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High protein diets are known to increase urinary calcium excretion in humans. A commonly held hypothesis is that the excess urinary calcium originates from bone because the acid generated by dietary protein requires buffering by bone. According to this hypothesis, the long-term consequence of a high protein diet would be to increase bone resorption, decrease bone density, and increase fractures. However, there are significant scientific data (including cross-sectional, longitudinal, and dietary intervention studies) in humans that suggest that high dietary protein is not detrimental to bone. In fact, many studies show that increasing protein is beneficial to skeletal health and there are several physiological mechanisms that support this observation. [ABSTRACT FROM AUTHOR]

BACKGROUND: It is estimated that 60% of pregnant women worldwide are anemic. OBJECTIVE: We aimed to examine the influence of iron status on iron absorption during pregnancy by measuring supplemental iron absorption, red blood cell iron incorporation, and iron status in pregnant women. DESIGN: Subjects were 45 pregnant Peruvian women (33+/-1 wk gestation), of whom 28 received daily prenatal supplements containing 60 mg Fe and 250 microg folate without (Fe group, n = 14) or with (Fe+Zn group, n = 14) 15 mg Zn, which were were consumed from week 10 to 24 of gestation until delivery. The remaining 17 women (control) received no prenatal supplementation. Iron status indicators and isotopes were measured in maternal blood collected 2 wk postdosing with oral (57Fe) and intravenous (58Fe) stable iron isotopes. RESULTS: Maternal serum ferritin and folate concentrations were significantly influenced by supplementation (P < 0.05). Serum iron was also significantly higher in the Fe than in the Fe+Zn (P < 0.03) or control (P < 0.001) groups. However, the supplemented groups had significantly lower serum zinc concentrations than the control group (8.4+/-2.3 and 10.9+/-1.8 micromol/L, respectively, P < 0.01). Although percentage iron absorption was inversely related to maternal serum ferritin concentrations (P = 0.036), this effect was limited and percentage iron absorption did not differ significantly between groups. CONCLUSIONS: Because absorption of nonheme iron was not substantially greater in pregnant women with depleted iron reserves, prenatal iron supplementation is important for meeting iron requirements during pregnancy. Copyright (c) 1999 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

BACKGROUND: Changes in dietary protein in adults are associated with changes in urinary calcium excretion. The mechanisms underlying this effect are not completely understood, but alterations in intestinal absorption of calcium are not thought to be involved. OBJECTIVE: We reexamined this mechanism by evaluating the effect of 2 amounts of dietary protein (low: 0.7 g/kg; and high: 2.1 g/kg) on fractional calcium absorption in 7 healthy, young women. DESIGN: The experiment consisted of 2 wk of a well-balanced diet containing moderate amounts of calcium, sodium, and protein followed by 5 d of an experimental diet that contained 1 of 2 amounts of protein and constant amounts of other nutrients known to influence calcium metabolism. Seven subjects received both amounts of dietary protein in random order. Blood and urine were sampled at baseline and on day 4. Fractional calcium absorption was measured by dual-stable calcium isotopes on day 5. In a second study of 5 additional women, we evaluated the effects of dietary fiber on calcitropic hormones. RESULTS: Subjects developed hypocalciuria and secondary hyperparathyroidism on day 4 of the low-protein diet. Urinary calcium excretion and the glomerular filtration rate were elevated significantly by day 4 of the high-protein compared with the low-protein diet. Fractional calcium absorption after the low-protein diet was 0.19+/-0.03, which was significantly lower than that after the high-protein diet (0.26+/-0.03, P=0.05). CONCLUSION: These data provide evidence that depressed intestinal calcium absorption explains, in part, low-protein-induced secondary hyperparathyroidism. Copyright (c) 1998 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Adequate calcium intake is essential for skeletal integrity, particularly during the period of peak bone mass acquisition from 9 to 17 y of age. Currently, the calcium intake of many adolescent girls is below the recommended dietary allowance. The purpose of this study was to evaluate the ability of girls to respond to acute periods of inadequate dietary calcium intake. Calcium absorption was evaluated in 11 girls aged 11.6 +/- 2.4 y after 10 d on both a low-calcium (7.05 +/- 2.03 mmol/d) and a high-calcium (35.30 +/- 2.28 mmol/d) diet. Fractional calcium absorption was determined by using oral (46Ca) and intravenous (42Ca) stable isotopes of calcium. During a low calcium intake, fractional calcium absorption was significantly greater (0.582 +/- 0.087 compared with 0.260 +/- 0.068, P < 0.0001) and urinary calcium excretion was significantly lower (1.30 +/- 0.83 compared with 3.08 +/- 1.98 mmol/d, P < 0.004) than values obtained during a high calcium intake. Concentrations of 1,25-dihydroxyvitamin D (combination of cholecalciferol and ergocalciferol) were greater during the low calcium intake, although the difference was not significant (108.7 +/- 30.6 compared with 90.0 +/- 25.1 pmol/L, P < 0.1; n = 9). Excretion of N-telopeptide was significantly greater during the low calcium intake (761 +/- 508 compared with 413 +/- 341 nmol bone collagen equivalent (BCM)/mmol creatinine, P < 0.02, n = 9), indicating that bone resorption was increased. These results suggest that during short periods of inadequate calcium intake, girls are able to significantly increase the efficiency of calcium absorption and decrease urinary calcium losses to conserve calcium required for bone mineral acquisition. (c) 1996 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

