Body mass index z-scores in the first 2 years of life were associated with adverse metabolic and anthropometric outcomes at 3 years of age.

AIM: We investigated associations between body mass index (BMI) z-scores for children aged 0-2 years and the BMI z-scores, body fat percentage and metabolic risk factors at 3 years of age. METHODS: This was a secondary analysis of the Lifestyle in Pregnancy and Offspring randomised controlled trial, carried out at two university hospitals in Denmark. It comprised 149 mothers with BMI ≥30 kg/m2 who did or did not receive a lifestyle intervention during pregnancy and a reference group of 97 mothers with normal-weight, with follow-up of their 3-year-old offspring. The children in these three groups were pooled for the data analyses, due to similar characteristics between groups. The BMI z-scores were calculated at 5 weeks, 5 months and 1, 2 and 3 years, using Danish reference groups. Their anthropometrics and metabolic outcomes were examined at 3 years of age. RESULTS: BMI z-scores at 5 months to 2 years were associated with BMI z-scores and body fat percentage at 3 years of age and BMI z-scores were not associated with metabolic risk factors at 3 years. CONCLUSION: BMI z-scores from 5 weeks of age were associated with adverse anthropometric outcomes but not with metabolic risk factors at 3 years of age.

Vitamin D status in pregnancy and childhood associates with intelligence quotient at age 7 years: An Odense child cohort study.

OBJECTIVES: Animal studies indicate a key role for vitamin D in brain development and function, but observational studies in humans only suggests a borderline positive association between prenatal vitamin D exposure and cognitive development in the offspring. Knowledge gaps include insights in exposure time window and differences by sex for the association. We aimed to investigate the association between blood concentrations of serum 25-hydroxyvitamin D measured at four different time points and intelligence quotient score at the age of 7 years, including analyses spilt by child sex. METHODS: In Odense child cohort, we included 1404 mother-child pairs with serum 25-hydroxyvitamin D data from early pregnancy to age 7 years. Full-scale intelligence quotient was assessed with Wechsler Intelligence Scale for Children - fifth edition. Associations were adjusted for maternal education, pre-pregnancy body mass index, gestational age, sex and head circumference. Subanalyses stratified by sex were performed. RESULTS: The median (interquartile range) serum 25-hydroxyvitamin D in cord was 45.88 (31.15-61.08) nmol/L; early pregnancy, 66.45 (51.29-78.74); late pregnancy, 79.13 (59.69-97.31); 7 years, 66.29 (53.45-80.23) nmol/L. The mean (standard deviation) full-scale intelligence quotient was 99.44 (11.98). In adjusted analyses, cord serum 25-hydroxyvitamin D < 50 nmol/L was associated with 2.2 points lower full-scale intelligence quotient compared to the reference (50-75 nmol/L) in boys, ß = -2.2; 95% confidence interval = [-4.3, -0.1], p = 0.039. The same association with full-scale intelligence quotient was found for early pregnancy serum 25-hydroxyvitamin D, ß = -2.5 [-4.6, -0.3], p = 0.025, primarily driven by an association in boys, ß = -4.0 [-7.2, -0.8], p = 0.015; and for serum 25-hydroxyvitamin D at 7 years in girls, ß = -3.0 [-6.0, -0.1], p = 0.042. CONCLUSION: In this cohort, serum 25-hydroxyvitamin D < 50 nmol/L in both early gestation and cord blood in boys and current serum 25-hydroxyvitamin D < 50 nmol/L in girls were independent risk factors for two to four points lower full-scale intelligence quotient at the age of 7 years. Vulnerability to hypovitaminosis D, especially in pregnancy, may relate to child sex.

