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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

Camilla Lomholt Kjersgaard,1 Linn Håkonsen Arendt,1,2 Andreas Ernst,1,3 Morten Søndergaard Lindhard,4,5 Jørn Olsen,1,6 Tine Brink Henriksen,5 Katrine Strandberg-Larsen,7 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Obstetrics and Gynecology, Horsens Regional Hospital, Horsens, Denmark; 3Department of Urology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Pediatrics, Randers Regional Hospital, Randers, Denmark; 5Perinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark; 6Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 7Department of Public Health, Section of Epidemiology, Copenhagen University, Copenhagen, DenmarkCorrespondence: Camilla Lomholt KjersgaardDepartment of Public Health, Research Unit for Epidemiology, Aarhus University, Bartholins Allé 2, Aarhus, 8000, DenmarkTel +45 40 19 44 38Email ck@ph.au.dkPurpose: Hypospadias is one of the most frequent male congenital malformations. It remains controversial whether maternal lifestyle during pregnancy may affects the risk of having a son with hypospadias, especially for smoking with many suggesting lower risk. We assessed the individual and joint associations between maternal cigarette smoking, pre-pregnancy body mass index (BMI), alcohol consumption, binge drinking, and caffeine consumption and occurrence of hypospadias in sons.Patients and Methods: This cohort study utilized the Danish National Birth Cohort and the Aarhus Birth Cohort, holding detailed information on lifestyle factors in early pregnancy between 1989 and 2012. The Danish health registers were used to identify boys with hypospadias, according to International Classification of Diseases. Potential confounders and covariates were identified by literature search and use of directed acyclic graphs. Missing data were handled by multiple imputation and Cox proportional hazards models were applied to analyse data.Results: In total, 85,923 live-born singleton boys were included in the study of whom 502 (0.6%) were diagnosed with hypospadias. Maternal smoking in early pregnancy was associated with lower occurrence of hypospadias. An increase of one cigarette smoked per day was associated with lower risk of having a son with hypospadias (adjusted hazard ratio (HR) 0.97 (95% confidence interval (CI) 0.94, 1.00)). However, sub-analyses suggested that the results may be prone to unadjusted confounding. We found no association between pre-pregnancy BMI, alcohol consumption, binge drinking, or caffeine consumption and hypospadias.Conclusion: Maternal smoking during pregnancy was associated with lower occurrence of hypospadias but we cannot exclude uncontrolled confounding. The other investigated maternal lifestyle factors were not associated with hypospadias in sons.Keywords: smoking, prenatal exposures, alcohol, caffeine, BMI, birth defects

Anne Gaml-Sørensen,1 Nis Brix,1,2 Gunnar Toft,3,4 Tine Brink Henriksen,5 Andreas Ernst,1,6 Linn Håkonsen Arendt,1,7 Sandra Søgaard Tøttenborg,8 Katia Keglberg Hærvig,8,9 Karin Sørig Hougaard,9,10 Jens Peter Ellekilde Bonde,8,9 Cecilia Høst Ramlau-Hansen1 1Department of Public Health, Research Unit for Epidemiology, Bartholins Allé 2, Aarhus University, Aarhus C, 8000, Denmark; 2Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, 8200, Denmark; 3Department of Clinical Epidemiology, Aarhus University, Aarhus N, 8200, Denmark; 4Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, 8200, Denmark; 5Perinatal Epidemiology Research Unit, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus N, 8200, Denmark; 6Department of Urology, Aarhus University Hospital, Aarhus N, 8200, Denmark; 7Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus N, 8200, Denmark; 8Department of Occupational and Environmental Medicine, Bispebjerg and Frederiksberg Hospital, Copenhagen NV, 2400, Denmark; 9Department of Public Health, University of Copenhagen, København K, 1014, Denmark; 10National Research Centre for the Working Environment, Copenhagen East, 2100, DenmarkCorrespondence: Anne Gaml-SørensenDepartment of Public Health, Research Unit for Epidemiology, Bartholins Allé 2, Aarhus University, Aarhus C, 8000, Denmark, Tel +45 40868183Email ags@ph.au.dkPurpose: Parental separation may be a stressful life event with the potential to influence hormonal regulation of offspring reproductive health and thereby affect semen quality in young men. We aimed to study the association between parental separation in pregnancy or in childhood and semen quality in young men and to study whether the timing of parental separation in childhood was important.Patients and Methods: We conducted a follow-up study of 1058 young men born 1998– 2000 from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort. Data on parental separation were obtained longitudinal by self-report. Parental separation in pregnancy was dichotomized, and parental separation in childhood was both dichotomized and categorized according to the timing of parental separation (from birth, from early childhood (0– 5 years), and from late childhood (6– 10 years)). Semen volume, concentration, total sperm count, motility, morphology, and testes volume were analysed using multivariable negative binomial regression models.Results: Parental separation in pregnancy was not associated with semen quality. The association between parental separation in childhood and semen quality differed with the timing of parental separation. Parental separation from birth was associated with higher semen volume of 25%, 95% CI (− 5; 64); higher total sperm count of 62%, 95% CI (− 6; 179); and higher proportion of morphologically normal spermatozoa of 59%, 95% CI (20; 111). Parental separation in early childhood was associated with lower semen volume of − 14%, 95% CI (− 24; − 3); lower concentration of − 15%, 95% CI (− 28; 1); lower total sperm count of − 17%, 95% CI (− 32; 2) and lower testes volume of − 11%, 95% CI (− 18; − 3).Conclusion: The timing of parental separation was important, and parental separation from birth was associated with higher semen quality, and parental separation in early childhood was associated with lower semen quality.Keywords: stressful life-events, parental divorce, semen analysis, sperm quality, male infertility, epidemiology