High dietary protein intakes are known to increase urinary calcium excretion and, if maintained, will result in sustained hypercalciuria. To date, the majority of calcium balance studies in humans have not detected an effect of dietary protein on intestinal calcium absorption or serum parathyroid hormone. Therefore, it is commonly concluded that the source of the excess urinary calcium is increased bone resorption. Recent studies from our laboratory indicate that alterations in dietary protein can, in fact, profoundly affect intestinal calcium absorption. In short-term dietary trials in healthy adults, we fixed calcium intake at 20 mmol/d while dietary protein was increased from 0.7 to 2.1 g/kg. Increasing dietary protein induced hypercalciuria in 20 women [from 3.4 +/- 0.3 ( +/- SE) during the low-protein to 5.4 +/- 0.4 mmol/d during the high-protein diet]. The increased dietary protein was accompanied by a significant increase in intestinal calcium absorption from 18.4 +/- 1.3% to 26.3 +/- 1.5% (as determined by dual stable isotopic methodology). Dietary protein intakes at and below 0.8 g/kg were associated with a probable reduction in intestinal calcium absorption sufficient to cause secondary hyperparathyroidism. The long-term consequences of these low-protein diet-induced changes in mineral metabolism are not known, but the diet could be detrimental to skeletal health. Of concern are several recent epidemiologic studies that demonstrate reduced bone density and increased rates of bone loss in individuals habitually consuming low-protein diets. Studies are needed to determine whether low protein intakes directly affect rates of bone resorption, bone formation, or both. [ABSTRACT FROM AUTHOR]

Context: The adverse skeletal effects of type 1 diabetes (T1D) include deficient bone accrual and lifelong increased fracture risk. The contributors to impaired bone accrual in people with T1D are incompletely understood., Objective: To determine if urinary calcium excretion is associated with impaired bone accrual in youth with T1D and to characterize the contribution of glycemic control and markers of bone mineral metabolism to urinary calcium excretion., Design: Observational study., Participants: 50 participants with T1D aged 6-20 years completed a 12-month longitudinal study of bone accrual. A second cohort of 99 similarly aged participants with T1D completed cross-sectional 24-hr urine and blood collections., Main Outcome Measure: Whole body less head bone mineral content (WBLH BMC) velocity Z-score and fractional excretion of calcium (FeCa)., Results: Participants in the bone accrual cohort had lower WBLH BMC velocity compared to a healthy reference dataset (Z-score -0.3 ± 1.0, p=0.03). FeCa was negatively associated with WBLH BMC velocity Z-score, ρ= -0.47, p=0.001. In the urinary calcium excretion cohort, intact parathyroid hormone (β= -0.4, p=0.01), beta c-telopeptide (β=0.35, p=0.007), and either hemoglobin A1c (HbA1c, β=0.08, p=0.03) or urine fractional glucose excretion (β=0.07, p=0.03) were associated with FeCa in multivariable regression models that included known determinants of urinary calcium excretion., Conclusions: Urinary calcium excretion was negatively associated with bone accrual in this cohort of youth with T1D. Mechanistic studies are needed to determine if interventions to reduce urinary calcium excretion could increase bone accrual and reduce skeletal fragility in people with T1D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Mendelian randomization (MR) studies suggest a causal effect of iron status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables on CVD risk factors. We aimed to investigate the effect of iron status on CVD risk controlling for CVD risk factors., Methods and Results: Iron biomarker instrumental variables (total iron-binding capacity [n=208 422], transferrin saturation [n=198 516], serum iron [n=236 612], ferritin [n=257 953]) were selected from a European genome-wide association study meta-analysis. We performed 2-sample univariate MR of each iron trait on CVD outcomes (all-cause ischemic stroke, cardioembolic ischemic stroke, large-artery ischemic stroke, small-vessel ischemic stroke, and coronary heart disease) from MEGASTROKE (n=440 328) and CARDIoGRAMplusC4D (Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics) (n=183 305). We then implemented multivariate MR conditioning on 7 CVD risk factors from independent European samples to evaluate their potential confounding or mediating effects on the observed iron-CVD associations. With univariate MR analyses, we found higher genetically predicted iron status to be associated with a greater risk of cardioembolic ischemic stroke (transferrin saturation: odds ratio, 1.17 [95% CI, 1.03-1.33]; serum iron: odds ratio, 1.21 [95% CI, 1.02-1.44]; total iron-binding capacity: odds ratio, 0.81 [95% CI, 0.69-0.94]). The detrimental effects of iron status on cardioembolic ischemic stroke risk remained unaffected when adjusting for CVD risk factors (all P <0.05). Additionally, we found diastolic blood pressure to mediate between 7.1 and 8.8% of the total effect of iron status on cardioembolic ischemic stroke incidence. Univariate MR initially suggested a protective effect of iron status on large-artery stroke and coronary heart disease, but controlling for CVD factors using multivariate MR substantially diminished these associations (all P >0.05)., Conclusions: Higher iron status was associated with a greater risk of cardioembolic ischemic stroke independent of CVD risk factors, and this effect was partly mediated by diastolic blood pressure. These findings support a role of iron status as a modifiable risk factor for cardioembolic ischemic stroke.

