Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.

Vitamin D Supplementation and Vitamin D Status during Pregnancy and the Risk of Congenital Anomalies-A Systematic Review and Meta-Analysis.

Maternal dietary factors have been suggested as possible contributing influences for congenital anomalies (CAs). We aimed to assess the association between vitamin D supplementation or vitamin D status (s-25OHD) during pregnancy and CAs in the offspring. A comprehensive literature search was conducted in the three electronic databases: PubMed, Embase, and Cochrane Library. Included studies were critically appraised using appropriate tools (risk of bias 2, ROBINS-I). A protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019127131). A meta-analysis of four randomised controlled trials (RCTs) including 3931 participants showed no effect of vitamin D supplementation on CAs, a relative risk of 0.76 (95% CI 0.45; 1.30), with moderate certainty in the effect estimates by GRADE assessment. Of the nine identified observational studies, six were excluded due to a critical risk of bias in accordance with ROBINS-I. Among the included observational studies, two studies found no association, whereas one case-control study identified an association between s-25OHD < 20 nmol/L and neural tube defects, with an adjusted odds ratio of 2.34 (95% CI: 1.07; 5.07). Interpretation of the results should be cautious given the low prevalence of CAs, RCTs with onset of supplementation after organogenesis, and low-quality observational studies.

Diagnosis and Incidence of Congenital Combined Pituitary Hormone Deficiency in Denmark-A National Observational Study.

CONTEXT: Congenital combined pituitary hormone deficiency (cCPHD) is the loss of ≥2 pituitary hormones caused by congenital factors. OBJECTIVE: We aimed to estimate the national incidence of cCPHD diagnosed before age 18 years and in subgroups. METHODS: Patients with cCPHD were identified in the Danish National Patient Registry and Danish hospital registries in the period 1996-2020. Hospital files were reviewed and incidences calculated using background population data. Incidence was the main outcome measure. RESULTS: We identified 128 patients with cCPHD; 88 (68.8%) were males. The median (range) age at diagnosis was 6.2 (0.01-19.0) years. The median (25th;75th percentile) number of hormone deficiencies at diagnosis was 3 (3; 4) at <1 year vs 2 (2; 2) at 1-17 years, P < .0001. Abnormal pituitary magnetic resonance imaging findings were seen in 70.3% (83/118). For those born in Denmark aged <18 years at diagnosis (n = 116/128) the estimated national incidence (95% CI) of cCPHD was 10.34 (7.79-13.72) per 100 000 births, with an annual incidence rate of 5.74 (4.33-7.62) per million. In subgroup analysis (diagnosis <1 vs 1-17 years), the incidence was highest in the 1-17 years subgroup, 7.97 (5.77-11.00) vs 1.98 (1.39-2.84) per 100 000 births, whereas the annual incidence rate was highest at <1 year, 19.8 (13.9-28.4) vs 4.69 (3.39-6.47) per million births. CONCLUSION: cCPHD had the highest incidence rate and the most hormone deficiencies in those diagnosed at <1 year. The incidence was highest in the 1-17 years age group, underscoring the need for multiple pituitary hormone investigations throughout childhood and adolescence in children with only 1 hormone deficiency.

Higher Maternal Cortisol Associated With Lower Blood Pressure in Offspring From 3 Months to 5 Years of Age in the Odense Child Cohort.

BACKGROUND: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP). OBJECTIVE: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP. METHODS: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models. RESULTS: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (ß=-0.003 mmHg [95% CI, -0.005 to -0.0003]) and diastolic blood pressure (ß=-0.002 mmHg [95% CI, -0.004 to -0.0004]) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (ß=-0.01 mmHg [95% CI, -0.01 to -0.004]) and diastolic blood pressure (ß=-0.010 mmHg [95% CI, -0.012 to -0.011]) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors. CONCLUSIONS: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.

Vitamin D status and tooth enamel hypomineralization are not associated in 4-y-old children: An Odense Child Cohort study.