Health anxiety symptoms in Danish children during the first lockdown period of the COVID-19 pandemic: an Odense Child Cohort study.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has a severe impact on the general population. During the pandemic, children may develop emotional and psychological symptoms, including increased worries about health and illness, known as health anxiety symptoms (HASs). We aimed to explore HAS in 7-9-year-old children from the Danish Odense Child Cohort (OCC) during the first COVID-19 lockdown period in Denmark, and to examine associations with potential risk factors. MATERIAL AND METHODS: OCC is a cohort of children born between 2010 and 2012, which originally recruited 2874 of 6707 pregnancies (43%). Among the current OCC population of 2430 singleton children, 994 participated in this study (response rate 40%). Children and their parents filled out questionnaires about child HAS, family exposure to COVID-19 infection and parental HAS. Adjusted odds ratios (aORs) were calculated between high score child HAS (≥90th percentile) and covariates by use of logistic regression. RESULTS: Most children (n = 686, 69%) reported few worries about their health. Children reporting high score HAS also had higher levels of internalizing symptoms at age 5; aOR 2.15 (1.20;3.85), p = .010, and higher levels of maternal and paternal HAS; aOR 2.40 (1.44;3.97), p = .001, and 2.00 (1.10;3.65), p = .023, whereas no association with child sex or familial exposure to COVID-19 was detected (n = 65, 6.5%). CONCLUSIONS: High score child HAS during the first lockdown period of the COVID-19 pandemic was not associated with family exposure to COVID-19 infection, but to being a more anxious child a priori and to HAS in parents.

Free thyroxine in early pregnancy is an independent negative predictor of 3rd trimester HbA1c. Odense child cohort.

BACKGROUND: Lower thyroid function outside pregnancy is associated with an increased risk of type 2 diabetes mellitus. The relationship between thyroid function in early pregnancy and glucose status in 3rd trimester has not been investigated. AIMS: To study the association between 1st trimester thyroid function and 3rd trimester glucose status. DESIGN: In the prospective study Odense Child Cohort (OCC), 1,041 women had 1st trimester blood samples analysed for thyroid-stimulating hormone (TSH), free T4 (FT4), thyroid peroxidase antibody and HbA1c. Third trimester (week 28) fasting blood samples included plasma glucose, insulin and HbA1c. Oral glucose tolerance test (OGTT, 75 g glucose) was performed in 509 women. First trimester FT4 was dichotomized >vs. ≤ the 25th percentile (25p = 12.9 pmol/L). Homeostatic model assessment-insulin resistance (HOMA)-IR and HOMA-ß were calculated. RESULTS: Women with FT4 ≤25p had significantly higher HbA1c in 1st and 3rd trimesters and higher 3rd trimester fasting glucose, insulin, HOMA-IR and HOMA-ß compared to women with FT4 >25p. In multiple regression analyses, FT4 was an independent negative predictor of 3rd trimester HbA1c. FT4 levels in 3rd and 4th quartiles (high-normal FT4 levels) showed closest inverse associations with HbA1c (p-trend <.001). TSH was not associated with 3rd trimester HbA1c. CONCLUSION: Women with lower levels of FT4 in early pregnancy had higher HbA1c in 3rd trimester and FT4 was an independent negative predictor of 3rd trimester HbA1c.

PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only.

Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole-exome sequencing or targeted next-generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%-20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH-only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH-only phenotype of PHKA2.

Bone mineral density at age 7 years does not associate with adherence to vitamin D supplementation guidelines in infancy or vitamin D status in pregnancy and childhood: an Odense Child Cohort study.

Vitamin D supplementation in infancy is recommended to prevent rickets. At the population level, its effects on bone mineralisation are largely unknown. We aimed to explore whether adherence to national vitamin D supplementation guidelines (10 µg/d up to the age of 2 years), supplementation at the ages of 5 and 7 years, and serum 25-hydroxyvitamin D (s-25(OH)D) at various time points associated with bone mineral density (BMD) at the age of 7 years in the Odense Child Cohort, Denmark (n 1194). High adherence was defined as supplementation with 10 µg of vitamin D 6-7 times per week during ≥80 % of the observation time. s-25(OH)D was analysed using LC-MS/MS. Total-body-less-head (TBLH) BMD was measured by dual-energy X-ray absorptiometry. At the median age of 18·1 months, 53·9 % (n 475/881) reported high adherence. The median s-25(OH)D was 64·7, 78·8, 46·0 and 71·8 nmol/l in early pregnancy, late pregnancy, cord blood and at 5 years, respectively. The mean TBLH BMD at the median age of 7·1 years was 0·613 (SD 0·049) g/cm2 (z-score +0·363 (SD 0·824)). In adjusted analyses, vitamin D supplementation up to 18 months, and at 5 and 7 years, was not associated with TBLH BMD. Similarly, no robust associations were found between TBLH BMD and s-25(OH)D at any time point. No associations were found for TBLH bone mineral concentration or bone area. In this population with relatively high s-25(OH)D concentrations, no consistent associations were found between adherence to vitamin D supplementation recommendations or vitamin D status in pregnancy or childhood, and bone mineralisation at the age of 7 years.