Aerobic exercise reduces circulating ionized Ca (iCa) and increases parathyroid hormone (PTH), but the cause and consequences on Ca handling are unknown. The objective of this study was to determine the effects of strenuous exercise on Ca kinetics using dual stable Ca isotopes. Twenty-one healthy women (26.4 ± 6.7 yr) completed a randomized, crossover study entailing two 6-d iterations consisting of either 60 min of treadmill walking at 65% VO2max wearing a vest weighing 30% body weight on study days 1, 3, and 5 (exercise [EX]), or a rest iteration (rest [REST]). On day 1, participants received intravenous 42Ca and oral 44Ca. Isotope ratios were determined by thermal ionization mass spectrometry. Kinetic modeling determined fractional Ca absorption (FCA), Ca deposition (Vo+), resorption (Vo-) from bone, and balance (Vbal). Circulating PTH and iCa were measured before, during, and after each exercise/rest session. Data were analyzed by paired t-test or linear mixed models using SPSS. iCa decreased and PTH increased (P < .001) during each EX session and were unchanged during REST. On day 1, urinary Ca was lower in the EX pool (25 ± 11 mg) compared to REST (38 ± 16 mg, P = .001), but did not differ over the full 24-h collection (P > .05). FCA was greater during EX (26.6 ± 8.1%) compared to REST (23.9 ± 8.3%, P < .05). Vbal was less negative during EX (-61.3 ± 111 mg) vs REST (-108 ± 23.5 mg, P < .05), but VO+ (574 ± 241 vs 583 ± 260 mg) and VO- (-636 ± 243 vs -692 ± 252 mg) were not different (P > .05). The rapid reduction in circulating iCa may be due to a change in the miscible Ca pool, resulting in increased PTH and changes in intestinal absorption and renal Ca handling that support a more positive Ca balance., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Total iron (TI) intake and differentiation between heme iron (HI) and nonheme iron (NHI) are uncommon despite markedly different bioavailability., Objectives: To create a database compiling information from studies that directly assessed the HI content of animal products using the Hornsey method, and to explore differences in estimates of HI intake between the data compiled and the Monsen method., Methods: A literature search identified studies that chemically characterized the HI content of animal-based foods using the Hornsey method; HI, NHI, and TI contents (mg/100 g) were compiled. Information was grouped by animal type and cooking method, and mean (± SD) HI% was calculated. Using a 24-h dietary record, differences in HI and NHI intake using the compiled information and the Monsen approach were explored., Results: Actual HI% values ranged from 7% to 94%. Raw foods had the highest HI% [raw duck (94% ± 4%), raw blood curd (82% ± 4%), and raw beef (79% ± 9%)]. Boiled foods had the lowest HI% [boiled shrimp (11% ± 5%) and meatballs (15% ± 6%)]. Cooked foods with the highest HI% were beef (70% ± 10%) and lamb (70% ± 9%). In many instances, applying actual HI% from the complied database produced markedly different measures of the HI content of foods [cooked beef (Monsen: 1.3 mg/100 g); (Hornsey: 2.3 mg/100 g)]. Estimation of iron intake in a 24-h recall demonstrated that using animal-specific HI% results in different estimates of HI intake [Monsen: 1.2 mg HI (40%); Hornsey: 1.8 mg HI (59%)]., Conclusions: Animal-based foods have variable HI%. A fixed HI:NHI ratio does not reflect this variation and could give rise to inaccurate estimates of HI content in food and HI intake. Consideration of this variation in HI% may improve our ability to link dietary intake with iron status and important health outcomes., (© 2024 The Authors.)