Linn Håkonsen Arendt,1– 3 Lars Henning Pedersen,1,4 Lars Pedersen,5 Per Glud Ovesen,1,6 Tine Brink Henriksen,7 Morten Søndergaard Lindhard,8 Jørn Olsen,2,5 Henrik Toft Sørensen,5 Cecilia Høst Ramlau-Hansen2 1Department of Obstetrics and Gynecology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Public Health, Research Unit for Epidemiology, Aarhus University, Aarhus, Denmark; 3Department of Obstetrics and Gynecology, Regional Hospital Horsens, Horsens, Denmark; 4Department of Biomedicine, Aarhus University, Aarhus, Denmark; 5Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 6Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; 7Department of Child and Adolescent Health, Aarhus University Hospital, Aarhus, Denmark; 8Department of Child and Adolescent Health, Regional Hospital Randers, Aarhus, DenmarkCorrespondence: Linn Håkonsen ArendtDepartment of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; Department of Public Health, Research Unit for Epidemiology, Aarhus, DenmarkTel +45 27 21 09 81Email lha@clin.au.dkPurpose: To study the occurrence of major congenital abnormalities in children of women with type 1 and type 2 diabetes and investigate the association between glycated haemoglobin (HbA1c) and major congenital malformations according to type 1 diabetes and type 2 diabetes separately.Patients and methods: In this register-based study, all singletons born alive from January 1, 2000 to December 31, 2015 in the North Denmark and Central Denmark regions of Denmark and their mothers were included. We used data from Danish health registers and the LABKA database. Logistic regression models were used to compute crude and adjusted prevalence odds ratios (cORs and aORs) with 95% confidence intervals (CIs) for major congenital malformations overall and for subtypes, by type of maternal pre-existing diabetes and HbA1c levels.Results: Among 314,245 infants included, 2020 (0.64%) had mothers with type 1 diabetes and 498 (0.16%) had mothers with type 2 diabetes. We found an aOR of 2.9 (95% CI: 2.5, 3.5) and 1.9 (95% CI: 1.3; 2.8) for major malformations for type 1 and type 2 diabetes, respectively. The highest occurrence was seen for major congenital heart diseases, but we also observed higher occurrence of several other non-cardiac malformations. For both type 1 and type 2 diabetes, the prevalence of major congenital malformations increased with higher levels of maternal HbA1c with no safe threshold level. Mothers with type 1 diabetes had higher risks than those without diabetes irrespective of HbA1c, and women with HbA1c levels ≥ 9.5% had 8 times the odds of major congenital malformations [aOR 8.7 (95% CI: 5.4; 14.5)].Conclusions: The prevalence of major congenital malformations progressively increased with poorer glycemic control during pregnancy, with no obvious safe threshold level, for both type 1 and type 2 diabetes.Keywords: congenital heart diseases, diabetes, epidemiology, malformations, pregnancy, register-based research

