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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., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Decreased heart rate variability (HRV) may be a biomarker of brain injury severity in neonatal hypoxic-ischemic encephalopathy for which therapeutic hypothermia is standard treatment. While therapeutic hypothermia may influence the degree of brain injury; hypothermia may also affect HRV per se and obscure a potential association between HRV and hypoxic-ischemic encephalopathy. Previous results are conflicting. This study aimed to investigate the effect of hypothermia on HRV in healthy, anaesthetised, newborn piglets. Six healthy newborn piglets were anaesthetised. Three piglets were first kept normothermic (38.5-39.0 °C) for 3 h, then exposed to hypothermia (33.5-34.5 °C) for 3 h. Three piglets were first exposed to hypothermia for 3 h, then rewarmed to normothermia for 3 h. Temperature and ECG were recorded continuously. HRV was calculated from the ECG in 5 min epochs and included time domain and frequency domain variables. The HRV variables were compared between hypothermia and normothermia. All assessed HRV variables were higher during hypothermia compared to normothermia. Heart rate was lower during hypothermia compared to normothermia and all HRV variables correlated with heart rate. Hypothermia was associated with an increase in HRV; this could be mediated by bradycardia during hypothermia., (© 2022. The Author(s).)

Background: We have previously investigated neurological outcomes following remote ischemic postconditioning (RIPC) in a newborn piglet model of hypoxic-ischemic encephalopathy. The aim of this study was to further investigate potential mechanisms of neuroprotection by comparing newborn piglets subjected to global hypoxia-ischemia (HI) treated with and without RIPC with regards to measures of cerebral blood flow and oxygenation assessed by functional magnetic resonance imaging., Materials and Methods: A total of 50 piglets were subjected to 45 min global HI and randomized to either no treatment or RIPC treatment. Magnetic resonance imaging was performed 72 h after the HI insult with perfusion-weighted (arterial spin labeling, ASL) and oxygenation-weighted (blood-oxygen-level-dependent, BOLD) sequences in the whole brain, basal ganglia, thalamus, and cortex. Four sham animals received anesthesia and mechanical ventilation only., Results: Piglets treated with RIPC had higher measures of cerebral blood flow in all regions of interest and the whole brain (mean difference: 2.6 ml/100 g/min, 95% CI: 0.1; 5.2) compared with the untreated controls. They also had higher BOLD values in the basal ganglia and the whole brain (mean difference: 4.2 T2*, 95% CI: 0.4; 7.9). Measures were similar between piglets treated with RIPC and sham animals., Conclusion: Piglets treated with RIPC had higher measures of cerebral blood flow and oxygenation assessed by magnetic resonance imaging in the whole brain and several regions of interest compared with untreated controls 72 h after the HI insult. Whether this reflects a potential neuroprotective mechanism of RIPC requires further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kerrn-Jespersen, Andersen, Bennedsgaard, Andelius, Pedersen, Kyng and Henriksen.)

Background: Group B Streptococcus (GBS) infection in infants may result in both respiratory, cardiovascular, and neurological dysfunction and ultimately death of the infant. Surveillance of GBS strains in infants and their clinical characteristics guide development of effective vaccines and other potential treatments and may have implications for future prognostics and infant care. Therefore, we aimed to study GBS serotypes and clonal complexes (CC) in Danish infants with early onset infection (EOD) (0-6 days of life) and late-onset infection (LOD) (7-89 days of life) and to estimate the association between GBS strain and different clinical outcomes., Methods: We included Danish infants less than 3 months of age with GBS isolates from blood or cerebrospinal fluid between 1999 and 2009. GBS isolates were analyzed by serotyping and multilocus sequence typing with classification of isolates into clonal complexes. Clinical characteristics were obtained by questionnaires completed by tending pediatrician including gestational age, Apgar scores, age at onset, meningitis, symptom severity, treatment duration, and mortality. Symptom severities were reported within neurological symptoms, need for respiratory or circulatory support, and treatment of disseminated intravascular coagulation., Results: A total of 212 GBS isolates were collected with 129 from EOD and 83 from LOD. The dominating GBS strains were III/CC17 (41%), Ia/CC23 (17%), III/CC19 (15%), Ib/CC8-10 (7%), and V/CC1 (6%). Strain Ia/CC23 was mostly found in EOD, while III/CC17 was widespread in LOD, though being the most common in both EOD and LOD. Strain III/CC17 and Ia/CC23 had highest percentage of samples from cerebrospinal fluid (26%), while III/CC19 had the least (8%). Strain III/CC19 had highest mortality with about one fifth of infected infants dying (22%) followed by Ia/CC23 (16%), Ib/CC8-10 (9%), and then III/CC17 (6%). The symptom severity varied between strains, but with no strain consistently resulting in more severe symptoms., Conclusion: Some potential differences in disease severity were observed between the different strains. These findings emphasize the continuous need for multimodal surveillance of infant GBS strains and their clinical characteristics to optimize development of GBS vaccines and other potential treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Andersen, Smith, Murra, Nielsen, Slotved and Henriksen.)

Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and accumulate in humans. PFAS are suspected to affect the neuropsychological function of children, but only few studies have evaluated the association with childhood attention and executive function., Objectives: To investigate the association between intrauterine exposure to PFAS and offspring attention and executive function., Methods: A total of 1593 children from the Danish National Birth Cohort, born 1996-2003, were included. The levels of 16 PFAS were measured in maternal plasma during pregnancy. At 5 years of age, the Test of Everyday Attention for Children at Five (TEACh-5) and the Behavior Rating Inventory of Executive Function (BRIEF) were performed. TEACh-5 scores were standardized to a mean of 0 and standard deviation (SD) of 1. BRIEF scores were standardized to a mean of 50 and a SD of 10. The associations between levels of seven PFAS and TEACh-5 and BRIEF were examined by multivariable linear regression adjusted for potential confounders., Results: Perfluorooctane sulfonamide (PFOSA) was associated with poorer selective attention [standardized mean difference (95% confidence interval) -0.5 (-0.7, -0.3), highest versus lowest quartile]. Other PFAS were not clearly associated with selective attention, and we found no clear associations between PFAS exposure and sustained attention. For parent rated executive function, perfluorooctanoate (PFOA) was associated with poorer scores, standardized mean difference 3.8 (95% confidence interval 1.6, 6.0), highest versus lowest quartile. Regarding other PFAS, the associations were less clear. We found no clear associations between any PFAS and executive function rated by preschool teachers., Conclusion: Intrauterine exposure to PFOSA was associated with poorer selective attention, while PFOA was associated with poorer executive function. Given the widespread nature of PFAS exposure, these findings may have public health implications, warranting further investigation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Complications to preterm birth are numerous, including the presence of a patent ductus arteriosus (PDA). The biological understanding of the PDA is sparse and treatment remains controversial. Herein, we speculate whether the PDA is more than a cardiovascular imbalance, and may be a marker in response to immature core molecular and physiological processes driven by biological systems, such as inflammation. To achieve a new biological understanding of the PDA, we performed echocardiography and collected plasma samples on day 3 of life in 53 consecutively born neonates with a gestational age at birth below 28 completed weeks. The proteome of these samples was analyzed by mass spectrometry (nanoLC-MS/MS) and immunoassay of 17 cytokines and chemokines. We found differences in 21 proteins and 8 cytokines between neonates with a large PDA (>1.5 mm) compared to neonates without a PDA. Amongst others, we found increased levels of angiotensinogen, periostin, pro-inflammatory associations, including interleukin (IL)-1β and IL-8, and anti-inflammatory associations, including IL-1RA and IL-10. Levels of complement factors C8 and carboxypeptidases were decreased. Our findings associate the PDA with the renin-angiotensin-aldosterone system and immune- and complement systems, indicating that PDA goes beyond the persistence of a fetal circulatory connection of the great vessels.

