Prediction of large-for-gestational-age at birth using fetal biometry in type 1 and type 2 diabetes: A retrospective cohort study.

OBJECTIVE: To compare ultrasound-assessed fetal head circumference (HC), abdominal circumference (AC), HC/AC ratio, and estimated fetal weight (EFW) in prediction of large-for-gestational-age (LGA) at birth in pregnancies affected by type 1 (T1DM) and type 2 (T2DM) diabetes. METHODS: This retrospective cohort study included all women with T1DM and T2DM giving birth to singletons between 2010 and 2019 at Aalborg University Hospital, Denmark. Ultrasound scans were performed at 16, 20, 28 and 34 weeks of pregnancy. LGA was defined as birth weight deviation of 15% or greater from the expected for gestational age (≥90th centile). Prediction of LGA was assessed by logistic regression adjusted for maternal characteristics and glycated hemoglobin (HbA1c) and area under the receiver operating characteristics curve (AUC). RESULTS: Among 180 T1DM pregnancies, 118 (66%) had an LGA neonate at birth. At 28 weeks of pregnancy, they were predicted with AUCHC/AC = 0.67, AUCAC = 0.85, and AUCEFW = 0.86. The multivariate analysis did not improve the predictive performance of the HC/AC ratio or AC. Among 87 T2DM pregnancies, 36 (41%) had an LGA neonate at birth. At 28 weeks, they were predicted with AUCHC/AC = 0.73, AUCAC = 0.83, and AUCEFW = 0.87. In T2DM, the multivariate analysis significantly improved the predictive performance for both HC/AC ratio and AC from 20 weeks of pregnancy. CONCLUSION: In T1DM and T2DM pregnancies, LGA is characterized by a general fetal overgrowth including both AC and HC. Therefore, AC and EFW perform better than the HC/AC ratio in the prediction of LGA. In T2DM, as opposed to T1DM, the predictive performance was improved by the inclusion of maternal characteristics and HbA1c in the analysis.

Maternal stress in pregnancy and pubertal timing in girls and boys: A cohort study.

OBJECTIVE: To investigate if 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. SUBJECTS: In total, 14 702 girls and boys from the Puberty Cohort, nested within The Danish National Birth Cohort (DNBC). EXPOSURE: Maternal stress was obtained from a computer-assisted telephone interview in gestational week 30-32 as maternal life stress and emotional distress in pregnancy using questions based on validated screening tools. Maternal life stress and emotional distress in pregnancy was analysed 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, -0.8) and -0.9 months (95% CI: -1.8, 0.0)), high maternal emotional distress (combined estimate: -1.5 months (95% CI: -2.5, -0.5) and -1.7 months (95% CI: -2.8, -0.7)), and both high maternal life stress and emotional distress (combined estimate: -2.8 months (95% CI: -4.2, -1.4) and -1.7 months (95% CI: -3.1, -0.2)) was 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.

Maternal intake of paracetamol during pregnancy and biomarkers of male fecundity in young adult sons.

Paracetamol is suggested to have endocrine disrupting properties possibly affecting fetal programming of reproductive health that might lead to impaired semen quality and changes in reproductive hormones. In this longitudinal study, we included 1058 young adult men born 1998-2000 into the Danish National Birth Cohort with follow-up at 18-21 years of age. The exposure, maternal intake of paracetamol, was modelled in three ways: dichotomized, trimester-specific, and as duration of exposure categorized into: short (1-2 weeks), medium (3-9 weeks) or long duration (>9 weeks) vs. no intake. Outcomes included semen characteristics, self-measured testis volume, and reproductive hormone levels. We used negative binominal regression to estimate the percentage difference and 95% confidence interval (CI) for each outcome. In total, 547 (48%) sons were prenatally exposed to paracetamol due to maternal intake at least once. Maternal intake of paracetamol during pregnancy was not associated with any of the biomarkers in the dichotomized or trimester-specific exposure models. For duration of exposure, sons of mothers with long duration of maternal intake of paracetamol showed tendencies towards lower semen concentration (-14% [95% CI: -31%; 8%]), a higher proportion of nonprogressive and immotile spermatozoa (8% [95% CI: -4%; 21%]) and higher DNA Fragmentation Index (16% [95% CI: -1%; 36%]) compared to son of mothers with no intake. Maternal intake of paracetamol during pregnancy was not clearly associated with biomarkers of male fecundity in adult sons. However, it cannot be ruled out that long duration of maternal intake of paracetamol might be associated with impaired semen characteristics.