Background: Murine data suggest that the placenta downregulates ferroportin (FPN) when iron is limited to prioritize iron for its own needs. Human data on the impact of maternal and neonatal iron status on placental FPN expression are conflicting., Objectives: This study aimed to identify determinants of placental FPN protein abundance and to assess the utility of the placental iron deficiency index (PIDI) as a measure of maternal/fetal iron status in newborns at high risk for anemia., Methods: Placental FPN protein abundance was measured by western blots in placentae collected from 133 neonates born to adolescents (17.4 ± 1.1 y) carrying singletons (delivery gestational age [GA]: 39.9 ± 1.3 wk) and from 130 neonates born to 65 females (30.4 ± 5.2 y) carrying multiples (delivery GA: 35.0 ± 2.8 wk). Placental FPN and the PIDI (FPN:transferrin receptor 1) were evaluated in relation to neonatal and maternal iron-related markers (hemoglobin [Hb], serum ferritin [SF], soluble transferrin receptor [sTfR], total body iron [TBI], hepcidin, erythropoietin [EPO], erythroferrone)., Results: FPN protein was detected in all placentae delivered between 25 and 42 wk GA. Placental FPN protein abundance was associated with neonatal iron and erythropoietic markers (EPO: β: 0.10; 95% confidence interval [CI]: 0.06, 0.35; sTfR: β: 0.20; 95% CI: 0.03, 0.18; hepcidin: β: -0.06; 95% CI: -0.13, -0.0003; all P < 0.05). Maternal sTfR was only indirectly associated with placental FPN, with neonatal sTfR as the mediator (β-indirect: 0.06; 95% CI; 0.03, 0.11; P = 0.003). The PIDI was associated with neonatal Hb (β: -0.02; 95% CI: -0.03, -0.003), EPO (β: 0.07; 95% CI: 0.01, 0.14), and sTfR (β: 0.13; 95% CI: 0.004, 0.3) and with maternal SF (β: 0.08, 95% CI: 0.02, 0.14), TBI (β: 0.02; 95% CI: 0.009, 0.04), EPO (β: -0.10; 95% CI: -0.19, -0.01), sTfR (β: -0.16: 95% CI: -0.27, -0.06), and hepcidin (β: 0.05; 95% CI: 0.002, 0.11) at delivery (all P < 0.05)., Conclusions: Placental FPN abundance was positively associated with neonatal indicators of increased erythropoietic activity and poor iron status. The PIDI was associated with maternal and neonatal iron-related markers but in opposite directions. More data are needed from a lower-risk normative group of females to assess the generalizability of findings. These trials were registered at clinicaltrials.gov as NCT01019902 and NCT01582802., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Developmental responses to nutrient deprivation may differ by fetal sex. Despite this, relationships between maternal prenatal iron biomarkers and birth outcomes when stratifying by offspring sex are poorly described, especially in healthy cohorts., Objectives: This study aimed to determine associations between maternal iron biomarkers and birth weights (BWs) and birth head circumferences (BHCs) among female and male newborns to assess whether the potential predictive ability of iron biomarkers on birth outcomes differs by offspring sex., Methods: The Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study recruited 2189 pregnant individuals from Calgary and Edmonton, Canada. Maternal blood was drawn at each trimester and 3 mo postpartum. Maternal serum ferritin (SF) concentrations were measured using chemiluminescent immunoassays and erythropoietin (EPO), hepcidin, and soluble transferrin receptor (sTfR) using enzyme-linked immunosorbent assays. Ratios of sTfR:SF and hepcidin:EPO were calculated and birth outcomes accessed through delivery records. Directed acyclic graphs informed multivariate regression models., Results: The risk of maternal iron deficiency increased throughout pregnancy because ∼61% showed depleted iron stores (SF < 15 μg/L) by the third trimester. Maternal hepcidin, SF, sTfR, and sTfR:SF concentrations changed across time (P < 0.01), and participants carrying female fetuses consistently (across 6 biomarkers) showed a lower iron status during the third trimester compared with those with male fetuses (P < 0.05). Higher maternal SF and hepcidin:EPO during the third trimester was associated with lower BWs in males (P = 0.006 for SF; P = 0.03 for hepcidin:EPO) and females (P = 0.02 for SF; P = 0.02 for hepcidin:EPO). There were additional inverse associations between BWs and third trimester maternal hepcidin (P = 0.03) and hemoglobin (P = 0.004) and between BHCs and maternal SF (second trimester; P < 0.05) and Hb (third trimester P = 0.02) but only in males., Conclusions: Relationships between maternal iron biomarkers and BWs and BHCs may depend on the timing of pregnancy and offpsring sex. There was a high risk of third trimester iron storage depletion among generally healthy pregnant individuals., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: The iron regulatory hormones erythroferrone (ERFE), erythropoietin (EPO), and hepcidin, and the cargo receptor nuclear receptor coactivator 4 (NCOA4) are expressed in the placenta. However, determinants of placental expression of these proteins and their associations with maternal or neonatal iron status are unknown., Objectives: To characterize expression of placental ERFE, EPO, and NCOA4 mRNA in placentae from newborns at increased risk of iron deficiency and to evaluate these in relation to maternal and neonatal iron status and regulatory hormones., Methods: Placentae were collected from 114 neonates born to adolescents carrying singletons (14-18 y) and 110 