Neonatal herpes simplex disease (HSV) is a rare but life-threatening infection associated with high rates of morbidity and mortality. Recent studies indicate that the incidence rate has continued to rise over the past decades, while the mortality remains unchanged. Early clinical suspicion of HSV and parenteral antiviral treatment of acute disease is essential for the prognosis. The subsequent use of suppressive therapy with oral acyclovir has further enhanced the long-term prognosis. This review presents evidence of risk factors, clinical presentation, prevention, and management of HSV in newborns.

Introduction: Obesity is associated with many pregnancy complications, including both fetal macrosomia and prolonged labour. As a result, there is often also an increased risk of caesarean section. In other settings, labour induction near to term reduces adverse outcomes such as stillbirth and birth injury, without causing more caesarean deliveries. It has been suggested that induction will reduce adverse events in this setting too, but there have been no trials and the effect on caesarean section is unknown. The objective of this study is to compare induction of labour in gestational week 39 with expectant management on the risk of caesarean section in women with body mass index ≥30 kg/m 2 ., Methods and Analysis: An open label randomised controlled multicentre trial are conducted at Danish delivery departments with an in-house neonatal intensive care unit. Recruitment started October 2020. A total of 1900 women with a prepregnancy body mass index ≥30 kg/m 2 are randomised in a 1:1 ratio to either labour induction at 39 weeks and 0 to 3 days of gestation or to expectant management; that is, waiting for spontaneous labour onset or induction if medically indicated. The primary outcome is caesarean section. Data will be analysed according to intention-to-treat., Ethics and Dissemination: The Central Denmark Region Committee on Biomedical Research Ethics approved the study. The study is conducted in accordance with the ethical principles outlined in the latest version of the 'Declaration of Helsinki' and the 'Guideline for Good Clinical Practice' related to experiments on humans. The trial findings will be disseminated to participants, clinicians, commissioning groups and via peer-reviewed publications., Trial Registration Number: NCT04603859., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Emerging evidence shows that women with endometriosis face a higher risk of preterm birth. However, the pathways are unclear. The objective of this study is to further investigate at different gestational ages the association between endometriosis and different pathways of preterm birth including, medically indicated preterm birth, premature pre-labor rupture of membranes (PPROM), and spontaneous labor contractions., Material and Methods: In this population-based cohort study we linked singleton pregnancies from the Aarhus Birth Cohort to the Danish National Patient Registry, the Danish Medical Birth Registry, the Danish National Pathology Registry and Data Bank, and the Danish in vitro fertilization registry to gather information on endometriosis status, outcomes and maternal characteristics. We investigated preterm birth before 37 completed weeks of gestation and very preterm birth before 32 completed weeks of gestation. We explored different pathways including medically indicated preterm birth defined as induction of labor with intact membranes and no prior labor contractions, PPROM defined as rupture of membranes, and spontaneous labor contractions defined as contractions with intact membranes resulting in labor., Results: We found that women with endometriosis had an increased risk of preterm birth before 37 gestational weeks overall (adjusted hazard rate [aHR] 1.6, 95% confidence interval [CI] 1.3-1.9) and very preterm birth before 32 gestational weeks (aHR 1.8, 95% CI 1.1-2.9) compared with women without endometriosis. Medically indicated preterm birth was more prominent in women with endometriosis in deliveries before 37 gestational weeks (aHR 2.4, 95% CI 1.8-3.2) whereas spontaneous labor contractions were more common before 32 gestational weeks (aHR 2.2, 95% CI 1.1-4.5) in women with endometriosis compared with women without endometriosis. Further, in the analyses restricted to women with a histologically verified diagnosis of endometriosis, the results were strengthened overall and showed that women with endometriosis had an increased risk of PPROM before 32 gestational weeks (aHR 3.49, 95% CI1.36-8.98)., Conclusions: Endometriosis was associated with both preterm and very preterm birth; however, apparently through different pathways. Women with endometriosis were more prone to have medically indicated preterm births before 37 gestational weeks and spontaneous preterm births before 32 gestational weeks compared with women without endometriosis., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objectives: The rare event of handling critically ill children often challenge the emergency care team. Several studies have investigated effects of simulation-based team training to prepare for such events, but the body of evidence remains to be compiled. We performed a systematic review of the effects of simulation-based team training on clinical performance and patient outcome., Methods: From a search of MEDLINE, Embase, CINAHL, and Cochrane Library, we included studies of team training in emergency pediatric settings with reported clinical performance and patient outcomes. We extracted data using a predefined template and assessed risk of bias using the Cochrane risk-of-bias tool for randomized trials 2.0 and the Newcastle Ottawa Quality Assessment Scale., Results: We screened 1926 abstracts and included 79 studies. We identified 15 studies reporting clinical health care professional performance or patient outcomes. Four studies reported survival data, 5 reported time-critical clinical events, 5 reported adherence to guidelines, checklists or tasks, and 2 reported on airway management. Randomized studies revealed improved team performance in simulated reevaluations 2 to 6 months after intervention. A meta-analysis was impossible because of heterogeneous interventions and outcomes. Most included studies had significant methodological limitations., Conclusions: Pediatric simulation-based team training improves clinical performance in time-critical tasks and adherence to guidelines. Improved survival was indicated but not concluded because of high risk of bias. Team performance and technical skills improved for at least 2 to 6 months. Future research should include longer-term measures of skill retention and patient outcomes or clinical measures of treatment quality whenever possible., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

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., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: To compare early neurocognitive development in children born with and without isolated CHD using the Bayley Scales of Infant and Toddler Development (3rd edition) and the Ages and Stages Questionnaire (3rd edition)., Methods: Recruitment took place before birth. Women expecting fetuses with and without CHD causing disturbances in the flow of oxygenated blood to the fetal brain were included in a prospective cohort study comprising fetal MRI (previously published) and neurodevelopmental follow-up. We now present the 18- and 36-month neurodevelopmental follow-up using the Bayley Scales according to age and the 6-month-above-age Ages and Stages Questionnaire in 15 children with and 27 children without CHD., Results: Children with CHD had, compared with the children without CHD, an increased risk of scoring ≤ 100 in the Bayley Scales cognition category at 18 and 36 -months; relative risk 1.7 (95% confidence interval (CI): 1.0-2.8) and 3.1 (CI: 1.2-7.5), respectively. They also achieved lower scores in the 6-month-above-age Ages and Stages Questionnaires (24 and 42 months) communication; mean z-score difference -0.72 (CI: -1.4; -0.1) and -1.06 (CI: -1.8; -0.3) and gross motor; mean z-score difference: -0.87 (CI: -1.7; -0.1) and -1.22 (CI: -2.4; -0.02) categories., Conclusions: The children with CHD achieved lower scores in the Bayley Scales cognition category and the Ages and Stages Questionnaire communication and gross motor categories possibly indicative of early neurodevelopmental deficiencies. We recommend early screening and monitoring for neurodevelopmental delays in children with CHD in order to improve further neurodevelopment and educational achievements.