Linn Håkonsen Arendt,1,2,* Andreas Ernst,1,3,* Morten Søndergaard Lindhard,2 Anne Aggerholm Jønsson,1 Tine Brink Henriksen,2 Jørn Olsen,4 Jorgen Thorup,5 L Henning Olsen,3 Cecilia Høst Ramlau-Hansen1 *These authors contributed equally to this work 1Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark; 2Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Department of Urology, Section for Paediatric Urology, Aarhus University Hospital, Aarhus, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Paediatric Surgery, Rigshospitalet and Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Purpose: The Danish National Health registers provide a valuable data source that offers unique opportunities for observational research, including studies on the congenital anomaly hypospadias. The accuracy of the diagnosis and surgical treatment registration of hypospadias in the Danish National Patient Register (DNPR) remains unknown. Patients and methods: We randomly sampled 500 patients diagnosed with hypospadias in the DNPR from January 1, 1995 to December 31, 2012. Among these, 384 patients were also registered with surgical treatment for hypospadias. Medical records were collected and reviewed independently by two investigators. Any classification disagreements were resolved by consensus. Using the medical records as the gold standard, we estimated positive predictive values (PPVs) with 95% confidence intervals (CIs) for the hypospadias diagnoses and surgical treatment registrations overall, as well as for the clinical subtypes. Results: We were able to retrieve medical records for 463 (92.6%) patients with hypospadias diagnoses and for 329 (85.7%) patients registered with surgical treatment. Presence of hypospadias was confirmed in 450 of 463 patients, yielding an overall PPV (95% CI) of 97.6% (95.8%–98.7%). For subtypes of hypospadias, the PPVs ranged between 37.5% and 72.7%. For surgical treatment of hypospadias, the overall PPV was 99.7% (97.9%–99.9%). Conclusion: The validity of the registration of hypospadias diagnoses as well as surgical treatment for hypospadias in the DNPR is overall very high. For the specific subtypes of hypospadias diagnoses codes and the specific surgical treatment codes, the PPVs are lower and cautious use is warranted. However, the DNPR remains a valuable tool for future observational research on hypospadias. Keywords: data quality, epidemiology, hospital register diagnoses, ICD-10, positive predictive value

Objective: To study the effect of antenatal magnesium sulphate (MgSO4) 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 MgSO4 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 MgSO4 group and the placebo group were 2.0% and 3.3%, respectively. The adjusted odds of moderate to severe CP were lower in the MgSO4 group than in the placebo group (odds ratio 0.61; 95% CI 0.23–1.65). Conclusions: Antenatal MgSO4 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. Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation. Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation. [ABSTRACT FROM AUTHOR]

Background: Ordinary meta-analyses indicate that magnesium sulphate (MgSO4 ) 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 MgSO4 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 MgSO4 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). MgSO4 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 MgSO4 , 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. [ABSTRACT FROM AUTHOR]

An association between pre-eclampsia and febrile convulsions has been reported, but the association may not be causal. We compared the risk of febrile convulsions in 14 974 children who had [...]

Objective: To investigate the impact of prenatal antidepressant exposure on behavioural problems in children at 7 years of age.Design: Nationwide population-based study.Setting: Danish National Birth Cohort.Population: A cohort of 49 178 pregnant women recruited between 1996 and 2002.Methods: Data obtained from computer-assisted telephone interviews twice during pregnancy were used to identify children born to: (i) depressed women who took antidepressants during pregnancy (n = 210); (ii) depressed women who did not take any antidepressants during pregnancy (n = 231); and (iii) healthy women who were not depressed (n = 48 737). Childhood behavioural problems at 7 years of age were examined using the validated Danish parent-report version of the Strengths and Difficulties Questionnaire (SDQ).Main Outcome Measures: SDQ scores.Results: No associations were observed between prenatal antidepressant exposure and abnormal SDQ scores for overall problem behaviour (adjusted relative risk, aRR 1.00; 95% confidence interval, 95% CI 0.49-2.05), hyperactivity/inattention (aRR 0.99; 95% CI 0.56-1.75), or peer problems (aRR 1.04; 95% CI 0.57-1.91). Although prenatal antidepressant exposure appeared to be associated with abnormal SDQ scores on the subscales of emotional symptoms (aRR 1.68; 95% CI 1.18-2.38) and conduct problems (aRR 1.58; 95% CI 1.03-2.42), these associations were significantly attenuated following adjustment for antenatal mood status (aRR 1.20; 95% CI 0.85-1.70 and aRR 1.19; 95% CI 0.77 1.83, respectively). Untreated prenatal depression was associated with an increased risk of all behavioural outcomes evaluated, compared with unexposed children, with significant attenuation following adjustment for antenatal mood status.Conclusions: The results of this study suggest that independent of maternal illness, prenatal antidepressant exposure is not associated with an increased risk of behavioural problems in children at 7 years of age.Tweetable Abstract: Prenatal antidepressant exposure is not associated with an increased risk of child behavioural problems. [ABSTRACT FROM AUTHOR]

