Cognitive function and skeletal size and mineral density at age 6-7 years: Findings from the Southampton Women's Survey.

INTRODUCTION: Poor cognitive function and osteoporosis commonly co-exist in later life. In women, this is often attributed to post-menopausal estrogen loss. However, a common early life origin for these conditions and the associations between cognitive function and bone mineral density (BMD) in childhood have not previously been explored. We examined these relationships at age 6-7 years in the Southampton Women's Survey (SWS) mother-offspring cohort. METHODS: Child occipitofrontal circumference (OFC), a proxy for brain volume, intelligence quotient (IQ) [Wechsler Abbreviated Scale of Intelligence] and visual recognition and working memory [CANTAB® Delayed Matching to Sample (DMS) and Spatial Span Length (SSP), respectively] were assessed. Whole-body-less-head (WBLH) and lumbar spine dual-energy X-ray absorptiometry [Hologic Discovery] (DXA) were performed to measure bone area (BA), bone mineral content (BMC), BMD and bone mineral apparent density (BMAD). Linear regression was used to examine associations between age and sex standardized variables (ß represent standard deviation (SD) difference per SD of cognitive function). RESULTS: DXA was performed in 1331 children (mean (SD) age 6.8 (0.33) years, 51.5 % male), with OFC, IQ, DMS and SSP assessed in 1250, 551, 490 and 460, respectively. OFC (ß = 0.25 SD/SD, 95%CI 0.20,0.30), IQ (ß = 0.11 SD/SD, 95%CI 0.02,0.19), and DMS (ß = 0.11, SD/SD, 95%CI 0.01,0.20) were positively associated with WBLH BA, with similar associations for lumbar spine BA. OFC and DMS were also positively associated with WBLH BMC, but only OFC was associated with BMD (WBLH: ß = 0.38 SD/SD, 95%CI 0.33,0.43; LS: ß = 0.19 SD/SD, 95%CI 0.13,0.24). CONCLUSION: Childhood brain volume was positively associated with measures of skeletal size and BMD, whereas IQ and memory were associated only with skeletal size. These findings suggest that common early life determinants for skeletal growth and BMD and cognitive function should be explored to identify potential early-life approaches to preventing osteoporosis and cognitive decline.

Association of endoscopic biopsy sampling methods with detection of precursor lesions of gastric cancer.

BACKGROUND AND AIMS: The yield of various endoscopic biopsy sampling methods for detection of precursor lesions of noncardia gastric cancer in a real-world setting remains unclear. Our objective was to evaluate the association of endoscopic biopsy sampling methods with detection of gastric intestinal metaplasia (GIM) and gastric dysplasia (GD). METHODS: We conducted a case-control study of adult patients who underwent EGD with biopsy sampling between 2010 and 2021 in a racially and ethnically diverse U.S. healthcare system. Cases were patients with histopathologic findings of GIM and/or GD. Control subjects were matched 1:1 by age, procedure date, and medical center. We compared the detection of GIM and GD using 4 different biopsy sampling methods: unspecified, specified stomach location, 2+2, and the Sydney protocol. Additionally, we assessed trends in use of sampling methods (Cochrane-Armitage) and identified patient and endoscopist factors associated with their use (logistic regression). RESULTS: We identified 20,938 GIM and 455 GD matched pairs. A greater proportion of GIM cases were detected using 2+2 (31.3% vs 25.3%, P < .0001) and the Sydney protocol (9.1% vs 1.0%, P < .0001) compared with control subjects. Similarly, a greater proportion of GD cases were detected using the Sydney protocol (15.6% vs .4%, P < .0001). We observed an increasing trend in the use of the Sydney protocol during the study period (3.8%-16.1% in cases, P < .0001; 1%-1.1% in control subjects, P = .005). Male and Asian American patients were more likely to undergo 2+2 or the Sydney protocol, whereas female and Hispanic endoscopists were more likely to perform sampling using these protocols. CONCLUSIONS: The application of the Sydney protocol is associated with an increased detection of precursor lesions of gastric cancer in routine clinical practice.

Safety and Efficacy of Intramuscular Tixagevimab-Cilgavimab in Prevention of COVID-19 in Patients Who Are Immunocompromised.