Background: Little is known about the importance of non-technical skills for the adherence to guidelines, when teams of midwives, obstetricians, anesthesiologists, and pediatricians resuscitate and support the transition of newborns. Non-technical skills are competences underpinning successful teamwork in healthcare. These are usually referred to as leadership, situational awareness, communication, teamwork, decision making, and coping with stress and fatigue., Objective: By review of videos of teams managing newborns with difficult transition, we aimed to investigate whether the level of the teams' non-technical skills was associated with the degree of adherence to guidelines for newborn resuscitation and transitional support at birth., Methods: Four expert raters independently assessed 43 real-life videos of teams managing newborns with transitional difficulties, two assessed the non-technical score and two assessed the clinical performance. Exposure was the non-technical score, obtained by the Global Assessment Of Team Performance checklist (GAOTP). GAOTP was rated on a Likert Scale 1-5 ( 1 = poor, 3 = average and 5 = excellent). The outcome was the clinical performance score of the team assessed according to adherence of the European Resuscitation Counsel (ERC) guideline for neonatal resuscitation and transitional support. The ERC guideline was adapted into the checklist TeamOBS-Newborn to facilitate a structured and simple performance assessment (low score 0-60, average 60-84, high 85-100). Interrater agreement was analyzed by intraclass correlation (ICC), Bland-Altman analysis, and Cohen's kappa weighted. The risk of high and low clinical performance was analyzed on the logit scale to meet the assumptions of normality and constant standard deviation., Results: Teams with an excellent non-technical score had a relative risk 5.5 [95% confidence interval (CI) 2.4-22.5] of high clinical performance score compared to teams with average non-technical score. In addition, we found a dose response like association. The specific non-technical skills associated with the highest degree of adherence to guidelines were leadership and teamwork, coping with stress and fatigue, and communication with parents. Inter-rater agreement was high; raters assessing non-technical skills had an interclass coefficient (ICC) 0.88 (95% CI 0.79-0.94); the neonatologists assessing clinical performance had an ICC of 0.81 (95% CI 0.66-0.89)., Conclusion: Teams with an excellent non-technical score had five times the chance of high clinical performance compared to teams with average non-technical skills. High performance teams were characterized by good leadership and teamwork, coping with stress, and fatigue and communication with parents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brogaard, Hvidman, Esberg, Finer, Hjorth-Hansen, Manser, Kierkegaard, Uldbjerg and Henriksen.)

Objective: A theory has emerged, suggesting that abnormalities in the auditory system may be associated with sudden infant death syndrome (SIDS). However, current clinical evidence has never been systematically reviewed., Design: A systematic review was conducted according to the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analyses., Data Sources: PubMed, Embase and Web of Science were systematically searched through 7 September 2020., Eligibility Criteria for Selecting Studies: Only human studies with a reference group were included. Studies were eligible for inclusion if they examined infants exposed to otoacoustic emissions (OAEs), auditory brainstem response (ABR) or had autopsies with brainstem histology of the auditory system. SIDS was the primary outcome, while the secondary outcome was near-miss sudden infant death syndrome episodes., Data Extraction and Synthesis: Two independent reviewers extracted data and assessed risk of bias, and the quality of evidence. Due to high heterogeneity, a narrative synthesis was conducted. Risk of bias and quality of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation., Results: Twelve case-control studies were included. Seven studies on OAEs or ABR had a high degree of inconsistency. Contrarily, four out of five studies reporting on brainstem histology found that auditory brainstem abnormalities were more prevalent in SIDS cases than in controls. However, the quality of evidence across all studies was very low., Conclusion: This systematic review found no clear association between auditory system pathology and SIDS. The higher prevalence of histological abnormalities in the auditory system of SIDS may indicate an association. However, further studies of higher quality and larger study populations are needed to determine whether these findings are valid., Prospero Registration Number: CRD42020208045., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe the clinical characteristics of women admitted to a specialized unit for bereaved parents and to identify the characteristics of women who stayed more than 2 days., Design: A population-based descriptive study., Setting: A midwifery-led specialized unit for bereaved parents at Aarhus University Hospital, Denmark., Participants: Women with miscarriage (>14 weeks), missed abortion (>14 weeks), termination of pregnancy (>14 weeks), stillbirth, or death of their neonate during the first 48 hours after birth., Methods: We collected information from the electronic health care records for women admitted to the unit from January 2012 through December 2018, including parity, type of loss, gestational age, mode and duration of birth, pain relief, and duration of stay., Results: From January 1, 2012. to December 31, 2018, 579 women were admitted to the unit. Hospitalization varied from 1 day to 1 week. More women with a loss after 22 gestational weeks stayed for more than 2 days. In multivariate analyses, the hazard ratio (HR) of staying longer than 2 days was 1.3 times greater for primiparous women than for multiparous women (HR = 1.3, 95% confidence interval [1.0, 1.7]) and 2.4 times greater for women with near-term loss compared to women with perinatal loss before gestational week 22 (HR = 2.4, 95% confidence interval [1.7, 3.6])., Conclusion: Providing unlimited stay at a specialized unit for perinatal loss resulted in variation in length of stay. Primiparous women and women who lost neonates or fetuses closer to term gestation were more likely to stay in the unit for up to 8 days. This may indicate a need for individual support not available in standard care., Competing Interests: Conflict of Interest The authors report no conflicts of interest or relevant financial relationships., (Copyright © 2021 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)

Background: Two meta-analyses concluded that jaundice was associated with an increased risk of autism. We hypothesize that these findings were due to methodological limitations of the studies included. Neonatal jaundice affects many infants and risks of later morbidity may prompt physicians towards more aggressive treatment., Methods: To conduct a systematic literature review and a meta-analysis of the association between neonatal jaundice and autism with particular attention given to low risk of bias studies. Pubmed, Scopus, Embase, Cochrane, and Google Scholar were searched for publications until February 2019. Data was extracted by use of pre-piloted structured sheets. Low risk of bias studies were identified through predefined criteria., Results: A total of 32 studies met the inclusion criteria. The meta-analysis of six low risk of bias studies showed no association between neonatal jaundice and autism; cohort studies risk ratio 1.09, 95% CI, 0.99-1.20, case-control studies odds ratio 1.29 95% CI 0.95, 1.76. Funnel plot of all studies suggested a high risk of publication bias., Conclusions: We found a high risk of publication bias, selection bias, and potential confounding in all studies. Based on the low risk of bias studies there was no convincing evidence to support an association between neonatal jaundice and autism., Impact: Meta-analysis of data from six low risk of bias studies indicated no association between neonatal jaundice and autism spectrum disorder. Previous studies show inconsistent results, which may be explained by unadjusted confounding and selection bias. Funnel plot suggested high risk of publication bias when including all studies. There is no evidence to suggest jaundice should be treated more aggressively to prevent autism., (© 2020. International Pediatric Research Foundation, Inc.)