Update of variants identified in the pancreatic ß-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the ß-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.

A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion.

Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in EDEM2, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of Edem2 in rat RIN-m ß-cells resulted in a decrease in insulin genes Ins1 to 67.9% (p = 0.006) and Ins2 to 16.8% (p < 0.001) and reduced insulin secretion by 60.4% (p = 0.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including Glut2 and Pxd1, with mRNA suppression to 54% (p < 0.001) and 85.7% (p = 0.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe EDEM2 as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of ß-cell genes involved in the glucose-stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.

Comparative meta-analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia.

BACKGROUND AND OBJECTIVE: Kabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta-analysis. METHODS: Data of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics. RESULTS: Seven new patients were identified with seven different pathogenic variants in KDM6A (n = 4) or KMT2D (n = 3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta-analysis, 24 KS patients with HH had a significantly higher frequency of variants in KDM6A compared to 373 KS patients without HH (50% vs 11.5%, P < .001), and KDM6A-KS was more likely to be associated with HH than KMT2D-KS (21.8% vs. 3.5%, P < .001). Sex distribution and other phenotypic features did not differ between KS with and without HH. CONCLUSION: The higher incidence of HH in KDM6A-KS compared to KMT2D-KS indicates that KDM6A loss of function variants predispose more specifically to beta cell dysfunction compared to KMT2D variants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.

The difficult management of persistent, non-focal congenital hyperinsulinism: A retrospective review from a single, tertiary center.

BACKGROUND/OBJECTIVE: Congenital hyperinsulinism (CHI) is a rare, heterogeneous disease with transient or persistent hypoglycemia. Histologically, focal, diffuse, and atypical forms of CHI exist, and at least 11 disease-causing genes have been identified. METHODS: We retrospectively evaluated the treatment and outcome of a cohort of 40 patients with non-focal, persistent CHI admitted to the International Hyperinsulinism Center, Denmark, from January 2000 to May 2017. RESULTS: Twenty-two patients (55%) could not be managed with medical monotherapy (diazoxide or octreotide) and six (15%) patients developed severe potential side effects to medication. Surgery was performed in 17 (43%) patients with resection of 66% to 98% of the pancreas. Surgically treated patients had more frequently KATP -channel gene mutations (surgical treatment 12/17 vs conservative treatment 6/23, P = .013), highly severe disease (15/17 vs 13/23, P = .025) and clinical onset <30 days of age (15/17 vs 10/23, P = .004). At last follow-up at median 5.3 (range: 0.3-31.3) years of age, 31/40 (78%) patients still received medical treatment, including 12/17 (71%) after surgery. One patient developed diabetes after a 98% pancreatic resection. Problematic treatment status was seen in 7/40 (18%). Only 8 (20%) had clinical remission (three spontaneous, five after pancreatic surgery). Neurodevelopmental impairment (n = 12, 30%) was marginally associated with disease severity (P = .059). CONCLUSIONS: Persistent, non-focal CHI remains difficult to manage. Neurological impairment in 30% suggests a frequent failure of prompt and adequate treatment. A high rate of problematic treatment status at follow-up demonstrates an urgent need for new medical treatment modalities.

Correction to: Neurodevelopmental outcomes after moderate to severe neonatal hypoglycemia.

The family name of the co-author of the article mentioned above was incorrectly presented. The correct name should have been "Annett Helleskov Rasmussen" instead of "Annett Rasmussen Helleskov".

Neurodevelopmental outcomes after moderate to severe neonatal hypoglycemia.

