Marlene Hammerl - Academia.edu (original) (raw)

Papers by Marlene Hammerl

The journal of pediatrics/The Journal of pediatrics, May 1, 2024

Neonatology, Dec 31, 2022

Introduction: Perinatal asphyxia is a leading cause of neon... more Introduction: Perinatal asphyxia is a leading cause of neonatal death. Up to one-third of asphyxiated neonates suffer from hypoxic-ischaemic encephalopathy (HIE) with substantial long-term morbidity. Currently available diagnostic and prognostic tools bear limitations, and additional reliable biomarkers are needed for all stages of clinical management. A novel tool in neuroscientific research is micro-ribonucleic acid (miRNA) profiling. The aim of the present study was to determine miRNA expression profiles of healthy and asphyxiated neonates with and without HIE and to assess their potential as diagnostic and prognostic biomarkers. Methods: We prospectively enrolled 49 neonates with a gestational age of ≥36 weeks, 15 of which fulfilled the diagnostic criteria of perinatal asphyxia and 34 served as healthy controls. Dried blood spots were collected from umbilical cord blood (UCB) and from venous blood upon admission to neonatal intensive care unit (NICU) and at 48 h of life. Samples were analysed by means of FirePlex™ technology (Abcam, Cambridge, MA, USA). Results: In the UCB, miRNA expression levels of hsa-mir-124-3p, hsa-mir-1285-5p, and hsa-mir-331-5p were significantly lower in asphyxiated neonates compared to healthy controls. Asphyxiated neonates requiring therapeutic hypothermia had significantly increased expression of hsa-miR-30e-5p and significantly decreased expression of hsa-miR-142-3p, hsa-miR-338-3p, hsa-miR-34b-3p, hsa-miR-497-5p, and hsa-miR-98-5p at the time of admission to the NICU. At 48 h, infants suffering from moderate/severe HIE with a poor long-term neurodevelopmental outcome showed a significant increase in hsa-mir-145-5p. Discussion/Conclusion: MiRNA profiling shows promise as a biomarker for perinatal asphyxia, hypothermia-requiring HIE, and poor neurodevelopmental outcome. Confirmatory studies are called for.

Introduction: Very preterm infants are at risk for adverse ... more Introduction: Very preterm infants are at risk for adverse neurodevelopmental outcome. To better identify children without brain injury at risk for developmental sequelae, we assessed predictive values of supratentorial brain metrics in relation to outcome. Methods: Very preterm infants underwent magnetic resonance imaging (MRI) at term-equivalent age. Infants with any grade of supra- or infratentorial brain injury according to Kidokoro et al. [Pediatrics 2014;134:e444–53] were excluded. Supratentorial brain metrics (biparietal width, extracerebral space, interhemispheric distance) were measured and categorised using existing cut-off values. The Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) were assessed using the Bayley Scales of Infant Development, second and third edition, at 2 years of age. Developmental delay was defined as a score <85. Positive and negative predictive values for developmental delay were calculated. Results: A total of 237 very preterm infants were enrolled. Of all infants, 59 (21.2%) showed developmental delay. Infants with z-scores less than –0.5 for biparietal width had significantly lower PDI (p = 0.039) and MDI (p = 0.042) than infants with normal z-scores. Enlargement of extracerebral spaces was also related to lower PDI (p = 0.047) and MDI (p = 0.036). Negative predictive value was highest when all brain metrics were within the normal range (PDI <85: 96.6%, MDI <85: 90.0%). Combining the biparietal width and the interhemispheric distance showed highest positive predictive values for developmental delay (MDI or PDI <85: 58.3%). Discussion: Supratentorial brain metrics are predictive for neurodevelopmental outcome in infants with ostensibly normal MRI. A combination of supratentorial brain metrics is most meaningful for identifying infants at risk for long-term sequelae.