Study Question: Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy?, Summary Answer: Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood., What Is Known Already: Clomiphene citrate is among the most commonly prescribed drugs for fertility treatment. However, concerns have been raised as to whether the treatment may harm the developing fetus., Study Design, Size, Duration: This nationwide cohort study included all pregnancies in Denmark from 1 July 1995 resulting in a live-born singleton child before 31 December 2013. The children were followed until 31 December 2016., Participants/materials, Setting, Methods: Children conceived after fertility treatment with clomiphene citrate were identified from the Danish National Prescription Registry. The primary outcomes were childhood epilepsy, idiopathic generalized epilepsy, and focal epilepsy identified from the Danish National Patient Register and from antiepileptic drug prescriptions in the Danish National Prescription Registry. All analyses were conducted using Cox proportional hazards regression., Main Results and the Role of Chance: A total of 1 081 291 pregnancies were included; 12 644 children (1.2%) developed epilepsy. Fertility treatment with clomiphene citrate was associated with a small increased risk of childhood epilepsy (hazard ratio [HR]: 1.10; 95% CI: 1.00-1.22), idiopathic generalized epilepsy (HR: 1.41; 95% CI: 1.16-1.72), and focal epilepsy (HR: 1.26; 95% CI: 1.04-1.53)., Limitations, Reasons for Caution: The increased risk of idiopathic generalized epilepsy may be due to confounding from time stable parental characteristics related to treatment with clomiphene citrate, since the association was strongest with the lowest administered dosage of clomiphene citrate prior to conception, and the association disappeared in a sibling analysis., Wider Implications of the Findings: The increased risk of focal epilepsy may be related to the hormonal treatment, since the association tended to increase with increasing cumulative dosage of clomiphene citrate prior to conception, and the association persisted in a sibling analysis. This finding may be of clinical importance, since alternative hormones are available for fertility treatment., Study Funding/competing Interest(s): Financial support from Aarhus University and the Aase and Ejnar Danielsen Foundation. U.S.K. received personal teaching fees from Merck, outside the submitted work., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: For more than two decades several initiatives have emerged to increase recruitment of paediatric patients in drug trials. While trials of newly approved drugs have successfully included paediatric patients in their drug development plan, the collection of safety and efficacy data in paediatric patients treated with off-patent drugs poses a major challenge., Aim: This paper aims to draw attention to problems and solutions across countries in investigator-initiated trials with off-patent drugs and recommendations for improvement., Discussion: Off-patent drugs represent a particular challenge when they are included in a paediatric trial; these trials are frequently investigator-initiated and have limited resources, off-patent drugs are used in clinical settings and the trial protocol must accommodate e.g. flexible dosing and specimen sampling schedules, off-patent drugs typically exist in few formulations and concentrations which necessitates special or imported formulations. Paediatric trials are in some countries confined by e.g. consent from both parents, regardless of whether the Investigational Medicinal Product (IMP) is a well-known drug or a new experimental drug., Conclusion: Facilitation of research in off-patent drugs can improve evidence-based and safe treatment for the paediatric population. The following supportive initiatives are recommended: Harmonised regulatory change that improves the consent process in low risk trials to prevent inadequate recruitment. Pharmaceutical expertise should be prioritized to secure the best choice of IMP and supply. Constant focus on flexibility in design to accommodate a multifaceted paediatric population and ensure that trial protocols fit in well with routine clinical care and family life., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Context: Several neonatal simulation-training programs have been deployed during the last decade, and in a growing number of studies, researchers have investigated the effects of simulation-based team training. This body of evidence remains to be compiled., Objective: We performed a systematic review of the effects of simulation-based team training on clinical performance and patient outcome., Data Sources: Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library., Study Selection: Two authors included studies of team training in critical neonatal situations with reported outcomes on clinical performance and patient outcome., Data Extraction: Two authors extracted data using a predefined template and assessed risk of bias using the Cochrane risk-of-bias tool 2.0 and the Newcastle-Ottawa quality assessment scale., Results: We screened 1434 titles and abstracts, evaluated 173 full texts for eligibility, and included 24 studies. We identified only 2 studies with neonatal mortality outcomes, and no conclusion could be reached regarding the effects of simulation training in developed countries. Considering clinical performance, randomized studies revealed improved team performance in simulated re-evaluations 3 to 6 months after the intervention., Limitations: Meta-analysis was impossible because of heterogenous interventions and outcomes. Kirkpatrick's model for evaluating training programs provided the framework for a narrative synthesis. Most included studies had significant methodologic limitations., Conclusions: Simulation-based team training in neonatal resuscitation improves team performance and technical performance in simulation-based evaluations 3 to 6 months later. The current evidence was insufficient to conclude on neonatal mortality after simulation-based team training because no studies were available from developed countries. In future work, researchers should include patient outcomes or clinical proxies of treatment quality whenever possible., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Aim: Our aim was to explore the under-researched associations between an elective Caesarean section (C-section) at early-term or full-term gestation and behaviour at 6-8 years of age., Methods: We identified 1220 eligible children born by elective C-sections at Danish hospital from 2009 to 2011. Their mothers were randomised to elective C-sections at either 38+3 (early-term) or 39+3 (full-term) weeks of gestation. From December 2017 to August 2018, the parents completed the Strengths and Difficulties Questionnaire. The results were adjusted for maternal education, parity and the child's sex., Results: Of the 574 (45%) children followed up, 288 were delivered early-term and 286 were delivered full-term. The groups had similar baseline characteristics. There were no differences in the total difficulties score, subscale scores or the risk of being classified as having a possible or probable psychiatric disorder. Early-term boys had a lower risk of being classified as having a possible or probable psychiatric disorder and early-term girls had higher risk, but the results were not statistically significant., Conclusion: We found no difference in behaviour at 6-8 years of age between children born by elective C-section at early- versus full-term gestation., (©2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: This systematic review and meta-analysis summarizes the evidence for the association between endometriosis and adverse pregnancy outcome, including gestational hypertension, pre-eclampsia, low birth weight, and small for gestational age, preterm birth, placenta previa, placental abruption, cesarean section, stillbirth, postpartum hemorrhage, spontaneous hemoperitoneum in pregnancy, and spontaneous bowel perforation in pregnancy., Methods: We performed the literature review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), by searches in PubMed and EMBASE, until 1 November 2020 (PROSPERO ID CRD42020213999). We included peer-reviewed observational cohort studies and case-control studies and scored them according to the Newcastle-Ottawa Scale, to assess the risk of bias and confounding., Results: 39 studies were included. Women with endometriosis had an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth, compared to women without endometriosis. These results remained unchanged in sub-analyses, including studies on spontaneous pregnancies only. Spontaneous hemoperitoneum in pregnancy and bowel perforation seemed to be associated with endometriosis; however, the studies were few and did not meet the inclusion criteria., Conclusions: The literature shows that endometriosis is associated with an increased risk of gestational hypertension, pre-eclampsia, preterm birth, placenta previa, placental abruption, cesarean section, and stillbirth.