INTRODUCTION: Patients who are immunocompromised face an increased chance of severe COVID-19 infection compared with patients who are immunocompetent. However, vaccine efficacy for COVID-19 appears to be lower in patients who are immunocompromised. Tixagevimab-cilgavimab are monoclonal antibodies designed to enhance immune defense against COVID-19. Nevertheless, the safety and efficacy of tixagevimab-cilgavimab specifically in patients who are immunocompromised remains unknown. METHODS: The authors conducted a retrospective case study of patients who were immunocompromised and received tixagevimab-cilgavimab between January 3, 2022 to July 31, 2022 at Kaiser Permanente Southern California. All patients were monitored for 180 days following tixagevimab-cilgavimab administration. Patients who were immunocompromised included those with solid tumors, hematologic malignancies, primary immunodeficiencies, recipients of solid organ or hematopoietic stem cell transplants, and patients undergoing treatment with immunosuppressive medications (eg, chemotherapy, high-dose corticosteroids, tumor necrosis factor blockers, and certain biologic agents). RESULTS: A total of 2352 patients who were immunocompromised were included in the study. Among them, 101 patients (4.3%) tested positive for COVID-19, and 13 patients (0.6%) required COVID-19-related hospital admissions. Notably, no deaths were reported within 180 days following tixagevimab-cilgavimab administration. Additionally, 4 patients (0.17%) sought same-day medical care after receiving tixagevimab-cilgavimab. Within 30 days, there were 39 non-COVID-19-related hospital admissions (1.7%) and within 7 days, 11 hospital admissions (0.5%) occurred after tixagevimab-cilgavimab administration. DISCUSSION: Tixagevimab-cilgavimab demonstrated a low incidence of COVID-19 and COVID-19-related hospital admissions in patients who were immunocompromised, with no reported mortality. Furthermore, there were no significant adverse effects associated with the use of these monoclonal antibodies. CONCLUSION: Tixagevimab-cilgavimab exhibited a low incidence of COVID-19 and adverse effects in patients who were immunocompromised.

Syndrome of inappropriate secretion of anti-diuretic hormone due to hypothalamic hamartoma: use of tolvaptan.

OBJECTIVES: Hypothalamic hamartoma (HH) typically presents with gonadotrophin-dependent precocious puberty and/or seizures. Other endocrine disturbances are rare. We describe an infant with syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) and a HH. CASE PRESENTATION: A 6-week-old infant presented with seizures and life-threatening hyponatremia. A HH was identified on magnetic resonance imaging. Clinical examination and biochemistry were consistent with SIADH, and serum copeptin was high during hyponatremia, further supporting this diagnosis. Tolvaptan was effective in normalizing plasma sodium and enabling liberalization of fluids to ensure sufficient nutritional intake and weight gain and manage hunger. CONCLUSIONS: Hyponatremia due to SIADH is novel at presentation of a HH, and can be challenging to diagnose and manage. Successful management of hyponatremia in this case was achieved using tolvaptan.

Real-world evidence: new opportunities for osteoporosis research. Recommendations from a Working Group from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

This narrative review summarises the recommendations of a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) for the conduct and reporting of real-world evidence studies with a focus on osteoporosis research. PURPOSE: Vast amounts of data are routinely generated at every healthcare contact and activity, and there is increasing recognition that these real-world data can be analysed to generate scientific evidence. Real-world evidence (RWE) is increasingly used to delineate the natural history of disease, assess real-life drug effectiveness, understand adverse events and in health economic analysis. The aim of this work was to understand the benefits and limitations of this type of data and outline approaches to ensure that transparent and high-quality evidence is generated. METHODS: A ESCEO Working Group was convened in December 2022 to discuss the applicability of RWE to osteoporosis research and approaches to best practice. RESULTS: This narrative review summarises the agreed recommendations for the conduct and reporting of RWE studies with a focus on osteoporosis research. CONCLUSIONS: It is imperative that research using real-world data is conducted to the highest standards with close attention to limitations and biases of these data, and with transparency at all stages of study design, data acquisition and curation, analysis and reporting to increase the trustworthiness of RWE study findings.

Early Life Programming of Skeletal Health.

PURPOSE OF REVIEW: Increasing bone mineral accrual during childhood might delay the onset of osteoporosis. We discuss the scientific evidence for early life approaches to optimising skeletal health. RECENT FINDINGS: There is an ever-growing body of evidence from observational studies suggesting associations between early life exposures, particularly during foetal development, and bone mineral density (BMD). The findings of such studies are often heterogeneous, and for some exposures, for example, maternal smoking and alcohol intake in pregnancy or age at conception, intervention studies are not feasible. The most frequently studied exposures in intervention studies are calcium or vitamin D supplementation in pregnancy, which overall suggest positive effects on offspring childhood BMD. Maternal calcium and/or vitamin D supplementation during pregnancy appear to have positive effects on offspring BMD during early childhood, but further long-term follow-up is required to demonstrate persistence of the effect into later life.

The effect of pregnancy vitamin D supplementation on offspring bone mineral density in childhood: a systematic review and meta-analysis.

