, and the mean weight was 1206 (350) g. Burdjalov scores increased with increasing gestational age. Higher scores were observed in every dimension of the amplitude-integrated electroencephalograms for newborns of lower gestational age when compared to newborns of higher gestational age of the same postmenstrual age. There was a significant correlation between gestational age and parameters of amplitude-integrated electroencephalograms at all time points. CONCLUSIONS: A higher gestational age has a positive effect on the bioelectrical activity of amplitude-integrated electroencephalograms. Increasing postnatal age affected amplitude-integrated electroencephalograms more than gestational age. Our hypothesis that the bioelectrical activity of the brain matures faster for premature newborns after birth than in the womb was confirmed.

Cardiac biomarkers and left ventricular systolic function in former very preterm infants and term controls at preschool age.

Introduction: Due to improvements in perinatal care, survival rates of preterm infants have improved during the last decades. However, these infants remain at risk of developing cardiovascular sequelae later in life. This study aimed to investigate the cardiac biomarkers and left ventricular systolic function in former preterm infants in comparison with term controls at preschool age. Methods: The study included children aged 5-7 years old born below 32 weeks of gestational age. The control group consisted of same-age children born at term. Basic data of study participants were collected using questionnaires and follow-up databases. During the study visit, we recorded anthropometric data and blood pressure readings, determined high-sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentrations, and calculated fractional shortening (FS) and left ventricular mass (LVM). Results: Term-born (n = 25; median gestational age, 40.1 weeks) compared with preterm-born infants (n = 80; median gestational age 29.6 weeks) showed no significant differences in the median concentration of hs-cTnT [median, 3.5 (IQR 3.5; 3.5) vs. 3.5 (3.5; 3.5) ng/L, p = 0.328] and the median concentration of NT-pro-BNP [median, 91.0 (IQR 40.8; 150.3) vs. 87.5 (50.1; 189.5) ng/L, p = 0.087]. FS and LVM/LVMI were not significantly different between the two groups. Conclusion: At preschool age, we observed no significant differences in cardiac biomarkers and left ventricular systolic function in preterm infants. Further studies are warranted to explore the potential of cardiac biomarkers as a prognostic tool for subclinical cardiac alterations after preterm birth.

Amplitude-integrated electroencephalography showed no differences in cerebral activity between preterm singletons and twins in the first 4 weeks of life.

AIM: Genetic influences on cerebral activity have been described previously, but data are scarce in preterms. We aimed to investigate whether a genetic influence causes amplitude-integrated electroencephalography (aEEG) signals to differ between singletons and twin preterm newborns. METHODS: This was a retrospective single-centre study conducted at Innsbruck Medical University Hospital, Austria. Preterm infants born before 32 weeks of gestation between 6 November 2010 and 6 December 2022 were eligible for the study. The aEEG was analysed for the total maturation score, its component scores and the number of sleep-wake cycles per hour. RESULTS: We enrolled 240 preterm twin infants (57.5% male) with a mean gestational age of 30 (range: 24-32) weeks and a mean birth weight of 1324 (range: 600-2116) grams. We compared 240 singleton matched preterms. No differences were found between preterm singletons and twin preterm infants regarding the total maturation and component scores, or the number of sleep-wake cycles. aEEG showed no difference between monozygotic and dizygotic twins. CONCLUSION: Compared to singletons, twin infants born preterm showed no differences in aEEG signals in the first 4 weeks of life. Future studies should include more complex non-invasive functional neuroimaging methods to gain more insight into this important topic.

Determinants of non-alcoholic fatty liver disease in young people: Maternal, neonatal, and adolescent factors.