Objective To estimate the rate and time to next live birth by mode of delivery. Design Hospital-based cohort. Setting Aarhus University Hospital ( AUH), Denmark. Population All pregnant women attending AUH were invited to enroll in the Aarhus Birth Cohort ( ABC) study between 1989 and 2010 ( n = 91 625). Methods Women were followed from their first live birth until the subsequent live birth or until censoring due to study end using Cox regression models. Main outcome measures Rate and time to subsequent live birth according to mode of delivery. Results 46 162 index live births were identified, of which 22 462 (49%) had a subsequent live birth. Women with any type of caesarean had a 6% reduction in the rate of subsequent live birth ( HR 0.94, 95% CI 0.89, 0.98), which remained unchanged in the analysis by type (emergency, HR 0.95, 95% CI 0.89, 1.02; elective, HR 0.91, 95% CI 0.85, 0.98) compared with women who had a spontaneous vaginal delivery ( SVD). Operative vaginal delivery was associated with an 8% reduction in subsequent live birth rates ( HR 0.92, 95% CI 0.86, 0.98) and vaginal delivery complicated by shoulder dystocia with a 19% reduction compared with SVD. Median time to next birth in days was shortest in women with a first caesarean (994 days, 95% CI 973, 1026) and longest in women with a vaginal delivery complicated by shoulder dystocia (1065 days, 95% CI 994, 1191). In women with planned pregnancies, the shortest median time to second birth was in women with breech vaginal deliveries (859 days, 95% CI 737, 1089) and the longest in women with vaginal deliveries complicated by shoulder dystocia (1193 days, 95% CI 1028, 1430). Conclusion The impact of mode of delivery on subsequent rate and time to next birth was minimal in this study. The greatest reduction was among women with assisted vaginal delivery complicated by shoulder dystocia. This study is strengthened by data on pregnancy planning as well as information on complications of pregnancy, delivery and neonatal morbidities, all of which may influence a woman's decision on subsequent birth. [ABSTRACT FROM AUTHOR]

Background Caesarean section rates are increasing worldwide, and the long-term effects are unknown. Objective To evaluate the risk of subsequent ectopic pregnancy in women with a previous caesarean section, compared with vaginal delivery. Search strategy Systematic review of the literature using CINAHL, the Cochrane Library, Embase, Medline, Pub Med, SCOPUS and Web of Knowledge, published from 1945 until 17 July 2011. Selection criteria Cohort and case-control designs reporting on the mode of delivery and subsequent ectopic pregnancy. Two reviewers independently assessed the titles, abstracts, and full articles to identify eligible studies, using a standardised data collection form, and also assessed the study quality. Reference lists of the studies included were also cross-checked. Data collection and analysis Odds ratios ( ORs) were combined using a random-effect model to estimate the overall association between caesarean section delivery and the risk of subsequent ectopic pregnancy. Main results Thirteen studies were included, which recruited a total of 61 978 women. Five studies reported adjustment for confounding factors, and the pooled OR of subsequent ectopic pregnancy following a caesarean section was 1.05 (95% CI 0.51-2.15). The removal of one study that reported outlier results yielded a pooled OR of 0.82 (95% CI 0.42-1.61). The pooled crude OR for all 13 studies was 1.36 (95% CI 0.99-1.88). Author's conclusions This review found no evidence of an association between prior caesarean section delivery and the occurrence of a subsequent ectopic pregnancy, but the studies included were of poor or variable quality, and only a small number adjusted for potential confounding factors. Further research of a higher methodological quality is required to assess any potential association between mode of delivery and subsequent ectopic pregnancy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate pregnancy-associated plasma protein A (PAPP-A) and free [beta]-human chorionic gonadotrophin ([beta]-hCG) in relation to admission to a neonatal intensive care unit (NICU) and neonatal disease. METHODS: 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 [beta]-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. RESULTS: Both PAPP-A and free [beta]-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 [beta]-hCG with jaundice. CONCLUSION: Low PAPP-A and free [beta]-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. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate whether measuring pregnancy-associated plasma protein A (PAPP-A) and free [beta]-human chorionic gonadotrophin ([beta]-hCG) before 10 weeks of gestation affect the association between these biomarkers and adverse pregnancy outcomes. METHODS: Singleton pregnant women (9450) who attended the prenatal screening program, Aarhus University Hospital, Denmark, were included. Maternal serum levels of PAPP-A and free [beta]-hCG were measured between week 8 and 13 weeks and 6 days. The risk of preterm delivery (<37 weeks) and small for gestational age (SGA) (= 10 weeks) biochemical testing. RESULTS: A stronger association between low PAPP-A and SGA was found with early serum sampling compared to late, but the difference was not statistically significant [odds ratio (OR) 3.2 vs 1.8; P value = 0.11]. This difference did not apply to PAPP-A and preterm delivery. For free [beta]-hCG, a stronger association with preterm delivery was found with early testing (OR 1.9 vs 1.1; P value = 0.31), whereas this difference was not found regarding SGA. CONCLUSION: Biochemical testing before 10 weeks does not affect the association between low PAPP-A and free [beta]-hCG and adverse pregnancy outcomes. Whether the association is actually stronger with early testing, requires further study. [ABSTRACT FROM AUTHOR]

