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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]

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 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]

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]