AIM: To assess the impact of maternal, neonatal, and adolescent factors on the development of non-alcoholic fatty liver disease (NAFLD) in a cohort of 14- to 19-year-old adolescents. METHODS: This study is part of the Early Vascular Ageing in the YOUth study, a single-center cross-sectional study conducted in western Austria. Maternal and neonatal factors were extracted from the mother-child booklet, adolescent factors were evaluated by a face-to-face interview, physical examination, and fasting blood analyses. Liver fat content was assessed by controlled attenuation parameter (CAP) using signals acquired by FibroScan® (Echosense, Paris, France). The association of maternal, neonatal, and adolescent factors with CAP values was analyzed using linear regression models. RESULTS: In total, 595 adolescents (27.2% male) aged 17.0 ± 1.3 years were included. 4.9% (n = 29) showed manifest NAFLD with CAP values above the 90th percentile. Male sex (p < 0.001), adolescent triglyceride levels (p = 0.021), Homeostatic Model Assessment for Insulin Resistance index and BMI z-score (p < 0.001, each) showed a significant association with liver fat content in the multivariable analysis. Maternal pre-pregnancy BMI was associated with CAP values after adjustment for sex, age, and birth weight for gestational age (p < 0.001), but this association was predominantly mediated by adolescent BMI (indirect effect b = 1.18, 95% CI [0.69, 1.77]). CONCLUSION: Components of the metabolic syndrome were the most important predictors of adolescent liver fat content. Therefore, prevention of NAFLD should focus on lifestyle modification in childhood and adolescence.

Early Brain Activity in Very Preterm Infants of Mothers with Gestational Diabetes Mellitus: A Pilot Study.

INTRODUCTION: Neurological consequences of preterm infants born to mothers with gestational diabetes mellitus (GDM) are unclear. In this pilot study, we investigated the effect of GDM on brain activity in very preterm infants. METHODS: Preterm infants <32 gestational weeks of mothers with GDM compared to gestational age- and sex-matched controls born between 2011 and 2018 were included. Amplitude-integrated electroencephalography (aEEG) was assessed for total maturation and individual component scores according to Burdjalov and colleagues, the dominating visual background, and the presence of sleep-wake cycles per hour in the first 72 h of life and weekly at days 7, 14, 21, and 28. RESULTS: We included 47 infants of mothers with GDM and 94 control infants. Both the aEEG total maturation score and its individual component scores, as well as the percentage of continuous background pattern, increased equally during the first 4 weeks after birth in both groups. GDM-exposed infants showed a slightly but significantly higher number of sleep-wake cycles per hour. CONCLUSION: We found normal maturation of brain activity in the first 4 weeks after birth in very preterm infants born to mothers with GDM, not differing from a very preterm control group. The higher number of sleep-wake cycles per hour in GDM-exposed infants could indicate transiently enhanced maturation. Further studies on brain activity and brain development in very preterm infants of mothers with GDM are needed to validate our results.

Association of aEEG and brain injury severity on MRI at term-equivalent age in preterm infants.

AIM: Measures to detect and monitor brain injury in preterm infants are amplitude-integrated electroencephalography (aEEG) and magnetic resonance imaging (MRI). To investigate the association between aEEG and MRI in a large cohort of preterm infants. Five hundred and twenty-three preterm infants were included in the study. METHODS: AEEG was interpreted for the total maturation score (TMS) according to Burdjalov. Cerebral MRI was evaluated using a validated scoring system by Kidokoro. RESULTS: One hundred and forty-six infants (27.9%) showed some form of brain injury, with 111 infants (21.2%) showing mild injury and 35 (6.7%) showing severe injury. TMS were significantly higher in infants without injury compared to severe injury. When comparing infants with isolated intraventricular haemorrhage  to infants without brain injury, TMS were significantly lower. CONCLUSION: Prediction of adverse outcome is an important aspect of neonatal care. The combination of diagnostic measures evaluating brain injury might enhance our abilities in neonatal care to provide accurate information about later outcome. Early aEEG is predictive for the severity of brain injury detected by MRI at term-equivalent age. Whether aEEG is also predictive for neurodevelopmental outcome needs to be further investigated in relation to the various patterns of preterm brain injury.

