Vitamin D3 among neonates born after in vitro fertilization compared with neonates from the general population.

INTRODUCTION: Sufficient levels of vitamin D have been associated with higher chances for both clinical pregnancy and live birth among women undergoing assisted reproductive techniques, whereas low levels of maternal vitamin D have been associated with preeclampsia and late miscarriage. In Denmark, subgroups at risk for low vitamin D levels, including neonates and toddlers, are recommended to use supplementation. The aim was to study the level of vitamin D3 among neonates born after in vitro fertilization compared with neonates from the general population. MATERIAL AND METHODS: In this cohort study a random sample of 1326 neonates representing the general population and 1200 neonates conceived by in vitro fertilization born in Denmark from 1995 to 2002 were identified from registries covering the whole Danish population. Information on use of assisted reproduction was collected from the Danish In Vitro Fertilization register, ICD-10 code: DZ358F. 25-Hydroxyvitamin D was measured from dried blood spots routinely collected by heel prick 48-72 h after birth and corrected according to the hematocrit fraction for capillary blood of neonates. Linear regression analysis was performed, both crude and adjusted, for predefined putative confounders, identified through directed acyclic graphs. RESULTS: Vitamin D3 analysis could be performed from a total of 1105 neonates from the general population and 1072 neonates conceived by in vitro fertilization that were subsequently included in the study. The median vitamin D3 was 24.0 nmol/L (interquartile range [IQR] 14.1-39.3) and 33.0 nmol/L (IQR 21.3-48.8) among neonates from the general population and neonates conceived by in vitro fertilization, respectively. The adjusted mean difference between neonates from the general population and those conceived by in vitro fertilization was 6.1 nmol/L (95% confidence interval 4.1-8.1). CONCLUSIONS: In this study, children born after in vitro fertilization have a higher vitamin D3 than a random sample of neonates in Denmark.

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.

Longitudinal Trajectories of Dietary Fibre Intake and Its Determinants in Early Childhood: Results from the Melbourne InFANT Program.

BACKGROUND: Optimal nutrition during early childhood, including dietary fibre intake, is important for children's health and development. Knowledge of fibre intake and its determinants in early childhood is limited. We aimed to describe fibre intake and sources and to identify trajectories of fibre intake at age 9, 18, 42, and 60 months and its child and maternal determinants. Associations between fibre trajectory groups and BMI z-scores and child overweight status were also assessed. METHODS: This is a secondary analysis of longitudinal data from the Melbourne InFANT Program, trial registration: Current Controlled Trials (ISRCTN81847050). Group-based trajectory modelling was used to identify trajectories of fibre intake from ages 9 to 60 months (n = 503). Multivariable logistic or linear regression was used to assess the determinants of fibre intake trajectories and the association between fibre intake trajectories and obesity outcomes. RESULTS: Four fibre intake trajectory groups were identified, with three groups following stable, rising trajectories of "Low" (52.3%), "Moderate" (32.2%), and "High" (13.3%), respectively. The remaining followed an "unstable" trajectory (2.2%). Girls versus boys were more likely to follow the "Low" fibre intake trajectory, whereas children who were breastfed for ≥6 months and whose mother had a university education were less likely to follow the "Low" fibre trajectory. No association was found between fibre trajectory groups and obesity outcomes. CONCLUSION: Most children followed a stable, rising trajectory of low fibre intake in early childhood. Child sex, breastfeeding duration and maternal education were significant determinants of low fibre intake trajectory.

The role of prenatal vitamin D on the development of childhood asthma and wheeze: An umbrella review of systematic reviews and meta-analyses.