Early fetal stages of tooth development are vitamin D-dependent, suggesting an impact of vitamin D status in pregnancy on tooth mineralization in human populations. We examined the association between pregnancy and cord serum 25-hydroxyvitamin D (s-25(OH)D) and hypomineralization of the second primary molars (HSPM) in the 4-year-old children in the prospective, population-based Odense Child Cohort, Denmark. S-25(OH)D was measured in early pregnancy (<20 weeks, n = 753); late pregnancy (≥20 weeks, n = 841); and in umbilical cord blood (n = 1,241) using liquid chromatography-tandem mass spectrometry. HSPM was scored using modified European Academy of Paediatric Dentistry judgment criteria. The median [Q1;Q3] s-25(OH)D was 65.0 [49.4;78.0], 79.2 [60.4;95.8], and 45.1 [31.2;60.5] nmol/L in early pregnancy, late pregnancy, and cord blood, respectively. The prevalence of HSPM was 54.7%; creamy/white demarcated opacities 79.5%; yellowish/brownish demarcated opacities 14.9%; post-eruptive breakdown 5.2%; atypical restoration 0.4%. No univariate or adjusted associations with HSPM were detected for pregnancy or cord s-25(OH)D as a continuous variable or categorized into quartiles or routine clinical cut-offs, or when classifying HSPM by severity. In exploratory multiple regression analysis, HSPM was inversely associated with the length of gestation, adjusted odds ratio (aOR) 0.82 (95% C.I 0.74-0.92, p < 0.001), and directly associated with maternal education, aOR 1.57 (95% C.I 1.18-2.08, p = 0.002). In a population with relatively high s-25(OH)D concentrations and generally healthy mothers and children, pregnancy and cord blood vitamin D status was not associated with HSPM. The associations between HSPM and shorter gestational length and higher maternal education warrant further study.

Maternal Testosterone Concentrations in Third Trimester and Offspring Handgrip Strength at 5 Years: Odense Child Cohort.

BACKGROUND: Maternal testosterone in pregnancy may have conditioning effects on offspring muscle strength. PURPOSE: To investigate possible associations between maternal testosterone concentrations in third trimester and offspring handgrip strength (HGS) at 5 years. METHODS: In the prospective, population-based Odense Child Cohort, total testosterone (TT) at gestational week 27-28 and 5-year HGS were measured in 1017 mother-child pairs. TT was measured by liquid chromatography-tandem mass spectrometry and free testosterone (FT) was calculated from TT and sex hormone-binding globulin (SHBG). Multivariable regression analyses were performed with HGS < 10th percentile as cutoff for low HGS. RESULTS: Third-trimester FT concentration was 0.004 (0.002-0.007) nmol/L, geometric mean (mean - SD; mean + SD). The mean (SD) 5-year HGS was 8.7 (1.8) kg in boys and 8.1 (1.7) kg in girls (P < 0.001). Higher FT concentrations were associated with lower HGS (ß = -0.186, P = 0.048), after adjustment for maternal age, parity, offspring sex, and 5-year height and weight. FT > 0.004 nmol/L was associated with higher risk of 5-year HGS < 10th percentile with odds ratios (95% CI) of 1.58 (1.01, 2.47; P = 0.047; n = 1,017) and 1.69 (1.05, 2.74; P = 0.032) after further adjustment for children's organized sports in subgroup analysis (n = 848). Lower HGS in relation to higher FT concentrations was found in all linear models but was not always statistically significant. HGS was not associated with maternal TT and SHBG levels. CONCLUSION: Third trimester FT was inversely associated with offspring muscle strength assessed by HGS at 5 years of age, which may suggest a negative effect of maternal FT on offspring muscle strength.

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.

Transient congenital hyperinsulinism and hemolytic disease of a newborn despite rhesus D prophylaxis: a case report.