neonates born to 54 adults (20-46 y) carrying multiples. Placental EPO, ERFE, and NCOA4 mRNA expression were measured by RT-qPCR and compared with maternal and neonatal iron status indicators (SF, sTfR, total body iron, serum iron) and hormones., Results: Placental ERFE, EPO, and NCOA4 mRNA were detected in all placentae delivered between 25 and 42 wk of gestation. Relationships between placental ERFE and EPO differed by cohort. In the multiples cohort, placental EPO and ERFE were positively correlated (P = 0.004), but only a positive trend (P = 0.08) was evident in the adolescents. Placental EPO and ERFE were not associated with maternal or neonatal iron status markers or hormones in either cohort. Placental NCOA4 was not associated with placental EPO or ERFE in either cohort but was negatively associated with maternal SF (P = 0.03) in the multiples cohort and positively associated with neonatal sTfR (P = 0.009) in the adolescents., Conclusions: The human placenta expresses ERFE, EPO, and NCOA4 mRNA as early as 25 wk of gestation. Placental expression of ERFE and EPO transcripts was not associated with maternal or neonatal iron status. Greater placental NCOA4 transcript expression was evident in women and newborns with poor iron status (lower SF and higher sTfR, respectively). Further research is needed to characterize the roles of these proteins in the human placenta., Trial Registration Number: These clinical trials were registered at clinicaltrials.gov as NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902) and NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802)., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Few normative longitudinal hemoglobin data are available to estimate the prevalence and risk factors for anemia among a multiethnic United States pregnant population., Objectives: The aim of this study was to characterize hemoglobin distributions and prevalence of anemia in a pregnant population receiving care at a large urban medical center., Methods: A retrospective medical chart review was undertaken in 41,226 uncomplicated pregnancies of 30,603 pregnant individuals who received prenatal care between 2011 and 2020. Mean hemoglobin concentrations and anemia prevalence in each trimester and incidence of anemia during pregnancy in a subset of 4821 women with data in each trimester were evaluated in relation to self-reported race and ethnicity and other possible risk factors. Risk ratios (RRs) of anemia were determined using generalized linear mixed-effects models. Smoothed curves describing changes in hemoglobin across pregnancy were created using generalized additive models., Results: The overall prevalence of anemia was 26.7%. The observed fifth percentiles of the hemoglobin distributions were significantly lower than the United States CDC anemia cutoffs in the second and third trimesters (T3). The RR (95% CI) of anemia were 3.23 (3.03, 3.45), 6.18 (5.09, 7.52), and 2.59 (2.48, 2.70) times higher in Black women than that in White women in each trimester, respectively. Asian women recorded the lowest risk of anemia compared with other racial groups in T3 (compared with White womenRR: 0.84; 95% CI: 0.74, 0.96). Hispanic women presented a higher risk of anemia in T3 than non-Hispanic women (RR: 1.36; 95% CI: 1.28, 1.45). In addition, adolescents, individuals with higher parity, and those carrying multiple fetuses experienced a higher risk of developing anemia in late gestation., Conclusions: Anemia was evident in more than one-quarter of a multiethnic United States pregnant population despite current universal prenatal iron supplementation recommendations. Prevalence of anemia was higher among Black women and lowest among Asian and White women., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Erythroferrone (ERFE) is an erythroblast-secreted regulator of iron metabolism. The production of ERFE increases during stress erythropoiesis, leading to decreased hepcidin expression and mobilization of iron. Pregnancy requires a substantial increase in iron availability to sustain maternal erythropoietic expansion and fetal development and is commonly affected by iron deficiency. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized mouse models expressing a range of ERFE levels: transgenic (TG) mice overexpressing ERFE, wild-type (WT), and ERFE knockout (KO) mice. We altered maternal iron status using diets with low or standard iron content and performed the analysis at E18.5. Iron deficiency increased maternal ERFE in WT pregnancy. Comparing different maternal genotypes, ERFE TG dams had lower hepcidin relative to their liver iron load but similar hematological parameters to WT dams on either diet. In ERFE KO dams, most hematologic and iron parameters were comparable to WT, but mean corpuscular volume (MCV) was decreased under both iron conditions. Similar to dams, TG embryos had lower hepcidin on both diets, but their hematologic parameters did not differ from those of WT embryos. ERFE KO embryos had lower MCV than WT embryos on both diets. The effect was exacerbated under iron-deficient conditions where ERFE KO embryos had higher hepcidin, lower Hb and Hct, and lower brain iron concentration compared to WT embryos, indicative of iron restriction. Thus, under iron-deficient conditions, maternal and embryo ERFE facilitate iron mobilization for embryonic erythropoiesis., (© 2022 Wiley Periodicals LLC.)

