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Yuelian Sun,1– 4 Jesper Padkær Petersen,5 Chunsen Wu,6,7 Julie Werenberg Dreier,3,8 Rikke Damkjær Maimburg,9– 11 Tine Brink Henriksen,5 Jakob Christensen1,2 1Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark; 5Department of Paediatrics, Clinical Institute, Aarhus University, Aarhus University Hospital, Aarhus, Denmark; 6Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 7Department of Gynaecology and Obstetrics, Odense University Hospital, Odense, Denmark; 8Centre for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark; 9Department of Clinical Medicine, Aarhus University, Denmark; Department of Occupational Health, Aarhus University Hospital, Aarhus, Denmark; 10Department of Midwifery, University College of Northern Denmark, Hjørring, Denmark; 11School of Nursing and Midwifery, Western Sydney University, Blacktown, NSW, AustraliaCorrespondence: Yuelian Sun, Department of Neurology, Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, Email ys@clin.au.dkPurpose: 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.Keywords: Danish National Patient Registry, health administrative data, neonates, hyperbilirubinemia, neonatal jaundice, phototherapy

Introduction: SARS-CoV-2 infection during pregnancy may cause viral inflammation of the placenta, resulting in fetal demise even without fetal or newborn infection. The impact of timing of the infection and the mechanisms that cause fetal morbidity and mortality are not well understood.Material and methods: To describe placental pathology from women with confirmed SARS-CoV-2 infection during pregnancy, a SARS-CoV-2 immunohistochemistry-positive placenta and late miscarriage, stillbirth, neonatal death, or medically indicated birth due to fetal distress.Results: The triad of trophoblastic necrosis, inflammatory intervillous infiltrates, and increased perivillous fibrinoid deposition was present in all 17 placentas; the pregnancies resulted in eight stillbirths, two late miscarriages (19 and 21 weeks' gestation), and seven liveborn children, two of which died shortly after delivery. The severity of maternal COVID-19 was not reflected by the extent of the placental lesions. In only one case, SARS-CoV-2 was detected in lung tissue samples from the fetus. The majority events (miscarriage, stillbirth, fetal distress resulting in indicated birth, or livebirth, but neonatal death) happened shortly after maternal SARS-CoV-2 infection was diagnosed. Seven of eight sequenced cases were infected with the Delta (B.1.617.2) virus strain.Conclusion: We consolidate findings from previous case series describing extensive SARS-CoV-2 placentitis and placental insufficiency leading to fetal hypoxia. We found sparse evidence to support the notion that SARS-CoV-2 virus had infected the fetus or newborn. Introduction: SARS-CoV-2 infection during pregnancy may cause viral inflammation of the placenta, resulting in fetal demise even without fetal or newborn infection. The impact of timing of the infection and the mechanisms that cause fetal morbidity and mortality are not well understood.Material and methods: To describe placental pathology from women with confirmed SARS-CoV-2 infection during pregnancy, a SARS-CoV-2 immunohistochemistry-positive placenta and late miscarriage, stillbirth, neonatal death, or medically indicated birth due to fetal distress.Results: The triad of trophoblastic necrosis, inflammatory intervillous infiltrates, and increased perivillous fibrinoid deposition was present in all 17 placentas; the pregnancies resulted in eight stillbirths, two late miscarriages (19 and 21 weeks' gestation), and seven liveborn children, two of which died shortly after delivery. The severity of maternal COVID-19 was not reflected by the extent of the placental lesions. In only one case, SARS-CoV-2 was detected in lung tissue samples from the fetus. The majority events (miscarriage, stillbirth, fetal distress resulting in indicated birth, or livebirth, but neonatal death) happened shortly after maternal SARS-CoV-2 infection was diagnosed. Seven of eight sequenced cases were infected with the Delta (B.1.617.2) virus strain.Conclusion: We consolidate findings from previous case series describing extensive SARS-CoV-2 placentitis and placental insufficiency leading to fetal hypoxia. We found sparse evidence to support the notion that SARS-CoV-2 virus had infected the fetus or newborn.