The aim was to study the association between preschool behavioural problems and emotional symptoms in 10- to 12-year-old children. The study was based on the Aarhus Birth cohort, Denmark, and included 1,336 children. Based on the parent-administered preschool behaviour questionnaire (PBQ), we identified three not mutually exclusive preschool behavioural categories: anxious–fearful ( n = 146), hyperactive–distractible ( n = 98), and hostile–aggressive ( n = 170). Children without any known symptoms were considered well adjusted ( n = 1,000). Borderline emotional ( n = 105) and emotional difficulties ( n = 136) were measured at age 10–12 years with the parent-administered strength and difficulties questionnaire (SDQ). Multinomial logistic regression analyses were used to adjust for potential confounding factors. We found that anxious–fearful behaviour and hostile–aggressive preschool behaviour were associated with twice the risk of school-age emotional difficulties. Comorbidity or confounding failed to explain these results. Hyperactive–distractible preschool behaviour was not associated with school-age emotional difficulties. Preschool anxious–fearful behaviour was associated with school-age emotional difficulties, suggesting internalizing symptom stability in some children from early childhood. Preschool hostile–aggressive behaviour was also associated with school-age emotional difficulties, which suggests transformation of one behavioural dimension into another through childhood, and the need to focus on both early internalizing difficulties and hostile–aggressive behaviour as risk factors for later internalizing difficulties. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate early fetal growth and the biomarkers, pregnancy-associated plasma protein A (PAPP-A) and free [beta]-human chorionic gonadotrophin ([beta]-hCG), in relation to preterm delivery. METHODS: A cohort study of 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital between January 2005 and December 2007, was conducted. PAPP-A and free [beta]-hCG were measured in the first trimester. Early fetal growth was estimated by (GA(20)- GA(12))/Days(calendar), where GA(12) reflects the gestational age in days calculated from the crown-rump length at a 12-week scan, GA(20) reflects the gestational age in days calculated from the biparietal diameter at a 20-week scan, and Days(calendar) is the number of calendar days between the two scans. RESULTS: Low PAPP-A and low free [beta]-hCG were significantly associated with preterm delivery (<37 weeks). The association was even stronger when low PAPP-A and slow early fetal growth were combined, resulting in an adjusted odds ratio of 3.8 (95% CI, 1.6-8.7). Fast early fetal growth, but neither high PAPP-A nor high free [beta]-hCG, was significantly associated with preterm delivery. CONCLUSION: Two different biological pathways leading to spontaneous preterm delivery are suggested: fast early fetal growth and the combination of low PAPP-A and slow early fetal growth. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A strong association between stress in pregnancy and small head circumference in infants at birth was reported in 1994. This important finding has never been replicated. In a follow-up study of 4211 participants with singleton pregnancies, information on life events was collected twice during pregnancy and head circumference measured shortly after birth following standard procedures. No association was found between experienced or perceived stress as a result of life events during pregnancy and head circumference in the infants. In conclusion, stress in pregnancy may influence foetal brain development in many ways, but we found no support for an effect on the size of the brain as measured by head circumference at birth. [ABSTRACT FROM AUTHOR]

Aims: To study the association between smoking during pregnancy and sudden infant death syndrome (SIDS) using prospectively collected data, making it possible to account for a number of potential confounders.Design: Prospective follow up study (n = 24 986).Results: The overall rate of SIDS was 0.80 per 1000 live births (n = 20). Children of smokers had more than three times the risk of SIDS compared with children of non-smokers (OR = 3.5; 95% CI 1.4-8.7), and the risk of SIDS increased with the number of cigarettes smoked per day (p < 0.05). Adjustment for parity, alcohol, and caffeine intake during pregnancy, maternal height and weight before pregnancy, years of school, occupational status, marital status, and number of antenatal care visits did not change the results. Adjustment for mother's age marginally reduced the risk of SIDS associated with smoking (OR = 3.0; 95% CI 1.2-7.3).Conclusions: Given the prospective nature of the study, the number of deaths is small; however, if our results reflect a true association between smoking during pregnancy and SIDS, approximately 30-40% of all cases of SIDS could be avoided if all pregnant women stopped smoking in a population with 30% pregnant smokers. Our study adds to earlier evidence for an association between smoking during pregnancy and SIDS. The strengths of the study are the possibility to adjust for a number of potential confounders and the fact that information about smoking habits during pregnancy was prospectively collected. [ABSTRACT FROM AUTHOR]