Hemoglobin A1c Trajectories During Pregnancy and Adverse Outcomes in Women With Type 2 Diabetes: A Danish National Population-Based Cohort Study.

OBJECTIVE: To identify and characterize groups of pregnant women with type 2 diabetes with distinct hemoglobin A1c (HbA1c) trajectories across gestation and to examine the association with adverse obstetric and perinatal outcomes. RESEARCH DESIGN AND METHODS: This was a retrospective Danish national cohort study including all singleton pregnancies in women with type 2 diabetes, giving birth to a liveborn infant, between 2004 and 2019. HbA1c trajectories were identified using latent class linear mixed-model analysis. Associations with adverse outcomes were examined with logistic regression models. RESULTS: A total of 1,129 pregnancies were included. Three HbA1c trajectory groups were identified and named according to the glycemic control in early pregnancy (good, 59%; moderate, 32%; and poor, 9%). According to the model, all groups attained an estimated HbA1c <6.5% (48 mmol/mol) during pregnancy, with no differences between groups in the 3rd trimester. Women with poor glycemic control in early pregnancy had lower odds of having an infant with large-for-gestational-age (LGA) birth weight (adjusted odds ratio [aOR] 0.57, 95% CI 0.40-0.83), and higher odds of having an infant with small-for-gestational age (SGA) birth weight (aOR 2.49, 95% CI 2.00-3.10) and congenital malformation (CM) (aOR 4.60 95% CI 3.39-6.26) compared with women with good glycemic control. There was no evidence of a difference in odds of preeclampsia, preterm birth, and caesarean section between groups. CONCLUSIONS: Women with poor glycemic control in early pregnancy have lower odds of having an infant with LGA birth weight, but higher odds of having an infant with SGA birth weight and CM.

Reduced T2*-weighted placental MRI predicts foetal growth restriction in women with chronic rheumatic disease-a Danish explorative study.

OBJECTIVES: Women with chronic rheumatic disease (CRD) are at greater risk of foetal growth restriction than their healthy peers. T2*-weighted magnetic resonance imaging of placenta (T2*P-MRI) is superior to conventional ultrasonography in predicting birth weight and works as a proxy metabolic mirror of the placental function. We aimed to compare T2*P-MRI in pregnant women with CRD and healthy controls. In addition, we aimed to investigate the correlation between T2*P-MRI and birth weight. METHODS: Using a General Electric (GE) 1.5 Tesla, we consecutively performed T2*-weighted placental MRI in 10 women with CRD and 18 healthy controls at gestational week (GW)24 and GW32. We prospectively collected clinical parameters during pregnancy including birth outcome and placental weight. RESULTS: Women with CRD had significantly lower T2*P-MRI values at GW24 than healthy controls (median T2*(IQR) 92.1 ms (81.6; 122.4) versus 118.6 ms (105.1; 129.1), p = 0.03). T2*P-MRI values at GW24 showed a significant correlation with birth weight, as the T2*P-MRI value was reduced in all four pregnancies complicated by SGA at birth. Three out of four pregnancies complicated by SGA at birth remained undetected by routine antenatal ultrasound. CONCLUSION: This study demonstrates reduced T2*P-MRI values and a high proportion of SGA at birth in CRD pregnancies compared to controls, suggesting an increased risk of placental dysfunction in CRD pregnancies. T2*P-MRI may have the potential to focus clinical vigilance by identifying pregnancies at risk of SGA as early as GW24. Key Points • Placenta-related causes of foetal growth restriction in women with rheumatic disease remain to be investigated. • T2*P-MRI values at gestational week 24 predicted foetuses small for gestational age at birth. • T2*P-MRI may indicate pregnant women with chronic rheumatic disease (CRD) in need of treatment optimization.

