BACKGROUND:Vitamin D may play a role in early lung development, yet epidemiologic evidence on its association with later asthma risk is mixed. We aimed to investigate the associations of neonatal 25-hydroxyvitamin D (25(OH)D) and vitamin D-binding protein (DBP) and their corresponding genetic predictors with asthma risk. METHODS:We conducted a population-based cohort study of a random sample of individuals born in Denmark during 1991-2005 from the iPSYCH2012 study. Neonatal concentrations of 25(OH)D and DBP were measured via dried blood spots, and asthma cases were identified through diagnoses or asthma prescriptions after age 5 years. Cox regression was used to estimate hazard ratios (HRs) for asthma in relation to 25(OH)D, DBP, and polygenic scores (PGSs) for these traits and asthma to assess genetic liability to vitamin D status and asthma. RESULTS:Of 14,005 individuals, 2308 (16.5%) developed asthma over a maximum follow-up of 25 years. We found no association between neonatal 25(OH)D (HR = 1.04, 95% CI: 0.99-1.09 per SD increase) or DBP (HR = 1.01, 95% CI: 0.97-1.05) and asthma risk. Analyses using tertiles to assess potential non-linear associations yielded similar null results. A higher asthma PGS was associated with increased asthma risk (HR = 1.42, 95% CI: 1.36-1.47 per SD increase), whereas PGSs for 25(OH)D (HR = 1.00, 95% CI: 0.96-1.05) and DBP (HR = 0.99, 95% CI: 0.95-1.04) were not. CONCLUSIONS:Our study suggests that neonatal vitamin D status is not associated with asthma risk. Similarly, genetic liability related to vitamin D status, as reflected in PGSs for 25(OH)D and DBP, is not associated with an increased risk of asthma.

BACKGROUND:There is growing evidence linking neonatal vitamin D deficiency to an increased risk of schizophrenia, ADHD, and autism spectrum disorder (ASD). The aim of this study was to examine the association between two vitamin D biomarkers (25 hydroxyvitamin D [25(OH)D] and vitamin D-binding protein [DBP], and their related genetic correlates) and the risk of six mental disorders. METHODS:We used a population-based, case-cohort sample of all individuals born in Denmark between 1981 and 2005. Using Danish health registers with follow-up to Dec 31, 2012, we identified individuals diagnosed with major depressive disorder, bipolar disorder, schizophrenia, ADHD, ASD, and anorexia nervosa based on ICD-10 criteria. Additionally, a random subcohort from the general population was selected. Based on neonatal dried blood spots, we measured concentrations of 25(OH)D and DBP. Our primary analyses were based on hazard ratios (HR) with 95% CI and absolute risks for the six mental disorders according to measured concentrations of 25(OH)D and DBP. As secondary analyses, we examined the association between genetic predictors of 25(OH)D and DBP, and the six mental disorders, and Mendelian randomisation analyses based on published summary statistics for 25(OH)D, DBP, and the six mental disorders. People with lived experience contributed to the development of the guiding hypothesis. FINDINGS:We used the total population from the iPSYCH2012 design (n=88 764), which included individuals who developed the six mental disorders, major depressive disorder (n=24 240), bipolar disorder (n=1928), schizophrenia (n=3540), ADHD (n=18 726), ASD (n=16 146), anorexia nervosa (n=3643), and the randomly sampled subcohort (n=30 000). Among those who met a range of inclusion criteria (eg, measured 25[OH]D, DBP or genotype, and predominantly European ancestry), we measured 25(OH)D or DBP in 71 793 individuals (38 118 [53·1%] male and 33 675 [46·9%] female); 65 952 had 25(OH)D and 66 797 the DBP measurements. Significant inverse relationships were found between 25(OH)D and schizophrenia (HR 0·82, 95% CI 0·78-0·86), ASD (HR 0·93, 95% CI 0·90-0·96), and ADHD (HR 0·89, 95% CI 0·86-0·92). A significant inverse relationship was found between DBP and schizophrenia (HR 0·84, 95% CI 0·80-0·88). Based on polygenic risk scores, higher concentrations of 25(OH)D (adjusted for DBP) were significantly associated with a reduced risk of both ASD and schizophrenia. Analyses based on Mendelian randomisation provided support for a causal association between both lower 25(OH)D and DBP concentrations and an increased risk of ADHD. INTERPRETATION:Convergent evidence finds that neonatal vitamin D status is associated with an altered risk of mental disorders. Our study supports the hypothesis that optimising neonatal vitamin D status might reduce the incidence of a range of neurodevelopmental disorders. FUNDING:The Danish National Research Foundation.