Systematic review and meta-analysis of the effect of moderate- to high-dose vitamin D supplementation in pregnancy on offspring bone mineralisation found a positive effect of vitamin D supplementation on offspring bone mineral density (BMD) at age 4-6 years, with a smaller effect on bone mineral content. PURPOSE: A systematic review and meta-analysis was performed to assess the effect of pregnancy vitamin D supplementation on offspring bone mineral density (BMD) in childhood. METHODS: A literature search was conducted for published RCTs of antenatal vitamin D supplementation with assessment of offspring BMD or bone mineral content (BMC) by dual-energy X-ray absorptiometry (DXA) using MEDLINE and EMBASE up to 13th July 2022. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Study findings were grouped in two age groups of offspring assessment: neonatal period and early childhood (3-6 years). Random-effects meta-analysis of the effect on BMC/BMD at 3-6 years was performed using RevMan 5.4.1, yielding standardised mean difference (SMD) (95% CI). RESULTS: Five RCTs were identified with offspring assessment of BMD or BMC; 3250 women were randomised within these studies. Risk of bias was low in 2 studies and "of concern" in 3. Supplementation regimes and the control used (3 studies used placebo and 2 used 400 IU/day cholecalciferol) varied, but in all studies the intervention increased maternal 25-hydroxvitamin D status compared to the control group. Two trials assessing BMD in the neonatal period (total n = 690) found no difference between groups, but meta-analysis was not performed as one trial represented 96.4% of those studied at this age. Three trials assessed offspring whole-body-less-head BMD at age 4-6 years. BMD was higher in children born to mothers supplemented with vitamin D [0.16 SD (95% confidence interval 0.05, 0.27), n = 1358] with a smaller effect on BMC [0.07 SD (95% CI - 0.04, 0.19), n = 1351]. CONCLUSIONS: There are few RCTs published to address this question, and these are inconsistent in methodology and findings. However, meta-analysis of three trials suggests moderate- to high-dose vitamin D supplementation in pregnancy might increase offspring BMD in early childhood, but further trials are required to confirm this finding. (Prospero CRD42021288682; no funding received).

Parent-Offspring Associations in Body Composition: Findings From the Southampton Women's Survey Prospective Cohort Study.

CONTEXT: Children born to parents who are overweight or obese have a high risk of adult obesity, but it is unclear if transgenerational associations relating to unfavorable body composition differ by parent. OBJECTIVE: To examine differential mother-offspring and father-offspring associations in body composition in early childhood. METHODS: A total of 240 mother-father-offspring trios from a prospective UK population-based pre-birth cohort (Southampton Women's Survey) were included for anthropometry and dual-energy x-ray absorptiometry assessment of whole-body-less-head body composition in the offspring at 3 different ages (4, 6-7, and 8-9 years) and in the mother and father at the 8- to 9-year offspring visit. Associations were assessed using linear regression adjusting for the other parent. RESULTS: Positive associations between mother-daughter body mass index (BMI) and fat mass were observed at ages 6 to 7 (BMI: ß = .29 SD/SD, 95% CI = .10, .48; fat mass ß = .27 SD/SD, 95% CI = .05, .48) and 8 to 9 years (BMI: ß = .33 SD/SD, 95% CI = .13, .54; fat mass ß = .31 SD/SD, 95% CI = .12, .49), with similar associations at age 4 years but bounding the 95% CI. The mother-son, father-son, and father-daughter associations for BMI and fat mass were weaker at each of the ages studied. CONCLUSION: A strong association between the fat mass of mothers and their daughters but not their sons was observed. In contrast, father-offspring body composition associations were not evident. The dimorphic parent-offspring effects suggest particular attention should be given to early prevention of unfavorable body composition in girls born to mothers with excess adiposity.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

BACKGROUND: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). METHODS: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. RESULTS: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode. CONCLUSIONS: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

Intracardiac thrombosis following intravenous zoledronate treatment in a child with steroid-induced osteoporosis.

OBJECTIVES: Bisphosphonates are used in childhood osteoporosis but can cause an acute phase reaction (APR) and hypocalcemia. We present a child with cardiac thrombosis following zoledronate, a previously unreported complication. CASE PRESENTATION: An 11-year-old with Duchenne muscular dystrophy and steroid-induced osteoporosis presented 48 h after first zoledronate infusion with fever, tachycardia, tachypnoea and hypoglycaemia. This was managed as acute adrenal crisis and possible sepsis. He also had hypocalcemia, hypophosphatemia, hyponatraemia and hypokalaemia. Echocardiography performed due to persistent chest pain and tachycardia revealed a left ventricular thrombus. CONCLUSIONS: Potential causes for intracardiac thrombosis in this patient include ventricular dysfunction due to acute adrenal crisis or electrolyte disturbance, and hypercoagulability due to the APR. Echocardiography should be considered in children with acute cardiovascular compromise following zoledronate. Stress-dose steroids to cover the APR and a reduced starting dose of zoledronate might have reduced the risk of this complication.