Danish Diabetes Birth Registry 2: a study protocol of a national prospective cohort study to monitor outcomes of pregnancies of women with pre-existing diabetes.

INTRODUCTION: Despite technological developments and intensified care, pregnancies in women with pre-existing diabetes are still considered high-risk pregnancies. The rate of adverse outcomes in pregnancies affected by diabetes in Denmark is currently unknown, and there is a limited understanding of mechanisms contributing to this elevated risk. To address these gaps, the Danish Diabetes Birth Registry 2 (DDBR2) was established. The aims of this registry are to evaluate maternal and fetal-neonatal outcomes based on 5 years cohort data, and to identify pathophysiology and risk factors associated with short-term and long-term outcomes of pregnancies in women with pre-existing diabetes. METHODS AND ANALYSIS: The DDBR2 registry is a nationwide 5-year prospective cohort with an inclusion period from February 2023 to February 2028 of pregnancies in women with all types of pre-existing diabetes and includes registry, clinical and questionnaire data and biological samples of mother-partner-child trios. Eligible families (parents age ≥18 years and sufficient proficiency in Danish or English) can participate by either (1) basic level data obtained from medical records (mother and child) and questionnaires (partner) or (2) basic level data and additional data which includes questionnaires (mother and partner) and blood samples (all). The primary maternal outcome is Hemoglobin A1c (HbA1c) levels at the end of pregnancy and the primary offspring endpoint is the birth weight SD score. The DDBR2 registry will be complemented by genetic, epigenetic and metabolomic data as well as a biobank for future research, and the cohort will be followed through data from national databases to illuminate possible mechanisms that link maternal diabetes and other parental factors to a possible increased risk of adverse long-term child outcomes. ETHICS AND DISSEMINATION: Approval from the Ethical Committee is obtained (S-20220039). Findings will be sought published in international scientific journals and shared among the participating hospitals and policymakers. TRIAL REGISTRATION NUMBER: NCT05678543.

Wider institutional research cultures and their influence on patient and public involvement and engagement in health research - An institutional ethnography.

Focus on patient and public involvement and engagement (PPIE) is increasing in health policy and research governance. PPIE is considered by some to be a democratic right, and by others to be a way to improve health care and research outcomes and implementation. Most recently, policy makers, funders and (clinical) research institutions are making PPIE a strategic requirement for health research urging researchers to invite patients and relatives into their research activities. Our study is based in a Danish university hospital where PPIE has been introduced as one of five strategic research goals. We investigated how researchers experienced this new practice and how their research practices connect to the wider context of the Danish health care system. Ten cases were studied during a year using observations, interviews, and document analysis. As our method of inquiry, we used institutional ethnography to look at researchers' work from their perspective and to understand how PPIE practices are part of a larger institutional research culture reaching far beyond the individual. We found that current research culture has implications for the selection of patients and relatives and for what they are asked to do. Researchers who experienced that PPIE outcomes aided their existing research practices felt motivated. Researchers who engaged patients and relatives before it was a strategy, were ideologically driven and their approaches resulted in an increased diversity of inclusion and researcher assimilation. These findings add to the current knowledge on PPIE practices and help us understand that further development towards collaborative research practices require a change in key performance indicators and training and perhaps call for attention to our shared acceptance of knowledge generation in research.

Birth by caesarean section and semen quality in adulthood: a Danish population-based cohort study.

