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Longitudinal Development of Brain Iron Is Linked to Cognition in Youth

Journal of Neuroscience 26 February 2020, 40 (9) 1810-1818; DOI:

Brain iron is vital to multiple aspects of brain function, including oxidative metabolism, myelination, and neurotransmitter synthesis. Atypical iron concentration in the basal ganglia is associated with neurodegenerative disorders in aging and cognitive deficits. However, the normative development of brain iron concentration in adolescence and its relationship to cognition are less well understood. Here, we address this gap in a longitudinal sample of 922 humans aged 8–26 years at the first visit (M = 15.1, SD = 3.72; 336 males, 486 females) with up to four multiecho T2* scans each. Using this sample of 1236 imaging sessions, we assessed the longitudinal developmental trajectories of tissue iron in the basal ganglia. We quantified tissue iron concentration using R2* relaxometry within four basal ganglia regions, including the caudate, putamen, nucleus accumbens, and globus pallidus. The longitudinal development of R2* was modeled using generalized additive mixed models (GAMMs) with splines to capture linear and nonlinear developmental processes. We observed significant increases in R2* across all regions, with the greatest and most prolonged increases occurring in the globus pallidus and putamen. Further, we found that the developmental trajectory of R2* in the putamen is significantly related to individual differences in cognitive ability, such that greater cognitive ability is increasingly associated with greater iron concentration through late adolescence and young-adulthood. Together, our results suggest a prolonged period of basal ganglia iron enrichment that extends into the mid-twenties, with diminished iron concentration associated with poorer cognitive ability during late adolescence.

Means RT. (2020). Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood Parameters. Nutrients , 12, . PMID: 32053933 DOI.

Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood Parameters Abstract A normal pregnancy consumes 500-800 mg of iron from the mother. Premenopausal women have a high incidence of marginal iron stores or iron deficiency (ID), with or without anemia, particularly in the less developed world. Although pregnancy is associated with a "physiologic" anemia largely related to maternal volume expansion; it is paradoxically associated with an increase in erythrocyte production and erythrocyte mass/kg. ID is a limiting factor for this erythrocyte mass expansion and can contribute to adverse pregnancy outcomes. This review summarizes erythrocyte and iron balance observed in pregnancy; its implications and impact on mother and child; and provides an overview of approaches to the recognition of ID in pregnancy and its management, including clinically relevant questions for further investigation. KEYWORDS: iron balance; iron deficiency; iron deficiency anemia; iron supplementation; laboratory testing; pregnancy PMID: 32053933 DOI: 10.3390/nu12020447

Stoltzfus RJ, Dreyfuss ML. Guidelines for the Use of Iron Supplements to Prevent and Treat Iron Deficiency Anemia. (1998) Geneva, Switzerland: International Nutritional Anemia Consultative Group/ UNICEF/WHO


Gynecol Endocrinol. 2019 Jan 1:1-4. doi: 10.1080/09513590.2018.1548593. [Epub ahead of print] Lower vitamin D levels during the second trimester are associated with developing gestational diabetes mellitus: an observational cross-sectional study. Ede G1, Keskin U2, Cemal Yenen M3, Samur G1. Author information Abstract In this study, we aimed to compare serum 25(OH)D levels in women with and without gestational diabetes mellitus (GDM), and to identify the serum 25(OH)D levels associated with GDM. We recruited 40 women with GDM and 40 healthy pregnant women, aged 20-40 years and in the second trimester, at Gulhane Education and Research Hospital. We excluded women with chronic diseases, preeclampsia, pre-GDM, multiple pregnancies, and those taking medications related to calcium or vitamin D metabolism. We took anthropometric measurements and blood samples during the second trimester. Of the 80 pregnant women, pre-pregnancy body mass index was significantly higher among the GDM group than the healthy group (26.4 ± 5.73 kg/m2 vs. 22.6 ± 3.56 kg/m2, p = .001). Serum 25(OH)D levels in women with GDM were significantly lower than those in healthy women (16.8 ± 9.90 ng/mL vs. 20.9 ± 8.16 ng/mL, p = .016). The prevalence of severe vitamin D deficiency was as high as 72.5% among women in the GDM group, with a 1.74-fold increased risk of deficient status. Levels of 25(OH)D lower than a cutoff value of 14.0 ng/mL were determined to be related to GDM. These study results suggest that maternal vitamin D deficiency in mid-pregnancy is significantly associated with development of GDM.

KEYWORDS: 25(OH)D; Gestational diabetes mellitus; pregnancy; second trimester; vitamin D deficiency PMID: 30599810 DOI: 10.1080/09513590.2018.1548593


The effect of Ramadan fasting during pregnancy on perinatal outcomes: a systematic review and meta-analysis

BMC Pregnancy Childbirth. 2018 Oct 25;18(1):421. doi: 10.1186/s12884-018-2048-y.