BACKGROUND: In neonates, rhesus D alloimmunization despite anti-D immunoglobulin prophylaxis is rare and often unexplained. Rhesus D alloimmunization can lead to hemolytic disease of the newborn with anemia and unconjugated hyperbilirubinemia. In past reports, transient congenital hyperinsulinism has been described as a rare complication of rhesus D alloimmunization. Our case report illustrates that rhesus D alloimmunization can result in a pseudosyndrome with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia, despite correctly administered anti-D immunoglobulin prophylaxis. CASE PRESENTATION: We report of a 36-year-old, Caucasian gravida 1, para 1 mother with A RhD negative blood type who received routine antenatal anti-D immunoglobulin prophylaxis. Her full term newborn boy presented with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia up to 295 µmol/L (ref. < 9), accounting for 64% of the total bilirubin. Syndromic congenital hyperinsulinism was suspected. Examinations showed a positive direct antiglobulin test, initially interpreted as caused by irregular antibodies; diffuse congenital hyperinsulinism by 18F-DOPA positron emission tomography/computed tomography scan; normal genetic analyses for congenital hyperinsulinism; mildly elevated liver enzymes; delayed, but present bile excretion by Tc99m-hepatobiliary iminodiacetic acid scintigraphy; and cholestasis and mild fibrosis by liver biopsy. The maternal anti-D titer was 1:16,000 day 20 postpartum. Y-chromosome material in the mother's blood could not be identified. This could, however, not exclude late intrapartum fetomaternal hemorrhage as the cause of immunization. No causative genetic findings were deetrmined by trio whole exome sequencing. The child went into clinical remission after 5.5 months. CONCLUSION: Our case demonstrates that rhesus D alloimmunization may present as a pseudosyndrome with transient congenital hyperinsulinism, anemia, and inspissated bile syndrome with conjugated hyperbilirubinaemia, despite anti-D immunoglobulin prophylaxis, possibly due to late fetomaternal hemorrhage.

Ketotic hypoglycemia in patients with Down syndrome.

BACKGROUND: Ketotic hypoglycemia (KH) without an identifiable underlying metabolic or hormonal disease is historically named idiopathic KH. The prevalence is unknown, but idiopathic KH is considered the most frequent cause of hypoglycemia beyond the neonatal period. KH in Down syndrome (DS) has not been reported. METHODS: We conducted a web-based survey on KH in DS through the non-profit patient organization Ketotic Hypoglycemia International. The responses were evaluated for consistency with KH by two authors. Two DS patient histories with documented KH were shared in more details. RESULTS: Survey data on 139 DS patients were obtained. After validation, 10 patients (7.2%) had reported episodes of documented hypoglycemia, ketosis, and/or symptoms compatible with KH beyond the neonatal period. Glucose concentrations ranged 1.2-2.9 mmol/L; betahydroxybutyrate was up to 5.5 mmol/L during hypoglycemia. One girl had trisomy 21 with no response to i.m. glucagon also had a heterozygous Xp22.23 deletion including GYG2, which protein, glycogenin 2, is a substrate for glycogen synthase. Treatment with extended release cornstarch was effective. CONCLUSION: This is the first demonstration of a possible high prevalence of KH in DS. Even though this finding needs to be confirmed in other research settings, identification of KH in DS could have a dramatic impact, as simple treatments with cornstarch, protein and frequent meals may prevent KH attacks and, analogous to other conditions with KH, improve growth, stamina and prevent overeating and obesity. GYG2 deletion may contribute to KH in DS, resembling glycogen storage disease type 0.

CRISPR/Cas9 ADCY7 Knockout Stimulates the Insulin Secretion Pathway Leading to Excessive Insulin Secretion.

Aim: Despite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI. Patient: A 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative. Methods: A trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR. Results: Hyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7, ADCY7 gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m(-/-Adcy7) cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis Adcy7 loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes Ins1 and Ins2 (p ≤ 0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of Scl2a2 and Gck via upregulation of Pdx1, and Foxa2 leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway. Conclusion: This study identified a novel candidate gene, ADCY7, to cause CHI via activation of the GSIS pathway.