BACKGROUND: The caesarean section (CS) rate has increased worldwide and there is an increasing public and scientific interest in the potential long-term health consequences for the offspring. CS is related to persistent aberrant microbiota colonization in the offspring, which may negatively interfere with sex hormone homeostasis and thus potentially affect the reproductive health. It remains unknown whether adult sons' semen quality is affected by CS. We hypothesize that CS is associated with lower semen quality. METHODS: This study was based on the Fetal Programming of Semen Quality cohort (FEPOS, enrolled from 2017 to 2019) nested within the Danish National Birth Cohort (DNBC, enrolled from 1996 to 2002). A total of 5697 adult sons of mothers from the DNBC were invited to the FEPOS cohort, and 1044 young men participated in this study. Information on mode of delivery was extracted from the Danish Medical Birth Registry, and included vaginal delivery, elective CS before labor, emergency CS during labor and unspecified CS. The young men provided a semen sample for analysis of semen volume, sperm concentration, motility and morphology. Negative binomial regression models were applied to examine the association between CS and semen characteristics with estimation of relative differences in percentages with 95% confidence intervals (CIs). RESULTS: Among included sons, 132 (13%) were born by CS. We found a slightly lower non-progressive sperm motility (reflecting higher progressive sperm motility) among sons born by CS compared to sons born by vaginal delivery [relative difference (95% CI): - 7.5% (- 14.1% to - 0.4%)]. No differences were observed for other sperm characteristics. When CS was further classified into elective CS, emergency CS and unspecified CS in a sensitivity analysis, no significant differences in non-progressive motility were observed among sons born by any of the three types of CS compared to sons born vaginally. CONCLUSIONS: This large population-based cohort study found no significant evidence for an adverse effect on semen quality in adult sons born by CS.

Caesarean section is one of the most frequently used interventions during childbirth and global cesarean delivery rates continue to increase. The rising cesarean delivery rate has been reported to be related with series of adverse health outcomes in children, such as asthma, allergies, obesity, diabetes and even poor emotional, behavioral and educational outcomes. Still, it remains unknown whether children's reproductive health is affected by this delivery mode.Based on data from the Fetal Programming of Semen Quality cohort (FEPOS,) nested within the Danish National Birth Cohort, we have therefore analyzed the potential effect of caesarean section on son's semen quality in 1044 young men. We found a slightly higher progressive sperm motility among sons born by caesarean section compared to sons born by vaginal delivery. No differences, however, were observed for semen volume, sperm concentration and morphology between the two delivery modes.The FEPOS cohort is the largest population-based male offspring cohort worldwide. This is the first study aiming to examine the association between caesarean section and semen quality in adulthood. Although the findings need to be confirmed in other studies, it is reassuring that this large population-based cohort study finds no significant evidence for an adverse effect on semen quality in adult sons born by caesarean section.

Advances in extracellular vesicles as mediators of cell-to-cell communication in pregnancy.

Cell-to-cell communication mediated by Extracellular Vesicles (EVs) is a novel and emerging area of research, especially during pregnancy, in which placenta derived EVs can facilitate the feto-maternal communication. EVs comprise a heterogeneous group of vesicle sub-populations with diverse physical and biochemical characteristics and originate by specific biogenesis mechanisms. EVs transfer molecular cargo (including proteins, nucleic acids, and lipids) between cells and are critical mediators of cell communication. There is growing interest among researchers to explore into the molecular cargo of EVs and their functions in a physiological and pathological context. For example, inflammatory mediators such as cytokines are shown to be released in EVs and EVs derived from immune cells play key roles in mediating the immune response as well as immunoregulatory pathways. Pregnancy complications such as gestational diabetes mellitus, preeclampsia, intrauterine growth restriction and preterm birth are associated with altered levels of circulating EVs, with differential EV cargo and bioactivity in target cells. This implicates the intriguing roles of EVs in reprogramming the maternal physiology during pregnancy. Moreover, the capacity of EVs to carry bioactive molecules makes them a promising tool for biomarker development and targeted therapies in pregnancy complications. This review summarizes the physiological and pathological roles played by EVs in pregnancy and pregnancy-related disorders and describes the potential of EVs to be translated into clinical applications in the diagnosis and treatment of pregnancy complications.

Maternal pre-pregnancy BMI and reproductive health in adult sons: a study in the Danish National Birth Cohort.