Glazier JD1, Hayes DJL1, Hussain S1, D'Souza SW1, Whitcombe J2, Heazell AEP1, Ashton N3. Author information Abstract BACKGROUND: Although exempt, many pregnant Muslim women partake in the daily fast during daylight hours during the month of Ramadan. In other contexts an impoverished diet during pregnancy impacts on birth weight. The aim of this systematic review was to determine whether Ramadan fasting by pregnant women affects perinatal outcomes. Primary outcomes investigated were perinatal mortality, preterm birth and small for gestational age (SGA) infants. Secondary outcomes investigated were stillbirth, neonatal death, maternal death, hypertensive disorders of pregnancy, gestational diabetes, congenital abnormalities, serious neonatal morbidity, birth weight, preterm birth and placental weight. METHODS: Systematic review and meta-analysis of observational studies and randomised controlled trials was conducted in EMBASE, MEDLINE, CINAHL, Web of Science, Google Scholar, the Health Management Information Consortium and Applied Social Sciences Index and Abstracts. Studies from any year were eligible. Studies reporting predefined perinatal outcomes in pregnancies exposed to Ramadan fasting were included. Cohort studies with no comparator group or that considered fasting outside pregnancy were excluded, as were studies assuming fasting practice based solely upon family name. Quality of included studies was assessed using the ROBINS-I tool for assessing risk of bias in non-randomised studies. Analyses were performed in STATA. RESULTS: From 375 records, 22 studies of 31,374 pregnancies were included, of which 18,920 pregnancies were exposed to Ramadan fasting. Birth weight was reported in 21 studies and was not affected by maternal fasting (standardised mean difference [SMD] 0.03, 95% CI 0.00 to 0.05). Placental weight was significantly lower in fasting mothers (SMD -0.94, 95% CI -0.97 to  -0.90), although this observation was dominated by a single large study. No data were presented for perinatal mortality. Ramadan fasting had no effect on preterm delivery (odds ratio 0.99, 95% CI 0.72 to 1.37) based on 5600 pregnancies (1193 exposed to Ramadan fasting). CONCLUSIONS: Ramadan fasting does not adversely affect birth weight although there is insufficient evidence regarding potential effects on other perinatal outcomes. Further studies are needed to accurately determine whether Ramadan fasting is associated with adverse maternal or neonatal outcome. KEYWORDS: Birth weight; Fasting; Placenta; Pregnancy; Ramadan PMID: 30359228 PMCID: PMC6202808 DOI: 10.1186/s12884-018-2048-y

National Iodine Deficiency Disorders Control Programme: Current status & future strategy

Indian J Med Res. 2018 Nov;148(5):503-510. doi: 10.4103/ijmr.IJMR_1717_18.

Yadav K1, Pandav CS2. Author information Abstract Iodine deficiency disorders (IDDs) constitute a significant public health problem globally. In India, the entire population is prone to IDDs due to deficiency of iodine in the soil of the sub-continent and thus both animal and plant source food grown on the iodine-deficient soil. IDDs encompass the spectrum of disability and disease and include goitre, cretinism, hypothyroidism, abortion, stillbirth, brain damage, learning disabilities, mental retardation, psychomotor defects, hearing and speech impairment. Iodine deficiency is known to be the single largest cause of preventable brain damage. IDDs with their causal association with brain development, cognition, and learning disabilities impair the human resource development and progress of the country. The children born in iodine-deficient regions on an average have 13.5 intelligence quotient (IQ) points lesser than children born in iodine-sufficient regions. IDD control programme in India is a public health success story, with 92 per cent of the population consuming iodized salt. The partnership between government agencies, academic institutions, salt industry, development agencies and civil society has been key to achieve this success story. The sustainable elimination of iodine deficiency in India is within reach, what is required is accelerated and coordinated effort by all key stakeholder at national and State level. KEYWORDS: ICCIDD; iodine deficiency disorder; iodized salt; last mile; public health nutrition; success story; way forward PMID: 30666977 PMCID: PMC6366256 DOI: 10.4103/ijmr.IJMR_1717_18

Temperature-dependent vitamin D signaling regulates developmental trajectory associated with diapause in an annual killifish

Here we describe a molecular pathway that regulates dormancy in a vertebrate and highlights a mechanism that integrates environmental cues into a developmental program that has clear ecological and evolutionary significance. Further, we provide compelling evidence that vitamin D signaling is critical for normal vertebrate development and can induce a diapause-like arrest in embryos of zebrafish. The vitamin D receptor is homologous to nuclear receptors (NRs) that regulate dormancy in Caenorhabditis elegans and Drosophila. This conservation of function suggests a conserved role for hormones derived from 7-DHC and their associated NRs in the control of metabolic dormancy and major life history transitions in animals.

Antenatal Vitamin D Status Is Not Associated with Standard Neurodevelopmental Assessments at Age 5 Years in a Well-Characterized Prospective Maternal-Infant Cohort

McCarthy EK, Murray DM, Malvisi L, Kenny LC, O'B Hourihane J, Irvine AD & Kiely ME. (2018). Antenatal Vitamin D Status Is Not Associated with Standard Neurodevelopmental Assessments at Age 5 Years in a Well-Characterized Prospective Maternal-Infant Cohort. J. Nutr. , , . PMID: 30169669 DOI.

McCarthy EK1,2, Murray DM2,3, Malvisi L1,2, Kenny LC4, O'B Hourihane J2,3, Irvine AD2,5,6,7, Kiely ME1,2. Author information Abstract BACKGROUND: Although animal studies show evidence for a role of vitamin D during brain development, data from human studies show conflicting signals. OBJECTIVE: We aimed to explore associations between maternal and neonatal vitamin D status with childhood neurodevelopmental outcomes. METHODS: Comprehensive clinical, demographic, and lifestyle data were collected prospectively in 734 maternal-infant dyads from the Cork BASELINE Birth Cohort Study. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were quantified at 15 weeks of gestation and in umbilical cord sera at birth via a CDC-accredited liquid chromatography-tandem mass spectrometry method. Children were assessed at age 5 y through the use of the Kaufman Brief Intelligence Test (2nd Edition, KBIT-2) and the Child Behaviour Checklist (CBCL). Linear regression was used to explore associations between 25(OH)D and neurodevelopmental outcomes. RESULTS: 25(OH)D concentrations were <30 nmol/L in 15% of maternal and 45% of umbilical cord sera and <50 nmol/L in 42% of mothers and 80% of cords. At age 5 y, the mean ± SD KBIT-2 intelligence quotient (IQ) composite score was 104.6 ± 8.6; scores were 107.2 ± 10.0 in verbal and 99.8 ± 8.8 in nonverbal tasks. Developmental delay (scores <85) was seen in <3% of children across all domains. The mean ± SD CBCL total problem score was 21.3 ± 17.5; scores in the abnormal/clinical range for internal, external, and total problem scales were present in 12%, 4%, and 6% of participants, respectively. KBIT-2 and CBCL subscale scores at 5 y were not different between children exposed to low antenatal vitamin D status, either at 30 or 50 nmol/L 25(OH)D thresholds. Neither maternal nor cord 25(OH)D (per 10 nmol/L) were associated with KBIT-2 IQ composite scores [adjusted β (95% CI): maternal -0.01 (-0.03, 0.02); cord 0.01 (-0.03, 0.04] or CBCL total problem scores [maternal 0.01 (-0.04, 0.05); cord 0.01 (-0.07, 0.09)]. CONCLUSION: In this well-characterized prospective maternal-infant cohort, we found no evidence that antenatal 25(OH)D concentrations are associated with neurodevelopmental outcomes at 5 y. The BASELINE Study was registered at as NCT01498965; the SCOPE Study was registered at as ACTRN12607000551493.