The long-term consequences of transient neonatal hypoglycemia are sparsely studied. We performed a follow-up of a cohort of neonates with blood glucose recordings < 1.7 mmol/L (< 30 mg/dL), treated with > 2.5 mmol/L (> 45 mg/dL), compared with healthy siblings. Exclusion criteria were gestational age < 35 weeks, severe asphyxia, head injury, and other cerebral diseases. In 71 children with neonatal hypoglycemia and 32 control siblings, Wechsler IV cognitive test, Movement ABC-2 test, and Child Behavior Checklist were performed at mean age 7.75 and 9.17 years, respectively. No significant changes were detected for cognitive function by using Wechsler IV or for behavior by using Child Behavior Checklist. In univariate analysis, the hypoglycemia group had lower age-adjusted fine motor scores by using the Movement ABC-2 test compared with control siblings, 42.6 ± 31.2 vs. 57.2 ± 30.8 percentile (p = 0.03). In the sibling-paired analysis, the decrease in total motor score was highly significant, p = 0.009, driven by a decrease in fine motor score, p = 0.008. In the hypoglycemia group, adjusted analysis showed a lower fine motor function for boys, ß = - 16.4, p = 0.048.Conclusion: Neonatal hypoglycemia treated with > 2.5 mmol/L was associated with lower fine motor scores within the normal range, particularly in boys. No associations with cognitive function or behavior were detected. What is Known: • Transient neonatal hypoglycemia is associated with acute neurologic dysfunction and long-term neurodevelopment impairment in 18 months of age. What is New: • Neonatal hypoglycemia treated with > 2.5 mmol/L is associated with lower fine motor function within the normal range, particularly in boys, but not to changes in cognitive function or behavior.

Glycemic control and bone mineral density in children and adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: Fracture risk is increased in patients with type 1 diabetes. We aimed to evaluate bone mineral density (BMD) and to identify risk factors associated to lower BMD in Danish children and adolescents with type 1 diabetes. METHODS: In this cross-sectional study BMD Z-score were determined by dual-energy X-ray absorptiometry (DXA) from a cohort of otherwise healthy children and adolescents with type 1 diabetes. Puberty Tanner stage, hemoglobin A1c (HbA1c), disease duration, and age at diabetes onset were investigated for associations to DXA results. RESULTS: We included 85 patients, 39 girls, 46 boys, with a median (range) age of 13.2 (6-17) years; disease duration 4.2 (0.4-15.9) years; HbA1c of the last year 61.8 (41-106) mmol/mol. Our patients were taller and heavier than the background population. When adjusted for increased height SD and body mass index SD, no overall difference in BMD Z-score was found. When stratified by sex, boys had significantly increased adjusted mean BMD Z-score, 0.38 (95% confidence interval [CI]: 0.13;0.62), girls; -0.27 (95% CI: -0.53;0.00). For the whole cohort, a negative correlation between mean latest year HbA1c and BMD Z-score was found, adjusted ß -0.019 (95%CI: -0.034;-0.004, P = 0.01). Poor glycemic control (HbA1c > 58 mmol/mol [7.5%]) within the latest year was likewise negatively correlated with BMD Z-score, adjusted ß -0.35 (95%CI: -0.69;-0.014, P = 0.04). CONCLUSIONS: Our study suggests that elevated blood glucose has a negative effect on the bones already before adulthood in patients with type 1 diabetes, although no signs of osteoporosis were identified by DXA.

18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation.