STUDY QUESTION: Is maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons? SUMMARY ANSWER: Maternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity. WHAT IS KNOWN ALREADY: Evidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons. STUDY DESIGN, SIZE, DURATION: A population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998-2019, was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1058 adult sons (median age 19 years, 2 months), born 1998-2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons' birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: We found no consistent associations between maternal pre-pregnancy BMI and semen characteristics or testes volume. Sons of mothers with higher pre-pregnancy BMI had higher oestradiol and lower SHBG levels, both in a dose-dependent manner. Sons of mothers with pre-pregnancy obesity (≥30 kg/m2) had higher LH levels and a higher FAI than sons born by mothers with normal pre-pregnancy BMI (18.5-24.9 kg/m2). The mediation analyses suggested that the effect of maternal pre-pregnancy BMI on higher levels of oestrogen, LH, and FAI was partly mediated by the sons' birthweight, in addition to adult fat mass and BMI measured at the clinical examination, whereas most of the effect on lower levels of SHBG was primarily mediated by the sons' own fat mass and BMI. Paternal BMI was not a strong confounder of the associations in this study. LIMITATIONS, REASONS FOR CAUTION: This study was based in a population-based cohort with a low prevalence of overweight and obesity in both mothers and adult sons. Some men (10%) had blood for reproductive hormone assessment drawn in the evening. While several potential confounding factors were accounted for, this study's inherent risk of residual and unmeasured confounding precludes provision of causal estimates. Therefore, caution should be given when interpreting the causal effect of maternal BMI on sons' reproductive health. WIDER IMPLICATIONS OF THE FINDINGS: Given the widespread occurrence of overweight and obesity among pregnant women, it is imperative to thoroughly examine the potential consequences for reproductive hormone levels in adult sons. The potential effects of maternal pre-pregnancy obesity on sons' reproductive hormone profile may potentially be partly avoided by the prevention of overweight and obesity in the sons. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall's Fond, Aarhus University, Independent Research Fund Denmark (9039-00128B), and the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

Sleep duration and biomarkers of fecundity in young men: a cross-sectional study from a population-based cohort.

BACKGROUND: Poor male fecundity is of concern and warrants the identification of potential modifiable risk factors. Short and long sleep duration might be risk factors for poor male fecundity although evidence in this research field is inconsistent. OBJECTIVES: To investigate the association between sleep duration and biomarkers of male fecundity in young men. MATERIALS AND METHODS: We conducted a cross-sectional study of 1,055 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, Denmark, 2017-2019. Sleep duration was obtained from an online survey answered by the participants prior to the clinical visit, where semen and blood samples were obtained, and testis volume was self-assessed using an Orchidometer. Percentage differences in semen characteristics, testes volume, and reproductive hormone levels were analysed according to sleep duration using multivariable negative binomial regression models. Sleep duration was dichotomised (recommended (6-9 h/night) versus deviant sleep) and visualised continuously as restricted cubic spline plots. RESULTS: Deviation from recommended sleep duration was associated with higher high DNA stainability (HDS) of 5% (95% CI: -1%; 13%), higher testosterone of 3% (95% CI: 0%; 7%) and higher free androgen index (FAI) of 6% (95% CI: 0%; 13%). The spline plots overall supported these results, suggesting u-shaped associations between sleep duration and HDS, testosterone and FAI, a linear association between sleep duration and semen volume and sex hormone binding globulin (SHBG) and an inverse u-shaped association with normal morphology. DISCUSSION: Information on sleep duration was obtained by self-report in broad categories with at least 3 h intervals. We were not able to investigate short or long sleep duration separately, since only few participants reported this. CONCLUSION: Sleep duration was associated with some biomarkers of fecundity in young men. Maintaining a recommended sleep duration may thus be beneficial for young men with regard to reproductive health.

Early Mortality in Paroxysmal Nocturnal Hemoglobinuria.

OBJECTIVES:  The elevated mortality risk among patients with paroxysmal nocturnal hemoglobinuria (PNH) has been suggested to derive from a high risk of thromboembolism (TE); however, the risks of coexisting cardiovascular risk factors are not well described. We studied mortality associated with PNH taking comorbidity and treatment into account. METHODS: Patients with PNH (n=115) were identified in the 1977-2016 Danish National Patient Register (DNPR). For each patient with PNH, we identified 50 age- and sex-matched general population comparators. Using the Kaplan-Meier estimator and Cox regression, we compared the overall survival of patients with comparators. Cumulative incidences were used to analyze the effects of comorbidity and the causes of death. RESULTS: One-year survival among patients and comparators was 92.2% and 99.4%, and after 10 years, it was 68.4% and 85.8%, respectively. Early mortality was associated with older age, higher levels of comorbidity, and solid malignancies prior to PNH diagnosis. The leading causes of death were infections and associated hematological diseases. Patients with early mortality were less likely to have received treatment with eculizumab and/or warfarin. Cardiovascular risk factors were evenly distributed between patients and comparators at diagnosis. CONCLUSION: We conclude that early mortality in PNH is associated with older age, cardiovascular comorbidity, and hematological malignancies.