Prevalence of Vitamin D Deficiency during Second Trimester of Pregnancy in Shanghai China, Risk Factors and Effects on Pregnancy Outcomes

Yang L, Song L, Xu X, Liu Y, Li H & Tang L. (2018). Prevalence of Vitamin D Deficiency during Second Trimester of Pregnancy in Shanghai China, Risk Factors and Effects on Pregnancy Outcomes. Iran. J. Public Health , 47, 1145-1150. PMID: 30186786

Yang L1, Song L2, Xu X2, Liu Y2, Li H2, Tang L1. Author information Abstract BACKGROUND: Vitamin D plays important roles in various physiological processes. Vitamin D deficiency is common among pregnant women in some regions, such as China. Our study aimed to determine the prevalence of Vitamin D deficiency during second trimester of pregnancy in Shanghai China, and explore its risk factors and effects on pregnant outcomes. METHODS: Overall, 23100 pregnant women (2013 to 2017, Shanghai, China) were included and vitamin D concentrations were measured at 16 weeks of gestation. Correlations between vitamin D concentrations and participants' general data and maternal and infant outcomes were analyzed by chi square test. Non-conditional multivariate logistic regression analysis was used to screen the independent risk factors for vitamin D deficiency. RESULTS: Vitamin D deficiency was significantly correlated with aging, education level, smoking, dirking, BMI before pregnancy, body weight gain during pregnancy (P<0.01), the use of vitamin D supplement and milk consumption, and older than 30 years, drinking, smoking, BMI before pregnancy> 36, body weight gain during pregnancy< 40g per day, no daily milk consumption, no vitamin D supplement, and education lever below college were independent risk factors for vitamin D deficiency in second trimester of pregnancy. In addition, vitamin D deficiency in second trimester of pregnancy was closely correlated with the occurrence of a serious of adverse maternal and infant outcomes. CONCLUSION: Vitamin D deficiency was still common among women in second trimester of pregnancy in Shanghai China. Vitamin D deficiency was closely correlated with the occurrence of a serious of adverse maternal and infant outcomes. KEYWORDS: Pregnant outcome; Prevalence; Risk factor; Second trimester of pregnancy; Vitamin D deficiency PMID: 30186786

Effects of micronutrients on placental function: evidence from clinical studies to animal models

Baker BC1, Hayes D2, Jones RL3.


Micronutrient deficiencies are common in pregnant women due to low dietary intake and increased requirements for fetal development. Low maternal micronutrient status is associated with a range of pregnancy pathologies involving placental dysfunction, including fetal growth restriction (FGR), small for gestational age (SGA), pre-eclampsia and preterm birth. However, clinical trials commonly fail to convincingly demonstrate beneficial effects of supplementation of individual micronutrients, attributed to heterogeneity and insufficient power, potential interactions and lack of mechanistic knowledge of effects on the placenta. We aimed to provide current evidence of relationships between selected micronutrients (vitamin D, vitamin A, iron, folate, vitamin B12) and adverse pregnancy outcomes, combined with understanding of actions on the placenta. Following a systematic literature search, we reviewed data from clinical, in vitro and in vivo studies of micronutrient deficiency and supplementation. Key findings are potential effects of micronutrient deficiencies on placental development and function, leading to impaired fetal growth. Studies in human trophoblast cells and rodent models provide insights into underpinning mechanisms. Interestingly, there is emerging evidence that deficiencies in all micronutrients examined induce a pro-inflammatory state in the placenta, drawing parallels with the inflammation detected in FGR, pre-eclampsia, stillbirth and preterm birth. Beneficial effects of supplementation are apparent in vitro and in animal models, and for combined micronutrients in clinical studies. However, greater understanding of the roles of these micronutrients, and insight into their involvement in placental dysfunction, combined with more robust clinical studies, is needed to fully understand ascertain the potential benefits of supplementation in pregnancy. PMID: 29844225 DOI: 10.1530/REP-18-0130

Association of maternal nutrition with transient neonatal hyperinsulinism

PLoS One. 2018 May 3;13(5):e0195383. doi: 10.1371/journal.pone.0195383. eCollection 2018.

Louvigne M1,2, Rouleau S1,3, Caldagues E4, Souto I2, Montcho Y5, Bouvagnet AM6, Baud O7, Carel JC8, Gascoin G8, Coutant R1.