Objectives: To estimate the association between major types of congenital heart defects (CHD) and spontaneous preterm birth, and to assess the potential underlying mechanisms., Study Design: This nationwide, registry-based study included a cohort of all singleton pregnancies in Denmark from 1997 to 2013. The association between CHD and spontaneous preterm birth was estimated by multivariable Cox regression, adjusted for potential confounders. The following potential mechanisms were examined: maternal genetics (sibling analyses), polyhydramnios, preterm prelabor rupture of membranes, preeclampsia, and indicators of fetal and placental growth., Results: The study included 1 040 474 births. Compared with the general population, CHD was associated with an increased risk of spontaneous preterm birth, adjusted hazard ratio 2.1 (95% CI, 1.9-2.4). Several subtypes were associated with increased risks, including pulmonary stenosis combined with a septal defect, 5.2 (95% CI, 3.7-7.5); pulmonary stenosis or atresia, 3.1 (95% CI, 2.4-4.1); tetralogy of Fallot 2.5 (95% CI, 1.6-3.8); coarctation or interrupted aortic arch 2.2 (95% CI, 1.5-3.2); and hypoplastic left heart syndrome, 2.0 (95% CI, 1.0-4.1). Overall, preterm prelabor rupture of membranes mediated more than one-half of the association. Maternal genetics, polyhydramnios, or indicators of fetal or placental growth did not explain the reported associations., Conclusions: CHD, especially right ventricular outflow tract obstructions, were associated with an increased risk of spontaneous preterm birth. The risk was carried by the CHD and not by maternal genetics. Moreover, preterm prelabor rupture of membranes was identified as a potential underlying mechanism., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We aimed to assess remote ischemic postconditioning (RIPC) as a neuroprotective strategy after perinatal hypoxia-ischemia (HI) in a piglet model., Methods: Fifty-four newborn piglets were subjected to global HI for 45 min. One hour after HI, piglets were randomized to four cycles of 5 min of RIPC or supportive treatment only. The primary outcome was brain lactate/N-acetylaspartate (Lac/NAA) ratios measured by magnetic resonance spectroscopy at 72 h. Secondary outcomes included diffusion-weighted imaging and neuropathology., Results: RIPC was associated with a reduction in overall and basal ganglia Lac/NAA ratios at 72 h after HI, but no effect on diffusion-weighted imaging, neuropathology scores, neurological recovery, or mortality., Conclusions: The selective effect of RIPC on Lac/NAA ratios may suggest that the metabolic effect is greater than the structural and functional improvement at 72 h after HI. Further studies are needed to address whether there is an add-on effect of RIPC to hypothermia, together with the optimal timing, number of cycles, and duration of RIPC., Impact: RIPC after HI was associated with a reduction in overall and basal ganglia Lac/NAA ratios at 72 h, but had no effect on diffusion-weighted imaging, neuropathology scores, neurological recovery, or mortality. RIPC may have a selective metabolic effect, ameliorating lactate accumulation without improving other short-term outcomes assessed at 72 h after HI. We applied four cycles of 5 min RIPC, complementing existing data on other durations of RIPC. This study adds to the limited data on RIPC after perinatal HI and highlights that knowledge gaps, including timing and duration of RIPC, must be addressed together with exploring the combined effects with hypothermia.

Children born preterm have an increased risk of severe morbidity, e.g. cerebral palsy (CP), compared to children born at term. CP cannot be treated, which is why a prophylactic approach is essential, as argued in this review. Six randomised controlled trials (RCTs) have provided data on MgSO4 treatment as CP neuroprotection in preterm birth, including a new RCT from Denmark. Recently, an updated meta-analysis with trial sequential analysis detected a significant neuroprotective effect of MgSO4 treatment in preterm birth. There is now sufficient evidence, that MgSO4 treatment should be used as neuroprotection in preterm birth.

Only 30% of medication used for children and adolescents and 10% of the medication used for neonates has been evaluated for use in these populations. Infants and children differ from adults regarding pharmacodynamic and -kinetics, but they also differ from each other due to e.g. age, weight, and body composition, as we argue in this review. There is only limited knowledge within this area leading to the use of off-label, extemporaneous and unlicensed medication. Greater national vigilance in medication for children and adolescent is warranted to secure better and safer medicine for newborns, infants, children and adolescents.