Maternal Intake of Vitamin D Supplements during Pregnancy and Pubertal Timing in Children: A Population-Based Follow-Up Study.

Maternal vitamin D may be important for several organ systems in the offspring, including the reproductive system. In this population-based follow-up study of 12,991 Danish boys and girls born 2000-2003, we investigated if maternal intake of vitamin D supplements during pregnancy was associated with pubertal timing in boys and girls. Information on maternal intake of vitamin D supplements was obtained by self-report in mid-pregnancy. Self-reported information on the current status of various pubertal milestones was obtained every six months throughout puberty. Mean differences in months at attaining each pubertal milestone and an average estimate for the mean difference in attaining all pubertal milestones were estimated according to maternal intake of vitamin D supplements using multivariable interval-censored regression models. Lower maternal intake of vitamin D supplements was associated with later pubertal timing in boys. For the average estimate, boys had 0.5 months (95% CI 0.1; 0.9) later pubertal timing per 5 µg/day lower maternal vitamin D supplement intake. Maternal intake of vitamin D supplements was not associated with pubertal timing in girls. Spline plots and sensitivity analyses supported the findings. Whether the observed association with boys' pubertal timing translates into an increased risk of disease in adulthood is unknown.

Parental age at birth and biomarkers of fecundity in young Danish men.

BACKGROUND: High parental age is associated with adverse birth and genetic outcomes, but little is known about fecundity in male offspring. OBJECTIVES: We investigated if high parental age at birth was associated with biomarkers of male fecundity in a large population-based sample of young men. MATERIALS AND METHODS: We conducted a study of 1057 men from the Fetal Programming of Semen Quality (FEPOS) cohort, a sub-cohort of sons born 1998-2000 into the Danish National Birth Cohort. Semen characteristics and reproductive hormone concentrations were measured in samples provided by the men 2017-2019. Testis volume was determined by self-measurement. Data on the parental age was drawn from registers. Adjusted relative difference in percentage with 95% confidence intervals were estimated for each outcome according to pre-specified maternal and paternal age groups (< 30 (reference), 30-34 and ≥ 35) as well as for combinations of parental age groups, using multivariable negative binomial regression models. RESULTS: We did not observe consistent associations between parental age and biomarkers of fecundity, although sons of mothers ≥ 35 years had lower sperm concentration (-15% (95% CI: -30, 3)) and total sperm count (-10% (95% CI: -25, 9)). The analysis with parental age combinations showed lower sperm concentration with high age of the parents (both ≥ 35 years: -27%, 95% CI: -40, -19) when compared to the reference where both parents were below 30 years. DISCUSSION AND CONCLUSION: We found no strong association between higher parental age and biomarkers of fecundity in young men. However, we cannot exclude poorer semen characteristics in sons born by older mothers or with high age of both parents.

Venetoclax-based therapy for relapsed or refractory acute myeloid leukaemia following intensive induction chemotherapy.

BACKGROUND: The treatment of relapsed or refractory (R/R) acute myeloid leukaemia (AML) remains challenging and outcomes extremely poor. The introduction of venetoclax has transformed the treatment of AML and emerging data suggest that venetoclax-based therapy may enforce salvage treatment. MATERIALS AND METHODS: In this nationwide Danish retrospective study, we analysed treatment outcomes of venetoclax-based salvage treatment for R/R AML between 2019 and 2022. Only venetoclax-naive patients who had previously received treatment with intensive chemotherapy therapy were included. RESULTS: The cohort consisted of 43 R/R patients with a median age of 57 years. Nine (20.9%) were primary refractory and 34 (79.1%) patients had relapsed, including 21 after previous allogeneic stem cell transplantation. The overall response rate was 76.2% including 61.9% with composite complete remission (CRc: CR + CRi). Among CRc-responders with information on measurable residual disease (MRD), 8/13 (61.5%) obtained an MRD-negativity response. The overall survival was 9.3 months for all patients with an estimated 1-year overall survival of 34%. For CRc-responders the median overall survival was 13.3 months, and the median relapse-free survival was 12.8 months. CONCLUSION: Venetoclax-based salvage treatment for R/R AML produced high response rates; however, for most patients the response was of limited duration. This study is limited by an observational design and prone to selection bias.