Relationship between Brain Function and Microstructural Brain Maturation in Preterm Infants.

INTRODUCTION: Preterm infants are at risk for impairment in brain maturation at term equivalent age (TEA). Diffusion tensor imaging (DTI) is a powerful magnetic resonance imaging (MRI) technique, quantitatively reflecting microstructural brain development of white matter regions with parameters such as fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Amplitude-integrated electroencephalography (aEEG) assesses electrocortical activity and brain function. METHODS: Aim of this study was to investigate a possible correlation between functional and microstructural brain maturation using neonatal aEEG and DTI-MRI at TEA. The study was conducted as a retrospective single-center study in 446 infants born below 32 gestational weeks. Spearman rank's correlation coefficients were calculated between aEEG (total maturation score) and FA/ADC value. To compare aEEG and DTI-MRI to neurodevelopmental outcome at 24 months of corrected age, we performed a multivariate linear regression analysis. RESULTS: Analysis showed an all-time significant correlation between total maturation score and FA/ADC values of the corpus callosum at TEA with the strongest correlation at day 2, day 3, week 3, and week 4. After including perinatal variables in the model, this correlation remained highly significant at day 2 and 3. When comparing the association of aEEG and DTI-MRI to outcome, both the total maturation score at day 2, day 3, and FA/ADC of the splenium of the corpus callosum showed a significant correlation. CONCLUSION: This study indicates that early monitoring of functional brain maturation may predict later assessment of microstructural brain development of corpus callosum in preterm infants with a relation to neurodevelopmental outcome.

Striatal Lacunar Infarction in a Late Preterm Infant Born to a Mother with Active Peripartum SARS-CoV-2 Infection.

Background: The current literature suggests that neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections generally have a mild course. Data on how in utero exposure to maternal infection affects neonatal health outcomes are limited, but there is evidence that neurological damage to the fetus and thromboembolic events may occur. Case Presentation. We describe the case of a late preterm infant, who presented with striatal lacunar infarction in the neonatal period, born to a mother with active peripartum SARS-CoV-2 infection. Diagnostic workup did not identify risk factors apart from the maternal SARS-CoV-2 infection. Repeated reverse transcription-polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 using oropharyngeal swab specimens of the patient were negative. IgG, but not IgM antibodies against spike protein S1 receptor-binding domain (S1RBD) epitope were detectable in umbilical cord blood and neonatal serum collected at 48 hours of life. Anti-SARS-CoV-2 total antibody titers against nucleocapsid protein in umbilical cord blood were negative. Conclusions: Bearing in mind a possible association of in utero exposure to SARS-CoV-2 and neonatal thromboembolic events, neonatologists should be aware of these complications even in well-appearing preterm infants.

Microstructural Brain Development and Neurodevelopmental Outcome of Very Preterm Infants of Mothers with Gestational Diabetes Mellitus.

INTRODUCTION: There are data linking gestational diabetes mellitus (GDM) with adverse neurodevelopmental outcome in the offspring. We investigated the effect of GDM on microstructural brain development and neurodevelopmental outcome of very preterm infants. MATERIALS AND METHODS: Preterm infants <32 gestational weeks of mothers with GDM obtained cerebral magnetic resonance imaging (MRI) including diffusion-tensor imaging at term-equivalent age. For every infant, two gestational age-, sex-, and MRI scanner type-matched controls were included. Brain injury was assessed and fractional anisotropy (FA) and apparent diffusion coefficient (ADC) measured in 14 defined cerebral regions. Neurodevelopmental outcome was quantified at the corrected age of 24 months using the Bayley Scales of Infant Development. RESULTS: We included 47 infants of mothers with GDM and 94 controls. There were no differences in neonatal morbidity between the groups, nor in any type of brain injury. The GDM group showed significantly higher FA values in the centrum semiovale, the posterior limb of the internal capsule and the pons bilaterally, in the corpus callosum and the right occipital white matter, as well as lower ADC values in the right centrum semiovale, the right occipital white matter and the corpus callosum. Neurodevelopmental outcome did not differ between the groups. CONCLUSION: We found no impairment of brain development in GDM-exposed infants compared to matched controls, but differences in white matter microstructure in specific regions indicating an enhanced maturation. However, neurodevelopmental outcome was equal in both groups. Further studies are needed to better understand brain maturation in preterm infants exposed to GDM.