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.

Towards enhanced understanding of idiopathic ketotic hypoglycemia: a literature review and introduction of the patient organization, Ketotic Hypoglycemia International.

BACKGROUND: Idiopathic Ketotic hypoglycemia (IKH) is a diagnosis of exclusion. Although considered as the most frequent cause of hypoglycemia in childhood, little progress has been made to advance the understanding of IKH since the medical term was coined in 1964. We aimed to review the literature on ketotic hypoglycemia (KH) and introduce a novel patient organization, Ketotic Hypoglycemia International (KHI). RESULTS: IKH may be diagnosed after the exclusion of various metabolic and hormonal diseases with KH. Although often mild and self-limiting, more severe and long-lasting IKH occurs. We therefore divide IKH in physiological KH and pathological KH, the latter defined as recurrent symptomatic, or occasionally symptomatic, episodes with beta-hydroxybutyrate ≥ 1.0 mmol/L and blood glucose < 70 mg/dL (3.9 mol/L), in the absence of prolonged fasting, acute infections and chronic diseases known to cause KH. Pathological KH may represent undiscovered diseases, e.g. glycogen storage disease IXa, Silver-Russel syndrome, and ketone transporter defects, or suggested novel disease entities identified by exome sequencing. The management of KH aims to prevent hypoglycemia, fatty acid oxidation and protein deficiency by supplying adequate amounts of carbohydrates and protein, including nutritional therapy, uncooked cornstarch, and sometimes continuous tube feeding by night. Still, intravenous dextrose may be needed in acute KH episodes. Failure to acknowledge that IKH can be more than normal variation may lead to under-treatment. KHI is a non-profit, patient-centric, global organization established in 2020. The organization was created by adult IKH patients, patient family members, and volunteers. The mission of KHI is to enhance the understanding of IKH while advocating for patients, their families and the continued research into KH. CONCLUSION: IKH is a heterogeneous disorder including physiological KH and pathological KH. IKH may represent missed diagnoses or novel disease entities, but shares common management principles to prevent fatty acid oxygenation. KHI, a novel patient organization, aims to enhance the understanding of IKH by supporting IKH families and research into IKH.

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.

Congenital hyperinsulinism: 2 case reports with different rare variants in ABCC8.

Congenital hyperinsulinism (CHI) is a rare glucose metabolism disorder characterized by unregulated secretion of insulin that leads to hyperinsulinemic hypoglycemia (HH). Most cases are caused by mutations in the KATP-channel genes ABCC8 and KCNJ11. We report 2 patients that experienced severe HH from the first day of life. Patient 1 developed midgut volvulus after initiating diazoxide and required intestinal resection. He was subsequently managed with a high-dose octreotide and glucose-enriched diet. Consistent with diffuse type CHI by 18F-dihydroxyphenylalanine positron emission tomography-computed tomography, genetic testing revealed a homozygous ABCC8 variant, c.1801G>A, p.(Val601Ile). The rare variant was previously reported to be diazoxide-responsive, and the patient responded well to diazoxide monotherapy, with clinical remission at 2 years of age. Patient 2 responded to diazoxide with spontaneous clinical remission at 15 months of age. However, an oral glucose tolerance test at 7 years of age revealed hyperinsulinism. Genetic testing revealed that the proband and several seemingly healthy family members harbored a novel, heterozygous ABCC8 variant, c.1780T>C, p.(Ser594Pro). Genetic findings identified previously unrecognized HH in the proband's mother. The proband's uncle had been diagnosed with monogenic ABCC8-diabetes and was successfully transitioned from insulin to glibenclamide therapy. We report findings of intestinal malrotation and volvulus occurring 2 days after initiation of diazoxide treatment. We also report a novel, heterozygous ABCC8 variant in a family that exhibited cases of CHI in infancy and HH and monogenic diabetes in adult members. The cases demonstrate the importance and clinical utility of genetic analyses for informing and guiding treatment and care.