BACKGROUND: We aimed to investigate the effect of epinephrine vs placebo on return of spontaneous circulation (ROSC) and brain magnetic resonance spectroscopy and imaging (MRS/MRI) in newborn piglets with hypoxic cardiac arrest (CA).METHODS: Twenty-five piglets underwent hypoxia induced by endotracheal tube clamping until CA. The animals were randomized to CPR + intravenous epinephrine or CPR + placebo (normal saline). The primary outcome was ROSC, and secondary outcomes included time-to-ROSC, brain MRS/MRI, and composite endpoint of death or severe brain MRS/MRI abnormality.RESULTS: ROSC was more frequent in animals treated with epinephrine than placebo; 10/13 vs 4/12, RR = 2.31 (95% CI: 1.09-5.77). We found no difference in time-to-ROSC (120 (113-211) vs 153 (116-503) seconds, p = 0.7) or 6-h survival (7/13 vs 3/12, p = 0.2). Among survivors, there was no difference between groups in brain MRS/MRI. We found no difference in the composite endpoint of death or severe brain MRS/MRI abnormality; RR = 0.7 (95% CI: 0.37-1.19).CONCLUSIONS: Resuscitation with epinephrine compared to placebo improved ROSC frequency after hypoxic CA in newborn piglets. We found no difference in time-to-ROSC or the composite endpoint of death or severe brain MRS/MRI abnormality.IMPACT: In a newborn piglet model of hypoxic cardiac arrest, resuscitation with epinephrine compared to placebo improved the rate of return of spontaneous circulation and more than doubled the 6-h survival. Brain MRS/MRI biomarkers were used to evaluate the effect of epinephrine vs placebo. We found no difference between groups in the composite endpoint of death or severe brain MRS/MRI abnormality. This study adds to the limited evidence regarding the effect and safety of epinephrine; the lack of high-quality evidence from randomized clinical trials was highlighted in the latest ILCOR 2020 guidelines, and newborn animal studies were specifically requested.

Background Training and assessment of operator competence for the less invasive surfactant administration (LISA) procedure vary. This study aimed to obtain international expert consensus on LISA training (LISA curriculum (LISA-CUR)) and assessment (LISA assessment tool (LISA-AT)). Methods From February to July 2022, an international three-round Delphi process gathered opinions from LISA experts (researchers, curriculum developers, and clinical educators) on a list of items to be included in a LISA-CUR and LISA-AT (Round 1). The experts rated the importance of each item (Round 2). Items supported by more than 80% consensus were included. All experts were asked to approve or reject the final LISA-CUR and LISA-AT (Round 3). Results A total of 153 experts from 14 countries participated in Round 1, and the response rate for Rounds 2 and 3 was >80%. Round 1 identified 44 items for LISA-CUR and 22 for LISA-AT. Round 2 excluded 15 items for the LISA-CUR and 7 items for the LISA-AT. Round 3 resulted in a strong consensus (99–100%) for the final 29 items for the LISA-CUR and 15 items for the LISA-AT. Conclusions This Delphi process established an international consensus on a training curriculum and content evidence for the assessment of LISA competence. Impact This international consensus-based expert statement provides content on a curriculum for the less invasive surfactant administration procedure (LISA-CUR) that may be partnered with existing evidence-based strategies to optimize and standardize LISA training in the future. This international consensus-based expert statement also provides content on an assessment tool for the LISA procedure (LISA-AT) that can help to evaluate competence in LISA operators. The proposed LISA-AT enables standardized, continuous feedback and assessment until achieving proficiency.

Background Despite therapeutic hypothermia, neonates with hypoxic–ischemic encephalopathy still develop neurological disabilities. We have previously investigated neuroprotection by remote ischemic postconditioning (RIPC) in newborn piglets following hypoxia–ischemia (HI). The aim of this study was to further investigate potential effects of RIPC on cerebral immunohistochemical markers related to edema, apoptosis, and angiogenesis. Methods Brain expression of aquaporin 4, caspase-3, B-cell lymphoma 2, and vascular endothelial growth factor was analyzed by immunohistochemistry in 23 piglets, randomly selected from a larger study of RIPC after HI. Twenty animals were subjected to 45 minutes of HI and randomized to treatment with and without RIPC, while three animals were randomized to sham procedures. RIPC was conducted by four conditioning cycles of 5-minute ischemia and reperfusion. Piglets were euthanized 72 hours after the HI insult. Results Piglets subjected to HI treated with and without RIPC were similar at baseline and following the HI insult. However, piglets randomized to HI alone had longer duration of low blood pressure during the insult. We found no differences in the brain expression of the immunohistochemical markers in any regions of interest or the whole brain between the two HI groups. Conclusion RIPC did not influence brain expression of markers related to edema, apoptosis, or angiogenesis in newborn piglets at 72 hours after HI. These results support previous findings of limited neuroprotective effect by this RIPC protocol. Our results may have been affected by the time of assessment, use of fentanyl as anesthetic, or limitations related to our immunohistochemical methods.

