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.

Amplitude-integrated electroencephalography shows alterations in children born preterm displaying poor literacy precursor skills.

AIM: To assess whether amplitude-integrated electroencephalography (aEEG) alterations in the newborn period are associated with poor precursor skills of literacy at five years of age in children born preterm. METHODS: Between October 2007 and September 2011 248 preterm infants were eligible for the study at Innsbruck Medical University Hospital. aEEG was analysed for dominating background activity, calculation of the percentage of continuous activity, the Burdjalov scoring system, the minimum, mean and maximum amplitude. At the age of five years, we evaluated preterm born children by the Bielefelder screening (BISC) to assess for early diagnosis of reading problems and weak spelling and classified them as normal performers (n = 64) or poor performers (n = 20). Completion of testing was not possible for one infant. RESULTS: The minimum amplitude was significantly lower in the poor BISC performance group as compared to the normal BISC performance group at postnatal week two. The percentage of continuous background activity was significantly higher in infants with normal BISC performance than in infants with poor BISC performance at postnatal week three. CONCLUSION: Children with poor developed precursor skills of literacy showed alterations in aEEG signals. The aEEG could be useful in further diagnosing preterm infants at risk for developmental complications.

Aortic Elastic Properties in Preschool Children Born Preterm.

OBJECTIVE: Preterm birth predisposes children to the development of cardiovascular diseases in adulthood. The aim of this study was to characterize elastic properties of the aorta at preschool age and test the hypothesis that prematurity is associated with decreased aortic distensibility and increased stiffness, both of which are predictors of increased cardiovascular risk. APPROACH AND RESULTS: In an observational study of 76 five- to seven-year-old children born at a gestational age <32 weeks and 79 term-born controls, elastic parameters of the ascending and descending abdominal aorta were determined noninvasively by means of M mode echocardiographic tracings and calculated using computerized wall contour analysis. Compared with children born at term, the preterm group showed significantly reduced distensibility and increased stiffness of the descending abdominal aorta. These results remained significant under multivariable adjustment for birth weight z score, maternal smoking in pregnancy, maternal education, family history of cardiovascular disease, breastfeeding, childhood nutrition, and current body mass index z score (multivariable odds ratios and 95% confidence intervals 5.1, 1.7-15.9; P=0.005 and 2.8, 1.0-7.9; P=0.046, respectively). Further adjustment for intravenous lipid therapy attenuated the strength of association. Elastic properties of the ascending aorta did not differ between the 2 study groups. CONCLUSIONS: Children born preterm are characterized by decreased elastic properties of the descending abdominal aorta potentially attributable to impaired viscoelastic properties of and lipid damage to the aorta. Clinical follow-up of preterm infants with a focus on aortic elastic properties may be useful for tailoring early prevention programs and counteracting cardiovascular risk in adulthood.

Amplitude-integrated electroencephalography can predict neurodevelopmental outcome at 12 months of corrected age in very preterm infants.

AIM: It is difficult to find diagnostic tools than can reliably predict neurodevelopmental outcomes in very preterm infants in clinical practice. This study evaluated whether amplitude-integrated electroencephalography predicted neurodevelopmental outcome in preterm infants when they reached 12 months of corrected age. METHODS: Between October 2007 and December 2013, we studied 232 preterm infants (51% male) at Innsbruck Medical University Hospital, Austria. Their mean birthweight was 1264 g, and their mean gestational age was 29.5 weeks. Amplitude-integrated electroencephalography was evaluated using the Burdjalov score, and outcomes were assessed using the Bayley Scales of Infant Development - Second Edition. RESULTS: The cohort was divided into three subgroups: 154 infants with normal outcomes, 53 infants with moderate delays and 25 infants with severe delays. The amplitude-integrated electroencephalography Burdjalov scores were lower in infants with moderate delays than in infants with normal outcomes and even lower in infants with severe delays. The highest area under the curve (0.776) for the Burdjalov score was at 18-24 hours of life. CONCLUSION: Our study confirmed the predictive value of amplitude-integrated electroencephalography and showed that this needed to be carried out early in life to provide reliable information on neurodevelopmental outcomes in very preterm infants.

Comparing growth charts demonstrated significant deviations between the interpretation of postnatal growth patterns in very preterm infants.