PURPOSE: Focal congenital hyperinsulinism (CHI) is curable by surgery, which is why identification of the focal lesion is crucial. We aimed to determine the use of 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) PET/CT vs. 68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic-acid-1-Nal3-octreotide (68Ga-DOTANOC) PET/CT as diagnostic tools in focal CHI. METHODS: PET/CT scans of children with CHI admitted to Odense University Hospital between August 2005 and June 2016 were retrospectively evaluated visually and by their maximal standardized uptake values (SUVmax) by two independent examiners, blinded for clinical, surgical and pathological data. Pancreatic histology was used as the gold standard. For patients without surgery, the genetic profile served as the gold standard. RESULTS: Fifty-five CHI patients were examined by PET/CT (18F-DOPA n = 53, 68Ga-DOTANOC n = 18). Surgery was performed in 34 patients, no surgery in 21 patients. Fifty-one patients had a classifiable outcome, either by histology (n = 33, 22 focal lesions, 11 non-focal) or by genetics (n = 18, all non-focal). The predictive performance of 18F-DOPA PET/CT to identify focal CHI was identical by visual- and cut-off-based evaluation: sensitivity (95% CI) of 1 (0.85-1); specificity of 0.96 (0.82-0.99). The optimal 18F-DOPA PET SUVmax ratio cut-off was 1.44 and the optimal 68Ga-DOTANOC PET SUVmax cut-off was 6.77 g/ml. The area under the receiver operating curve was 0.98 (0.93-1) for 18F-DOPA PET vs. 0.71 (0.43-0.95) for 68Ga-DOTANOC PET (p < 0.03). In patients subjected to surgery, localization of the focal lesion was correct in 91%, and 100%, by 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT, respectively. CONCLUSION: 18F-DOPA PET/CT was excellent in predicting focal CHI and superior compared to 68Ga-DOTANOC PET/CT. Further use of 68GA-DOTANOC PET/CT in predicting focal CHI is discouraged.

Cord serum 25-hydroxyvitamin D is not associated with cranial anthropometrics in infants up to 6 months of age. An Odense Child Cohort study.

Skull changes are poorly described in vitamin D insufficiency [serum 25-hydroxyvitamin D (s-25(OH)D) 25-50 nmol/L]. We aimed to investigate factors associated with cranial anthropometrics in infants, especially s-25(OH)D. In infants 2.5-6 months old from the Odense Child Cohort, associations between cord and pregnancy s-25(OH)D and anterior fontanel area (n = 765), head circumference (HC, n = 1776) and head shape (n = 1527) were investigated along with other factors. Age was corrected for preterm birth. The mean (SD) s-25(OH)D in early pregnancy was 65.97 (21.33) nmol/L; late pregnancy 78.61 (27.18) nmol/L; and cord 47.1 (21.7) nmol/L. At median (IQR) age 3.7 (2.5-5.9) months, the fontanel area was 225 (0-1690) mm2, and mean (SD) HC was 41.5 (1.5) cm. Asymmetric/flat head shape was present in 846 infants (55.3%). No associations were found between cord, early or late pregnancy s-25(OH)D and any cranial measure by univariate or adjusted analysis. Among significant, independent associations in multivariate analysis, fontanel area was associated inversely with gestational age (GA); HC was associated directly with GA, maternal pre-pregnancy overweight and caesarean section and inversely with smoking; and asymmetrical head shape showed a novel association with male sex: adjusted OR = 1.54 (95% CI 1.25; 1.89), p < 0.001. Other associations with asymmetrical head shape included parity 3+, gestational age and maternal age 30+ years (all protective). In conclusion, neither pregnancy nor cord s-25(OH)D was associated with fontanel size, HC or asymmetrical head shape despite a high prevalence of cord s-25(OH)D < 50 nmol/L. Lower GA was associated with larger fontanel size, lower HC and asymmetrical head shape, and boys more frequently had asymmetrical head shape, probably due to heavier heads.

Growth of children in Greenland exceeds the World Health Organization growth charts.

AIM: Previous studies have found high rates of stunted linear growth in Greenlandic children. We measured growth patterns in Greenland and compared them with international growth charts. METHODS: The study cohort comprised 279 healthy children aged 6-10 years in 2012. They participated in two pregnancy and birth cohorts in Greenland and longitudinal growth data as birth was extracted from their medical records. Growth reference ranges were estimated with the lambda-mu-sigma (LMS) method and compared with growth charts from Denmark and the World Health Organization (WHO). RESULTS: The children's mean length, weight and head circumference were significantly larger than the WHO growth charts (p < 0.001). We found that 21-28% of the children aged zero to one years exceeded the WHO growth chart for length by more than two standard deviations. For weight and head circumference, 9-16% of the children aged 0-10 years and 9-11% of the children from zero to two years exceeded the WHO charts by more than two standard deviations. The Danish references were exceeded to a lesser degree. CONCLUSION: This study showed that the growth of Greenlandic children up to 10 years was no longer stunted. Major determining factors suggested are genetic admixture, maternal overweight, changes in nutrition and improved health.

