Neonatal phototherapy and risk of epilepsy-A Danish population based study.

To evaluate the risk of epilepsy in children who received neonatal phototherapy. A cohort of live singletons born at a Danish hospital (2002-2016) with a gestational age ≥ 35 weeks. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy in children treated with neonatal phototherapy compared to children not treated with neonatal phototherapy in the general population, and in a subpopulation of children who had serum bilirubin measurement. Adjusted HRs (aHR) were computed using multivariable and propensity score matching models to take maternal and neonatal factors into consideration. Children were followed from day 29 after birth to diagnosis of epilepsy, death, emigration, or December 31, 2016. Among 65,365 children, 958 (1.5%) received neonatal phototherapy. Seven children (incidence rates (IRs): 10.8 /10,000 person-years) who received neonatal phototherapy and 354 children (IR: 7.7) who did not receive neonatal phototherapy were diagnosed with epilepsy. Neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 0.95, 95% CI: 0.43-2.09) and propensity score matched (aHR 0.94, 95% CI: 0.39-2.28) models. In the subpopulation of 9,378 children with bilirubin measurement, 928 (9.9%) received neonatal phototherapy. In the analysis of the subpopulation in which bilirubin level and age at the time of bilirubin measurement were further taking into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 1.26, 95% CI: 0.54-2.97) and propensity score matched (aHR 1.24, 95% CI: 0.47-3.25) models,Conclusions: Neonatal phototherapy was not associated with an increased risk of epilepsy after taking maternal and neonatal factors into consideration. What is known: • A few studies have suggested that neonatal phototherapy for hyperbilirubinemia may increase the risk of childhood epilepsy. • Whether the observed associations contribute to hyperbilirubinemia, phototherapy, or underlying factors requires further investigation. What is new: • This study revealed no increased risk of epilepsy in children treated with neonatal phototherapy compared to children not treated with phototherapy after taking maternal and neonatal factors into consideration. • After further taking bilirubin level and age at the time of bilirubin measurement into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy.

Neonatal Phototherapy and Clinical Characteristics: The Danish National Patient Registry 2000-2016.

Purpose: Phototherapy is the standard treatment for neonatal hyperbilirubinemia. It is important to collect data on phototherapy to support research related to the efficacy and safety of phototherapy. We explored the registration of phototherapy in the Danish National Patient Registry (DNPR) and the clinical characteristics of neonates treated with phototherapy. Methods: We identified children born alive in Denmark from 1 January 2000 through 30 November 2016 from the DNPR (N=1,044,502). We calculated the proportion of children registered that received phototherapy during the neonatal period and examined temporal trends, both nationwide and at the level of individual hospitals. In a sub-cohort of children born at Aarhus University Hospital (AUH) in 2002-2016 (N=71,781), we analyzed the proportions of children registered that received phototherapy, according to sex, gestational age, birth weight, and neonatal characteristics, like Apgar score, birth asphyxia, and infections. Results: We identified 11,295 (1.1%) registered that received phototherapy. The proportions of children registered that received phototherapy differed among hospitals (range: 0 to 4.1%). Nationwide registration was low during the study period, but it increased to 1.8% in 2016. For the AUH sub-cohort the proportion of children registered with phototherapy averaged 4.4% (N=3182, range:3.9-5.1%). The proportion of children registered with phototherapy was inversely correlated with gestational age and birth weight, and positively correlated with neonatal characteristics, including low Apgar score, birth asphyxia, and infections. Conclusion: Phototherapy was under-reported in the DNPR and the proportions of children registered that received phototherapy differed among hospitals. The non-compulsory policy for reporting treatment and care in hospitals to the DNPR might explain the variation. The most consistent reporting was observed among children born in an university hospital, where 4.4% of children registered that received phototherapy, and phototherapy was inversely associated with gestational age, birth weight, and positively associated with clinical characteristics like birth asphyxia, and infections.

Evaluation of the diagnostic process in neonates with conjugated hyperbilirubinaemia.