OBJECTIVE: The objective was to determine whether maternal nutritional factors are associated with transient neonatal hyperinsulinism (HI). DESIGN AND SETTING: Case control study in 4 French tertiary Obstetrics and Neonatology Departments between 2008 and 2015. METHODS: Sixty-seven mothers of neonates diagnosed with transient hyperinsulinism and 113 mothers of controls were included. The screening for hyperinsulinemic hypoglycemia in neonates was performed because of clinical symptoms suggestive of hypoglycemia or in the presence of conventional risk factors (small-for-gestational-age, prematurity, anoxo-ischemia, hypothermia, macrosomia, gestational diabetes). Hyperinsulinemic hypoglycemia was confirmed in the HI neonates and ruled out in the controls. This allowed for comparing maternal nutrition in cases and controls in a context of similar risk factors. One to 2 mothers of control neonates were included per case, and a food frequency questionnaire was addressed to the mothers between day 5 and day 10 after the birth of their newborn. RESULTS: Crude odds ratio showed that maternal weight gain, abnormal fetal rate, C-section, gender, consumption of fresh cooked vegetables, fresh fruits and fruit juices, low fat diary products, light fat products, and daily bread were significantly associated with hyperinsulinism. Maternal body mass index, hypertension, gestational diabetes, birth weight percentile, gestational age and 5-minute Apgar score were not related to HI. In a multiple backward logistic regression model, consumption of fresh cooked vegetable ≥1/day (OR = 0.33 [0.14-0.77]) and light-fat products ≥1/week (OR = 0.24 [0.08-0.71]) was protective against hyperinsulinism, whereas gestational weight gain >20 kg (OR = 9.5 [2.0-45.5]) and between 15-20 kg (OR = 4.0 [1.2-14.0]), abnormal fetal heart rate (OR = 4.4 [1.6-12.0]), and C-section (OR = 3.4 [1.3-8.9]) were risk factors. CONCLUSIONS: A diet rich in fresh cooked vegetable and reduced in fat, together with the avoidance of a high gestational weight gain may be protective against transient neonatal hyperinsulinism. PMID: 29723237 DOI: 10.1371/journal.pone.0195383


Vitamin D in human reproduction

Curr Opin Obstet Gynecol. 2017 Aug;29(4):189-194. doi: 10.1097/GCO.0000000000000375.

Franasiak JM1, Lara EE, Pellicer A.


PURPOSE OF REVIEW: Vitamin D deficiency has been associated with a wide range of human disease states and the global epidemic, particularly in reproductive aged women, has led to a focus on this complex hormones role in human reproduction. Indeed vitamin D receptors are found throughout the reproductive tract in the ovary, endometrium, and the placenta. It has roles both in calcium-dependent and independent pathways. However, agreement upon the most appropriate way to assess vitamin D status and ultimately its activity at various sites has proven challenging. RECENT FINDINGS: Investigators have studied vitamin D's role in assisted reproduction and found successful outcomes are correlated with vitamin D replete status. However, subsequent studies have found mixed results when parsing its role in folliculogenesis and oogenesis versus its impact on embryonic implantation in the endometrium. Correlation was shown in a donor oocyte model which suggests endometrial involvement; however, in a euploid blastocyst transfer model with attention to embryo and endometrial synchrony this was not seen. It may be that the major impact is proximal to blastocyst formation at the site of folliculogenesis as has been shown in a primate model. Taken together, these studies suggest that vitamin D's role may be more sophisticated when it comes to reproductive success. Further, it has become clear that the nonstandard method of determining vitamin D status in the clinical and research settings requires clarification to ensure more comparable data in future studies. SUMMARY: Vitamin D has clear roles in human health and disease, and its impact on human reproduction seems promising but requires clarification. With new techniques for assessing its status in patients and its impact at end organs as well as evolving theories regarding its potential to influence folliculogenesis, endometrial receptivity, and ovarian aging, we will soon gain additional clarity and hope to be able to impact reproductive success in a positive way. PMID 28562440 DOI: 10.1097/GCO.0000000000000375


The Current Recommended Vitamin D Intake Guideline for Diet and Supplements During Pregnancy Is Not Adequate to Achieve Vitamin D Sufficiency for Most Pregnant Women

PLoS One. 2016 Jul 1;11(7):e0157262. doi: 10.1371/journal.pone.0157262. eCollection 2016.

Aghajafari F1, Field CJ2, Kaplan BJ1, Rabi DM1, Maggiore JA3, O'Beirne M1, Hanley DA1, Eliasziw M4, Dewey D1, Weinberg A2, Ross SJ5; APrON Study Team.


BACKGROUND: The aims of this study were to determine if pregnant women consumed the recommended vitamin D through diet alone or through diet and supplements, and if they achieved the current reference range vitamin D status when their reported dietary intake met the current recommendations. METHODS: Data and banked blood samples collected in second trimester from a subset of 537 women in the APrON (Alberta Pregnant Outcomes and Nutrition) study cohort were examined. Frozen collected plasma were assayed using LC-MS/MS (liquid chromatography-tandem mass spectrometry) to determine 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3 concentrations. Dietary data were obtained from questionnaires including a Supplement Intake Questionnaire and a 24-hour recall of the previous day's diet. RESULTS: Participants were 87% Caucasian; mean (SD) age of 31.3 (4.3); BMI 25.8 (4.7); 58% were primiparous; 90% had education beyond high school; 80% had a family income higher than CAN $70,000/year. 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3) were identified in all of the 537 plasma samples;3-epi-25(OH)D3 contributed 5% of the total vitamin D. The median (IQR) total 25(OH)D (D2+D3) was 92.7 (30.4) nmol/L and 20% of women had 25(OH)D concentration < 75 nmol/L. The median (IQR) reported vitamin D intake from diet and supplements was 600 (472) IU/day. There was a significant relationship between maternal reported dietary vitamin D intake (diet and supplement) and 25(OH)D and 3-epi-25(OH)D3 concentrations in an adjusted linear regression model. CONCLUSIONS: We demonstrated the current RDA (600 IU/ day) may not be adequate to achieve vitamin D status >75 nmol/L in some pregnant women who are residing in higher latitudes (Calgary, 51°N) in Alberta, Canada and the current vitamin D recommendations for Canadian pregnant women need to be re-evaluated.