The Effect of Postnatal Cytomegalovirus Infection on (Micro)structural Cerebral Development in Very Preterm Infants at Term-Equivalent Age.

INTRODUCTION: There are some data indicating a negative impact of postnatal cytomegalovirus (CMV) infection on long-term neurodevelopmental outcome of preterm infants. So far, there is only little knowledge about a cerebral imaging correlate of these neurodevelopmental alterations induced by postnatal CMV infection in preterm infants. The aim of the current study was to investigate the effect of postnatal CMV infection on the incidence of brain injury and on microstructural brain maturation in very preterm infants at term-equivalent age. METHODS: Infants <32 gestational weeks (02/2011-11/2018) received cerebral MRI including axial diffusion-weighted images at term-equivalent age. All infants were screened for CMV infection using urine/saliva samples, and infection was regarded as acquired postnatal if a sample became positive >5 postnatal days. We compared brain injury as well as fractional anisotropy and apparent diffusion coefficient in 14 defined cerebral regions between infants with and without postnatal CMV infection. RESULTS: 401 infants were eligible, of whom 18 (4.5%) infants had a postnatal CMV infection. There were no significant differences in rates of brain injury or in microstructural brain development between both groups. This applied equally to the subgroup of infants <28 gestational weeks. CONCLUSION: Although infants with postnatal CMV infection were born more immature and more frequently suffered from complications related to immaturity, we neither observed a higher rate of preterm brain injury nor disadvantageous alterations in microstructural brain maturation at term-equivalent age.

Cardiovascular health profiles in adolescents being born term or preterm-results from the EVA-Tyrol study.

BACKGROUND AND AIMS: Preterm birth has been linked with an increased risk of cardiovascular (CV) disease from childhood into adolescence and early adulthood. In this study, we aimed to investigate differences in CV health profiles between former term- and preterm-born infants in a cohort of Tyrolean adolescents. METHODS: The Early Vascular Aging (EVA)-Tyrol study is a population-based non-randomized controlled trial, which prospectively enrolled 14- to 19-year-old adolescents in North Tyrol, Austria and South Tyrol, Italy between 2015 and 2018. Metrics of CV health (body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), smoking, physical activity, dietary patterns, total cholesterol and fasting blood glucose) were assessed and compared between former term- and preterm-born girls and boys. RESULTS: In total, 1,491 study participants (59.5% female, mean age 16.5 years) were included in the present analysis. SBP and DBP were significantly higher in former preterm-born adolescents (mean gestational age 34.6 ± 2.4 weeks) compared to term-born controls (p < 0.01). In the multivariate regression analysis these findings remained significant after adjustment for potential confounders in all models. No differences were found in all other CV health metrics. The number of participants meeting criteria for all seven health metrics to be in an ideal range was generally very low with 1.5% in former term born vs. 0.9% in former preterm born adolescents (p = 0.583). CONCLUSIONS: Preterm birth is associated with elevated SBP and DBP in adolescence, which was even confirmed for former late preterm-born adolescents in our cohort. Our findings underscore the importance of promoting healthy lifestyles in former term- as well as preterm-born adolescents. In addition, we advise early screening for hypertension and long-term follow-up in the group of preterm-born individuals.

Pituitary Stalk Interruption Syndrome - Clinical Presentation and Management of a Potentially Life-threatening Disease in Newborns.