BACKGROUND & OBJECTIVE: It has been suggested that prenatal vitamin D plays a role in the development of childhood asthma and wheeze. Several systematic reviews have been conducted, but the results are inconsistent, and the methodological quality has not been studied. Therefore, the objective of this umbrella review was to assess the internal validity of the evidence base and the evidence for an association between prenatal vitamin D and asthma or wheezing in the offspring. METHODS: We searched the electronic databases Embase, PubMed, and Cochrane Library for studies on prenatal vitamin D using search words such as vitamin D, 25-hydroxyvitamin D, calcidiol, fetal, and neonatal. The search was conducted in June 2020, and the databases were searched from their date of establishment. We included systematic reviews and/or meta-analyses of experimental and observational studies assessing the association between prenatal vitamin D or asthma and wheeze. We excluded narrative reviews, commentaries, and other umbrella reviews. The methodological quality of systematic reviews was assessed using AMSTAR 2 tool. PROSPERO reg. no. CRD42020151329. RESULTS: We identified 22 eligible systematic reviews (17 on asthma and 20 on wheeze). Using the AMSTAR 2 quality assessment tool, the methodological quality was rated as critically low in 21 out of 22 systematic reviews, suggesting that previous reviews and meta-analyses did not provide accurate and comprehensive summaries of the included studies and that conclusions reached were potentially flawed. The majority of the included reviews reported that prenatal vitamin D reduces the risk of wheeze in the offspring. CONCLUSION: Prior to informing public guidelines, high-quality systematic reviews of the current evidence are greatly warranted.

Vitamin D Concentrations at Birth and the Risk of Rheumatoid Arthritis in Early Adulthood: A Danish Population-Based Case-Cohort Study.

Background: Low vitamin D in pregnancy may impair the development of the fetal immune system and influence the risk of later development of rheumatoid arthritis (RA) in the offspring. The aim was to examine whether lower 25-hydroxyvitamin D3 (25(OH)D) concentrations at birth were associated with the risk of developing RA in early adulthood. Methods: This case-cohort study obtained data from Danish registers and biobanks. Cases included all individuals born during 1981−1996 and recorded in the Danish National Patient Register with a diagnosis of RA with age >18 years at first admission. The random comparison consisted of a subset of Danish children. Vitamin D concentrations were measured in newborn dried blood. In total, 805 RA cases and 2416 individuals from the subcohort were included in the final analysis. Weighted Cox regression was used to calculate hazard ratio (HR). Results: The median (interquartile rage (IQR)) 25(OH)D concentrations among cases were 24.9 nmol/L (IQR:15.4;36.9) and 23.9 nmol/L (IQR:13.6;36.4) among the subcohort. There was no indication of a lower risk of RA among individuals in the highest vitamin D quintile compared with the lowest (HRadj.:1.21 (0.90;1.63)). Conclusion: The risk of RA in early adulthood was not associated with vitamin D concentrations at birth.

Newly Diagnosed Celiac Disease and Bone Health in Young Adults: A Systematic Literature Review.

Celiac disease (CD), a gluten-induced autoimmune disease, is associated with low bone mineral density (BMD) among children. Unfortunately, it is often diagnosed in adulthood, which may lead to an increased risk of fragile bones. The aim of this systematic review was to report on BMD status among young adults newly diagnosed with CD, and to examine the effect of a gluten-free diet (GFD), nutritional supplements, such as vitamin D, or antiresorptive medications on BMD recovery. Databases searched were Medline, Embase, and Cochrane Library up to July 2nd, 2020. Both observational studies and clinical trials were considered, if patients were newly diagnosed and between 20 and 35 years of age and reported on BMD. We critically appraised the identified studies using ROBINS-I and summarized the findings narratively. Out of 3991 references, we identified 3 eligible studies: one cross-sectional study and two longitudinal studies. In total, 188 patients were included, and the study population consisted primarily of women with an age range between 29 and 37 years old. Compared to healthy controls, our target population had lower BMD. Moreover, a strict GFD may increase BMD during a follow-up period of up to 5 years. Newly diagnosed CD patients aged 20-35 years are at risk of lower BMD. Therefore, it may be crucial to assess BMD at time of diagnosis in young women. Whether the results can be extrapolated to young men is unknown. While strict GFD may improve BMD over time, there is a lack of robust evidence to demonstrate that nutritional supplements or antiresorptive agents are beneficial in the prevention of fragile bones in this age group.

Assessing Health Consequences of Vitamin D Fortification Utilizing a Societal Experiment Design: Methodological Lessons Learned from the D-Tect Project.