Background: Foods containing both prebiotics and probiotics (synbiotics) might enhance calcium bioavailability., Objectives: We investigated the acute effect in young adult women on calcium absorption of consuming (185 mL) a synbiotic yogurt (SYN) containing inulin (4 g) and Lactobacillus rhamnosus GG (>1 × 107 CFU/mL) compared with a control yogurt (CON)., Methods: Adult normal-weight women (25.0 ± 3.5 y, n = 30) participated in a 3-wk crossover study testing daily consumption of SYN compared with CON. Habitual dietary intake, bone mineral density (BMD), calcium biomarkers, and serum 25-hydroxyvitamin D were measured at baseline. Calcium absorption was tested after each phase of the study using a 42Ca oral tracer. Cumulative tracer recovery was measured in 0-4-h,  0-24-h, and 0-36-h urine pools collected postdosing. The SYN/CON tracer ratio from the timed urine pools was the primary outcome. A beneficial response to SYN was defined as 0-36-h SYN/CON tracer ratio >1., Results: Net 42Ca recovered increased over time in each of the SYN and CON urine pools postdosing (Friedman, P < 0.001), with a trend for higher 42Ca recovery in the 0-36-h urine pool postdosing in the SYN (1.14%) compared with the CON (0.90%) study (Wilcoxon, P = 0.07). For CON, the majority of total tracer was recovered in the 0-24-h pool (86%), whereas for SYN only 50% of total tracer was recovered in the 0-24-h pool (Friedman, P = 0.001). The SYN/CON tracer ratio in the 0-36-h pool (1.24) was >1 (Wilcoxon, P = 0.015). About two-thirds (n = 19) of women studied responded to the SYN treatment. Responders had higher vegetable intake (P = 0.03), tended to have higher potassium and calcium intakes (P ≤ 0.08), and had higher total body BMD (P = 0.09), than nonresponders., Conclusions: Short-term daily consumption of a synbiotic yogurt enhanced calcium absorption relative to a control yogurt in adult women. Given the observed time delays in tracer recovery, enhancement of calcium absorption likely occurred in the large intestine.The study was registered at clinicaltrials.gov (study registration ID: NCT03420716)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Mitochondria are essential for brain development. While previous studies linked dysfunctional mitochondria with autism spectrum disorder (ASD), the role of the mitochondrial genome (mtDNA) in ASD risk is largely unexplored. This study investigates the association of mtDNA heteroplasmies (co-existence of mutated and unmutated mtDNA) and content with ASD, as well as its inter-generational transmission and sex differences among two independent samples: a family-based study (n = 1,938 families with parents, probands and sibling controls) and a prospective birth cohort (n = 997 mother-child pairs). In both samples, predicted pathogenic (PP) heteroplasmies in children are associated with ASD risk (Meta-OR = 1.56, P = 0.00068). Inter-generational transmission of mtDNA reveals attenuated effects of purifying selection on maternal heteroplasmies in children with ASD relative to controls, particularly among males. Among children with ASD and PP heteroplasmies, increased mtDNA content shows benefits for cognition, communication, and behaviors (P ≤ 0.02). These results underscore the value of exploring maternal and newborn mtDNA in ASD., (© 2022. The Author(s).)