Medication errors in pediatric inpatients: a study based on a national mandatory reporting system.

The aim was to describe medication errors (MEs) in hospitalized children reported to the national mandatory reporting and learning system, the Danish Patient Safety Database (DPSD). MEs were extracted from DPSD from the 5-year period of 2010-2014. We included reports from public hospitals on patients aged 0-17 years and categorized by reporters as medication-related. Reports from psychiatric wards and outpatient clinics were excluded. A ME was defined as any medication-related error occurring in the medication process whether harmful or not. MEs were categorized as harmful if they resulted in actual harm or interventions to prevent harm. MEs were further categorized according to occurrence in the medication process, type of error, and the medicines involved. A total of 2071 MEs including 487 harmful MEs were identified. Most MEs occurred during prescribing (40.8%), followed by dispensing (38.7%). Harmful MEs occurred mainly during dispensing (40.3%). Dosing errors were the most reported type of error, 47.7% of all MEs and 45.4% of harmful MEs. Antibiotics and analgesics were the most frequently reported medication classes. Common medicines associated with MEs included morphine, paracetamol, and gentamicin. MEs caused no harm (74.9%), mild (11.7%), moderate (10.5%), or severe harm (1.3%), but none were lethal. CONCLUSION: MEs in hospitalized children occur in all medication processes and mainly involve dosing errors. Strategies should be developed to prevent MEs as these still threaten medication safety in pediatric inpatients. What is known: • Hospitalized children are more likely to experience medication errors than adults. • Voluntary national and local reporting and learning systems have previously been used to describe the nature and types of medication errors. What is new: • Medication errors in hospitalized children occur in all steps of the medication process, most frequently involving dosing errors and most commonly involving morphine, paracetamol, and gentamicin. • Of the medication errors, 1.3% cause severe harm, but no fatal errors were reported.

Inverse associations between cord vitamin D and attention deficit hyperactivity disorder symptoms: A child cohort study.

OBJECTIVE: To examine the association between cord 25-hydroxyvitamin D2+3 (25(OH)D) and attention deficit hyperactivity disorder symptoms in toddlers, using Child Behaviour Checklist for ages 1.5-5. METHOD: In a population-based birth cohort, a Child Behaviour Checklist for ages 1.5-5 questionnaire was returned from parents of 1233 infants with mean age 2.7 (standard deviation 0.6) years. Adjusted associations between cord 25(OH)D and Child Behaviour Checklist-based attention deficit hyperactivity disorder problems were analysed by multiple regression. Results The median cord 25(OH)D was 44.1 (range: 1.5-127.1) nmol/L. Mean attention deficit hyperactivity disorder problem score was 2.7 (standard deviation 2.1). In adjusted analyses, cord 25(OH)D levels >25 nmol/L and >30 nmol/L were associated with lower attention deficit hyperactivity disorder scores compared to levels ⩽25 nmol/L ( p = 0.035) and ⩽30 nmol/L ( p = 0.043), respectively. The adjusted odds of scoring above the 90th percentile on the Child Behaviour Checklist-based attention deficit hyperactivity disorder problem scale decreased by 11% per 10 nmol/L increase in cord 25(OH)D. CONCLUSION: An inverse association between cord 25(OH)D and attention deficit hyperactivity disorder symptoms in toddlers was found, suggesting a protective effect of prenatal vitamin D.

Early pregnancy angiogenic markers and spontaneous abortion: an Odense Child Cohort study.