BACKGROUND AND OBJECTIVE:This nationwide, single-cohort study provides a comprehensive analysis of the epidemiology of X-linked adrenoleukodystrophy (ALD) in Denmark. We examined incidence, age at symptom onset, and sex-stratified survival outcomes to explore differences in symptom development. Findings were compared with international cohorts to contextualize the Danish results. METHODS:We included all individuals with genetically confirmed ALD residing in Denmark, with no age restrictions. Patients were born between 1911 and 2020. Clinical data were retrospectively extracted from medical records. Where available, dried blood spots collected at birth and stored in the Danish National Biobank were analyzed using liquid chromatography-mass spectrometry to quantify C26:0-lysophosphatidylcholine (C26:0-LPC). Cumulative incidence functions were used to estimate the risk of developing specific ALD phenotypes over time. RESULTS:A total of 113 individuals (49 males, 64 females) met inclusion criteria. The point prevalence of ALD was 1.42 per 100,000, and the average birth incidence from 1932 to 2023 was 1.81 per 100,000 (males: 1.7; females: 1.9). Thirty-four distinct pathogenic ABCD1 variants were identified, with c.1679C > T, p.(Pro560Leu) being the most common (21 cases). By age 60, 76 % of males had developed adrenomyeloneuropathy (AMN), 44 % had developed cerebral ALD (cALD), and 44 % had adrenal insufficiency. Among females, 80 % had developed AMN by the same age. AMN was associated with the longest diagnostic delay, averaging 8 years in males and 9 years in females. DISCUSSION:This study offers a rare, nationwide view of ALD spanning over a century of births alongside measurement of C26:0-LPC in historical, neonatally collected dried blood spot cards from 14 individuals in this cohort. While the birth incidence aligns with some other natural history studies, it remains lower than in countries with universal newborn screening. The high frequency of AMN in both sexes highlights the need for greater clinical awareness. Notably, our findings confirm that the majority of women with ALD will develop neurological symptoms over time, challenging the long-standing perception of female carriers as largely asymptomatic. The relatively low detection of cALD and adrenal insufficiency in adults suggests possible underdiagnosis and calls for improved long-term follow-up, especially in adult neurology and endocrinology.

INTRODUCTION:Early detection of salt-wasting congenital adrenal hyperplasia (SW-CAH) is important to reduce CAH-related morbidity. However, neonatal screening has shown to have a low positive predictive value (PPV), especially among preterm newborns. Here, the Danish CAH screening is evaluated by comparing incidence and morbidity of SW-CAH 10 years before and after introduction of screening. Furthermore, sensitivity, specificity, and PPV are determined.METHODS:All newborns in Denmark born during 1999-2018 and diagnosed with SW-CAH were identified in the Danish National Patient Registry and/or at the Department of Clinical Genetics, Rigshospitalet. Newborns with a positive neonatal CAH screening were identified at Statens Serum Institut. Correct diagnosis was evaluated by medical record review.RESULTS:A total of 65 newborns with SW-CAH were identified. The incidence of SW-CAH was 5:100,000 both before and after introduction of screening. Performance of sensitivity and specificity of the screening were 97% and 100%, respectively, and the PPV was 55% for the given period. Stratified according to gestational age, the PPV was 33% and 61% for pre -and fullterm newborns, respectively. Though not significant, the proportion of newborns presenting with SW-crisis decreased after introduction of screening from 29% versus 10% (p = 0.07).DISCUSSION AND CONCLUSION:Neonatal screening for SW-CAH has not led to an increase in the incidence of newborns diagnosed with SW-CAH. The screening algorithm has effectively identified newborns with SW-CAH. After 2009, there was a tendency toward a lower proportion of newborns with SW-crisis at diagnosis. Finally, the study emphasizes the benefits of using second-tier screening as well as repeated screening of premature newborns.

Aim Low citrulline concentration is a marker of low functional enterocyte mass, which may predispose neonates to necrotising enterocolitis ( NEC ). We hypothesised that citrulline could be used to assess the NEC risk that could not be accounted for by gestational age and birthweight. This study investigated whether citrulline concentrations routinely measured in neonatal dried blood spots ( DBS ) could predict NEC . Methods We used national Danish registries to retrospectively identify all 361 babies born between 2003 and 2009 who were diagnosed with NEC and had a valid citrulline concentration measured from a DBS sample. The control group comprised 1083 healthy newborns, with three controls for every newborn with NEC , matched for birthweight and gestational age. Results Neonatal dried blood spots were collected between 2 and 21 days of life, with a median of 8 days. The results showed that NEC was not associated with low citrulline concentration, either in a direct comparison between the NEC and control groups or in a multivariate logistic regression (p = 0.73). Conclusion The findings of this study show that the citrulline concentrations found in routine DBS samples between 2003 and 2009 did not predict NEC in newborn babies.

Autism affects males more than females, giving rise to the idea that the influence of steroid hormones on early fetal brain development may be one important early biological risk factor. Utilizing the Danish Historic Birth Cohort and Danish Psychiatric Central Register, we identified all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) ( n =128) compared with matched typically developing controls. Concentration levels of Δ4 sex steroids (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) and cortisol were measured with liquid chromatography tandem mass spectrometry. All hormones were positively associated with each other and principal component analysis confirmed that one generalized latent steroidogenic factor was driving much of the variation in the data. The autism group showed elevations across all hormones on this latent generalized steroidogenic factor (Cohen’s d =0.37, P =0.0009) and this elevation was uniform across ICD-10 diagnostic label. These results provide the first direct evidence of elevated fetal steroidogenic activity in autism. Such elevations may be important as epigenetic fetal programming mechanisms and may interact with other important pathophysiological factors in autism.