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.

Perfluoroalkyl substances and time to pregnancy in couples from Greenland, Poland and Ukraine.

BACKGROUND: Perfluoroalkyl substances (PFAS) are suggested to affect human fecundity through longer time to pregnancy (TTP). We studied the relationship between four abundant PFAS and TTP in pregnant women from Greenland, Poland and Ukraine representing varying PFAS exposures and pregnancy planning behaviors. METHODS: We measured serum levels of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) in 938 women from Greenland (448 women), Poland (203 women) and Ukraine (287 women). PFAS exposure was assessed on a continuous logarithm transformed scale and in country-specific tertiles. We used Cox discrete-time models and logistic regression to estimate fecundability ratios (FRs) and infertility (TTP >13 months) odds ratios (ORs), respectively, and 95% confidence intervals (CI) according to PFAS levels. Adjusted analyses of the association between PFAS and TTP were done for each study population and in a pooled sample. RESULTS: Higher PFNA levels were associated with longer TTP in the pooled sample (log-scale FR = 0.80; 95% CI 0.69-0.94) and specifically in women from Greenland (log-scale FR = 0.72; 95% CI 0.58-0.89). ORs for infertility were also increased in the pooled sample (log-scale OR = 1.53; 95% CI 1.08-2.15) and in women from Greenland (log-scale OR = 1.97; 95% CI 1.22-3.19). However, in a sensitivity analysis of primiparous women these associations could not be replicated. Associations with PFNA were weaker for women from Poland and Ukraine. PFOS, PFOA and PFHxS were not consistently associated with TTP. CONCLUSIONS: Findings do not provide consistent evidence that environmental exposure to PFAS is impairing female fecundity by delaying time taken to conceive.

Attained body mass index among children attending rural outdoor or urban conventional kindergartens.

Objective: This study aimed to examine whether children in rural outdoor kindergartens had attained a lower body mass index z-score (BMIz) and were at lower risk of overweight after school entrance compared to children in urban conventional kindergartens. Methods: This is a longitudinal observational study of 1,544 children from outdoor kindergartens and 1,640 from conventional kindergartens. The mean age at kindergarten enrolment was 3.5 years (SD: 0.9) in the outdoor kindergartens and 3.6 years (SD: 1.0) in the conventional kindergartens. Anthropometry was measured after school entry by school health nurses when the children were 6 to 8 years old. Attained BMIz was included as the primary outcome. The risk of attaining overweight (including obesity) was included as a secondary outcome. Register-based information was available on potential confounding factors. Linear and logistic regression models were used to assess group differences in outcome measures. Results: Our basic models, with information on outcome, kindergarten type, and birth weight showed a borderline statistically significantly lower attained BMIz (-0.07 [95% CI: -0.14, 0.00], P = 0.060) and a lower risk of overweight (adjusted risk ratio: 0.83 [95% CI: 0.72, 0.97], P = 0.016) among children attending outdoor kindergartens. However, when adjusting for sociodemographic factors and parental BMI, there was no evidence of differences in attained BMIz (P = 0.153) or overweight (P = 0.967). Conclusion: When considering confounding factors, our findings indicate no differences in attained BMIz or risk of overweight after school entry among children attending rural outdoor kindergartens compared to those attending urban conventional kindergartens.

Substituting sedentary time with sleep or physical activity and subsequent weight-loss maintenance.

OBJECTIVE: In this study, the associations between the substitution of sedentary time with sleep or physical activity at different intensities and subsequent weight-loss maintenance were examined. METHODS: This prospective study included 1152 adults from the NoHoW trial who had achieved a successful weight loss of ≥5% during the 12 months prior to baseline and had BMI ≥25 kg/m2 before losing weight. Physical activity and sleep were objectively measured during a 14-day period at baseline. Change in body weight was included as the primary outcome. Secondary outcomes were changes in body fat percentage and waist circumference. Cardiometabolic variables were included as exploratory outcomes. RESULTS: Using isotemporal substitution models, no associations were found between activity substitutions and changes in body weight or waist circumference. However, the substitution of sedentary behavior with moderate-to-vigorous physical activity was associated with a decrease in body fat percentage during the first 6 months of the trial (-0.33% per 30 minutes higher moderate-to-vigorous physical activity [95% CI: -0.60% to -0.07%], p = 0.013). CONCLUSIONS: Sedentary behavior had little or no influence on subsequent weight-loss maintenance, but during the early stages of a weight-loss maintenance program, substituting sedentary behavior with moderate-to-vigorous physical activity may prevent a gain in body fat percentage.

A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment.

BACKGROUND: The fetal brain starts developing early and animal studies have suggested that iron plays several roles for the development, but results from epidemiological studies investigating associations between gestational iron and offspring neurodevelopment are inconsistent. OBJECTIVE: To systematically examine results from observational studies and RCTs on gestational iron and offspring neurodevelopment, with focus on the importance of four domains: iron status indicators, exposure timing, neurodevelopmental outcomes, and offspring age. METHODS: PRISMA guidelines were followed. Embase, PsychInfo, Scopus, and The Cochrane library were searched in September 2017 and February 2018. Overall, 3307 articles were identified and 108 retrieved for full-text assessment. Pre-specified eligibility criteria were used to select studies and 27 articles were included;19 observational and 8 RCTs. RESULTS: Iron status in pregnancy was associated with offspring behavior, cognition, and academic achievement. The direction of associations with behavioral outcomes were unclear and the conclusions related to cognition and academic achievement were based on few studies, only. Little evidence was found for associations with motor development. Observed associations were shown to persist beyond infancy into adolescence, and results depended on iron status indicator type but not on the timing of exposure. CONCLUSION: We conclude that there is some evidence that low pregnancy iron, possibly particularly in the 3rd trimester, may be associated with adverse offspring neurodevelopment. As most previous research used Hemoglobin, inferring results to iron deficiency should be done with caution. No conclusions could be reached regarding associations beyond early childhood, and supplementation with iron during pregnancy did not seem to influence offspring neurodevelopment.