Confidence, consent and chaperones for pubertal staging examinations: a national survey.

OBJECTIVE: General Medical Council (GMC) guidance describes an intimate examination as one that may be embarrassing for the patient, for example, breast or genitalia examination. Documentation of consent and use of a trained impartial observer (chaperone) is recommended. Pubertal staging is often necessitated for assessment of growth and puberty. We assessed current practice of pubertal staging by paediatricians and paediatric endocrinology nurse specialists (PENS) in the UK. METHODS: An electronic survey was distributed to paediatricians (consultants and trainees) and PENS across the UK. The survey enquired about training received, confidence in and typical practice for pubertal staging examinations. RESULTS: 235 responses were received. Low confidence in pubertal staging was commonly reported by trainees and consultants without an endocrinology interest.Most respondents consider pubertal staging to be an intimate examination for male (94.9%) and female (93.1%) patients. Consent to examination is always documented by 38.2% of respondents. 62.0% and 54.8% report always using a chaperone for male and female pubertal staging, respectively. However, many respondents use a parent as the chaperone. Few document the name of the chaperone used. Patient objections and availability of chaperones were commonly perceived barriers to chaperone use. CONCLUSION: Most clinicians consider pubertal staging an intimate examination, but documentation of consent and use of formal chaperones is not standard practice. The use of a parent as a chaperone was common but is not recommended by the GMC. Local chaperone policies should address these issues to protect patients and clinicians.

Advances in Diagnosis and Management of Childhood Osteoporosis

Childhood osteoporosis leads to increased propensity to fracture, and thus is an important cause of morbidity, pain and healthcare utilisation. Osteoporosis in children may be caused by a primary bone defect or secondary to an underlying medical condition and/or its treatment. Primary osteoporosis is rare, but there is an increasing number of children with risk factors for secondary osteoporosis. Therefore it is imperative that all paediatricians are aware of the diagnostic criteria and baseline investigations for childhood osteoporosis to enable timely referral to a specialist in paediatric bone health. This review will discuss the approach to diagnosis, investigation and management of childhood osteoporosis, with particular consideration to advances in molecular diagnosis of primary bone disorders, and current and emerging therapies for fracture reduction.

Pregnancy Vitamin D Supplementation and Childhood Bone Mass at Age 4 Years: Findings From the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial.

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm2; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm2, p = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Maternal antenatal vitamin D supplementation and offspring risk of atopic eczema in the first 4 years of life: evidence from a randomized controlled trial.

BACKGROUND: Evidence linking prenatal maternal vitamin D supplementation with the offspring's risk of atopic eczema is inconsistent, with most data coming from observational studies. OBJECTIVES: To examine the influence of maternal cholecalciferol supplementation during pregnancy on the risk of atopic eczema in the offspring at ages 12, 24 and 48 months. METHODS: Within the UK Maternal Vitamin D Osteoporosis Study (MAVIDOS) double-blind, randomized placebo-controlled trial, we examined the relationship of maternal vitamin D supplementation during pregnancy with offspring atopic eczema at ages 12, 24 and 48 months. In MAVIDOS, pregnant women were allocated to either cholecalciferol 1000 IU per day or matched placebo, taken from around 14 weeks' gestation until delivery, with the primary outcome of neonatal whole-body bone mineral content. The prevalence of atopic eczema in the offspring was ascertained at ages 12 (n = 635), 24 (n = 610) and 48 (n = 449) months, based on the UK Working Party criteria for the definition of atopic dermatitis. The trial was registered with ISRCTN (82927713) and EudraCT (2007-001716-23). RESULTS: The characteristics of mothers and offspring were similar between the intervention and placebo groups, apart from longer breastfeeding duration in the intervention group. Adjusting for breastfeeding duration, offspring of mothers who received cholecalciferol 1000 IU daily had a lower odds ratio (OR) of atopic eczema at age 12 months [OR 0·55, 95% confidence interval (CI) 0·32-0·97, P = 0·04]; this effect weakened and was not statistically significant at ages 24 months (OR 0·76, 95% CI 0·47-1·23) or 48 months (OR 0·75, 95% CI 0·37-1·52). The statistical interaction of intervention and breastfeeding duration in relation to eczema at age 12 months was not significant (P = 0·41), but stratification showed reduced infantile eczema risk in the intervention group for infants breastfed for ≥ 1 month (OR 0·48, 95% CI 0·24-0·94, P = 0·03) but not in those breastfed for < 1 month (OR 0·80, 95% CI 0·29-2·17, P = 0·66). CONCLUSIONS: Our data provide the first randomized controlled trial evidence of a protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema, with the effect potentially being via increased breast milk cholecalciferol levels. The findings support a developmental influence on atopic eczema, and point to a potentially modifiable perinatal influence on atopic eczema. What is already known about this topic? There are currently no antenatal interventions proven to reduce the incidence of infantile atopic eczema in the general population. However, observational studies have led to speculation that antenatal vitamin D supplementation may be beneficial.