Introduction: Cerebellar injury is increasingly recognized ... more Introduction: Cerebellar injury is increasingly recognized as a relevant complication of premature birth. However, the prevalence of reduced cerebellar growth and its consequences for neurodevelopmental outcome in preterm infants without overt brain injury remain to be defined in detail. The aim of this study was to assess the transcerebellar diameter (TCD) at term-equivalent age (TEA) in very preterm infants without brain injury and to evaluate whether TCD is related to neurodevelopmental outcome in this population. Methods: Very preterm infants underwent magnetic resonance imaging at TEA. Infants with any grade of supra- or infratentorial brain injury were excluded. TCD was measured and categorized using existing cut-off values as normal TCD and mild or severe TCD reduction. Psychomotor Developmental index (PDI) and Mental Developmental index (MDI) were assessed using Bayley Scales of Infant Development II and III at a corrected age of 2 years. Results: A total of 166 infants with a mean gestational age of 29.9 ± 1.8 weeks and a mean birth weight of 1,317 ± 393 g were included. Mean TCD of girls was significantly lower compared to the mean TCD of boys (p = 0.004). TCD reduction was present in 8 infants (4.8%). Infants with a mild TCD reduction achieved lower mean MDI than infants with normal TCD (p = 0.021). Discussion: We found that reduced TCD was associated with a 17% lower mean MDI at a corrected age of 2 years. Thus, TCD at TEA may be used as an imaging marker for adverse cognitive outcome in the apparently low-risk group of preterm infants without brain injury.

Neonatology

Introduction: There are data linking gestational diabetes mellitus (GDM) with adverse neurodevelo... more 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 ...

Neonatology, Sep 3, 2019

Introduction: Cerebellar injury is increasingly recognized as a relevant complication of prematur... more Introduction: Cerebellar injury is increasingly recognized as a relevant complication of premature birth. However, the prevalence of reduced cerebellar growth and its consequences for neurodevelopmental outcome in preterm infants without overt brain injury remain to be defined in detail. The aim of this study was to assess the transcerebellar diameter (TCD) at term-equivalent age (TEA) in very preterm infants without brain injury and to evaluate whether TCD is related to neurodevelopmental outcome in this population. Methods: Very preterm infants underwent magnetic resonance imaging at TEA. Infants with any grade of supra- or infratentorial brain injury were excluded. TCD was measured and categorized using existing cut-off values as normal TCD and mild or severe TCD reduction. Psychomotor Developmental index (PDI) and Mental Developmental index (MDI) were assessed using Bayley Scales of Infant Development II and III at a corrected age of 2 years. Results: A total of 166 infants with a mean gestational age of 29.9 ± 1.8 weeks and a mean birth weight of 1,317 ± 393 g were included. Mean TCD of girls was significantly lower compared to the mean TCD of boys (p = 0.004). TCD reduction was present in 8 infants (4.8%). Infants with a mild TCD reduction achieved lower mean MDI than infants with normal TCD (p = 0.021). Discussion: We found that reduced TCD was associated with a 17% lower mean MDI at a corrected age of 2 years. Thus, TCD at TEA may be used as an imaging marker for adverse cognitive outcome in the apparently low-risk group of preterm infants without brain injury.

RöFo, Apr 1, 2020

Zielsetzung: We aimed to evaluate if proton magnetic resonance spectroscopy (1H-MRS) and diffusio... more Zielsetzung: We aimed to evaluate if proton magnetic resonance spectroscopy (1H-MRS) and diffusion tensor images (DTI) quantified in very preterm infants (VPIs) at term equivalent age (TEA) enhance the predictive role of conventional MRI for their neurodevelopmental outcome (NDO) at the corrected age of 12 months using feed-forward neural-networks (fNNs). Material und Methoden: From 300 VPIs born before 32 completed gestational weeks who received an MRI scan at TEA between September 2013 and December 2017, 173 were excluded due to missing or poor-quality spectroscopy data and/or missing neurodevelopmental tests at 12 months corrected age. The data sets of 127 VPIs were considered for motor and cognitive development, of whom 13 and 7, respectively were categorized as delayed. We evaluated five metabolite ratios and two DTI characteristics, each in six areas of the brain. We performed a feature selection algorithm for receiving a subset of characteristics that were prevalent for the VPIs with developmental delay. To reduce bias by unbalanced classes, only VPIs that shared approximate values of those prevalent characteristics were considered for further calculations. We finally constructed predictors using fNNs. Ergebnisse: Predictors constructed by fNNs achieved a true positive rate of 85.7% and a positive predictive value of 100% for prediction of cognitive developmental delay, and a true positive rate of 76.9 % and a positive predictive value of 90.9 % for prediction of motor developmental delay. Schlußfolgerungen: 1H-MRS and DTI quantified at TEA in VPIs add to the predictive value of conventional MRI for motor and cognitive development at the corrected age of 12 months. The proposed approach applying fNNs is promising for the use in clinical practice for identifying those VPIs that would mostly benefit from early intervention services.