Associations between vitamin D status in pregnancy and offspring neurodevelopment: a systematic literature review.

CONTEXT: Vitamin D plays an important role in the development of the brain, which is one of the earliest fetal organs to develop. Results from epidemiological studies investigating associations between maternal levels of vitamin D during pregnancy and offspring neurodevelopment are mixed and inconclusive. OBJECTIVE: This systematic review of studies that examined vitamin D levels in pregnancy and offspring neurodevelopment used 3 specific domains-timing of exposure during pregnancy trimesters, neurodevelopmental outcomes, and offspring age at assessment of outcomes-to determine whether vitamin D status in pregnancy is associated with offspring neurodevelopment. DATA SOURCES: A search of the Embase, PsychInfo, Scopus, and The Cochrane Library databases in September 2017 and February 2018 identified 844 articles, of which 46 were retrieved for full-text assessment. STUDY SELECTION: Eligibility criteria were used to select studies. All authors examined the studies, and consensus was reached through discussion. Results were divided according to the 3 domains. DATA EXTRACTION: Authors examined the studies independently, and data from eligible studies were extracted using a modified version of the Cochrane data collection form. Using the modified Downs and Black checklist, 2 authors assessed the quality of the studies independently and were blinded to each other's assessment. Consensus was reached upon discussion and with the involvement of the third author. RESULTS: Fifteen observational studies were included. Vitamin D in pregnancy was associated with offspring language and motor skills in young children. Associations persisted into adolescence, and results were not dependent on the timing of vitamin D exposure during pregnancy. No supplementation studies were identified. CONCLUSIONS: There is some evidence that low vitamin D status in pregnancy is associated with offspring language and motor development, particularly in young children. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42017078312.

Exposure to perfluoroalkyl substances and sperm DNA global methylation in Arctic and European populations.

Perfluoroalkyl substances (PFASs) are widely used in a variety of industrial processes and products, and have been detected globally in humans and wildlife. PFASs are suspected to interfere with endocrine signaling and to adversely affect human reproductive health. The aim of the present study was to investigate the associations between exposure to PFASs and sperm global methylation levels in a population of non-occupationally exposed fertile men. Measurements of PFASs in serum from 262 partners of pregnant women from Greenland, Poland and Ukraine, were also carried out by liquid chromatography tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) were detected in 97% of the blood samples. Two surrogate markers were used to assess DNA global methylation levels in semen samples from the same men: (a) average DNA methylation level in repetitive DNA sequences (Alu, LINE-1, Satα) quantified by PCR-pyrosequencing after bisulfite conversion; (b) flow cytometric immunodetection of 5-methyl-cytosines. After multivariate linear regression analysis, no major consistent associations between PFASs exposure and sperm DNA global methylation endpoints could be detected. However, since weak but statistically significant associations of different PFASs with DNA hypo- and hyper-methylation were found in some of the studied populations, effects of PFASs on sperm epigenetic processes cannot be completely excluded, and this issue warrants further investigation.

Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men: a cross-sectional study.

Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml(-1) in Greenland (0.2-385.8 ng ml(-1)), 1.0 ng ml(-1) in Poland (0.2-6.4 ng ml(-1)) and 1.0 ng ml(-1) in Ukraine (0.2-4.9 ng ml(-1)). We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland (ß=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (ß=0.067, 95% CI=0.024 to 0.110). The association may be due to beneficial effects of polyunsaturated fatty acids (PUFAs), which are contained in seafood and fish. No significant association (P>0.05) was found between blood concentrations of mercury and any of the other measured semen characteristics (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormones (free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and LH × testosterone) in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng ml(-1) has adverse effects on biomarkers of male reproductive health.

Relationship between apoptotic markers in semen from fertile men and demographic, hormonal and seminal characteristics.

Apoptosis in the testis has two putative roles during normal spermatogenesis; limitation of the germ cell population to numbers that can be supported by the Sertoli cells, and, possibly, selective depletion of meiotic and postmeiotic abnormal germ cells. We investigated the demographic and biological correlates of the pro-apoptotic marker Fas and the anti-apoptotic marker Bcl-xL in sperm cells of fertile men. Six hundred and four men from Greenland, Poland and Ukraine were consecutively enrolled during their pregnant wife's antenatal visits. Semen analysis was performed as recommended by the World Health Organization. Immunofluorescence coupled to flow cytometry was utilized for detection of apoptotic markers in the sperm cell. DNA damage was assessed by flow cytometry using both the sperm chromatin structure assay (SCSA) and the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. The percentage of Fas-positive sperm cells was higher in men with high total sperm count (P<0.01), more motile sperms (P=0.04) and fewer sperm head defects (P=0.05). These associations were consistent within and across study regions. Furthermore, testosterone, follicle-stimulating hormone (FSH) and sexual hormone-binding globulin (SHBG) were significantly negatively correlated with Fas within and across regions as well. The data indicated no association between the anti-apoptotic Bcl-xL marker and semen or personal characteristics. The finding of Fas-positive sperm cells associated with better semen quality in a cohort of spouses of pregnant women seems different from previous data obtained in infertile men and warrants further investigation to clarify the biological significance of sperm apoptotic markers.