Maternal and Fetal Genetic Variation in Vitamin D Metabolism and Umbilical Cord Blood 25-Hydroxyvitamin D.

CONTEXT: Single nucleotide polymorphisms (SNPs) in vitamin D metabolism pathway genes are associated with circulating 25-hydroxyvitamin D (25(OH)D) in adults. Less is known about the relationships between mother and offspring SNPs and umbilical cord blood 25(OH)D. OBJECTIVE: (1) To undertake a meta-analysis of the relationships of maternal and offspring SNPs in the vitamin D metabolism pathway and cord blood 25(OH)D in pregnant women including novel data; and (2) to examine these relationships in women who received antenatal cholecalciferol supplementation in a clinical trial. METHODS: Novel data analysis from an observational mother-offspring cohort study (Southampton Women's Survey) and the MAVIDOS double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol supplementation in pregnancy, and an electronic literature search of published studies in PubMed up to 31 July 2021. Studies reporting associations between rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), or rs2282679 (GC) and cord blood 25(OH)D. One published study was included in addition to the novel data analysis. Associations between both maternal and offspring SNPs at rs2282679 (GC) and rs12785878 (DHCR7), and cord blood 25(OH)D were identified. When maternal genotype was adjusted for offspring genotype, and vice versa, there was persisting evidence for associations with maternal rs12785878 (ß [95% CI] 1.6 nmol/L [0.3, 2.8] per common allele), and offspring rs2282679 (ß 3.1 nmol/L ]2.0, 4.4] per common allele). Maternal and offspring SNPs at rs1074657 and rs613897 were not associated with cord blood 25(OH)D. RESULT: Associations between both maternal and offspring SNPs at rs2282679 (GC) and rs12785878 (DHCR7), and cord blood 25(OH)D were identified. When maternal genotype was adjusted for offspring genotype, and vice versa, there was persisting evidence for associations with maternal rs12785878 (ß [95% CI] 1.6 nmol/L [0.3, 2.8] per common allele), and offspring rs2282679 (ß 3.1 nmol/L ]2.0, 4.4] per common allele). Maternal and offspring SNPs at rs1074657 and rs613897 were not associated with cord blood 25(OH)D. CONCLUSION: Common genetic variation in the vitamin D metabolism pathway is associated with umbilical cord blood 25(OH)D.

Is the skull responsive to bone mineralisation stimuli in children?

BACKGROUND: Whole-body-less-head (WBLH) is the recommended skeletal region of interest (ROI) for dual-energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD) in children. Historically it has been suggested that the skull is less responsive than the rest of the skeleton to stimuli that affect BMD but there are few published data to support this notion. We compared the associations of BMD with anthropometric, body composition, diet, and activity variables across various ROI. METHODS: Children from the Southampton Women's Survey (SWS) mother-offspring cohort participated at age 6-7 years, including measurement of height, weight, and whole-body and lumbar spine (LS) BMD by DXA (Hologic Discovery). Physical activity was assessed by accelerometry (Actiheart) and diet by interviewer-led questionnaire. BMD was measured in the following skeletal ROI: whole-body, skull, WBLH and lower limbs (all derived from the whole-body scan) and LS. RESULTS: 1218 children participated. Height z-score, weight z-score, lean mass and milk intake were associated with skull BMD, but associations were weaker than observed for other ROI; for example, the association between lean mass and skull BMD was ß (95% CI) 0.11 (0.08, 0.14) SD/kg, compared with 0.32 (0.30, 0.34), 0.38 (0.37, 0.40) and 0.23 (0.21, 0.25) SD/kg for whole body, WBLH and lumbar spine, respectively. Relationships with whole-body BMD were attenuated compared with WBLH. CONCLUSION: Associations between skull BMD and anthropometry, body composition and dietary variables were weaker than for other DXA sites. These findings support, and importantly provide a quantitative basis for, the recommendation that the skull should be excluded from whole-body DXA analyses in children.

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit.

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.