By utilizing historical changes in Danish legislation related to mandatory vitamin D fortification of margarine, which was implemented in the mid 1930s and abruptly abandoned in June 1985, the studies in the D-tect project investigated the effects of vitamin D on health outcomes in individuals, who during gestation were exposed or unexposed to extra vitamin D from fortified margarine. This paper reviews and narratively summarizes the analytic approaches alongside the results of the societal fortification experiment studies from the D-tect project and addresses the challenges in designing societal experiment studies and evaluating their results. The latter are discussed as lessons learned that may be useful for designers of similar studies, expected to be extensively utilized while researching the health consequences of the COVID-19 pandemic by comparing individuals born before and after the epidemic. In the D-tect project, 16 articles based on the societal fortification experiment were published analyzing 10 different outcomes and using different statistical approaches. Lessons learned included the detail of the analysis of the historical information on the exposure, availability and validity of the outcome data, variety of analytical approaches, and specifics concerning vitamin D effect evaluation, such as consideration of the influence of sunshine or season. In conclusion, the D-tect project clearly demonstrated the cost-effectiveness and research potential of natural- or societal-experiment-based studies.

Age and Sex Specific Trends in Incidence of Juvenile Idiopathic Arthritis in Danish Birth Cohorts from 1992 to 2002: A Nationwide Register Linkage Study.

This study reports age- and sex-specific incidence rates of juvenile idiopathic arthritis (JIA) in complete Danish birth cohorts from 1992 through 2002. Data were obtained from the Danish registries. All persons born in Denmark, from 1992-2002, were followed from birth and until either the date of first diagnosis recording, death, emigration, 16th birthday or administrative censoring (17 May 2017), whichever came first. The number of incident JIA cases and its incidence rate (per 100,000 person-years) were calculated within sex and age group for each of the birth cohorts. A multiplicative Poisson regression model was used to analyze the variation in the incidence rates by age and year of birth for boys and girls separately. The overall incidence of JIA was 24.1 (23.6-24.5) per 100,000 person-years. The rate per 100,000 person-years was higher among girls (29.9 (29.2-30.7)) than among boys (18.5 (18.0-19.1)). There were no evident peaks for any age group at diagnosis for boys but for girls two small peaks appeared at ages 0-5 years and 12-15 years. This study showed that the incidence rates of JIA in Denmark were higher for girls than for boys and remained stable over the observed period for both sexes.

Vitamin D concentrations from neonatal dried blood spots and the risk of early-onset type 2 diabetes in the Danish D-tect case-cohort study.

AIMS/HYPOTHESIS: The aim of this study was to examine the influence of neonatal vitamin D concentration on the development of early-onset type 2 diabetes in a large population sample. METHODS: We conducted a case-cohort study utilising data from the Danish biobank and registers. Neonatal vitamin D was assessed measuring 25-hydroxyvitamin D3 [25(OH)D3] concentrations on the dried blood spot samples from the Biological Specimen Bank for Neonatal Screening. Cases of type 2 diabetes (n = 731) were retrieved from the Danish National Patient Register for all individuals born in Denmark between 1 May 1981 and 31 December 1992. The sub-cohort (n = 1765) was randomly selected from all children born in the same period. We used a weighted Cox proportional hazard model assessing the hazard of first type 2 diabetes diagnoses by quintiles of 25(OH)D3 and restricted cubic spline. RESULTS: The median 25(OH)D3 concentration (IQR) among cases was 21.3 nmol/l (13.3-34.1) and 23.9 nmol/l (13.7-35.7) in the sub-cohort. There was no indication of a potential lower risk of early-onset type 2 diabetes among individuals in the higher quintile of vitamin D concentration compared with the lowest (HRcrude 0.97 [95% CI 0.71, 1.33] p = 0.85; HRadjusted 1.29 [95% CI 0.92, 1.83] p = 0.14). CONCLUSIONS/INTERPRETATION: The results of this study do not support the hypothesis that higher neonatal vitamin D concentrations are associated with a lower risk of early-onset type 2 diabetes in adulthood.

Neonatal vitamin D status and risk of childhood epilepsy.