AIM: This study compared postnatal growth patterns calculated using different reference data in a large cohort of very preterm infants. METHODS: The weight, length and head circumference of 551 very preterm infants born in the Tyrol, Austria, between 2003 and 2011, were obtained at birth, discharge and the corrected ages of three, 12 and 24 months. Growth data are presented as Z-scores in relation to four reference populations: LMS growth by Pan et al., Fenton preterm growth charts, the Euro-Growth Study Group and the World Health Organization (WHO) Anthro programme. RESULTS: We observed significant differences in mean weight Z-scores using the four reference populations, with the WHO data being the highest. The mean head circumference Z-scores also differed significantly at all time points. We observed a pronounced gap in the microcephaly rate, which was 10 times higher at the age of 24 months if the Pan data were used instead of the WHO data. CONCLUSION: Our findings revealed significant deviations between the interpretation of postnatal growth depending on the reference data used, with the most striking differences seen in head circumference. The choice of reference data, and particularly the conclusions drawn from the data, must be interpreted with utmost care.

Poor postdischarge head growth is related to a 10% lower intelligence quotient in very preterm infants at the chronological age of five years.

AIM: This study examined the relationship between head growth and cognitive outcome at the age of five years in preterm infants born at less than 32 weeks of gestation from 2003 to 2009, as previous research has mostly focused on outcomes in toddlers. METHODS: The head circumference of 273 very preterm infants born in Tyrol, Austria, was measured at birth, discharge, the corrected ages of three, 12 and 24 months and the chronological age of five years. Suboptimal head size was defined as a head circumference of more than one standard deviation below the mean. Full-scale intelligence quotient (IQ) at five years was determined using Wechsler Preschool and Primary Scales of Intelligence, third edition. RESULTS: Infants with a suboptimal head size at the age of three months had a significantly lower median IQ than those with a normal head size (90 [20-122] versus 98 [20-138], p = 0.001) and from three months onwards they were more likely to exhibit cognitive delay. CONCLUSION: A suboptimal head size from the age of three months was consistently related to a 10% lower IQ, and this study adds further evidence that head growth failure, especially during the early postdischarge period, is related to impaired cognitive abilities.

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.

Poor postnatal head growth in very preterm infants is associated with impaired neurodevelopment outcome.

AIM: To examine the association between neurodevelopmental outcome and head circumference (HC) in a cohort of very preterm infants and in this context to investigate the relevance of suboptimal head size. METHODS: Somatometric data were obtained at birth, discharge and 3, 12 and 24 months for all infants born in Tyrol <32 weeks gestational age. Growth data are presented as z scores. HC was defined as microcephaly (>2 SD below mean), suboptimal (>1 SD below mean) or normal head size (<1 SD below mean). Neurodevelopmental outcome was quantified at 12 and 24 months using the Bayley Scales of Infant Development II. RESULTS: The percentage of infants with suboptimal head size increased until the age of 24 months and was related to adverse outcome. The association was strongest between HC at 3 months and psychomotor and mental outcome as quantified using the Bayley Scales of Infant Development. CONCLUSION: Poor postnatal head growth was common in our study cohort. Both microcephaly and suboptimal head size were associated with impaired neurodevelopmental outcome. Suboptimal head size at 3 months was found to be particularly associated with adverse neurodevelopmental outcome.

Early risk predictors for impaired numerical skills in 5-year-old children born before 32 weeks of gestation.

AIM: To unravel risk predictors for impaired numerical skills at 5 years of age in a population-based cohort of very preterm infants. METHODS: Between January 2003 and August 2006, we prospectively enrolled all infants born in Tyrol with <32 weeks of gestation. A total of 161 of 223 preterm infants (participation rate 72.2%) had a detailed examination at 5 years of age including cognitive assessment (Hannover-Wechsler Intelligence Test for preschool children, third edition (HAWIVA-III) or Snijders-Oomen Nonverbal Intelligence Test (SON-R)). In 135 children, numerical abilities were assessed with the dyscalculia test TEDI-MATH. The association between pre- and postnatal factors and impaired numerical skills was analyzed by means of logistic regression analysis. RESULTS: Dyscalculia test showed delayed numerical skills (TEDI-MATH Sum T-score <40) in 27 of 135 children tested (20.0%). In half of the children tested, delayed numerical abilities were related to lower IQ scores. Smoking in pregnancy, intracerebral haemorrhage and chronic lung disease were predictive of delayed numerical skills at 5 years of age in the multivariate analysis. CONCLUSION: This study identified risk predictors for impaired numerical skills in preterm infants. Our data support the role of both pre- and perinatal factors in the evolution of mathematical deficits.