Background: Non-participation in aetiologic studies of pubertal timing is frequent. However, little effort has been given to explore the risk and potential impact of selection bias in studies of pubertal timing., Objective: We aimed to explore the risk of selection bias due to non-participation in a newly established puberty cohort., Methods: We evaluated whether three maternal exposures chosen a priori (pre-pregnancy obesity, smoking, and alcohol drinking during pregnancy) were associated with participation, whether pubertal timing was associated with participation, and whether selection bias influenced the associations between these exposures and pubertal timing. In total, 22 439 children from the Danish National Birth Cohort born 2000-2003 were invited to the Puberty Cohort and 15 819 (70%) participated. Exposures were self-reported during pregnancy. Pubertal timing was measured using a previously validated marker, "the height difference in standard deviations" (HD:SDS), which is the difference between pubertal height and adult height, both in standard deviations. For this study, pubertal height at around 13 years in sons and around 11 years in daughters was obtained from an external database, and adult height was predicted based on parental height reported by mothers., Results: Participation was associated with most exposures but not with pubertal timing, measured by HD:SDS. The associations between exposures and HD:SDS were comparable for participants only and all invited for participation., Conclusion: In conclusion, the risk of selection bias in aetiologic studies on pubertal timing in the Puberty Cohort appears minimal., (© 2020 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Objective: To describe the various combinations of medication used in Denmark in the latent phase of labor (i.e. for therapeutic rest) and to estimate the frequency of use., Methods: An informal e-mail survey based on personal information from Danish midwives or staff obstetricians. The main outcome measures were type and dosage of medications used individually or in combination ("cocktail") for therapeutic rest in Danish delivery wards during the latent phase of labor and also the frequency of their use., Results: All twenty-one delivery wards in Denmark participated in the survey. The types and dosages of medication varied substantially. Two delivery wards used prescriptions on morphine with no other medication for therapeutic rest. The remaining 19/21 delivery wards (90%) used a standard "cocktail" with two to four different types of medications; 19/21 wards (90%) used a mild analgesic (paracetamol), 17/21 (81%) used anxiolytics/hypnotics, and 14/21 (64%) wards used a strong analgesic (opioid) in their basic cocktail. Ten delivery wards (48%) combined an opioid, a sedative, and paracetamol in their basic cocktail. Between 7% and 21% of all pregnant women were given a cocktail., Conclusion: In a small country, we found considerable national variation in the medication or combinations of medication used in the latent phase of labor, and polypharmacy was standard in the majority of the delivery wards., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The evaluation of the patent ductus arteriosus (PDA) in the very premature neonate is a challenge. Echocardiography provides an interpretation of the hemodynamic condition. It is however, only a snapshot. Biomarkers may represent a physiological response to the hemodynamic alterations brought on by the PDA and may add to the identification of the clinical significant PDA., Aim: To investigate the association between mid regional proadrenomodulin (MR-proADM), N-terminal pro b-type natriuretic peptide (NT-proBNP), mid regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro endothelin-1 (CT-proET1) and copeptin and echocardiographic measures of PDA., Study Design: Cohort study with echocardiography performed on day 3 and 6. Blood samples from day 3., Subject: 139 consecutive neonates born at a gestational age <32 weeks., Outcome Measures: The main outcomes were presence of a PDA day 3 and 6, PDA diameter, left atrium to aorta ratio (LA:Ao-ratio), and descending aorta diastolic flow (DADF)., Results: Adjusted plasma levels of all investigated biomarkers, except CT-proET1, were found to be associated with both PDA diameter and LA:Ao-ratio, and also the presence of a large PDA. CT-proET1 and copeptin was found to be associated with abnormal DADF. Using pre-specified cut-off values NT-proBNP and MR-proANP day 3 seemed to be of value in identifying a large PDA day 3 and 6 in very preterm neonates., Conclusion: Among the investigated biomarkers NT-proBNP and MR-proANP performed best in relation to echocardiographic markers of PDA severity in very preterm neonates., Competing Interests: Declaration of competing interest The authors of this manuscript have none., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Ordinary meta-analyses indicate that magnesium sulphate (MgSO 4 ) treatment in women at imminent risk for preterm delivery decreases the offspring's risk of cerebral palsy (CP). However, repetitive testing of cumulative data calls for statistical caution, e.g. by trial sequential analysis (TSA), for which there are previously insufficient samples to draw a firm conclusion. Recently, a randomised controlled trial (RCT) provided additional data that potentially increased the sample size such that a new TSA might detect a statistically significant effect., Objectives: To assess the possible fetal neuroprotective effect of MgSO 4 for women at imminent risk for preterm delivery in an updated systematic review with meta-analysis and TSA., Search Strategy: We searched MEDLINE, Embase, Cochrane and ClinicalTrials.gov on 8 October 2019. The search strategy clustered terms describing the MgSO 4 intervention and preterm delivery., Selection Criteria: RCTs., Data Collection and Analysis: Two reviewers extracted the data. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed-effects models. A TSA was applied to the primary outcome, CP. The quality of the evidence was assessed using GRADE. The protocol was registered in PROSPERO (registration: CRD42019151441)., Main Results: We identified six eligible trials (5917 women). MgSO 4 intervention in women at imminent risk for preterm birth decreased the offspring's CP risk (meta-analysis RR 0.68, 95% CI 0.54-0.85; TSA RR 0.69, 95% CI 0.48-0.97)., Conclusions: This systematic review with meta-analysis and TSA shows conclusively that MgSO 4 , when given to women at imminent risk for preterm delivery, decreases the offspring's CP risk., Tweetable Abstract: Antenatal magnesium sulphate decreases the risk of cerebral palsy in children born preterm., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Objective: To study the effect of antenatal magnesium sulphate (MgSO 4 ) on cerebral palsy (CP) in a manner that also provides adequate power for a linked trial sequential analysis., Design: Double-blind, randomised, placebo-controlled, multi-centre trial., Setting: Fourteen Danish obstetric departments., Population: In total, 560 pregnant women at risk for preterm delivery before 32 weeks of gestation were randomised from December 2011 to January 2018. Those women gave birth to 680 children., Methods: Women were randomised to receive either a loading dose of 5 g MgSO 4 followed by 1 g/hour or a placebo in identical volumes. The children were followed up at a corrected age of 18 months or older with a review of their medical charts and with the Ages and Stages Questionnaire., Main Outcome Measure: The primary outcome measure was moderate to severe CP. Secondary outcomes included mortality, neonatal morbidity, blindness and mild CP., Results: The crude rates of moderate to severe CP in the MgSO 4 group and the placebo group were 2.0% and 3.3%, respectively. The adjusted odds of moderate to severe CP were lower in the MgSO 4 group than in the placebo group (odds ratio 0.61; 95% CI 0.23-1.65)., Conclusions: Antenatal MgSO 4 before 32 weeks of gestation decreases the likelihood of moderate to severe CP; these results are entirely consistent with other randomised evidence summarised in the linked trial sequential analysis., Tweetable Abstract: Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Objectives: To estimate a possible association between coffee intake during pregnancy and risk of childhood acute leukemia by using a cohort design., Methods: We included data from two birth cohorts; the Danish National Birth Cohort and the Aarhus Birth Cohort. Recruitment of 141,216 eligible pregnancies occurred from 1 August 1989 to 31 December 2012. Information on maternal prenatal coffee intake and covariates was collected in early second trimester of pregnancy. Information on childhood AL diagnosed in offspring was obtained from the Danish National Patient Register. We used competing risk time-to-event regression analysis, using the pseudo-observation method to estimate risk ratio (RR) with no coffee intake during pregnancy considered the reference group., Results: In total 96 children were diagnosed with AL, hereof 73 with acute lymphoblastic leukemia (ALL). Coffee intake of 0.5-3 cups/day during pregnancy was not associated with a higher risk of childhood AL; aRR = 0.89, 95 % confidence interval (CI): 0.48, 1.65, however, an intake of >3 cups/day resulted in aRR = 1.37, 95 % CI: 0.56, 3.32. Only including ALL as outcome we found similar results; aRR = 0.80, 95 % CI: 0.37-1.74 and aRR = 1.46 95 % CI: 0.52-4.09, respectively., Conclusion: We found no significant association between maternal coffee intake and risk of childhood AL but the number of cases was limited. The confidence limits does not exclude that a high prenatal coffee intake may increase the risk of childhood AL and larger studies based on prospective data are needed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Hypoxic ischemic encephalopathy (HIE) is a major cause of death and disability in children worldwide. Apart from supportive care, the only established treatment for HIE is therapeutic hypothermia (TH). As TH is only partly neuroprotective, there is a need for additional therapies. Intermittent periods of limb ischemia, called remote ischemic postconditioning (RIPC), have been shown to be neuroprotective after HIE in rats and piglets. However, it is unknown whether RIPC adds to the effect of TH. We tested the neuroprotective effect of RIPC with TH compared to TH alone using magnetic resonance imaging and spectroscopy (MRI/MRS) in a piglet HIE model. Methods: Thirty-two male and female piglets were subjected to 45-min global hypoxia-ischemia (HI). Twenty-six animals were randomized to TH or RIPC plus TH; six animals received supportive care only. TH was induced through whole-body cooling. RIPC was induced 1 h after HI by four cycles of 5 min of ischemia and 5 min of reperfusion in both hind limbs. Primary outcome was Lac/NAA ratio at 24 h measured by MRS. Secondary outcomes were NAA/Cr, diffusion-weighted imaging (DWI), arterial spin labeling, aEGG score, and blood oxygen dependent (BOLD) signal measured by MRI/MRS at 6, 12, and 24 h after the hypoxic-ischemic insult. Results: All groups were subjected to a comparable but mild insult. No difference was found between the two intervention groups in Lac/NAA ratio, NAA/Cr ratio, DWI, arterial spin labeling, or BOLD signal. NAA/Cr ratio at 24 h was higher in the two intervention groups compared to supportive care only. There was no difference in aEEG score between the three groups. Conclusion: Treatment with RIPC resulted in no additional neuroprotection when combined with TH. However, insult severity was mild and only evaluated at 24 h after HI with a short MRS echo time. In future studies more subtle neurological effects may be detected with increased MRS echo time and post mortem investigations, such as brain histology. Thus, the possible neuroprotective effect of RIPC needs further evaluation., (Copyright © 2020 Andelius, Pedersen, Andersen, Andersen, Hjortdal, Pedersen, Ringgaard, Hansen, Henriksen and Kyng.)