OBJECTIVE: Epilepsy is a nervous system abnormality that may be caused by unknown exposures during fetal development. Studies have shown neuroprotective effects of early exposure to vitamin D in other neurological disorders, and seasonal variation in birth of children with epilepsy. We aimed to investigate if neonatal 25(OH)D3 was associated with risk of childhood epilepsy. METHODS: This case-cohort study compared neonatal 25(OH)D3 levels from children with epilepsy (n = 403) and a random selected cohort of controls (n = 1163), assessing the hazard of first epilepsy diagnosis between 1 and 4 years of age from a weighted Cox proportional hazard model. Analyses were adjusted for parental education, maternal age, maternal epilepsy, maternal ethnicity, and gestational age, and additionally for season of birth and smoking during pregnancy. RESULTS: The mean (standard deviation [SD]) of neonatal 25(OH)D3 levels were 30.8(19.6) nmol/L among cases and 28.5(19.4) nmol/L among the cohort. The hazard ratio (HR) of epilepsy was in a dose-response pattern higher among children from the highest neonatal 25(OH)D3 quintiles (P-trend = .004). Results were unchanged after including season of birth in the analysis, where a significantly higher HR of epilepsy was observed among children in the two highest quintiles compared to children in the lowest quintile (Q4: HRadj  1.62, 95% CI 1.07-2.47 and Q5: HRadj  1.86, 95% CI 1.21-2.86). SIGNIFICANCE: In this study, the risk of childhood epilepsy increased with neonatal 25(OH)D3 categories in a dose-response pattern, suggesting an association between a high neonatal 25(OH)D3 and the risk of childhood epilepsy. Considering that adjusting for season of birth strengthened the results, we conclude that maternal intake of vitamin D, and not vitamin D from sun exposure, was the vitamin D source associated with epilepsy. Although we cannot, in the present study, control for compounds in the diet like pollutants or heavy metals, which may correlate with dietary vitamin D, future studies investigating fetal origin of epilepsy should focus on compounds correlating with vitamin D.

Neonatal Vitamin D Status and Risk of Asthma in Childhood: Results from the D-Tect Study.

BACKGROUND: low vitamin D status in pregnancy can influence the offspring's lung function and contribute to childhood asthma development. The objective of this study was to examine the influence of neonatal vitamin D status on the development of asthma among children age 3-9 years in a large population sample. METHOD: in a case-cohort study utilizing a Danish biobank and register data we examined the association between neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentrations and incidence of asthma among children aged 3-9 years. Cases of asthma (n = 911) were randomly selected among all cases of asthma in the Danish National Patient Register from children born between 1992 and 2002. The sub-cohort (n = 1423) was randomly selected among all children born in the same period. We used a weighted Cox proportional hazard model assessing the hazard of first asthma diagnoses by quintiles of 25(OH)D3. RESULTS: the median 25(OH)D3 (interquartile range) for asthma cases was 23 nmol/L (14-35) and the sub-cohort 25 nmol/L (14-40). The hazard ratio for developing asthma between ages 3 and 9 years was lower for children in the fifth quintile of neonatal 25(OH)D3 compared to children in the first quintile, both in the unadjusted (0.61 95% CI: 0.46-0.80) and adjusted (0.55 95% CI: 0.39-0.77) analyses. CONCLUSION: the results from our study suggest that higher neonatal vitamin D concentration may reduce the risk of developing childhood asthma at ages 3-9 years, indicating that neonatal vitamin D status as a proxy of vitamin D status during the prenatal period is important for normal immune- and lung development.

Neonatal vitamin D levels and cognitive ability in young adulthood.