INTRODUCTION: The Danish Health Authority (DHA) recommends diagnostic evaluation of infants who develop prolonged jaundice and a serum conjugated bilirubin (CB) concentration ≥ 17 µmol/l. This study aimed to assess the efficacy of the programme in identifying infants with biliary atresia (BA) or other liver disease. Infants born in the Central Denmark Region from 2016 to 2021 were investigated. METHODS: A total of 693 infants were identified in the Central Biochemical Database (Labka). From a review of all medical records, CB measurements, results from diagnostic procedures and the final diagnosis were documented. RESULTS: Four infants were identified with BA. They had a mean CB concentration of 105 µmol/l. A total of 33 infants were diagnosed with other cholestatic diseases; this group had a mean CB concentration of 58.9 µmol/l. The remaining 656 infants with a mean CB of 20.5 µmol/l recovered spontaneously without any sign of cholestatic disease. Approximately 75% of all HIDA scintigraphies (100/134) were conducted in 647 infants with a maximum CB concentration less-than 30 µmol/l. They all had bile drainage to the intestines. Among these infants, twelve were diagnosed as heterozygote for alfa-1-antitrypsin deficiency. CONCLUSION: The CB threshold limit recommended by the DHA detected all patients with BA, but its use leads to over-investigation and over-diagnosing. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Risk of complications in the late vs early days of the 42nd week of pregnancy: A nationwide cohort study.

INTRODUCTION: Uncertainty remains about the most appropriate timing of induction of labor in late-term pregnancies. To address this issue, this study aimed to compare the risk of neonatal morbidity and pregnancy- and birth-related complications between gestational age (GA) 41+4 -42+0 and GA 41+0 -41+3  weeks. MATERIAL AND METHODS: This nationwide registry-based cohort study included singleton births without major congenital malformations, with registered GA, and with intended vaginal delivery at GA 41+0 - 42+0  weeks between 2009 and 2018 in Denmark. Logistic regression models were used to estimate the crude risk ratio and adjusted risk ratio (RRA ) of neonatal and obstetric adverse outcomes in births at GA 41+4 - 42+0  weeks compared with GA 41+0 - 41+3  weeks. The results were adjusted for relevant confounders, including induction of labor. RESULTS: A higher incidence of neonatal morbidity and birth complications was observed in births at GA 41+4 -42+0  weeks than in births at GA 41+0 -41+3  weeks. Neonatal morbidities included an increased risk of low Apgar score (Apgar 0-6 after 5 min; RRA 1.17, 95% confidence interval [CI] 1.01-1.34), meconium aspiration (RRA 1.25, 95% CI 1.06-1.48), need for respiratory support (continuous positive airway pressure; RRA 1.09, 95% CI 1.03-1.15), and a composite outcome of need for comprehensive treatment at a neonatal department or neonatal death (RRA 1.65, 95% CI 1.29-2.11). Birth complications included emergency cesarean section (RRA 1.17, 95% CI 1.14-1.21), severe lacerations (RRA 1.11, 95% Cl 1.04-1.17), and increased blood loss after birth (RRA 1.13, 95% CI 1.06-1.21). CONCLUSIONS: Births at GA 41+4 -42+0  weeks were associated with an increased risk of neonatal morbidity and birth complications compared with births at GA 41+0 -41+3  weeks. The results of this study may aid clinicians in deciding when to recommend induction of labor in late-term pregnancies.

[Treatment and follow-up of preterm infants in Denmark].

This review summarises the treatment of preterm infants in Denmark, which is dependent on the collaboration between several medical specialities. The problems of the preterm infants are related to the degree of prematurity, and the treatment should counter these issues, reduce complications related to prematurity and ensure growth and development. Developmental problems are the most common sequelae. There seems to be a dose-effect association between the whole spectrum of gestational age and developmental problems with the highest risk among the extremely preterm children. However, even in this group, most of the children will develop normally.

Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation: A Randomized Clinical Trial.