PMID 27367800

Vitamin supplementation in pregnancy

Drug Ther Bull. 2016 Jul 11. pii: dtb.2016.7.0414. doi: 10.1136/dtb.2016.7.0414. [Epub ahead of print]

[No authors listed]


Ensuring that a woman is well-nourished, both before and during pregnancy, is crucial for the health of the woman and that of the unborn child.1 Maternal deficiency in key nutrients has been linked to pre-eclampsia, restricted fetal growth, neural tube defects, skeletal deformity and low birth weight.1,2 Many nutritional supplements containing vitamins, minerals and other micronutrients are heavily marketed to women for all stages of pregnancy. However, much of the evidence for vitamin supplementation in pregnancy comes from studies carried out in low-income countries,3 where women are more likely to be undernourished or malnourished than within the UK population. The challenges lie in knowing which supplements are beneficial and in improving uptake among those at most need. Here we summarise current UK guidance for vitamin supplementation in pregnancy and review the evidence behind it. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to PMID 27405305

Maternal BMI Associations with Maternal and Cord Blood Vitamin D Levels in a North American Subset of Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Participants

PLoS One. 2016 Mar 4;11(3):e0150221. doi: 10.1371/journal.pone.0150221. eCollection 2016.

Josefson JL1,2, Reisetter A3, Scholtens DM3, Price HE4, Metzger BE5, Langman CB2,4; HAPO Study Cooperative Research Group.


OBJECTIVE: Obesity in pregnancy may be associated with reduced placental transfer of 25-hydroxyvitamin D (25-OHD). The objective of this study was to examine associations between maternal BMI and maternal and cord blood levels of 25-OHD in full term neonates born to a single racial cohort residing at similar latitude. Secondary objectives were to examine associations between maternal glucose tolerance with maternal levels of 25-OHD and the relationship between cord blood 25-OHD levels and neonatal size. METHODS: This study was conducted among participants of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study meeting the following criteria: residing at latitudes 41-43°, maternal white race, and gestational age 39-41 weeks. Healthy pregnant women underwent measures of height, weight, and a 75-g fasting oral glucose tolerance test (OGTT) at approximately 28 weeks gestation. Maternal and cord blood sera were analyzed for total 25-OHD by HPLC tandem mass spectrometry. Statistical analyses included ANOVA and linear regression models. RESULTS: Maternal and cord blood (N = 360) mean levels (sd) of 25-OHD were 37.2 (11.2) and 23.4 (9.2) ng/ml, respectively, and these levels were significantly different among the 3 field centers (ANOVA p< 0.001). Maternal serum 25-OHD was lower by 0.40 ng/ml for BMI higher by 1 kg/m2 (p<0.001) in an adjusted model. Maternal fasting plasma glucose, insulin sensitivity, and presence of GDM were not associated with maternal serum 25-OHD level when adjusted for maternal BMI. Cord blood 25-OHD was lower by 0.26 ng/ml for maternal BMI higher by 1 kg/m2 (p<0.004). With adjustment for maternal age, field center, birth season and maternal serum 25-OHD, the association of cord blood 25-OHD with maternal BMI was attenuated. Neither birth weight nor neonatal adiposity was significantly associated with cord blood 25-OHD levels. CONCLUSION: These results suggest that maternal levels of 25-OHD are associated with maternal BMI. The results also suggest that interpretation of neonatal 25-OHD levels may need to incorporate specific maternal factors in addition to season of birth and latitude. PMID 26942930


Biomarkers of Nutrition for Development-Folate Review

J Nutr. 2015 Jul;145(7):1636S-1680S. doi: 10.3945/jn.114.206599. Epub 2015 Jun 3.

Bailey LB1, Stover PJ2, McNulty H3, Fenech MF4, Gregory JF 3rd5, Mills JL6, Pfeiffer CM7, Fazili Z7, Zhang M7, Ueland PM8, Molloy AM9, Caudill MA2, Shane B10, Berry RJ11, Bailey RL12, Hausman DB13, Raghavan R6, Raiten DJ14.

Abstract The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development. © 2015 American Society for Nutrition. KEYWORDS: BOND; RBC folate; folate biomarkers; homocysteine; serum folate PMID 26451605

Maternal Diabetes Leads to Adaptation in Embryonic Amino Acid Metabolism during Early Pregnancy

PLoS One. 2015 May 28;10(5):e0127465. doi: 10.1371/journal.pone.0127465. eCollection 2015.

Gürke J1, Hirche F2, Thieme R1, Haucke E1, Schindler M1, Stangl GI2, Fischer B1, Navarrete Santos A1.