Roles, outcomes, and enablers within research partnerships: A rapid review of the literature on patient and public involvement and engagement in health research.

BACKGROUND: Recent studies mention a need to investigate partnership roles and dynamics within patient and public involvement and engagement (PPIE) in health research, and how impact and outcomes are achieved. Many labels exist to describe involvement processes, but it is unknown whether the label has implications on partnerships and outcomes. This rapid review investigates how roles between patients, relatives and researchers in a broad variety of PPIE activities in health research are described in peer reviewed papers and explores what enables these partnerships. METHODS: Rapid review of articles published between 2012 and February 2022 describing, evaluating, or reflecting on experiences of PPIE in health research. All research disciplines and research areas were eligible. Four databases (Medline, Embase, PsychInfo and CINAHL) were searched between November 2021 and February 2022. We followed PRISMA guidelines and extracted descriptive factors: year, origin, research area and discipline, study focus, framework used and co-authorship. On a selection of articles, we performed a narrative analysis of partnership roles using Smits et al.'s. Involvement Matrix. Lastly, we performed a meta synthesis of reported enablers and outcomes of the partnerships. Patients and Relatives (PRs) have been involved in the whole rapid review process and are co-authors of this article. RESULTS: Seventy articles from various research disciplines and areas were included. Forty articles were selected for a narrative analysis of the role description of PRs and researchers, and a meta synthesis of enablers and outcomes. Most articles described researchers as decision-makers throughout the research cycle. PRs most often were partners when they were included as co-authors; they were mostly partners in the design, analysis, write-up, and dissemination stages. Enablers of partnerships included: PR training, personality of PRs and communication skills, trust, remuneration and time. CONCLUSIONS: Researchers' decision-making roles gives them control of where and when to include PRs in their projects. Co-authorship is a way of acknowledging patients' contributions which may lead to legitimation of their knowledge and the partnership. Authors describe common enablers, which can help future partnership formation.

This article investigates how other articles describe the roles patients, relatives and researchers have in patient and public involvement activities in health research. It also investigates which factors are supportive of creating these research partnerships. We searched four health research databases and found 70 relevant articles which somehow evaluated patient involvement activities in research. From these 70 articles we chose 40 which we closely investigated for descriptions of roles in the partnerships between researchers and patients and relatives. For this, we used a tool called the Involvement Matrix which uses five different roles: Listener (who is given information), Co-thinker (who is asked to give opinion), Advisor (who gives (un)solicited advice), Partner (who works as an equal partner) and Decision-maker (Who takes initiative and (final) decisions). We found that it is often researchers who take on the role of Decision-maker and that involvement often happens on their terms. We noticed that patients and relatives most often had the role of partner, when they were listed as co-authors of the article. This shows co-authorship as an authorization of their work during patient and public involvement activities. We found that patient and relative training, patients' and relatives' personality and communication skills, trust, financial reimbursement, and time were mentioned most often as enablers of good research partnerships.

Sleep problems in children and adolescents with neurological and psychiatric disorders.

Children and adolescents with psychiatric or neurologic disorders often suffer from sleep problems. Disrupted sleep might lead to different comorbidities in the child/adolescent. These symptoms often mimic other psychiatric symptoms, which makes the diagnostic process challenging. Sleep problems can lead to aggravation of existing symptoms, exacerbation into psychiatric problems, or arise as a response to pharmacological treatment. In order to provide an efficient and well-qualified treatment, it is important to understand the pathogenesis of sleep problems to be able to distinguish between the cause and consequence, as argued in this review.

Timing of puberty in relation to semen characteristics, testicular volume, and reproductive hormones: a cohort study.

