Introduction Pharmaceutical treatment in the neonatal intensive care unit (NICU) is challenging, and newborns are often exposed to numerous different medicines during their hospitalization There is currently insufficient knowledge of gestational age dependent medicine disposition, and accordingly the use of off-label medicines, i.e., use of medicines outside its approved marketing authorization, is high. This study aims to estimate the off-label medicine use in Danish neonatal departments. Methods By using data from the Danish National Pharmaceutical Hospital Purchase Database, we identified the most commonly occurring medicines and calculated the on/off-label ratios for premature and term neonates. Data was extracted on ATC level 5 and based on defined daily doses as per WHO. Results Data included was covering the 4 high-level NICUs and 10 of 13 of the intermediate/standard level neonatal departments in Denmark. Of the identified medicines, 87% and 70% did not have approved marketing authorization for use in premature and full-term neonates, respectively. Furthermore one-fifth of the top 100 medicines did not have a (Danish) marketing license. Overall, the presence of off-label medicines was widespread covering virtually all ATC groups and no ATC group had an off-label level lower than 50%. Finally, in 21% of the identified medicines, additives from 8 different chemical groups with potential deleterious effects for neonates were identified. Conclusion Off-label medication in the Danish neonatal departments is widespread, and the current state of neonatal official regulatory drug approval leaves both patients and neonatologists in a limbo between legal pharmaco-regulation and clinical need for pharmacotherapy in neonatology.

Objective To explore the effect of different delivery modes, vaginal delivery compared to caesarean section with or without initiation of labour, on the immune system and brain of the infants. Further, we aimed to elucidate gender and gestational ages’ effect on these biomarkers. Design Retrospective case control study Setting Dried blood spots from new-born screening biobank drawn 2-4 days after birth Population or Sample Mature new-borns divided into delivery by pre-labour (n=714), in-labour caesarean section (n=655), and vaginally (n=5897). Method The samples were analysed for inflammatory markers (IL-18, MCP-1, CRP, sTNF RI), stress- (HSP-70), growth- (EGF, VEGF-A), and neurotrophic factors (BDNF, NT-3, S100B). Main Outcome Measures Delivery by caesarean section with or without initiation of labour Results The neonatal levels of inflammatory and stress-markers were significantly lower, while the levels of growth factors were higher after pre-labour caesarean section compared to vaginal delivery. The biomarker levels were similar after in-labour caesarean section and vaginal delivery. Males had generally higher levels of inflammation and lower levels of growth and neurotrophic factors. Overall, the levels of inflammatory markers increased, and the growth factors decreased with increasing gestational age. Conclusion The biomarker levels indicates that the labour process has an important effect on the foetal immune system and level of stress, regardless if the delivery ends with caesarean section or vaginal birth. Funding ”Læge Sofus Carl Emil Friis og hustru Olga Doris Friis’ legat” and ”Fonden til Lægevidenskabens Fremme”. Keywords Inflammation; brain; CODIBINE; caesarean section; dried blood spot samples