Importance: Nasal continuous positive airway pressure (nCPAP) is a well-established treatment of respiratory distress syndrome in preterm infants. Suboptimal weaning from nCPAP may be associated with lung injury, pulmonary morbidity, and infant weight gain. To our knowledge, the best weaning strategy from nCPAP is unknown. Objective: To compare the effect of sudden wean and pressure wean from nCPAP in very preterm infants. Design, Setting, and Participants: A randomized, clinical, open-label, multicenter trial was conducted at 6 neonatal intensive care units in Denmark from September 2012 to December 2016 and included infants born before 32 weeks of gestation. Interventions: Sudden wean with discontinuation of nCPAP without a prior reduction in pressure. Pressure wean with gradual pressure reduction prior to the discontinuation of nCPAP. Main Outcome and Measures: The primary outcome was weight gain velocity from randomization to postmenstrual age 40 weeks. Secondary outcomes included other measures of growth, nCPAP and the duration of oxygen supplementation, postmenstrual age at successful wean and at discharge, successful wean at the first attempt, the number of attempts to wean, and the length of the hospital stay. Prespecified subgroup analyses by gestational age were performed. Results: Of the 372 randomized infants, 185 (49.7%) were randomized to sudden wean and 187 infants (50.3%) to pressure wean. A total of 177 infants in both groups completed the trial (median gestational age for sudden and pressure wean, 30 weeks [interquartile range, 29-31]; male: sudden wean, 89 [50%]; pressure wean, 96 [54%]). There was no difference in mean [SD] weight gain velocity from randomization to 40 weeks postmenstrual age between the 2 groups (22 [6] g/kg/day). No difference was found in any of the secondary outcomes. More infants born before 28 weeks of gestation were successfully weaned from nCPAP during the first attempt in the pressure wean group compared with the sudden wean group (risk difference, 31%; 95% CI, 13%-50%), but there was no difference in the duration of nCPAP and oxygen supplementation. Conclusions and Relevance: Overall, we found no difference in weight gain velocity or any of the secondary outcomes between very preterm infants who were randomized to sudden wean or pressure wean from nCPAP. However, among infants born before 28 weeks' gestation, infants from the pressure wean group were more often successfully weaned during the first attempt without a longer total duration of nCPAP treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01721629.

Surfactant Need by Gestation for Very Preterm Babies Initiated on Early Nasal CPAP: A Danish Observational Multicentre Study of 6,628 Infants Born 2000-2013.

BACKGROUND: In recent years, early nasal continuous positive airway pressure (nCPAP) as respiratory support for preterm infants is being advocated as an alternative to prophylactic surfactant and treatment with mechanical ventilation. A number of infants treated with early nCPAP do not need treatment with surfactant, but few studies provide data on this. Since the 1990s, the first approach to respiratory support to preterm infants in Denmark has been early nCPAP combined with surfactant administration by the INSURE method by which the infant is intubated and surfactant administration is followed by rapid extubation to nCPAP if possible. OBJECTIVES: To investigate how often surfactant was administered in preterm infants with a gestational age below 34 weeks treated with early nCPAP as a first approach to respiratory support. METHODS: An observational multicentre study including all inborn infants with a gestational age below 34 weeks admitted to 1 of the 4 level 3 neonatal intensive care units in Denmark in the period from 2000 to 2013. RESULTS: A total of 6,628 infants were included in this study. We found that surfactant was administered in 1,056 of 1,799 (59%; 95% CI: 57-61%), in 821 of 2,864 (29%; 95% CI: 27-31%), and in 132 of 1,796 (7%; 95% CI: 6-8%) of the infants with a gestational age from 24 to 27, 28 to 31, and 32 to 33 weeks and 6 days, respectively. CONCLUSIONS: A large proportion of preterm infants treated with early nCPAP as the first approach to respiratory support was never treated with surfactant.

UGT1A1*28 Genotypes and Respiratory Disease in Very Preterm Infants: A Cohort Study.