During pregnancy an adequate amino acid supply is essential for embryo development and fetal growth. We have studied amino acid composition and branched chain amino acid (BCAA) metabolism at day 6 p.c. in diabetic rabbits and blastocysts. In the plasma of diabetic rabbits the concentrations of 12 amino acids were altered in comparison to the controls. Notably, the concentrations of the BCAA leucine, isoleucine and valine were approximately three-fold higher in diabetic rabbits than in the control. In the cavity fluid of blastocysts from diabetic rabbits BCAA concentrations were twice as high as those from controls, indicating a close link between maternal diabetes and embryonic BCAA metabolism. The expression of BCAA oxidizing enzymes and BCAA transporter was analysed in maternal tissues and in blastocysts. The RNA amounts of three oxidizing enzymes, i.e. branched chain aminotransferase 2 (Bcat2), branched chain ketoacid dehydrogenase (Bckdha) and dehydrolipoyl dehydrogenase (Dld), were markedly increased in maternal adipose tissue and decreased in liver and skeletal muscle of diabetic rabbits than in those of controls. Blastocysts of diabetic rabbits revealed a higher Bcat2 mRNA and protein abundance in comparison to control blastocysts. The expression of BCAA transporter LAT1 and LAT2 were unaltered in endometrium of diabetic and healthy rabbits, whereas LAT2 transcripts were increased in blastocysts of diabetic rabbits. In correlation to high embryonic BCAA levels the phosphorylation amount of the nutrient sensor mammalian target of rapamycin (mTOR) was enhanced in blastocysts caused by maternal diabetes. These results demonstrate a direct impact of maternal diabetes on BCAA concentrations and degradation in mammalian blastocysts with influence on embryonic mTOR signalling.

PMID 26020623

The phenomenon of vitamin D

Postepy Hig Med Dosw (Online). 2015 Jan 23;69(0):127-39.

Gruber BM1.


The receptor of vitamin D (VDR) is present in most non-skeletal human cells, suggesting its role beyond the bone and calcium metabolism. The relationship between vitamin D and the respiratory tract is a consequence of its activity in the immune system. Some gastrointestinal diseases, such as inflammatory bowel disease, coeliac disease, liver, pancreas or cardiac diseases, lead to vitamin D deficiency. Many studies indicate a correlation between vitamin D and diabetes. VDR and 1α-hydroxylase have been detected in the cutaneous capillary vessels, endothelium, vascular smooth muscles, myocytes and cardiac fibroblasts. The influence of vitamin D on the expression of genes related to the vascular walls implies its role in the pathomechanisms of vascular diseases and the cardiovascular system. Due to the VDR detected in most immunocompetent cells, calcitriol can modulate the congenital and acquired immune system. The correlation between vitamin D and cancer development is also not surprising because of many functions which vitamin D has in the organism. The vitamin D-regulated genes encode the proteins which participate in differentiation, proliferation or apoptosis. This paper aims to focus on the less well known roles of vitamin D in the organism, especially considering that most "sun consumers" know only its antirachitic and bone reinforcing action. So, this article may be surprising, and first of all it should convince everyone to vitamin D supplemention.

PMID 25614680


Vitamin C Depletion in Prenatal Guinea Pigs as a Model of Lissencephaly Type II

Vet Pathol. 2014 Dec 8. pii: 0300985814561270. [Epub ahead of print]

Capo I1, Hinić N2, Lalošević D2, Vučković N3, Stilinović N4, Marković J5, Sekulić S6.


Humans and guinea pigs are unable to produce vitamin C, with deficiency resulting in a well-known disorder of collagen synthesis. Pial basement membrane structure preservation is essential in the proper migration of neurons. In our study, intrauterine deprivation of vitamin C in guinea pig fetuses led to a collagen synthesis disorder, weakness, and finally a breach of pial basement membrane. We found excessive migration of the external germinal layer cells into the subarachnoid space of the cerebellum through defects in the pial basement membrane. The changes ranged from focal rupture of pial basement membranes to their complete disintegration. The loss of proper folia formation resulted in macroscopically visible flattening of the cerebellar surface. Different grades of dysplastic changes in the folia of the cerebellar cortex were observed in 2 experimental groups assigned different limits to mark the time of commencement and duration of vitamin C deprivation. The most severe form of dysplastic changes was characterized by marked irregularity of the cerebellar cortex similar to that in lissencephaly type II. Thus, prenatal vitamin C deficiency represents a novel animal model to study the effects of collagen synthesis on development of breaches in the pial basement membrane, disordered migration of neurons, dysplasia of cerebellar cortex, and the pathogenesis of lissencephaly. © The Author(s) 2014. KEYWORDS: animal model; cerebellum; guinea pigs; lissencephaly; scurvy; vitamin c deficiency PMID 25487414


Retinoic acid regulation of male meiosis

Curr Opin Endocrinol Diabetes Obes. 2013 Jun;20(3):217-23. doi: 10.1097/MED.0b013e32836067cf.

Hogarth CA1, Griswold MD.


PURPOSE OF REVIEW: Description of new evidence to support the model for how retinoic acid regulates spermatogonial differentiation, male meiosis and the cycle of the seminiferous epithelium.

RECENT FINDINGS: It has been known since the 1920s that vitamin A is essential for spermatogenesis. However, only recently has significant progress been made toward understanding how the active metabolite of vitamin A, retinoic acid, regulates spermatogenesis at multiple different differentiation steps, including the onset of meiosis. Current publications suggest that the initiation and maintenance of the cycle of the seminiferous epithelium is linked to retinoic-acid-driving spermatogonial differentiation and meiotic onset.

SUMMARY: Retinoic acid appears to act in a pulsatile manner, periodically driving spermatogonial differentiation and meiotic onset at discrete points along testis tubules, and as a result, is likely to be responsible for generating and maintaining the cycle of the seminiferous epithelium.