We aimed to investigate the effect of epinephrine vs placebo on return of spontaneous circulation (ROSC) and brain magnetic resonance spectroscopy and imaging (MRS/MRI) in newborn piglets with hypoxic cardiac arrest (CA).Twenty-five piglets underwent hypoxia induced by endotracheal tube clamping until CA. The animals were randomized to CPR + intravenous epinephrine or CPR + placebo (normal saline). The primary outcome was ROSC, and secondary outcomes included time-to-ROSC, brain MRS/MRI, and composite endpoint of death or severe brain MRS/MRI abnormality.ROSC was more frequent in animals treated with epinephrine than placebo; 10/13 vs 4/12, RR = 2.31 (95% CI: 1.09-5.77). We found no difference in time-to-ROSC (120 (113-211) vs 153 (116-503) seconds, p = 0.7) or 6-h survival (7/13 vs 3/12, p = 0.2). Among survivors, there was no difference between groups in brain MRS/MRI. We found no difference in the composite endpoint of death or severe brain MRS/MRI abnormality; RR = 0.7 (95% CI: 0.37-1.19).Resuscitation with epinephrine compared to placebo improved ROSC frequency after hypoxic CA in newborn piglets. We found no difference in time-to-ROSC or the composite endpoint of death or severe brain MRS/MRI abnormality.In a newborn piglet model of hypoxic cardiac arrest, resuscitation with epinephrine compared to placebo improved the rate of return of spontaneous circulation and more than doubled the 6-h survival. Brain MRS/MRI biomarkers were used to evaluate the effect of epinephrine vs placebo. We found no difference between groups in the composite endpoint of death or severe brain MRS/MRI abnormality. This study adds to the limited evidence regarding the effect and safety of epinephrine; the lack of high-quality evidence from randomized clinical trials was highlighted in the latest ILCOR 2020 guidelines, and newborn animal studies were specifically requested.

BACKGROUND: Whether labour epidural analgesia impacts risk of neurodevelopmental disorders in offspring is unsettled, raising public and scientific concerns. We explored the association between maternal labour epidural analgesia and autism spectrum disorder, and specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy in offspring.METHODS: This nationwide population-based cohort study included 624 952 live-born singletons delivered by women who intended to deliver vaginally (i.e. vaginal and intrapartum Caesarean deliveries) in Denmark from 2005 to 2016. A total of 80 862 siblings discordant for exposure to labour epidural analgesia were analysed in a sibling-matched analysis. Both full-cohort and sibling-matched analyses were performed to estimate hazard ratios (HRs) of offspring risk of autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy, according to exposure to labour epidural analgesia, adjusted for maternal socio-economic, pregnancy, and perinatal covariates.RESULTS: In the full cohort, maternal labour epidural analgesia was associated with autism spectrum disorder in offspring (HR 1.11; 95% confidence interval [CI]: 1.04-1.18); however, in the sibling-matched analysis, no association with autism spectrum disorder was found (HR 1.03; 95% CI: 0.84-1.27). The association between labour epidural analgesia and specific developmental disorder (HR 1.12; 95% CI: 1.03-1.22) in the full cohort also disappeared in the sibling-matched analysis (HR 1.01; 95% CI: 0.78-1.31). No association between maternal labour epidural analgesia and the remaining neurodevelopmental disorders was found overall (attention-deficit hyperactivity disorder, HR 0.98; 95% CI: 0.92-1.03; intellectual disability, HR 0.98; 95% CI: 0.85-1.14; epilepsy, HR 0.89; 95% CI: 0.79-1.00) or in the sibling-matched analyses.CONCLUSIONS: Our findings did not support an association between maternal attention-deficit hyperactivity disorder and autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, or epilepsy.

Many paediatric clinical research studies, whether observational or interventional, have as an eventual aim the identification or quantification of causal relationships. One might ask: does screen time influence childhood obesity? Could overuse of paracetamol in infancy cause wheeze? How does breastfeeding affect later cognitive outcomes? In this review, we present causal directed acyclic graphs (DAGs) to a paediatric audience. DAGs are a graphical tool which provide a way to visually represent and better understand the key concepts of exposure, outcome, causation, confounding, and bias. We use clinical examples, including those outlined above, framed in the language of DAGs, to demonstrate their potential applications. We show how DAGs can be most useful in identifying confounding and sources of bias, demonstrating inappropriate statistical adjustments for presumed biases, and understanding threats to validity in randomised controlled trials. We believe that a familiarity with DAGs, and the concepts underlying them, will be of benefit both to the researchers planning studies, and practising clinicians interpreting them.