BACKGROUND: Respiratory disease in the very preterm infant is frequent and often severe. Bilirubin is both a potent neurotoxin and antioxidant, and may have a clinical impact on preterm respiratory disease. The Gilbert genotype, the UGT1A1*28 allele, is the major known genetic cause of variation in bilirubin. OBJECTIVES: To study the association between respiratory disease in the very preterm infant and the UGT1A1*28 allele. METHODS: This is a cohort study of 1,354 very preterm infants (gestational age <32 weeks) born in Jutland, Denmark in 1997-2011. Genotypes were obtained from the Danish Neonatal Screening Biobank, and clinical information was obtained from the databases of two tertiary neonatal intensive care units. Outcomes were the need for surfactant therapy, any need for and duration of supplementary oxygen and bronchopulmonary dysplasia (BPD). RESULTS: Per UGT1A1*28 allele, odds were increased for any need of supplementary oxygen (odds ratio 1.26; 1.05-1.50) and for BPD (odds ratio 1.71; 1.23-2.39), the need of supplementary oxygen increased by 6.38 days (1.87-10.89), and chance per day of no longer needing supplementary oxygen was reduced (hazard rate 0.84; 0.76-0.93). No effect was observed for need of surfactant treatment (odds ratio 1.08; 0.91-1.28). Hardy-Weinberg equilibrium was unlikely for the cohort (p < 0.012). This could be explained by death prior to genotype sampling. In tests of robustness this failed to explain the primary results. CONCLUSIONS: Compared to the common genotype, UGT1A1*28 genotypes were associated with an increased need of oxygen supplementation and risk of BPD in very preterm newborns.

Extreme neonatal hyperbilirubinemia and a specific genotype: a population-based case-control study.

OBJECTIVES: Extreme hyperbilirubinemia (plasma bilirubin ≥ 24.5 mg/dL) is an important risk factor for severe bilirubin encephalopathy. Several risk factors for hyperbilirubinemia are known, but in a large number of patients, a causal factor is never established. UGT1A1 is the rate-limiting enzyme in bilirubin's metabolism. The genotype of Gilbert syndrome, the UGT1A1*28 allele, causes markedly reduced activity of this enzyme, but its association with neonatal hyperbilirubinemia is uncertain and its relationship with extreme hyperbilirubinemia has not been studied. We examined whether the UGT1A1*28 allele is associated with extreme hyperbilirubinemia. METHODS: The UGT1A1*28 allele was assessed in a case-control study of 231 white infants who had extreme hyperbilirubinemia in Denmark from 2000 to 2007 and 432 white controls. Cases were identified in the Danish Extreme Hyperbilirubinemia Database that covers the entire population. Genotypes were obtained through the Danish Neonatal Screening Biobank. Subgroup analysis was done for AB0 incompatible cases. RESULTS: No association was found between the UGT1A1*28 allele and extreme hyperbilirubinemia. With the common genotype as reference, the odds ratio of extreme hyperbilirubinemia was 0.87 (range, 0.68-1.13) for UGT1A1*28 heterozygotes and 0.77 (range, 0.46-1.27) for homozygotes. Also, no association was found for AB0 incompatible cases. CONCLUSIONS: The UGT1A1*28 allele was not associated with risk for extreme hyperbilirubinemia in this study.

The Danish neonatal clinical database is valuable for epidemiologic research in respiratory disease in preterm infants.

BACKGROUND: We examined the quality of the information on the use of surfactant and the use of and duration of nasal continuous positive airway pressure (nCPAP), oxygen supplementation, and mechanical ventilation in the Danish Neonatal Clinical Database (NeoBase). METHODS: We included all neonates born with a gestational age < 32 weeks admitted to a Neonatal Intensive Care Unit (NICU) at two university hospitals in 2005. On discharge, the clinicians complete a structured form with information related to the delivery and course of stay in the NICU. These forms were entered into the NeoBase. The nurses' daily bedside documentation was used as reference standard. Concordance was used as a measure of agreement between the NeoBase and the reference standard. For the dichotomous variables the concordance was defined as the sensitivity of the information registered in the NeoBase. For the continuous variables, it was based on the discrepancy in days between the NeoBase and the reference standard. The percentage of concordance was described as high (> 90), moderate (70-90) or low (< 70). RESULTS: Overall, 153 infants participated in the study. Concordance was high for all dichotomous variables. The NeoBase slightly underestimated the duration of nCPAP and mechanical ventilation. The duration of oxygen therapy was neither over- nor underestimated in the NeoBase. Concordance was low for all continuous variables if we assumed that the registered information was identical. It was 100% for duration of mechanical ventilation and moderate for nCPAP and oxygen supplementation if we allowed for a discrepancy of 1 day. CONCLUSION: The NeoBase is a valuable tool for clinical and epidemiologic research and quality assurance regarding neonatal respiratory disease.