Several studies have suggested that breastfeeding has a long-term influence on brain development. However, interpretation of these findings is complicated by the presence of many potential confounding factors. Only a few studies have examined infants before 1 y of age, although very early assessment might reduce the role of environmental influence. We investigated the association between exclusive breastfeeding and three developmental milestones related to general and fine motor skills and early language development at the age of 8 mo. We followed 1656 healthy, singleton, term infants, with a birthweight of at least 2500 g, born between May 1991 and February 1992 in Aarhus, Denmark. Information was collected at 16 wk gestation, at delivery and when the infant was 8 mo old. Motor skills were evaluated by measurement of crawling and pincer grip. Early language development was defined as the ability to babble in polysyllables. The proportion of infants who mastered the specific milestones increased consistently with increasing duration of breastfeeding. The relative risk for the highest versus the lowest breastfeeding category was 1.3 (95% CI: 1.0-1.6) for crawling, 1.2 (95% CI: 1.1-1.3) for pincer grip and 1.5 (95% CI: 1.3-1.8) for polysyllable babbling. Little change was found after adjustment for confounding. In conclusion, our data support the hypothesis that breastfeeding benefits neurodevelopment. [ABSTRACT FROM AUTHOR]

The author's response to the article "Elective Ceasarean Section at 38 Weeks Versus 39 Weeks: Neonatal and Maternal Outcomes in a Randomised Controlled Trial" that was published in the previous issue is presented.

A response from the author of the article related to beneficial effect of a cervical occlusion is arbitrary in previous issue is presented.

A reply by the authors to a letter to the editor about their article "Elective caesarean section at 38 versus 39 weeks of gestation: balance between the perceived benefits and potential drawbacks" is presented.

A response from the authors of the article "Elective caesarean section at 38 weeks versus 39 weeks: neonatal and maternal outcomes in a randomised controlled trial" in the 2013 issue is presented.

Aim: To describe how fetal growth and gestational age affect infantile colic, while considering other potential risk factors.Study Design: A population based follow up study of 2035 healthy singleton infants without any disability born to Danish mothers. Information was collected by self administered questionnaires at 16 and 30 weeks of gestation, at delivery, and 8 months post partum. Infantile colic is defined according to Wessel's criteria, but symptoms are restricted to crying for more than three hours a day, for more than three days a week, and for more than three weeks.Results: The cumulated incidence of infantile colic was 10.9%. Low birth weight babies (< 2500 g) had more than twice the risk (odds ratio = 2.7, 95% confidence interval 1.2 to 6.1) of infantile colic when controlled for gestational age, maternal height, and smoking.Conclusion: Low birth weight may be associated with infantile colic, and further research will be aimed to focus on fetal growth and infantile colic. [ABSTRACT FROM AUTHOR]

To evaluate the risk of epilepsy in children who received neonatal phototherapy. A cohort of live singletons born at a Danish hospital (2002-2016) with a gestational age ≥ 35 weeks. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy in children treated with neonatal phototherapy compared to children not treated with neonatal phototherapy in the general population, and in a subpopulation of children who had serum bilirubin measurement. Adjusted HRs (aHR) were computed using multivariable and propensity score matching models to take maternal and neonatal factors into consideration. Children were followed from day 29 after birth to diagnosis of epilepsy, death, emigration, or December 31, 2016. Among 65,365 children, 958 (1.5%) received neonatal phototherapy. Seven children (incidence rates (IRs): 10.8 /10,000 person-years) who received neonatal phototherapy and 354 children (IR: 7.7) who did not receive neonatal phototherapy were diagnosed with epilepsy. Neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 0.95, 95% CI: 0.43-2.09) and propensity score matched (aHR 0.94, 95% CI: 0.39-2.28) models. In the subpopulation of 9,378 children with bilirubin measurement, 928 (9.9%) received neonatal phototherapy. In the analysis of the subpopulation in which bilirubin level and age at the time of bilirubin measurement were further taking into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 1.26, 95% CI: 0.54-2.97) and propensity score matched (aHR 1.24, 95% CI: 0.47-3.25) models,Conclusions: Neonatal phototherapy was not associated with an increased risk of epilepsy after taking maternal and neonatal factors into consideration. What is known: • A few studies have suggested that neonatal phototherapy for hyperbilirubinemia may increase the risk of childhood epilepsy. • Whether the observed associations contribute to hyperbilirubinemia, phototherapy, or underlying factors requires further investigation. What is new: • This study revealed no increased risk of epilepsy in children treated with neonatal phototherapy compared to children not treated with phototherapy after taking maternal and neonatal factors into consideration. • After further taking bilirubin level and age at the time of bilirubin measurement into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy., (© 2024. The Author(s).)