Background: Early puberty is a risk indicator for adult diseases. Identification of modifiable causes of earlier puberty is, therefore, warranted. We estimate the association between childhood body mass index (BMI) and pubertal timing in a cohort study and in a sibling-matched study to adjust for unobserved time-stable confounders shared within families., Methods: For the cohort study, 11 046 of 22 439 (49%) invited children, born 2000-203, from the Danish National Birth Cohort (DNBC) had information on childhood BMI at 7 years and self-reported, half-yearly puberty information from 11 years on Tanner stages, menarche, voice break, first ejaculation, acne, and axillary hair. For the sibling-matched study, 1700 brothers and sisters were included among 86 820 live-born singletons from the DNBC., Results: Childhood overweight (85th ≤ BMI < 95th percentile) and obesity (BMI ≥ 95th percentile) were associated with earlier age attaining the pubertal milestones in a dose-dependent manner in boys and girls. When modelling all pubertal milestones simultaneously, the pubertal milestones were attained earlier in: overweight boys: -3.1 [95% confidence interval (CI): -4.5, -1.7] months, overweight girls: -5.5 (95% CI: -7.1, -3.9) months, obese boys: -3.5 (95% CI: -5.1, -2.0) months, obese girls: -5.2 (95% CI: -7.1, -3.4) months compared with normal weight (BMI  < 85th percentile) children. In the sibling-matched study, higher BMI was associated with earlier age at attaining most pubertal milestones in girls, but only a tendency toward earlier pubertal timing was observed in boys., Conclusions: Childhood overweight and obesity were associated with earlier pubertal timing even after adjustment for unobserved time-stable confounders shared within families., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Early measures of cognitive function are of great public health interest. We aimed to estimate the association between head circumference at birth, a measure of cerebral size, and school performance., Methods: We conducted a nationwide cohort study of all liveborn singletons in Denmark, 1997-2005. The association between birth head circumference z score and test scores in reading and mathematics from a nationwide mandatory computer-based school test program (7-16 years) was estimated by multivariable linear regression adjusted for potential confounders., Results: The cohort included 536,921 children. Compared to normocephalic children, children with microcephaly [<-2 standard deviations (SD)] had lower mean reading scores: second grade: -0.08 SD (95% CI -0.10 to -0.06), eighth grade: -0.07 SD (95% CI -0.10 to -0.04). Macrocephaly (>+2 SD) was associated with higher scores. In normocephalic children, each SD increase in head circumference was associated with a 0.03 SD (95% CI 0.03 to 0.04) increase in mean reading scores. The results were similar across grades within both reading and mathematics., Conclusion: Prenatal brain growth may be causally related to childhood school performance. The demonstrated differences are unlikely to be clinically relevant at the individual level but may be important at a public health level.

Hypoxic-ischaemic encephalopathy is a common cause of death and disability in newborns. Brain damage related to a perinatal insult is the result of a dynamic process, and its progressing development over time allows for specific interventions to reduce total damage, as described in this review. Despite therapeutic hypothermia which currently is the only treatment available, a considerable number of newborns still have adverse outcomes. Prognosis is evaluated by clinical examination and paraclinical investigations. There is still a need for novel treatments and better prognostic and diagnostic tools to improve outcome.

This review gives a summary of Danish preterm care, which has been defined by national adaptation of antenatal corticosteroids in the 1970ies and continuous positive airway pressure in the 1980ies. Today, preterm survival in Denmark is high, by international standards, but lower than in the neighbouring countries Sweden and Norway. The lack of a national neonatal quality database may offer an explanation to this. Starting in 2019, the Danish Newborn Quality Database reports complete population-based measures of newborn survival and health and may help improve standards of care in the future.

In 2018, The Danish Society of Obstetrics and Gynecology and the Danish Paediatric Society agreed on a national consensus guideline on the treatment of imminent preterm delivery prior to 25 weeks. This review summarises the recommendations: at 22 weeks transfer to a tertiary hospital, at 23 weeks tocolysis, antenatal steroid and newborn resuscitation with parental consent, if the infant is viable, and at 24 weeks caesarean section due to foetal distress. Newborn resuscitation is standard of care, unless not indicated for other reasons at 24 weeks.

Aims: This study aimed to examine the feasibility of a web-based questionnaire when collecting information on alcohol consumption in pregnancy to identify women with risk drinking behaviour, and to describe factors associated with risk drinking behaviour, and the use of specialized care for prenatal risk drinking., Methods: In 2413 women referred to antenatal care at Odense University Hospital, Denmark, April-October 2018, self-reported alcohol intake was retrieved from a web-based questionnaire. Replies were screened for risk drinking behaviour: current intake of ≥7 drinks/week, ≥3 binge drinking episodes (intake of ≥5 drinks on a single occasion) in pregnancy, binge drinking after recognition of pregnancy and/or a TWEAK-score ≥ 2 points. Women with risk drinking behaviour were called to clarify the need for specialized care. A summary of the interview was obtained from the medical records., Results: Overall, 2168 (90%) completed the questionnaire. Of 2097 women providing information on alcohol intake, 77 (4%) had risk drinking behaviour. Risk drinking was associated with higher alcohol intake prior to pregnancy, spontaneous conception, younger age, nulliparity and higher level of physical activity in pregnancy. Amongst 47 women with risk drinking behaviour reached by phone, five (11%, 95% CI 4-23%) accepted examinations of the child by paediatrician and child psychologist, and <3 (not further specified due to small numbers) were referred to specialized antenatal care., Conclusions: A web-based questionnaire was feasible when collecting information on alcohol consumption in pregnancy to identify risk drinking behaviour. Women with risk drinking behaviour had a low acceptance of referral to specialized care., (© The Author(s) 2020. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Limited research has addressed whether maternal alcohol intake in early pregnancy increases the risk of spontaneous preterm birth. In the current study, we examined how alcohol binge drinking and weekly alcohol intake in early pregnancy were associated with spontaneous preterm birth in a contemporary cohort of Danish women., Methods: We included 15,776 pregnancies of 14,894 women referred to antenatal care at Copenhagen University Hospital, Denmark, between 2012 and 2016. Self-reported alcohol intake in early pregnancy was obtained from a Web-based questionnaire completed prior to the women's first visit at the department. Information on spontaneous preterm birth was extracted from the Danish Medical Birth Register. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of spontaneous preterm birth according to self-reported alcohol binge drinking and weekly intake of alcohol in early pregnancy were derived from Cox regression., Results: Women reporting 1, 2, and ≥ 3 binge drinking episodes had an aHR for spontaneous preterm birth of 0.88 (95% CI 0.68 to 1.14), 1.34 (95% CI 0.98 to 1.82), and 0.93 (95% CI 0.62 to 1.41), respectively, compared to women with no binge drinking episodes. Women who reported an intake of ≥ 1 drink per week on average had an aHR for spontaneous preterm birth of 1.09 (95% CI 0.63 to 1.89) compared to abstainers. When restricting to nulliparous women or cohabiting women with ≥ 3 years of higher education, this estimate was 1.28 (95% CI 0.69 to 2.40) and 1.20 (95% CI 0.67 to 2.15), respectively., Conclusion: We found no evidence that maternal alcohol intake in early pregnancy was associated with a higher risk of spontaneous preterm birth, neither for alcohol binge drinking nor for a low average weekly intake of alcohol., (© 2019 by the Research Society on Alcoholism.)