Pituitary stalk interruption syndrome (PSIS) is a rare congenital disease resulting in hypopituitarism of variable degree. Serious courses, due to severe combined pituitary insufficiency, are even rarer and associated with a very early manifestation immediately after birth. First clinical signs are elusive and lead to delayed diagnosis and treatment, often resulting in life-threatening complications. Objective of the current report is to point out early leading symptoms and key issues of neonatal manifested PSIS to increase the awareness, improve the clinical management and thereby enable an early diagnosis and treatment to prevent further complications. This report presents and compares the clinical course and management of two male newborns with manifested PSIS. Early leading symptoms were the same in both patients, including recurrent hypoglycaemia, hyponatraemia, jaundice, cholestasis, sucking weakness and genital abnormalities. Patient 1 developed an infection-induced adrenal crisis, persistent substitution-dependent thrombocytopenia and convulsions due to severe hypoglycaemia in delayed PSIS diagnosis. In patient 2, due to recognised above-mentioned symptoms, endocrine testing and a subsequent cerebral magnetic resonance imaging were performed early and he was diagnosed and treated before major complications occurred. Genetic testing was performed in both patients. GLI2 gene mutation (NM_005270.5:c.2537del; p.(Pro846Argfs*66)) heterozygous was detected in patient 1. No mutation was found in patient 2. Conclusively, the early diagnosis of neonatal PSIS is indispensable in the treatment and prevention of the possible severe clinical manifestation of this orphan disease. Therefore, increased awareness for early leading symptoms and proper clinical management are crucial.

Prophylactic low-dose paracetamol for ductal closure and neurodevelopmental outcome in very preterm infants.

AIM: To investigate the direct effect of prophylactic low-dose paracetamol administration for ductal closure on neurodevelopmental outcome in very preterm infants who did not receive ibuprofen or surgical ligation for treatment of a patent ductus arteriosus. METHODS: Infants < 32 gestational weeks born 10/2014-12/2018 received prophylactic paracetamol (paracetamol group, n = 216); infants born 02/2011-09/2014 did not receive prophylactic paracetamol (control group, n = 129). Psychomotor (PDI) and mental (MDI) outcome were assessed using Bayley Scales of Infant Development at 12 and 24 months corrected age. RESULTS: Our analyses showed significant differences in PDI and MDI at age 12 months (B = 7.8 (95% CI 3.90-11.63), p < 0.001 and B = 4.2 (95% CI 0.81-7.63), p = 0.016). At age 12 months, the rate of psychomotor delay was lower in the paracetamol group (OR 2.22, 95% CI 1.28-3.94, p = 0.004). There was no significant difference between the rates of mental delay at any time-point. All group differences remained significant after adjustment for potential confounders (PDI 12 months B = 7.8 (95% CI 3.77-11.34), p < 0.001, MDI 12 months B = 4.3 (95% CI 0.79-7.45), p = 0.013, PDI < 85 12 months OR 2.65 (95% CI 1.44-4.87), p = 0.002). CONCLUSION: We found no impairment of psychomotor and mental outcome at age 12 and 24 months in very preterm infants after prophylactic low-dose paracetamol administration.

Investigation of secretoneurin as a potential biomarker of brain injury in very preterm infants: A pilot study.

Neurodevelopmental impairment is a significant complication among survivors of preterm birth. To improve outcomes, reliable biomarkers for early detection of brain injury and prognostic assessment are required. Secretoneurin is a promising early biomarker of brain injury in adults and full-term neonates suffering from perinatal asphyxia. Data on preterm infants is currently lacking. The aim of this pilot study was to determine secretoneurin concentrations in preterm infants in the neonatal period, and to assess secretoneurin's potential as a biomarker of preterm brain injury. We included 38 very preterm infants (VPI) born at <32 weeks' gestation in the study. Secretoneurin concentrations were measured in serum samples obtained from the umbilical cord, at 48 hours and 3 weeks of life. Outcome measures included repeated cerebral ultrasonography, magnetic resonance imaging at term-equivalent age, general movements assessment, and neurodevelopmental assessment at a corrected age of 2 years by the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). In comparison to a term-born reference population, VPI had lower secretoneurin serum concentrations in umbilical cord blood and blood collected at 48 hours of life. When measured at 3 weeks of life, concentrations correlated with gestational age at birth. Secretoneurin concentrations did not differ between VPI with an imaging-based diagnosis of brain injury and those without, but when measured in umbilical cord blood and at 3 weeks of life correlated with and were predictive of Bayley-III motor and cognitive scale scores. Secretoneurin levels in VPI differ from term-born neonates. Secretoneurin seems unsuitable as a diagnostic biomarker of preterm brain injury, but bears some prognostic potential and is worthy of further investigation as a blood-based biomarker of preterm brain injury.