Background: Early biomarkers are needed to improve diagnosis and support antibiotic stewardship in neonatal sepsis. Heart rate variability (HRV) is proposed as such a biomarker. However, there is a lack of studies in term newborns. Infusion of lipopolysaccharide (LPS) from Escherichia coli induces systemic inflammation comparable to sepsis in newborns. We aimed to study the effect of systemic LPS induced inflammation on HRV in term newborn piglets., Methods: Baseline HRV was recorded for 1 h. This control period was compared to the hourly HRV for each piglet (n = 9) during 4 h of LPS infusion. For comparison, we used a mixed-effects regression model., Results: Systemic inflammation induced by LPS was found to reduce HRV. Compared to baseline, most measures of HRV decreased to lower values compared to baseline at 2 h, 3 h, and 4 h after initiation of LPS infusion. Heart rate (HR) was increased at 2 h, 3 h, and 4 h. When adjusting for HR in the mixed-effects regression model all reductions in HRV were explained by the increase in HR., Conclusions: Reduced HRV may be an early biomarker of neonatal sepsis. However, an increase in HR alone could be an already available, more accessible, and interpretable biomarker of sepsis in term neonates., Impact: In a term newborn piglet model, systemic inflammation induced by lipopolysaccharide from Escherichia coli reduced heart rate variability measures and increased heart rate. All reductions in heart rate variability were mediated by heart rate. While heart rate variability may be a biomarker of sepsis in term newborns, changes in heart rate alone could be a more readily available biomarker., (© 2024. The Author(s).)

Objective: To investigate whether maternal stress in pregnancy is associated with pubertal timing in girls and boys and to explore potential mediation by childhood body mass index (BMI) and childhood psychosocial stress., Design: Cohort study., Setting: Not applicable., Patients: In total, 14,702 girls and boys from the Puberty Cohort, nested within the Danish National Birth Cohort., Intervention: Maternal stress was obtained from a computer-assisted telephone interview in gestational weeks 30-32 as maternal life stress and emotional distress in pregnancy using questions on the basis of validated screening tools. Maternal life stress and emotional distress in pregnancy were analyzed separately and in an interaction analysis., Main Outcome Measures: Pubertal timing was measured half-yearly from age 11 years and throughout pubertal development and assessed as Tanner stages 1-5 (breast and pubic hair development in girls and genital and pubic hair development in boys), menarche in girls, voice break and first ejaculation in boys, and occurrence of acne and axillary hair in both girls and boys. A combined estimate for overall pubertal timing was derived using Huber-White robust variance estimation. Mean differences in age at attaining the pubertal milestones according to prenatal exposure to no (reference), low-, moderate-, or high-maternal stress in pregnancy were estimated using a multivariable censored regression model. Potential mediation by childhood BMI and childhood psychosocial stress was investigated in separate models., Results: After adjustment for potential confounding factors, prenatal exposure to high-maternal life stress (combined estimate: -1.8 months [95% CI, -2.7 to -0.8] and -0.9 months [95% CI, -1.8 to 0.0]), high maternal emotional distress (combined estimate: -1.5 months [95% CI, -2.5 to -0.5] and -1.7 months [95% CI, -2.8 to -0.7]), and both high-maternal life stress and emotional distress (combined estimate: -2.8 months [95% CI, -4.2, to -1.4] and -1.7 months [95% CI, -3.1 to -0.2]) were associated with earlier pubertal timing in girls and boys, respectively. The associations were not mediated by childhood BMI or childhood psychosocial stress., Conclusions: Prenatal exposure to maternal stress in pregnancy was associated with earlier pubertal timing in girls and boys in a dose-dependent manner. The associations were not mediated by childhood BMI or childhood psychosocial stress., Competing Interests: Declaration of Interests A.G.S. has nothing to disclose. N.B. has nothing to disclose. T.B.H. has nothing to disclose. C.H.R.H. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Healthcare systems worldwide face challenges related to patient safety, quality of care, and interprofessional collaboration. Simulation-based team training has emerged as a promising approach to address some of these challenges by providing healthcare professionals with a controlled and safe environment to enhance their teamwork and communication skills. The purpose of this study protocol is to describe an intervention using simulation-based team training in pediatric departments., Methods: Using a parallel-group, non-randomized controlled trial design, a simulation-based team training intervention will be implemented across four pediatric departments in Denmark. Another four pediatric departments will serve as controls. The intervention implies that healthcare professionals engage in simulation-based team training at a higher quantity and frequency than they did previously. Development of the intervention occurred from April 2022 to April 2023. Implementation of the intervention occurs from April 2023 to April 2024. Evaluation of the intervention is planned from April 2024 to April 2025. All simulation activity both before and during the intervention will be registered, making it possible to compare outcomes across time periods (before versus after) and across groups (intervention versus control). To evaluate the effects of the intervention, we will conduct four analyses. Analysis 1 investigates if simulation-based team training is related to sick leave among healthcare professionals. Analysis 2 explores if the simulation intervention has an impact on patient safety culture. Analysis 3 examines if simulation-based team training is associated with the treatment of critically ill newborns. Finally, Analysis 4 conducts a cost-benefit analysis, highlighting the potential return on investment., Discussion: The implemented simulation-based team training intervention can be defined as a complex intervention. Following the Medical Research Council framework and guidelines, the intervention in this project encompasses feasibility assessment, planning of intervention, implementation of intervention, and rigorous data analysis. Furthermore, the project emphasizes practical considerations such as stakeholder collaboration, facilitator training, and equipment management., Trial Registration: Registered as a clinical trial on clinicaltrials.gov, with the identifier NCT06064045., (© 2024. The Author(s).)