Background: Intellectual disability (ID) is a prevalent chronic disability affecting up to 1-3% of the general population. Small head circumference at birth, a surrogate measure of foetal cerebral growth, may be a risk factor for ID. We aimed to investigate the association between the full distribution of head circumference at birth and ID., Methods: This cohort study was based on Danish nationwide registries and included all Danish singletons born alive from 1997 to 2013. Follow-up ended at October 2015. The data was analysed using a Cox proportional hazards regression model adjusted for a large number of potential confounders., Results: The cohort comprised 986,909 infants. Neither microcephaly nor macrocephaly at birth was consistently associated with the risk of ID. Within the normal range of head circumference, larger head circumference was associated with a decreased risk of ID (HR per standard deviation increase in head circumference z score 0.85, 95% CI 0.81-0.88). The association detected within the normal range was consistent in all sensitivity analyses., Conclusions: Intrauterine brain growth restriction may be a risk factor for ID.

Background: The training required for accurate assessment of umbilical catheter placement by ultrasonography (US) is unknown., Objective: To describe the learning curve and provide an estimate of the accuracy of physicians' US examinations (US skills) and self-confidence when examining umbilical catheter tip placement., Methods: Twenty-one physicians with minimal experience in US completed a 1.5-hour eLearning module. Ten piglets with catheters inserted in the umbilical vessels were used as training objects. Following eLearning each physician performed up to twelve 10-min US examinations of the piglets. Expert examinations were reference standards. Sensitivity and specificity of physicians' skills in detecting catheter tip placement by US was used to describe the learning curve. Self-confidence was reported by Likert scale after each examination., Results: Physicians' detection of a correctly placed and misplaced umbilical artery catheter tip increased by an odds ratio of 1.6 (95% CI: 1.1, 2.3) and 3.6 (95% CI: 1.7, 7.8) per examination performed. A sensitivity of 0.97 (95% CI: 0.80, 0.99) and specificity of 0.95 (95% CI: 0.84, 0.99) was reached after 6 examinations. For the venous catheter, US skills in detecting a misplaced catheter tip increased with an odds ratio of 2.4 (95% CI: 1.2, 4.8) per US examination. Overall, performance and self-confidence plateaus were reached after 6 examinations., Conclusion: We found steep learning curves for targeted US examination of umbilical catheter placement. eLearning followed by 6 examinations was found to be adequate training to perform with a sufficiently high accuracy and self-confidence to allow for point-of-care use., (© 2019 S. Karger AG, Basel.)

Background: Little is known about maternal alcohol intake in early pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in children beyond 5 years of age. We examined the association between alcohol binge drinking and weekly alcohol intake in early pregnancy and the risk of ADHD in children followed from birth to 19 years of age., Methods: We included 48,072 children born between 1998 and 2012, whose mothers participated in the Aarhus Birth Cohort. Maternal alcohol intake was obtained from a self-administered questionnaire completed in early pregnancy. ADHD diagnoses were retrieved from the Danish Psychiatric Central Research Register and the Danish National Patient Register. Crude hazard ratio and adjusted hazard ratio (aHR) of ADHD according to alcohol binge drinking or weekly intake of alcohol were calculated using the Cox regression., Results: Compared to children of women with no binge drinking episodes, we observed an aHR for ADHD of 0.91 (95% CI 0.76 to 1.08), 0.73 (95% CI 0.56 to 0.96), and 0.77 (95% CI 0.57 to 1.06) among children of women reporting 1, 2, and 3 or more binge drinking episodes, respectively. Among children of women drinking <1 drink per week, 1 drink per week, 2 drinks per week, and 3 or more drinks per week, we observed an aHR for ADHD of 0.87 (95% CI 0.74 to 1.03), 0.63 (95% CI 0.40 to 0.98), 1.30 (95% CI 0.89 to 1.92), and 0.78 (95% CI 0.38 to 1.59), respectively, when compared to children of women not drinking on a weekly basis., Conclusion: We found no evidence that binge drinking or low alcohol intake in early pregnancy was associated with the risk of ADHD in children., (© 2019 by the Research Society on Alcoholism.)

We explored whether maternal alcohol intake in early pregnancy is associated with pubertal timing in sons and daughters. In total, 15,819 children, born 2000-2003 within the Danish National Birth Cohort, gave half-yearly, self-reported information on pubertal development (Tanner stages, voice break, first ejaculation, menarche, acne, and axillary hair) from 11 years during 2012-2018. Information on maternal average alcohol intake in first trimester and binge drinking episodes (intake of ≥5 drinks on the same occasion) in first trimester was self-reported by mothers during pregnancy. Average alcohol intake of 5+ weekly drinks in first trimester was not associated with pubertal timing in sons (with no alcohol intake as the reference). A tendency towards earlier pubertal timing was observed in daughters (-2.0 (95 % confidence interval: -4.2, 0.3) months) when combining the estimates for all pubertal milestones. Binge drinking was not associated with pubertal timing in neither sons nor daughters., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The purpose was to examine the association between exercise during pregnancy and intelligence score in offspring. We analyzed data from 4008 women from the Aarhus Birth Cohort, Aarhus University Hospital, Denmark, recruited during pregnancy from July 1989 to November 1991 and their sons who were registered at conscription at 17-20 years of age. The women gave information by self-administered questionnaires during the first trimester including leisure-time physical activity and weekly hours of sport. This information was linked to the sons' measures of intelligence by Børge Priens test scores from the Danish Conscription Registry. Only sons were included since very few women register at conscription in Denmark. The main outcome measure was the Børge Priens test score as a continuous variable and with a low score defined as <10% of the population score. Analyses were adjusted for maternal body mass index, years in school, and smoking. Sons of women with light and moderate to heavy leisure-time physical activity had lower risk of having a low intelligence score compared with sons of women with sedentary activity: adjusted odds ratio (aOR) 0.66 (95% CI 0.49;0.88) and 0.46 (95% CI 0.23;0.93), respectively. Furthermore, sons of women engaged in sports had lower risk of a low intelligence score: aOR 0.50 (95% CI 0.30; 0.83) for 1-2 h/wk and 0.62 (95% CI 0.35; 1.10) for ≥3 h/wk compared with no weekly sports activity. In conclusion, a higher level of physical activity during pregnancy was associated with a lower risk of low intelligence score in early adulthood in sons., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)