Early preterm infants with abnormal psychomotor neurodevelopmental outcome at age two show alterations in amplitude-integrated electroencephalography signals.

INTRODUCTION: Recent studies showed that neurodevelopment in preterm infants can be predicted by using amplitude-integrated electroencephalography (aEEG)-derived parameters. In our previous study we demonstrated that aEEG could be useful in predicting neurodevelopmental outcome in very preterm infants at the corrected age of 2 years. AIM: The aim of this study was to further evaluate aEEG for predicting neurodevelopmental outcome at the at the corrected age of 2 years in preterm infants. METHODS: Between July 2010 and June 2016 440 very preterm infants were eligible for the study at Innsbruck Medical University Hospital. The aEEG was evaluated for the Burdjalov score in 306 preterm infants (mean gestational age 29.5 weeks; range: 24.1-31.9 weeks). At the corrected age of 2 years outcome was assessed by the Bayley Scales of Infant and Toddler Development. RESULTS: The cohort was divided into three subgroups: 248 infants with normal outcome, 40 infants with delayed outcome and 18 infants with abnormal outcome. Burdjalov scores were lower in infants with delayed outcome than in infants with normal outcome and even lower in infants with abnormal outcome. Post-hoc analysis showed significant differences between normal and delayed psychomotor outcome at 18-24 h (5 (3;6) versus 3 (3;5), p = .024), 30-36 h (6 (4;8) versus 4 (4;6), p = .033), 42-48 h (7 (5;8.5) versus 4 (4;7), p = .003), 54-60 h (7 (6;9) versus 5 (4;7), p = .003), 66-72 h (8 (6;9) versus 6.5 (4.25;7.75), p = .027) and week one (8 (7;10) versus 6.5 (5;8), p = .021). Additionally, when comparing normal to abnormal outcome, a significant difference was found at week four (12 (9;12) versus 8 (7;10), p = .024). The Burdjalov score was only predictive for a delayed psychomotor outcome, presenting the highest area under the curve (0.690) at week two of life. CONCLUSION: We observed differences in aEEG signals and neurodevelopmental outcome at the corrected age of 2 years, especially for psychomotor outcome. The predictive value of the Burdjalov score regarding neurodevelopmental outcome at the corrected age of 2 years in preterm infants was low.

Outcome of infants born at < 32 weeks' gestation in a single-centre level III neonatology unit - relation to feeding strategy.

OBJECTIVE: This study aimed to determine survival, neonatal morbidity, and outcomes at 1 and 2 years in children who were born very preterm, and to analyse any relation to enteral feeding. METHODS: We performed a prospective, observational study on very preterm infants (range: 23-31 weeks' gestation) born at Innsbruck Medical University Hospital, Austria, between 2007 and 2014 (n = 557). RESULTS: The overall survival rate was 94.6%. Survival rates were 77.8%, 78.6%, 90.9%, and 90.9% among those born at 24, 25, 26, and 27 weeks, and 97.3%, 95.3%, 98.3%, and 100% among those born at 28, 29, 30, and 31 weeks of gestation, respectively. The overall prevalence of chronic lung disease among survivors was 7.3%. The prevalence of necrotizing enterocolitis requiring surgery, intraventricular haemorrhage grades 3 and 4, and severe retinopathy of prematurity was 3.1%, 2.1%, and 6.2%, respectively. There was no difference in short-term morbidity or neurodevelopmental outcome at 1 or 2 years of corrected age between infants who were fed with human milk at discharge and those who were formula-fed. CONCLUSION: In the current study, mortality and short-term morbidity rates were low. No differences regarding feeding strategy were detected.

Former Very Preterm Infants Show Alterations in Thyroid Function at a Preschool Age.