Breastfeeding and Infections in Early Childhood: A Cohort Study.

BACKGROUND: Studies on the association between breastfeeding and infections in children beyond the first year of life reveal conflicting results. In a population-based birth cohort, we investigated whether the duration of breastfeeding was associated with the number of hospitalizations due to infection and symptoms of infection at home. METHODS: In the Odense Child Cohort, text message questionnaires were used to register information on breastfeeding (weekly until end of weaning) and symptoms of infection (biweekly; 12-36 months of age). Hospitalization data were obtained from the Danish National Patient Registry. RESULTS: Of the 1087 invited, 815 mother-infant pairs were included. The median duration of any breastfeeding was 7.6 (interquartile range: 3.5-10.4) months and of exclusive breastfeeding was 2.1 (interquartile range: 0.7-4.4) months. Hospitalization due to infection was seen in 207 (25.4%) infants during the first 3 years of life. The adjusted incidence rate ratio (IRR) for hospitalization due to any infection decreased with a longer duration of any breastfeeding (adjusted IRR: 0.96; 95% confidence interval 0.93-0.99; P < .001). The strongest associations between the duration of any breastfeeding and hospitalizations due to infection were found within the first year of life, for lower respiratory tract infections, and other infections (P ≤ .05). For infants exclusively breastfed, the adjusted IRR for hospitalization was 0.88 (95% confidence interval: 0.80-0.96; P = .006). No protective associations were present between breastfeeding and infection symptoms registered at home from ages 12 to 36 months. CONCLUSIONS: The results suggest that increased duration of breastfeeding, especially exclusive breastfeeding, protects against infections requiring hospitalization in the first year of life but not hospitalizations or symptoms of infection at home beyond the first year.

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".

Lower estimated bone strength and impaired bone microarchitecture in children with type 1 diabetes.

INTRODUCTION: Patients with type 1 diabetes has an increased risk of fracture. We wished to evaluate estimated bone strength in children and adolescents with type 1 diabetes and assess peripheral bone geometry, volumetric bone mineral density (vBMD) and microarchitecture. RESEARCH DESIGN AND METHODS: In a cross-sectional study, high-resolution peripheral quantitative CT (HR-pQCT) was performed of the radius and tibia in 84 children with type 1 diabetes and 55 healthy sibling controls. Estimated bone strength was assessed using a microfinite element analysis solver. Multivariate regression analyses were performed adjusting for age, sex, height and body mass index. RESULTS: The median age was 13.0 years in the diabetes group vs 11.5 years in healthy sibling controls. The median (range) diabetes duration was 4.2 (0.4-15.9) years; median (range) latest year Hb1Ac was 7.8 (5.9-11.8) % (61.8 (41-106) mmol/mol). In adjusted analyses, patients with type 1 diabetes had reduced estimated bone strength in both radius, ß -390.6 (-621.2 to -159.9) N, p=0.001, and tibia, ß -891.9 (-1321 to -462.9) N, p<0.001. In the radius and tibia, children with type 1 diabetes had reduced cortical area, trabecular vBMD, trabecular number and trabecular bone volume fraction and increased trabecular inhomogeneity, adjusted p<0.05 for all. Latest year HbA1c was negatively correlated with bone microarchitecture (radius and tibia), trabecular vBMD and estimated bone strength (tibia). CONCLUSION: Children with type 1 diabetes had reduced estimated bone strength. This reduced bone strength could partly be explained by reduced trabecular bone mineral density, adverse microarchitecture and reduced cortical area. We also found increasing latest year HbA1c to be associated with several adverse changes in bone parameters. HR-pQCT holds potential to identify early adverse bone changes and to explain the increased fracture risk in young patients with type 1 diabetes.