Prophylactic Low-Dose Paracetamol Administration for Ductal Closure and Amplitude-Integrated Electroencephalography in Preterm Infants.

Introduction: Prophylactic low-dose paracetamol administration is used to induce closure of the ductus arteriosus in preterm infants. In our recent study we found no impairment on microstructural maturation processes in the brain of preterm infants at term-equivalent age following prophylactic low-dose paracetamol administration. We now assessed amplitude-integrated electroencephalography (aEEG) signals in preterm infants with and without exposure to prophylactic low-dose paracetamol administration. Methods: Infants <32 gestational weeks born between 10/2014 and 12/2018 received prophylactic paracetamol (10 mg/kg intravenously every 8 h until echocardiography after at least 72 h) and form the paracetamol group; infants born between 02/2011 and 09/2014 formed the control group. Four single parameters (continuity, cyclicity, amplitude of lower border, bandwidth span) together with their sum (Burdjalov total score) and presence of sleep-wake cycles were compared between the groups. Results: Included in the study were 338 infants. Two-hundred and seventeen infants received prophylactic paracetamol and 121 formed the control group. The paracetamol group showed a significantly higher number of sleep-wake cycles per hour and a significantly higher total scores compared to the control group (p < 0.05). Conclusion: Paracetamol exposure has been regarded critically with respect to safety in preterm infants in recent years. We found no impairment on amplitude-integrated electroencephalography signals in preterm infants receiving low-dose prophylactic paracetamol compared to controls. Growing awareness and greater availability of data may encourage the clinicians to administer prophylactic paracetamol for ductal closure in preterm infants. The clinical relevance of our findings has to be evaluated in long-term follow up studies on neurodevelopmental outcome.

Prophylactic Low-Dose Paracetamol Administration for Ductal Closure and Microstructural Brain Development in Preterm Infants.

INTRODUCTION: Prophylactic low-dose paracetamol administration is used to induce closure of the ductus arteriosus. Effects on the neurological outcome in preterm infants remain unknown. We compared microstructural brain development in very preterm infants with and without exposure to prophylactic paracetamol by using MR-based diffusion tensor imaging. MATERIALS AND METHODS: Infants aged <32 gestational weeks born between October 2014 and December 2018 received prophylactic paracetamol (10 mg/kg intravenously every 8 h until echocardiography after at least 72 h) and form the paracetamol group; infants born between February 2011 and September 2014 form the control group. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) at term-equivalent age were measured in 14 defined cerebral regions and compared between the groups. RESULTS: Included in the study were 340 infants, of whom 217 received prophylactic paracetamol, and 123 formed the control group. The paracetamol group showed significantly higher FA values and lower ADC values in the splenium of the corpus callosum, as well as higher FA values in the pons bilaterally, the left middle cerebellar peduncle, the right occipital white matter, and the right posterior limb of the internal capsule (p ≤ 0.02). CONCLUSION: The perceived safety of prenatal paracetamol exposure has been questioned in recent years. We found no impairment on microstructural maturation processes in the brain of preterm infants at term-equivalent age following early paracetamol administration. The clinical relevance of these imaging findings has to be determined in long-term follow-up studies on neurodevelopmental outcome.