OBJECTIVE: To investigate whether the timing of puberty is associated with semen characteristics, testicular volume, and reproductive hormone levels. DESIGN: Cohort study. SETTING: Not applicable. PATIENTS: The Danish National Birth Cohort and its subcohort, the Fetal Programming of Semen Quality cohort of 1,058 young men. INTERVENTION(S): Self-reported information on the timing (younger, same age, older than peers) of the pubertal markers: voice break (primary exposure), pubic hair growth, regular shaving, and axillary hair growth. MAIN OUTCOME MEASURES(S): We estimated the relative differences with 95% confidence intervals for semen characteristics (semen volume, sperm concentration, total sperm count, sperm motility, percentage of morphologically normal spermatozoa), testicular volume, and reproductive hormones (follicle stimulating hormone [FSH], luteinizing hormone, sex hormone-binding globulin [SHBG], testosterone, estradiol, and free androgen index [FAI]) obtained at a median age of 19.2 years according to timing of pubertal development. RESULT(S): Compared with men reporting voice break "same age as peers," men reporting voice break "older than peers" tended to have lower total sperm count (-12% [-25%, 4%]) and lower percent morphologically normal spermatozoa (-10% [-20%, 2%]), whereas men reporting voice break "younger than peers" tended to have a lower proportion of nonprogressive and immotile spermatozoa (-6% [-13%, 1%]) and larger testicular volume (7% [1%, 13%]). The pattern was less consistent for the other pubertal markers. For reproductive hormones, voice break "older than peers" tended to have higher FSH levels (24% [-1%, 55%]), higher SHBG levels (7% [0, 15%]), lower estradiol levels (-14% [-23%, -5%]), and lower FAI (-8% [-14%, -1%]), whereas voice break "younger than peers" tended to have higher luteinizing hormone levels (4% [-2%, 11%]), higher testosterone levels (5% [0%, 11%]), higher estradiol levels (17% [6%, 29%]), and higher FAI (4% [-2%, 11%]). When the categorical pubertal markers were analyzed as a linear term to assess dose dependence, older age at pubertal development was associated with higher FSH levels, higher SHBG levels, lower testosterone levels, lower estradiol levels, and lower FAI for most pubertal markers. CONCLUSION(S): These results lend weak support to the hypothesis that older age at pubertal development is associated with markers of reduced male fecundity, especially reproductive hormone levels, although associations with semen characteristics and testicular volume were statistically insignificant.

The estimated effect of season and vitamin D in the first trimester on pubertal timing in girls and boys: a cohort study and an instrumental variable analysis.

BACKGROUND: Season of birth has been associated with age at menarche. Maternal vitamin D levels in pregnancy may explain this effect. We investigated whether the season of first trimester or maternal 25-hydroxyvitamin D3 [25(OH)D3] levels were associated with pubertal timing in children. METHODS: We conducted a follow-up study of 15 819 children born in 2000-03 from the Puberty Cohort, nested in the Danish National Birth Cohort (DNBC). Mean differences in attaining numerous pubertal markers, including a combined estimate for the average age at attaining all pubertal markers, were estimated for low (November-April) relative to high (May-October) sunshine exposure season in the first trimester using multivariable interval-censored regression models. Moreover, we conducted a two-sample instrumental variable analysis using season as an instrument for maternal first-trimester 25(OH)D3 plasma levels obtained from a non-overlapping subset (n = 827) in the DNBC. RESULTS: For the combined estimate, girls and boys of mothers who had their first trimester during November-April had earlier pubertal timing than girls and boys of mothers whose first trimester occurred during May-October: -1.0 months (95% CI: -1.7 to -0.3) and -0.7 months (95% CI: -1.4 to -0.1), respectively. In the instrumental variable analysis, girls and boys also had earlier pubertal timing: respectively, -1.3 months (95% CI: -2.1 to -0.4) and -1.0 months (95% CI: -1.8 to -0.2) per SD (22 nmol/L) decrease in 25(OH)D3. CONCLUSIONS: Both first pregnancy trimester during November-April and lower 25(OH)D3 were associated with earlier pubertal timing in girls and boys.