Prenatal Exposures to Perfluoroalkyl Acids and Associations with Markers of Adiposity and Plasma Lipids in Infancy: An Odense Child Cohort Study.

BACKGROUND: Perfluoroalkyl acids (PFAA) are repellants that cross the placental barrier, enabling interference with fetal programming. Maternal PFAA concentrations have been associated with offspring obesity and dyslipidemia in childhood and adulthood, but this association has not been studied in infancy. OBJECTIVES: We investigated associations between maternal PFAA concentrations and repeated markers of adiposity and lipid metabolism in infancy. METHODS: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAA: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 649 women. Offspring were examined at birth (n=613) and at 3 months (n=602) and 18 months (n=503) of age. Total cholesterol, LDL, HDL, and triglyceride were evaluated at 3 months (n=262) and 18 months (n=198) of age. Mixed effects linear regression models estimated associations between PFAA and standardized (SDS) body mass index (BMI), ponderal index, and waist circumference. Associations between PFAA and body fat% (BF%) and plasma lipids SDS at 3 months and 18 months of age were investigated with linear regression models. RESULTS: PFNA and PFDA were associated with higher BMI SDS [adjusted ß=0.26; 95% confidence interval (CI): 0.03, 0.49 and ß=0.58; 95% CI: -0.03, 1.19, respectively, for 1-ng/mL increases] and ponderal index SDS (ß=0.36; 95% CI: 0.13, 0.59 and ß=1.02; 95% CI: 0.40, 1.64, respectively) at 3 and 18 months of age (pooled) in girls. Corresponding estimates for boys were closer to the null but not significantly different from estimates for girls. In boys and girls (combined), PFNA and PFDA were associated with BF% at age 3 months (for 1-ng/mL PFDA, ß=0.40; 95% CI: 0.04, 0.75), and PFDA was associated with total cholesterol SDS at 18 months (ß=1.06; 95% CI: 0.08, 2.03) (n=83). DISCUSSION: Prenatal PFAA were positively associated with longitudinal markers of adiposity and higher total cholesterol in infancy. These findings deserve attention in light of rising rates of childhood overweight conditions and dyslipidemia. https://doi.org/10.1289/EHP5184.

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.

Maternal prolactin is associated with glucose status and PCOS in pregnancy: Odense Child Cohort.

OBJECTIVE: Low circulating prolactin is a potential marker of metabolic risk during pregnancy. We aimed to investigate associations between prolactin and glucose status in pregnant women with and without gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS). DESIGN: Prospective observational cohort study. From the Odense Child Cohort, 1497 pregnant women were included. METHODS: Blood samples were assessed during first, second (prolactin, hemoglobin A1c (HbA1c)) and third trimester (fasting prolactin, testosterone, HbA1c, insulin, glucose). Oral glucose tolerance test (OGTT) was performed around gestation week 28 in 350 women with risk factors for GDM and in 272 randomly included women. GDM was defined by 2-h plasma glucose ≥9.0 mmol/L. RESULTS: The median (IQR) prolactin increased from 633 (451-829) mIU/L in first-second trimester to 5223 (4151-6127) mIU/L at third trimester. Prolactin was inversely associated with HbA1c in first (r = -0.19, P < 0.001) and third trimester (r = -0.07, P = 0.014). In third trimester, women with GDM (n = 37; 6.0%) had lower prolactin compared to women without GDM (4269 vs 5072 mIU/L, P = 0.004). Third trimester prolactin multiple of the median (MoM) was inversely associated with risk of GDM in multivariate regression analysis (OR 0.30, P = 0.034). PCOS was diagnosed in 10.0% (n = 146). Early pregnancy prolactin MoM was positively associated to PCOS diagnosis (OR 1.38, P = 0.051). CONCLUSIONS: Low prolactin levels during pregnancy were associated with higher HbA1c and risk of GDM. A diagnosis of PCOS was associated with higher early pregnancy prolactin levels.