René Mathiasen

Socio-Economic Achievements of Individuals Born Very Preterm at the Age of 27 to 29 Years: A Nationwide Cohort Study.

Aim  To describe the socio economic achievement of individuals born very preterm (VPT) at the age of 27 to 29 years.

The risk of psychiatric disorders in individuals born prematurely in Denmark from 1974 to 1996

Aim:  To investigate the risk of developing psychiatric disorders in individuals born prematurely (born before 37 weeks of gestation).

Prematurity and Prescription Asthma Medication from Childhood to Young Adulthood: A Danish National Cohort Study

Introduction Preterm birth is associated with increased risk of asthma-like symptoms and purchase of prescription asthma medication in childhood. We investigated whether this association persists into adulthood and whether it is affected by accounting for neonatal respiratory morbidity (acute respiratory disease and bronchopulmonary dysplasia). Methods A national cohort of all infants born in Denmark in the period 1980–2009 was included in this register study. Data on purchase of asthma medication (combination of inhaled β-2 agonists and other drugs for obstructive airway disease) in 2010–2011 were obtained from the Danish National Prescription Registry. Associations between gestational age (GA), neonatal respiratory morbidity and a cross-sectional evaluation of asthma medication purchase were explored by multivariate logistic regressions. Results A full dataset was obtained on 1,790,241 individuals, 84.6% of all infants born in the period. Odds-ratios (95% CI) for the association between GA and purchase of asthma medication during infancy were: 3.86 (2.46–6.04) in GA 23–27 weeks, 2.37 (1.84–3.04) in GA 28–31 weeks and 1.59 (1.43–1.77) in GA 32–36 weeks compared to term infants with GA 37–42 weeks. Associations weakened in older age groups and became insignificant in young adults born extremely and very preterm with odds-ratios: 1.41 (0.63–3.19) and 1.15 (0.83–1.60) in GA 23–27 and 28–31 respectively. When adjusting for neonatal respiratory morbidity, the associations weakened but persisted both in childhood and adolescence. Conclusion There was a strong dose-response association between gestational age and the purchase of prescription asthma medication in infancy and childhood. This association weakened during adolescence and was mostly non-significant in young adulthood. The increased risk of prescription asthma medication purchase in ex-preterm children could only partly be explained by neonatal respiratory morbidity.

Personality in Adults Who Were Born Very Preterm

Aim To investigate the personality in very preterm individuals (VPT; gestational age, GA, <32 weeks) at adult age in two cohorts born in 1974–76 and 1980–82, respectively, and to illuminate the effect of increased survival rates and the clinical implications of deviations in personality. Method Demographic data were extracted for all individuals born in Denmark in 1974–76 and 1980–82. From each period one index-group each comprising 150 individuals with the lowest gestational age was selected. Thereafter two control groups born at term were matched by gender, age and residential area. Personality was assessed with the short version of NEO PI-R, and psychiatric diagnoses were obtained from the Danish Psychiatric Central Research Register. Results Of all the individuals born <32 weeks of gestation in 1980–82 67% were alive in 2006 vs. 43% of those born in 1974–76 (p<0.0001). A total of 433 individuals participated in the study, 76% of the VPT groups (n = 227, mean GA = 27.9) and 69% of the control groups (n = 206). There were no significant differences on personality scores between the two VPT groups. Compared to the control groups, the combined VPT groups scored higher on neuroticism (p = 0.005) and agreeableness (p = 0.012), but lower on extraversion (p = 0.002). Psychiatric disorder was strongly associated with higher scores on neuroticism and lower scores on extraversion. Interpretation Improved survival of VPT infants was not associated with increased deviances in the personality as adults. The personality traits in VPT individuals differ moderately from those of term born controls. High scores in neuroticism and low scores in extraversion were associated with increased risk psychiatric disorders. VPT adults also showed signs of positive adaptation in the form of an agreeable and confident attitude towards others. What this paper adds The much improved survival rate in very preterm infants during the early years of active neonatology was not associated with increased risk of personality deviation. There are signs of positive adaptation in the form of increased agreeableness in young adults born very preterm.

Follow‐up of extreme neonatal hyperbilirubinaemia in 5‐ to 10‐year‐old children: a Danish population‐based study

To investigate whether infants with neonatal hyperbilirubinaemia but without intermediate or advanced bilirubin encephalopathy develop long‐term sequelae, with impairment of motor development, executive function, or hearing.

Low 5-min Apgar score in moderately preterm infants; association with subsequent death and cerebral palsy: a register based Danish national study.