PMID 23511242;jsessionid=Vryp5mrMvTR4FJpQksSwKvwWDctkJGwp9TcvYZ9Q3FxyhLnVdsF7!-672478046!181195629!8091!-1?issn=1752-296X&volume=20&issue=3&spage=217

CDC finds cluster of newborns in Tennessee with bleeding disorder

Report highlights importance of vitamin K shot at birth

American Academy of Pediatrics Report Of Committee On Nutrition - Vitamin K Compounds And The Water-Soluble Analogues (1961) PEDIATRICS Vol. 28 No. 3 September 1, 1961 pp. 501 -507


The correlation between third-trimester maternal and newborn-serum 25-hydroxy-vitamin D in a selected South Australian group of newborn samples

BMJ Open. 2011 Jan 1;1(2):e000236. Thomas SD, Fudge AN, Whiting M, Coates PS. Source Department of Chemical Pathology, SA Pathology, Adelaide, South Australia, Australia. Abstract BACKGROUND: Although vitamin D insufficiency is prevalent in the community, only a few population-based studies have measured serum 25-hydroxy-vitamin D (25OHD) levels during pregnancy and in newborns. Maternal vitamin D deficiency has been linked to pregnancy complications, as well as hypocalcaemia and rickets in the newborn. Here, the authors report third-trimester maternal and newborn-serum 25OHD concentrations in 101 neonates whose serum samples were sent for testing. METHODS: The newborn 25OHD levels were correlated with the third-trimester maternal serum 25OHD levels using a least-square regression analysis. All samples were measured using an enzyme immunoassay (EIA). Ten randomly selected newborn serum samples were also measured using liquid chromatography/tandem mass spectrometry LC-MSMS, and correlated with the EIA method. RESULTS: Out of 99 mothers of the newborns, only 19, 42 and 68 had their 25OHD level measured in the first, second and third trimester respectively. The mean maternal age was 30 years, while the mean maternal third-trimester 25OHD concentration was 48 nmol/l. Of the newborns, 53% were female, and 85% were term deliveries. The mean newborn-serum 25OHD was 68 nmol/l. Neonatal 25OHD was related to maternal third-trimester levels measured by EIA (r=0.3; newborn 25OHD=0.42(maternal 25OHD)+44.2; p=0.02). EIA and LC-MSMS concentrations for newborns correlated significantly over a range between 20 and 103 nmol/l by EIA (r=0.9; EIA=1.04(LCMSMS)+10.1; p<0.00 (slope); p=0.18 (intercept)). The mean 25OHD concentration in women who suffered pre-eclampsia and premature rupture of membranes were 45 and 39 nmol/l respectively. CONCLUSIONS: Newborn-serum 25OHD concentrations depend on the maternal circulating plasma 25OHD level at least during the third trimester. Neonatal 25OHD levels obtained by EIA correlated well with LC-MSMS. Although the EIA values for neonates were greater than LC-MSMS values, this difference was not statistically significant.

PMID 22021888

Vitamin A in reproduction and development

Nutrients. 2011 Apr;3(4):385-428. Epub 2011 Mar 29.

Clagett-Dame M, Knutson D. Source Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.


The requirement for vitamin A in reproduction was first recognized in the early 1900's, and its importance in the eyes of developing embryos was realized shortly after. A greater understanding of the large number of developmental processes that require vitamin A emerged first from nutritional deficiency studies in rat embryos, and later from genetic studies in mice. It is now generally believed that all-trans retinoic acid (RA) is the form of vitamin A that supports both male and female reproduction as well as embryonic development. This conclusion is based on the ability to reverse most reproductive and developmental blocks found in vitamin A deficiency induced either by nutritional or genetic means with RA, and the ability to recapitulate the majority of embryonic defects in retinoic acid receptor compound null mutants. The activity of the catabolic CYP26 enzymes in determining what tissues have access to RA has emerged as a key regulatory mechanism, and helps to explain why exogenous RA can rescue many vitamin A deficiency defects. In severely vitamin A-deficient (VAD) female rats, reproduction fails prior to implantation, whereas in VAD pregnant rats given small amounts of carotene or supported on limiting quantities of RA early in organogenesis, embryos form but show a collection of defects called the vitamin A deficiency syndrome or late vitamin A deficiency. Vitamin A is also essential for the maintenance of the male genital tract and spermatogenesis. Recent studies show that vitamin A participates in a signaling mechanism to initiate meiosis in the female gonad during embryogenesis, and in the male gonad postnatally. Both nutritional and genetic approaches are being used to elucidate the vitamin A-dependent pathways upon which these processes depend.

PMID 22254103

Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis

BMJ. 2011 Aug 25;343:d5094. doi: 10.1136/bmj.d5094.

Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Source Centre for Evidence-Based Intervention, Department of Social Policy and Intervention, University of Oxford, Barnett House, Oxford OX1 2ER, UK.


OBJECTIVE: To determine if vitamin A supplementation is associated with reductions in mortality and morbidity in children aged 6 months to 5 years.

DESIGN: Systematic review and meta-analysis. Two reviewers independently assessed studies for inclusion. Data were double extracted; discrepancies were resolved by discussion. Meta-analyses were performed for mortality, illness, vision, and side effects.

DATA SOURCES: Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, Embase, Global Health, Latin American and Caribbean Health Sciences, metaRegister of Controlled Trials, and African Index Medicus. Databases were searched to April 2010 without restriction by language or publication status. Eligibility criteria for selecting studies Randomised trials of synthetic oral vitamin A supplements in children aged 6 months to 5 years. Studies of children with current illness (such as diarrhoea, measles, and HIV), studies of children in hospital, and studies of food fortification or β carotene were excluded.

RESULTS: 43 trials with about 215 633 children were included. Seventeen trials including 194 483 participants reported a 24% reduction in all cause mortality (rate ratio=0.76, 95% confidence interval 0.69 to 0.83). Seven trials reported a 28% reduction in mortality associated with diarrhoea (0.72, 0.57 to 0.91). Vitamin A supplementation was associated with a reduced incidence of diarrhoea (0.85, 0.82 to 0.87) and measles (0.50, 0.37 to 0.67) and a reduced prevalence of vision problems, including night blindness (0.32, 0.21 to 0.50) and xerophthalmia (0.31, 0.22 to 0.45). Three trials reported an increased risk of vomiting within the first 48 hours of supplementation (2.75, 1.81 to 4.19).