Acta Paediatrica, May 12, 2023

AimTo investigate the direct effect of prophylactic low‐dose paracetamol administration for ducta... more AimTo 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.MethodsInfants < 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.ResultsOur 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).ConclusionWe found no impairment of psychomotor and mental outcome at age 12 and 24 months in very preterm infants after prophylactic low‐dose paracetamol administration.

European Radiology, Jul 18, 2020

Objectives We aimed to evaluate the ability of feed-forward neural networks (fNNs) to predict the... more Objectives We aimed to evaluate the ability of feed-forward neural networks (fNNs) to predict the neurodevelopmental outcome (NDO) of very preterm neonates (VPIs) at 12 months corrected age by using biomarkers of cerebral MR proton spectroscopy (1 H-MRS) and diffusion tensor imaging (DTI) at term-equivalent age (TEA). Methods In this prospective study, 300 VPIs born before 32 gestational weeks received an MRI scan at TEA between September 2013 and December 2017. Due to missing or poor-quality spectroscopy data and missing neurodevelopmental tests, 173 VPIs were excluded. Data sets consisting of 103 and 115 VPIs were considered for prediction of motor and cognitive developmental delay, respectively. Five metabolite ratios and two DTI characteristics in six different areas of the brain were evaluated. A feature selection algorithm was developed for receiving a subset of characteristics prevalent for the VPIs with a developmental delay. Finally, the predictors were constructed employing multiple fNNs and fourfold cross-validation. Results By employing the constructed fNN predictors, we were able to predict cognitive delays of VPIs with 85.7% sensitivity, 100% specificity, 100% positive predictive value (PPV) and 99.1% negative predictive value (NPV). For the prediction of motor delay, we achieved a sensitivity of 76.9%, a specificity of 98.9%, a PPV of 90.9% and an NPV of 96.7%. Conclusion FNNs might be able to predict motor and cognitive development of VPIs at 12 months corrected age when employing biomarkers of cerebral 1 H-MRS and DTI quantified at TEA. Key Points • A feed-forward neuronal network is a promising tool for outcome prediction in premature infants. • Cerebral proton magnetic resonance spectroscopy and diffusion tensor imaging can be used for the construction of early prognostic biomarkers. • Premature infants that would most benefit from early intervention services can be spotted at the time of optimal neuroplasticity.

Frontiers in Pediatrics, May 23, 2022

Introduction: Prophylactic low-dose paracetamol administration is used to induce closure of the d... more 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.

Neonatology, 2022

Introduction: Perinatal asphyxia is a leading cause of neonatal death. Up to one-third of asphyxi... more Introduction: Perinatal asphyxia is a leading cause of neonatal death. Up to one-third of asphyxiated neonates suffer from hypoxic-ischaemic encephalopathy (HIE) with substantial long-term morbidity. Currently available diagnostic and prognostic tools bear limitations, and additional reliable biomarkers are needed for all stages of clinical management. A novel tool in neuroscientific research is micro-ribonucleic acid (miRNA) profiling. The aim of the present study was to determine miRNA expression profiles of healthy and asphyxiated neonates with and without HIE and to assess their potential as diagnostic and prognostic biomarkers. Methods: We prospectively enrolled 49 neonates with a gestational age of ≥36 weeks, 15 of which fulfilled the diagnostic criteria of perinatal asphyxia and 34 served as healthy controls. Dried blood spots were collected from umbilical cord blood (UCB) and from venous blood upon admission to neonatal intensive care unit (NICU) and at 48 h of life. Samples were analysed by means of FirePlex™ technology (Abcam, Cambridge, MA, USA). Results: In the UCB, miRNA expression levels of hsa-mir-124-3p, hsa-mir-1285-5p, and hsa-mir-331-5p were significantly lower in asphyxiated neonates compared to healthy controls. Asphyxiated neonates requiring therapeutic hypothermia had significantly increased expression of hsa-miR-30e-5p and significantly decreased expression of hsa-miR-142-3p, hsa-miR-338-3p, hsa-miR-34b-3p, hsa-miR-497-5p, and hsa-miR-98-5p at the time of admission to the NICU. At 48 h, infants suffering from moderate/severe HIE with a poor long-term neurodevelopmental outcome showed a significant increase in hsa-mir-145-5p. Discussion/Conclusion: MiRNA profiling shows promise as a biomarker for perinatal asphyxia, hypothermia-requiring HIE, and poor neurodevelopmental outcome. Confirmatory studies are called for.