Objective: Timing of administration of antibiotics and concentrations in maternal blood and the umbilical cord blood are important prerequisites for optimal intrapartum antibiotic prophylaxis (IAP) of neonatal early-onset group B streptococcus (GBS) disease. This cohort study aimed to explore penicillin concentrations in mothers and infants at birth in relation to time elapsed from administration to delivery and to the minimal inhibitory concentration (MIC) for GBS., Main Outcome Measures: Penicillin G concentrations in maternal and umbilical cord blood in relation to time and dose from administration to time of delivery., Results: In 44 mother-infant dyads, median maternal penicillin G concentration was 0.2 mg/L (IQR 0-0.8 mg/L; range 0-1.6 mg/L). Median infant penicillin G concentration was 1.2 mg/L (IQR 0.5-5.0 mg/L; range 0-12.7 mg/L). In all infants (N=38) born less than 4 hours after the latest IAP administration, penicillin G concentrations far exceeded MIC (0.125 mg/L), even after short time intervals between IAP administration and birth. The highest plasma concentrations were reached in umbilical cord blood within 1 hour from IAP administration to birth.For 44 mother-infant dyads, maternal concentrations were very low compared with their infants'; particularly, very high concentrations were seen in the 20 infants with only one dose of IAP., Conclusion: High concentrations of penicillin G were found in umbilical cord blood of infants born less than 4 hours after IAP administration, well above the MIC for GBS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Early biomarkers of cerebral damage are essential for accurate prognosis, timely intervention, and evaluation of new treatment modalities in newborn infants with hypoxia and ischemia at birth. Hyperpolarized 13 C magnetic resonance imaging (MRI) is a novel method with which to quantify metabolism in vivo with unprecedented sensitivity. We aimed to investigate the applicability of hyperpolarized 13 C MRI in a newborn piglet model and whether this method may identify early changes in cerebral metabolism after a standardized hypoxic-ischemic (HI) insult. Six piglets were anesthetized and subjected to a standardized HI insult. Imaging was performed prior to and 2 h after the insult on a 3-T MR scanner. For 13 C studies, [1- 13 C]pyruvate was hyperpolarized in a commercial polarizer. Following intravenous injection, images were acquired using metabolic-specific imaging. HI resulted in a metabolic shift with a decrease in pyruvate to bicarbonate metabolism and an increase in pyruvate to lactate metabolism (lactate/bicarbonate ratio, mean [SD]; 2.28 [0.36] vs. 3.96 [0.91]). This is the first study to show that hyperpolarized 13 C MRI can be used in newborn piglets and applied to evaluate early changes in cerebral metabolism after an HI insult., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)