To assess the association between serum pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotropin (free β-hCG) in the first trimester and perinatal complications in post-date pregnancies.A total of 4948 women, who delivered after 40 gestational weeks, were included. Labour was not induced routinely until 42 weeks. Serum levels of PAPP-A and free β-hCG were determined at the first-trimester screening for Down syndrome. Neonatal complications were obtained from specific registration forms filled out by senior neonatologists.In post-date pregnancies, PAPP-A 0.4 multiples of the median was associated with Apgar score of less than 7 at 5 min (ORadj 5.4, 95% CI 2.0-14.3), admission to the neonatal intensive care unit (ORadj 1.5, 95% CI 1.0-2.3) and newborn hypoglycaemia (ORadj 3.4, 95% CI 1.8-6.4). In small for gestation (SGA) neonates, the risk of hypoglycaemia was further increased (OR 14.6, 95% CI 3.4-58.0). Similar analyses were made with free β-hCG, but no statistically significant associations were found.Low first-trimester serum PAPP-A was associated with increased neonatal morbidity in post-date pregnancies, particularly in newborns with SGA. Thus, PAPP-A may qualify the timing of induction of labour in these pregnancies.

Childhood infections have been found to be associated with autism spectrum disorder (ASD) in previous studies using hospital data or medical records to identify infections. We aimed to replicate these findings using maternal reports of childhood infection.We used the Danish National Birth Cohort consisting of 92 583 live singletons born from 1997 to 2003 in Denmark. ASD diagnoses were retrieved from the Danish Psychiatric Central Register, and a total of 945 children from the cohort were diagnosed with ASD. Data were analysed using Cox proportional hazards regression. We studied the association between ASD and maternal reports of infectious disease in the child from birth to 19 months. Furthermore, we performed secondary analyses using hospital registers to investigate the association between ASD and hospital contact in general as well as hospital contact for various infections.We did not find a general association between maternal reports of infectious illness and ASD. However, hospital contact for all causes was associated with an increased risk for an ASD diagnosis. Danish children with ASD do not appear to have a general pattern of illness from infection in early life, but do have more contact with medical specialists for infections and other indications compared with the general population.[corrected] Hospital data should be used cautiously when studying the co-morbidity of ASD; if the increased rate of hospital contact overall for children with ASD is not considered, then misleading interpretations might be made of observed associations between specific diseases and ASD.

To evaluate pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotrophin (β-hCG) in relation to admission to a neonatal intensive care unit (NICU) and neonatal disease.A total of 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital between January 2005 and December 2007 were included. PAPP-A and free β-hCG were measured between gestational weeks 8 and 13 and converted into multiples of the median (MoM) values. Information about neonatal outcome was obtained from specific registration forms completed by senior neonatologists at the time of admission to and discharge from the NICU.Both PAPP-A and free β-hCG 0.4 MoM were associated with admission to NICU (odds ratio 1.6; 95% confidence interval, 1.2-2.0 and odds ratio 1.5; 95% confidence interval, 1.1-2.1). The results could not be explained by preterm delivery or low birth weight, because adjusting for these factors did not affect the results. Low PAPP-A was also significantly associated with neonatal hypoglycemia, jaundice, and low Apgar score and low free β-hCG with jaundice.Low PAPP-A and free β-hCG were significantly associated with admission to NICU and neonatal disease, independently from what could be expected because of preterm delivery or low birth weight.

There is conflicting evidence regarding the effect of coeliac disease (CD) in the father on birthweight and preterm birth. We investigated the association between paternal CD and birthweight and preterm birth. Medical records of all singleton live-born children in Denmark between 1 January 1979 and 31 December 2004 were linked to information about parents' diseases. Fathers who were diagnosed with CD were then identified. Fathers with CD were considered treated if they were diagnosed before pregnancy and untreated if they were diagnosed after the date of conception. The outcome measures were: birthweight, small-for-gestational age (birthweight10th centile for gestational age) and preterm birth (37 weeks). We compared the offspring of men without CD (n = 1 472 352) and offspring of those with CD [untreated (n = 138) and treated (n = 473)]. There was no significant association between untreated CD in the father and birthweight (adjusted mean difference = -3 g; [95% CI -46, 40]) or preterm birth (adjusted odds ratio (OR) = 0.86, [95% CI 0.53, 1.37]) (compared with no CD). There was some evidence for an association between treated paternal CD and birthweight (adjusted mean difference = -81 g; [95% CI -161, -3]), but not preterm birth (adjusted OR = 1.76, [95% CI 0.95, 3.26]). Untreated paternal CD was not associated with an increased risk of reduced birthweight, or of preterm birth. There was some evidence that diagnosis and presumed treatment of paternal CD with a gluten-free diet is associated with reduced birthweight.