PURPOSE: Intelligence has a strong influence on life capability, and thus, identifying early modifiable risk factors related to cognitive ability is of major public health interest. During pregnancy, vitamin D is transported from the mother to the fetus through the placenta in the form of 25-hydroxyvitamin D (25(OH)D). Levels of 25(OH)D have in some studies been associated with childhood neurodevelopment; however, results from all studies are not in agreement. We investigated if neonatal 25(OH)D3 concentrations were associated with Børge Priens IQ test score (BPP) in young adulthood. METHODS: In this nested cohort study, 25(OH)D3 concentrations were measured in dried blood spots from 818 newborns. We followed the children for their IQ BPP test scores in the Danish Conscription Register, which holds information on test results from the BPP test on individuals who have been recruited for Danish mandatory military draft board examination. Using general linear models, we investigated the crude and adjusted relationship between quintiles of 25(OH)D3 concentrations and BPP IQ test results. RESULTS: The study population consisted of 95.8% men, with a mean age of 19.4 years. The median and range of the neonatal 25(OH)D3 levels were 26.2 nmol/L (0-104.7 nmol/L). The overall Wald test did not show an association between neonatal 25(OH)D3 levels and BPP IQ scores (p = 0.23); however, individuals within the 3rd (BPP IQ = 101.0, 98.0-103.9) and 4th (BPP IQ = 101.2, 99.1-104.3) quintiles had slightly higher BPP IQ scores than individuals from the first quintile (BPP IQ = 97.6, 94.6-100.6). CONCLUSIONS: Our results support the hypothesis that individuals with the lowest levels of neonatal vitamin D might have slightly lower BPP. However, more studies are needed with larger study populations to confirm our results.

Exposure to Vitamin D Fortification Policy in Prenatal Life and the Risk of Childhood Asthma: Results From the D-Tect Study.

Prenatal vitamin D insufficiency may be associated with an increased risk of developing childhood asthma. Results from epidemiological studies are conflicting and limited by short follow-up and small sample sizes. The objective of this study was to examine if children born to women exposed to the margarine fortification policy with a small dose of extra vitamin D during pregnancy had a reduced risk of developing asthma until age 9 years, compared to children born to unexposed women. The termination of a Danish mandatory vitamin D fortification policy constituted the basis for the study design. We compared the risk of inpatient asthma diagnoses in all Danish children born two years before (n = 106,347, exposed) and two years after (n = 115,900, unexposed) the termination of the policy. The children were followed in the register from 0-9 years of age. Data were analyzed using Cox proportional hazards regression. The Hazard Ratio for the first inpatient asthma admission among exposed versus unexposed children was 0.96 (95%CI: 0.90-1.04). When stratifying by sex and age, 0-3 years old boys exposed to vitamin D fortification showed a lower asthma risk compared to unexposed boys (HR 0.78, 95%CI: 0.67-0.92). Prenatal exposure to margarine fortification policy with extra vitamin D did not affect the overall risk of developing asthma among children aged 0-9 years but seemed to reduce the risk among 0-3 years old boys. Taking aside study design limitations, this could be explained by different sensitivity to vitamin D from different sex-related asthma phenotypes in children with early onset, and sex differences in lung development or immune responses.

In utero exposure to extra vitamin D from food fortification and the risk of subsequent development of gestational diabetes: the D-tect study.

BACKGROUND: The primary aim of this study was to assess whether exposure during fetal life to extra vitamin D from food fortification was associated with a reduction in the risk of subsequently developing gestational diabetes mellitus (GDM). Furthermore, we examined whether the effect of the vitamin D from fortification differed by women's season of birth. METHODS: This semi-ecological study is based on the cancellation in 1985 of the mandatory policy to fortify margarine with vitamin D in Denmark, with inclusion of entire national adjacent birth cohorts either exposed or unexposed to extra vitamin D in utero. The identification of GDM cases later in life among both exposure groups was based on the Danish national health registers. Logistic regression analyses generating odds ratios (ORs) and 95% confidence intervals (95% CIs) were performed. RESULTS: Women who were prenatally exposed to the extra vitamin D from fortification tended to have a lower risk of subsequently developing GDM than unexposed women (OR 0.87, 95%CI 0.74,1.02, P = 0.08). When analyses were stratified by women's season of birth, exposed women born in spring had a lower risk of developing GDM compared to unexposed subjects (OR 0.68, 95%CI 0.50,0.94, p = 0.02). CONCLUSION: This study suggests that prenatal exposure to extra vitamin D from mandatory fortification may lower the risk of developing gestational diabetes among spring-born women. TRIAL REGISTRATION: This study is part of the D-tect project, which is registered on clinicaltrials.gov: NCT03330301 .