The human placenta is a highly specialized organ that is responsible for housing, protecting, and nourishing the fetus across gestation. The placenta is essential as it functions among other things as the liver, lungs, and gut while also playing key immunological and endocrine roles. The structure and transport capacity of this temporary organ must evolve as gestation progresses while also adapting to possible alterations in maternal nutrient availability. All nutrients needed by the developing fetus must cross the human placenta. Iron (Fe) is one such nutrient that is both integral to placental function and to successful pregnancy outcomes. Iron deficiency is among the most common nutrient deficiencies globally and pregnant women are particularly vulnerable. Data on the partitioning of Fe between the mother, placenta and fetus are evolving yet many unanswered questions remain. Hepcidin, erythroferrone and erythropoietin are regulatory hormones that are integral to iron homeostasis. The mother, fetus and placenta independently produce these hormones, but the relative function of these hormones varies in each of the maternal, placental, and fetal compartments. This review will summarize basic aspects of Fe physiology in pregnant women and the maternal, fetal, and placental adaptations that occur to maintain Fe homeostasis at this key life stage., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: During pregnancy iron can be obtained from the diet, body iron stores, or iron released from RBC catabolism. Little is known about the relative use of these sources to support fetal iron acquisition., Objectives: To describe longitudinal change in iron absorption and enrichment across gestation and partitioning of RBC iron to the fetus., Methods: Fifteen pregnant women ingested an oral stable iron isotope (57Fe) in the second trimester (T2) of pregnancy (weeks 14-16) to label the RBC pool, and a second oral stable isotope (58Fe) in the third trimester (T3) (weeks 32-35). Absorption was measured at T2 and T3. Change in RBC 57Fe enrichment was monitored (18.8-26.6 wk) to quantify net iron loss from this pool. Iron transfer to the fetus was determined based on RBC 57Fe and 58Fe enrichment in umbilical cord blood at delivery., Results: Iron absorption averaged 9% at T2 and increased significantly to 20% (P = 0.01) by T3. The net increase in iron absorption from T2 to T3 was strongly associated with net loss in maternal total body iron (TBI) from T2 to T3 (P = 0.01). Mean time for the labeled RBC 57Fe turnover based on change in RBC enrichment was 94.9 d (95% CI: 43.5, 207.1 d), and a greater decrease in RBC 57Fe enrichment was associated with higher iron absorption in T2 (P = 0.001). Women with a greater decrease in RBC 57Fe enrichment transferred more RBC-derived iron to their fetus (P < 0.05)., Conclusions: Iron absorption doubled from T2 to T3 as maternal TBI declined. Women with low TBI had a greater decrease in RBC iron enrichment and transferred more RBC-derived iron to their neonate. These findings suggest maternal RBC iron serves as a significant source of iron for the fetus, particularly in women with depleted body iron stores., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Based on limited data, it is estimated that the placenta retains 90 mg of iron. Little is known about determinants of placental iron content. Animal data indicate that the placenta prioritizes iron for its own needs, but this hypothesis has not been evaluated in humans., Objectives: To characterize placental iron content and placental iron concentration (p[Fe]) in pregnant women at risk of iron insufficiency and identify determinants of p[Fe]., Methods: Placentas were collected from 132 neonates born to teens carrying singletons (≤18 y) and 101 neonates born to 48 women carrying multiples (20-46 y). Maternal and neonatal iron status indicators [hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), serum iron, total body iron (TBI)] and hormones (erythropoietin, hepcidin) were measured. p[Fe] was measured using inductively coupled plasma-mass spectrometry. Correlation analyses and mixed-effects models were constructed to identify determinants of p[Fe]., Results: Mean placental iron content was 23 mg per placenta (95% CI: 15, 33 mg) in the multiples and 40 mg (95% CI: 31, 51 mg) in the teens (P = 0.03). Mean p[Fe] did not differ between the cohorts. p[Fe] was higher in anemic (175 μg/g; 95% CI: 120, 254 μg/g) compared with nonanemic (46 μg/g; 95% CI: 26, 82 μg/g) women carrying multiples (P = 0.009), but did not differ between anemic (62 μg/g; 95% CI: 40, 102 μg/g) and nonanemic (73 μg/g; 95% CI: 56, 97 μg/g) teens. In women carrying multiples, low maternal iron status [lower SF (P = 0.002) and lower TBI (P = 0.01)] was associated with higher p[Fe], whereas in teens, improved iron status [lower sTfR (P = 0.03) and higher TBI (P = 0.03)] was associated with higher p[Fe]., Conclusions: Placental iron content was ∼50% lower than previously estimated. p[Fe] is significantly associated with maternal iron status. In women carrying multiples, poor maternal iron status was associated with higher p[Fe], whereas in teens, improved iron status was associated with higher p[Fe]. More data are needed to understand determinants of p[Fe] and the variable iron partitioning in teens compared with mature women., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The plasma pool of the hormone 1,25-dihydroxyvitamin D (1,25(OH) 2 D) is increased throughout most of human pregnancy. Mechanisms behind this adaptation are unclear, in part due to limited data on vitamin D kinetics during pregnancy. Stable isotopes make it possible to study vitamin D kinetics in vulnerable study populations like pregnant women. We conducted a pilot study of vitamin D kinetics in nonpregnant and pregnant women. We evaluated a clinical protocol and developed analytical methods to assess the serum appearance and disappearance of trideuterated vitamin D 3 (d3-vitamin D 3 ) and trideuterated 25-hydroxyvitamin D 3 (d3-25(OH)D 