BACKGROUND: Spontaneous abortion is the most commonly observed adverse pregnancy outcome. The angiogenic factors soluble Fms-like kinase 1 and placental growth factor are critical for normal pregnancy and may be associated to spontaneous abortion. OBJECTIVE: We investigated the association between maternal serum concentrations of soluble Fms-like kinase 1 and placental growth factor, and subsequent spontaneous abortion. STUDY DESIGN: In the prospective observational Odense Child Cohort, 1676 pregnant women donated serum in early pregnancy, gestational week <22 (median 83 days of gestation, interquartile range 71-103). Concentrations of soluble Fms-like kinase 1 and placental growth factor were determined with novel automated assays. Spontaneous abortion was defined as complete or incomplete spontaneous abortion, missed abortion, or blighted ovum <22+0 gestational weeks, and the prevalence was 3.52% (59 cases). The time-dependent effect of maternal serum concentrations of soluble Fms-like kinase 1 and placental growth factor on subsequent late first-trimester or second-trimester spontaneous abortion (n = 59) was evaluated using a Cox proportional hazards regression model, adjusting for body mass index, parity, season of blood sampling, and age. Furthermore, receiver operating characteristics were employed to identify predictive values and optimal cut-off values. RESULTS: In the adjusted Cox regression analysis, increasing continuous concentrations of both soluble Fms-like kinase 1 and placental growth factor were significantly associated with a decreased hazard ratio for spontaneous abortion: soluble Fms-like kinase 1, 0.996 (95% confidence interval, 0.995-0.997), and placental growth factor, 0.89 (95% confidence interval, 0.86-0.93). When analyzed by receiver operating characteristic cut-offs, women with soluble Fms-like kinase 1 <742 pg/mL had an odds ratio for spontaneous abortion of 12.1 (95% confidence interval, 6.64-22.2), positive predictive value of 11.70%, negative predictive value of 98.90%, positive likelihood ratio of 3.64 (3.07-4.32), and negative likelihood ratio of 0.30 (0.19-0.48). For placental growth factor <19.7 pg/mL, odds ratio was 13.2 (7.09-24.4), positive predictive value was 11.80%, negative predictive value was 99.0%, positive likelihood ratio was 3.68 (3.12-4.34), and negative likelihood ratio was 0.28 (0.17-0.45). In the sensitivity analysis of 54 spontaneous abortions matched 1:4 to controls on gestational age at blood sampling, the highest area under the curve was seen for soluble Fms-like kinase 1 in prediction of first-trimester spontaneous abortion, 0.898 (0.834-0.962), and at the optimum cut-off of 725 pg/mL, negative predictive value was 51.4%, positive predictive value was 94.6%, positive likelihood ratio was 4.04 (2.57-6.35), and negative likelihood ratio was 0.22 (0.09-0.54). CONCLUSION: A strong, novel prospective association was identified between lower concentrations of soluble Fms-like kinase 1 and placental growth factor measured in early pregnancy and spontaneous abortion. A soluble Fms-like kinase 1 cut-off <742 pg/mL in maternal serum was optimal to stratify women at high vs low risk of spontaneous abortion. The cause and effect of angiogenic factor alterations in spontaneous abortions remain to be elucidated.

Validation of hospital discharge diagnoses for hypertensive disorders of pregnancy.

INTRODUCTION: A correct diagnosis of preeclampsia and gestational hypertension is important for treatment and epidemiological studies. Changes in diagnostic criteria and underreporting in certain subsets of patients may hamper validity of the diagnoses. MATERIALS AND METHODS: We validated the discharge diagnoses of preeclampsia and gestational hypertension, which are reported to the Danish National Patient Registry, in a cohort of 2163 pregnant women by retrospective evaluation of electronic hospital data. RESULTS: A preeclampsia discharge diagnosis was found in 113 (5.2%) of the participants. After validation, significantly more patients fulfilled criteria for diagnosis of preeclampsia (n = 163, 7.5%, p = 0.002); more had severe preeclampsia, 14 (0.6%) vs. 70 (3.2%), p < 0.001 and gestational hypertension, 62 (2.9%) vs. 46 (2.1%), p = 0.12. The diagnostic sensitivity for preeclampsia by discharge diagnosis was 55.8%; severe preeclampsia 18.6%; gestational hypertension 39.1%. Corresponding positive predictive values were 80.5, 92.9 and 29.0%. Misclassification occurred in 4.3, 2.7 and 3.3%, respectively. Misclassification was more prevalent in obese compared to lean women (10% vs. 3.6%, p < 0.0001). CONCLUSIONS: Discharge diagnoses substantially underestimated the prevalence of preeclampsia, especially severe preeclampsia. Misclassification was most common in obese preeclamptic women. These findings depict the limitations associated with the direct use of discharge diagnoses of hypertensive disorders in pregnancy for research purposes.