Perinatal hypoxic ischemic encephalopathy (HIE) occurs in 1–6 ⁄ 1000 newborns and is associated with a high risk of death or subsequent neurodevelopmental disabilities (1,2). A recent meta-analysis including datasets on 1320 born at term infants suffering from HIE confirms that treating mature infants with moderate hypothermia therapy is associated with a reduction in death and neurological impairment at 18 months (3). The entry criteria for therapy were based on evidence of birth asphyxia combined with signs of moderate or severe encephalopathy. Therapeutic hypothermia is feasible in clinical practice and has a good safety record with only few and benign side effects (4). Currently, there is no other brain protective treatments available for infants suffering from HIE, and moderate hypothermia therapy have recently been implemented in many neonatal departments. Animal studies support that preterm infants with a perinatal hypoxic ischemic brain injury may also benefit from moderate hypothermia therapy, (5) but as human clinical trials have only included infants with a gestational age ‡36 weeks there are no human data to support this. The Apgar scoring system is used for rapid assessment of newborns and the score is included as an entry criterion for hypothermia therapy, as a marker of perinatal asphyxia in the newborn. The value of the Apgar score in predicting outcome has been questioned (6,7) although there is a strong association between a low Apgar score and death or later neurological impairments (8,9). In a Norwegian population based study including 235,000 mature newborns, infants with 5-min Apgar scores of 0–3 had a 386-fold increased risk of neonatal death and an 81-fold increased risk of cerebral palsy compared with infants who had 5-min Apgar scores of 7–10 (10). Similarly, a Swedish population based study of 1,028,705 term newborns found an increase in the risk of cerebral palsy with decreasing 5-min Apgar score (11). However, the association between Apgar score and outcome in moderately preterm infants (gestational age 32– 35 weeks) has not been well investigated. The present study is a register-based study from Denmark including all infants born in the period 1982–2002. We used the 5-min Apgar score as a marker of perinatal asphyxia and investigated (i) the incidence of a low 5-min Apgar score (Apgar score £5) in moderately preterm infants and (ii) the association between a low 5-min Apgar score and subsequent death or cerebral palsy in these infants. Using the Danish Central Person Registry (CPR) to gain information on the CPR numbers of all live born infants in the period 1982–2002, data were then extracted from registries held by Statistics Denmark. From the national birth registry, data on birth weight, gestational age, gender and Apgar score were obtained. Birth weight and gestational age were evaluated by calculating a birth weight Z-score using the normal foetal growth data of Marsál (12). We tried to eliminate misclassifications by excluding (i) infants with a birth weight three standard deviations or more from the mean, and (ii) infants with a 5-min Apgar score of 0 or 1 who were not admitted to the neonatal department within the first day of life. Infants without a registered Apgar score were also excluded. Mortality (death before year 2009) was investigated through the Cause-of-Death Registry held by the National Board of Health. Diagnoses of neurological disease were extracted from the National Patients Registry. Diagnoses were coded according to the ICD-10 (since 1993) and the ICD-8 (before 1993) classification, and for the purpose of this study we determined the prevalence of cerebral palsy (CP) using ICD-8: 34.30–34.50 and ICD-10: G80–G82. Logistic Regression was used to estimate associations between a low 5-min Apgar score and subsequent death or Acta Pædiatrica ISSN 0803–5253

Defining Smallness for Gestational Age in the Early Years of the Danish Medical Birth Registry

Background Being born small for gestational age (SGA) is associated with decreased insulin sensitivity and increased blood pressure in childhood, but the association with clinical disease in early adulthood is less certain. The Danish Medical Birth Registry has registered all births in Denmark since 1973, but due to variable data quality, data is most often used only from 1981 onwards, and birth registers in other countries may have similar problems for the early years. We wanted to examine whether the data can be used for identification of children born SGA and used in future research. Methodology/Principal Findings All persons born between 1974 and 1996 were identified in the Danish Medical Birth Registry (n = 1.704.890). Immigrants and children without data on gestational age and birth weight were excluded, and a total of 1.348.106 children were included in the analysis. The difference between the different variables used in the history of the registry were examined, and the quality of data in the birth registry from 1974-1981 was examined and compared to subsequent years. Data on birth weight and gestational age in the early years of the registry is inconsistent, and the identification of children born SGA is inaccurate, with 49% false-positives. The biggest source of error is due to the rough and inaccurate intervals used for gestational age. By using –3 standard deviations as a cut-off for the identification of children born SGA, the number of false-positives was reduced to 9%, while the amount of false-negatives were increased. Conclusion Choosing –3 standard deviations for identifying children born SGA is a viable, though not optimal solution for identifying children born SGA. Overall the data in the registry is of sufficient quality to be used in further medical research.

Importance of Comprehensive Molecular Profiling for Clinical Outcome in Children With Recurrent Cancer

Purpose: Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Patients and Methods: Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0–17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3–4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Results: Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. Conclusion: The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.