CONCLUSIONS: Vitamin A supplementation is associated with large reductions in mortality, morbidity, and vision problems in a range of settings, and these results cannot be explained by bias. Further placebo controlled trials of vitamin A supplementation in children between 6 and 59 months of age are not required. However, there is a need for further studies comparing different doses and delivery mechanisms (for example, fortification). Until other sources are available, vitamin A supplements should be given to all children at risk of deficiency, particularly in low and middle income countries.

PMID 21868478

The supply of choline is important for fetal progenitor cells

Semin Cell Dev Biol. 2011 Jun 12.

Zeisel SH. Source Nutrition and Pediatrics, Nutrition Research Institute, School of Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Kannapolis, NC 28081, United States.


Fetal progenitor cells proliferate, migrate, differentiate and undergo apoptosis at specific times during fetal development. Choline is needed by these cells for membrane synthesis and for methylation. There is growing evidence that this nutrient also modulates epigenetic regulation of gene expression in both neuronal and endothelial progenitor cells, thereby modifying brain development. It is likely that these mechanisms explain why, in rodent models, maternal dietary intake of choline influences both angiogenesis and neurogenesis in fetal hippocampus, and results in life-long changes in memory function. This also may explain why women eating diets low in choline have a greater risk of having a baby with a birth defect. Choline is mainly found in foods that contain fat and cholesterol, and intake of such foods has diminished in response dietary advice from nutritionists and physicians. Forty years ago, diets commonly contained choline-rich foods but now women in the USA tend to eat diets low in choline content. Premenopausal women normally may require less choline in their diet than do men and postmenopausal women, because estrogen induces the gene for the enzyme catalyzing endogenous biosynthesis of the choline-containing phospholipid phosphatidylcholine. However, many women have a single nucleotide polymorphism (SNP) that blocks the induction of endogenous biosynthesis, thereby making them require more dietary choline. When these women eat diets low in choline, the supply of this nutrient to the fetus is likely to be inadequate, and may perturb progenitor cell proliferation, migration, differentiation and apoptosis.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID 21693194

Does prenatal micronutrient supplementation improve children's mental development? A systematic review

Leung BM, Wiens KP, Kaplan BJ. BMC Pregnancy Childbirth. 2011 Feb 3;11:12. Review.

PMID 21291560

Vitamin D dependent rickets type I

Korean J Pediatr. 2011 Feb;54(2):51-4. Epub 2011 Feb 28.

Kim CJ. Source Department of Pediatrics, Chonnam National University Medical School, Gwangju, Korea.


Vitamin D is present in two forms, ergocalciferol (vitamin D(2)) produced by plants and cholecalciferol (vitamin D(3)) produced by animal tissues or by the action of ultraviolet light on 7-dehydrocholesterol in human skin. Both forms of vitamin D are biologically inactive pro-hormones that must undergo sequential hydroxylations in the liver and the kidney before they can bind to and activate the vitamin D receptor. The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D], plays an essential role in calcium and phosphate metabolism, bone growth, and cellular differentiation. Renal synthesis of 1,25(OH)(2)D from its endogenous precursor, 25-hydroxyvitamin D (25OHD), is the rate-limiting and is catalyzed by the 1α-hydroxylase. Vitamin D dependent rickets type I (VDDR-I), also referred to as vitamin D 1α-hydroxylase deficiency or pseudovitamin D deficiency rickets, is an autosomal recessive disorder characterized clinically by hypotonia, muscle weakness, growth failure, hypocalcemic seizures in early infancy, and radiographic findings of rickets. Characteristic laboratory features are hypocalcemia, increased serum concentrations of parathyroid hormone (PTH), and low or undetectable serum concentrations of 1,25(OH)(2)D despite normal or increased concentrations of 25OHD. Recent advances have showed in the cloning of the human 1α-hydroxylase and revealed mutations in its gene that cause VDDR-I. This review presents the biology of vitamin D, and 1α-hydroxylase mutations with clinical findings.

PMID: 21503197 [PubMed] PMCID: PMC3077501


Nutritional status of children with attention deficit hyperactivity disorder: a pilot study

Int J Pediatr. 2010;2010:767318. Epub 2010 Jun 28.

Kiddie JY, Weiss MD, Kitts DD, Levy-Milne R, Wasdell MB. Source Food Nutrition and Health, University of British Columbia, Vancouver, BC, Canada V6T 1Z4. Abstract Objectives. This is a pilot study of the dietary intake and nutrient status of children with Attention Deficit Hyperactivity Disorder (ADHD). Method. Nutritional assessment of 43 children aged 6-12 with ADHD was performed using a 3-day food record, 24-hour recall, and serum assessors. Results. Macronutrient intake and consumption of Low-Nutrient Foods were comparable to population norms; however, 66% were found to be deficient in zinc and 23% in copper. Conclusions. This pilot study reports the food intake and nutrient status of children with ADHD and shows a predisposition for low zinc and copper status in ADHD.

PMID 20652039 PMCID: PMC2905905


Nutrient Reference Values for Australia and New Zealand Including Recommended Dietary Intakes

  • The Nutrient Reference Values outline the levels of intake of essential nutrients considered to be adequate to meet the known nutritional needs of practically all healthy people for prevention of deficiency states. The document can be used by health professionals to assess the likelihood of inadequate intake in individuals or groups of people.
  • Report used to prepare some content on topic page.



Vitamins in infant nutrition. Predisposing conditions which may be responsible for vitamin deficiencies Arthur F. Abt Q Bull Northwest Univ Med Sch. 1942 Summer; 16(2): 81–99. PMCID: PMC3802386