Preterm birth is frequently associated with altered thyroid hormone levels in the newborn period. Recent data suggest a role of prematurity independent of birth size also in childhood thyroid dysfunction. Whether the high-risk population of former very preterm infants (VPI) is particularly susceptible to thyroid hormone alterations is currently unknown. The aim of the present study was to assess whether former VPI display changes in thyroid hormone status in comparison to term-born controls at a preschool age. Free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) concentrations were determined in former VPI and same-aged children born at term at five to seven years of age. 31 former term infants and 82 former VPI were included in the study. In comparison to children born at term, former VPI had lower fT4 (16.1 ± 1.8 versus 17.0 ± 2.1 pmol/l), higher fT3 (6.8 ± 0.7 versus 6.5 pmol/l), and higher TSH levels (3.0 ± 1.4 versus 2.3 ± 1.0 µU/l), independent of major neonatal morbidities. As subclinical changes in thyroid hormone status are potentially associated with adverse health profiles, close follow-up of these children is warranted.

Former Very Preterm Infants Show an Unfavorable Cardiovascular Risk Profile at a Preschool Age.

Cardiovascular disease is the leading cause of death worldwide. Evidence points towards an unfavorable cardiovascular risk profile of former preterm infants in adolescence and adulthood. The aim of this study was to determine whether cardiovascular risk predictors are detectable in former very preterm infants at a preschool age. Five- to seven-year-old children born at <32 weeks' gestational age were included in the study. Same-aged children born at term served as controls. Basic data of study participants were collected by means of follow-up databases and standardized questionnaires. At study visit, anthropometric data, blood pressure readings and aortic intima-media thickness were assessed. Blood samples were obtained after an overnight fast. In comparison to children born at term, former preterm infants had higher systolic and diastolic blood pressure readings (odds ratio [95% confidence interval] per 1-SD higher blood pressure level 3.2 [2.0-5.0], p<0.001 and 1.6 [1.1-1.2], p = 0.008), fasting glucose levels (OR [95% CI] 5.2 [2.7-10.1], p<0.001), homeostasis model assessment index (OR [95% CI] 1.6 [1.0-2.6], p = 0.036), and cholesterol levels (OR [95% CI] 2.1 [1.3-3.4], p = 0.002). Systolic prehypertension (23.7% vs. 2.2%; OR [95% CI] 13.8 [3.1-60.9], p = 0.001), elevated glucose levels (28.6% vs. 5.9%; OR [95% CI] 6.4 [1.4-28.8], p = 0.016), and hypercholesterolemia (77.4% vs. 52.9%; OR [95% CI] 3.0 [1.3-7.1], p = 0.010) were significantly more prevalent in the preterm group. As former very preterm infants display an unfavorable cardiovascular risk profile already at a preschool age, implementation of routine cardiovascular follow-up programs might be warranted.

Processing of intentional and automatic number magnitudes in children born prematurely: evidence from fMRI.

This study examined the neural correlates of intentional and automatic number processing (indexed by number comparison and physical Stroop task, respectively) in 6- and 7-year-old children born prematurely. Behavioral results revealed significant numerical distance and size congruity effects. Imaging results disclosed (1) largely overlapping fronto-parietal activation for intentional and automatic number processing, (2) a frontal to parietal shift of activation upon considering the risk factors gestational age and birth weight, and (3) a task-specific link between math proficiency and functional magnetic resonance imaging (fMRI) signal within distinct regions of the parietal lobes-indicating commonalities but also specificities of intentional and automatic number processing.

Brain structure, number magnitude processing, and math proficiency in 6- to 7-year-old children born prematurely: a voxel-based morphometry study.

The aim of the present voxel-based morphometry study was to examine the link between brain structure and number skills in a group of 6-7-year-old children born prematurely, which are considered to be an at-risk population for mathematical learning disabilities. Therefore, gray and white matter density values were extracted from brain areas previously reported to be relevant for number processing in developing brain systems and, thereafter, correlated with response time results tapping semantic number knowledge [i.e. numerical distance effect (NDE) derived from a number comparison task] as well as with general math proficiency (as indexed by a standardized calculation test). Behavioral results disclosed a significant NDE, thus indicating well-established number magnitude representations for one-digit numerals in our study group. Significant positive correlations between gray matter and NDE emerged in parietal regions (including the right anterior inferior and the left superior parietal lobe) and in the right superior temporal gyrus. Moreover, white matter and NDE were negatively correlated in the right anterior inferior parietal lobe and the right inferior frontal gyrus. Overall, our results are novel insofar as they show that in 6-7-year-old children born prematurely, individual differences in gray and white matter structures are associated with numerical skills. Importantly, in our study group the observed link between brain structure and behavioral performance emerges only regarding an experimental task tapping semantic number knowledge, whereas general math proficiency does not seem to be related to individual differences in brain structure in our study group.