The Journal of Pediatrics, Nov 1, 2021

OBJECTIVES To establish longitudinal reference values for cerebral ventricular size in the most v... more OBJECTIVES To establish longitudinal reference values for cerebral ventricular size in the most vulnerable patients at risk for intraventricular hemorrhage and posthemorrhagic ventricular dilatation (PHVD). STUDY DESIGN This retrospective study included neurologically healthy preterm neonates born at 23+0 to 26+6 weeks gestational age (GA) between September 2011 and April 2019. Patients were treated at two Austrian tertiary centers (Medical University of Vienna and Medical University of Innsbruck). All available cerebral ultrasound scans until 30 weeks corrected age were analyzed. Ventricular measurements included Ventricular Index (VI), Anterior Horn Width (AHW), and Thalamo-occipital Distance (TOD) and longitudinal percentiles were created. RESULTS The study cohort consisted of 244 preterm neonates. Median GA was 25+3 (24+4-26+0), median birth weight 735 grams (644-849). A total of 993 ultrasound scans were available for analysis resulting in >1800 measurements of VI, AHW and TOD. Special attention was given to the 97th percentile as well as 2mm and 4mm above the 97th percentile, internationally used as cutoffs for intervention in the presence of PHVD. CONCLUSIONS We present percentile charts based on a cohort of extremely premature infants including neonates born at the border of viability suited to follow-up the most vulnerable patients at risk for intraventricular hemorrhage and PHVD. Furthermore, we provide an extensive literature research and comparison of all available reference values focusing on VI, AHW and TOD.

PLOS ONE, Apr 6, 2023

Neurodevelopmental impairment is a significant complication among survivors of preterm birth. To ... more 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.

Neonatology, 2020

Introduction: Very preterm infants are at risk for adverse neurodevelopmental outcome. To better ... more Introduction: Very preterm infants are at risk for adverse neurodevelopmental outcome. To better identify children without brain injury at risk for developmental sequelae, we assessed predictive values of supratentorial brain metrics in relation to outcome. Methods: Very preterm infants underwent magnetic resonance imaging (MRI) at term-equivalent age. Infants with any grade of supra- or infratentorial brain injury according to Kidokoro et al. [Pediatrics 2014;134:e444–53] were excluded. Supratentorial brain metrics (biparietal width, extracerebral space, interhemispheric distance) were measured and categorised using existing cut-off values. The Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI) were assessed using the Bayley Scales of Infant Development, second and third edition, at 2 years of age. Developmental delay was defined as a score <85. Positive and negative predictive values for developmental delay were calculated. Results: A total of 237 very preterm infants were enrolled. Of all infants, 59 (21.2%) showed developmental delay. Infants with z-scores less than –0.5 for biparietal width had significantly lower PDI (p = 0.039) and MDI (p = 0.042) than infants with normal z-scores. Enlargement of extracerebral spaces was also related to lower PDI (p = 0.047) and MDI (p = 0.036). Negative predictive value was highest when all brain metrics were within the normal range (PDI <85: 96.6%, MDI <85: 90.0%). Combining the biparietal width and the interhemispheric distance showed highest positive predictive values for developmental delay (MDI or PDI <85: 58.3%). Discussion: Supratentorial brain metrics are predictive for neurodevelopmental outcome in infants with ostensibly normal MRI. A combination of supratentorial brain metrics is most meaningful for identifying infants at risk for long-term sequelae.