3 ) after a single oral dose of 25 μg of [6,19,19- 2 H]-vitamin D 3 (d3-vitamin D 3 ). Blood was collected at baseline and 2, 4, 6, 24, 168, 264, and 456 hours post-dosing. We then described the serum kinetic profiles of d3-vitamin D 3 and d3-25(OH)D 3 in nonpregnant and pregnant women. Serum kinetic profiles of d3-vitamin D 3 and d3-25(OH)D 3 followed a time course in line with previous pharmacokinetic studies. There was marked variability between participants in the area under the concentration-time curve (AUC) of d3-25(OH)D 3 over the 20-day study period. This AUC of d3-25(OH)D 3 was positively correlated with the serum vitamin D binding protein (DBP) concentration, which was higher in pregnant compared with nonpregnant women. The mean serum half-life of 25(OH)D 3 was longer but not significantly different in pregnant women (18.8 days) compared with nonpregnant women (13.6 days). Our pilot study demonstrated that a single oral dose of 25 μg of d3-vitamin D 3 can be used to study vitamin D kinetics. Serum DBP concentration is an important predictor of vitamin D kinetics, and more research is needed to fully understand the significance of elevated DBP concentration during pregnancy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Iron is unique among all minerals in that humans have no regulatable excretory pathway to eliminate excess iron after it is absorbed. Iron deficiency anemia occurs when absorbed iron is not sufficient to meet body iron demands, whereas iron overload and subsequent deposition of iron in key organs occur when absorbed iron exceeds body iron demands. Over time, iron accumulation in the body can increase risk of chronic diseases, including cirrhosis, diabetes, and heart failure. To date, only ∼30% of the interindividual variability in iron absorption can be captured by iron status biomarkers or iron regulatory hormones. Much of the regulation of iron absorption may be under genetic control, but these pathways have yet to be fully elucidated. Genome-wide and candidate gene association studies have identified several genetic variants that are associated with variations in iron status, but the majority of these data were generated in European populations. The purpose of this review is to summarize genetic variants that have been associated with alterations in iron status and to highlight the influence of ethnicity on the risk of iron deficiency or overload. Using extant data in the literature, linear mixed-effects models were constructed to explore ethnic differences in iron status biomarkers. This approach found that East Asians had significantly higher concentrations of iron status indicators (serum ferritin, transferrin saturation, and hemoglobin) than Europeans, African Americans, or South Asians. African Americans exhibited significantly lower hemoglobin concentrations compared with other ethnic groups. Further studies of the genetic basis for ethnic differences in iron metabolism and on how it affects disease susceptibility among different ethnic groups are needed to inform population-specific recommendations and personalized nutrition interventions for iron-related disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: The developing fetus requires adequate iron and produces its own hormones to regulate this process. Erythroferrone (ERFE) is a recently identified iron regulatory hormone, and normative data on ERFE concentrations and relations between iron status and other iron regulatory hormones at birth are needed., Objectives: The objective of this study was to characterize cord ERFE concentrations at birth and assess interrelations between ERFE, iron regulatory hormones, and iron status biomarkers in 2 cohorts of newborns at higher risk of neonatal anemia., Methods: Umbilical cord ERFE concentrations were measured in extant serum samples collected from neonates born to women carrying multiples (age: 21-43 y; n = 127) or teens (age: 14-19 y; n = 164). Relations between cord blood ERFE and other markers of iron status or erythropoiesis in cord blood were assessed by linear regression and mediation analysis., Results: Cord ERFE was detectable in all newborns delivered between 30 and 42 weeks of gestation, and mean concentration at birth was 0.73 ng/mL (95% CI: 0.63, 0.85 ng/mL). Cord ERFE was on average 0.25 ng/mL lower in newborns of black as opposed to white ancestry (P = 0.04). Cord ERFE was significantly associated with transferrin receptor (β: 1.17, P < 0.001), ferritin (β: -0.27, P < 0.01), and hemoglobin (Hb) (β: 0.04, P < 0.05). However, cord hepcidin and the hepcidin:erythropoietin (EPO) ratio captured the most variance in newborn iron and hematologic status (>25% of variance explained)., Conclusions: Neonates born to teens and women carrying multiples were able to produce ERFE in response to neonatal cord iron status and erythropoietic demand. ERFE, however, did not capture significant variance in newborn iron or Hb concentrations. In these newborns, cord hepcidin and the hepcidin:EPO ratio explained the most variance in iron status indicators at birth., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

People with type 1 diabetes (T1D) are at increased risk of developing low bone mineral density and fractures. Optimization of calcium intake is a key component of pediatric bone health care. Despite the known risk factors for impaired bone health in T1D and the known benefits of calcium on bone accrual, there are limited data describing calcium intake in youth with T1D. In this cross-sectional study, calcium intake was assessed in 238 youth with T1D. One third of study participants were found to have inadequate calcium intake. Female sex, especially during adolescence, and obesity were identified as specific risk factors for inadequate calcium intake. Given the known adverse effects of T1D on bone health, efforts to promote calcium intake in youth with T1D should be considered., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Maintaining adequate iron status during pregnancy is important for the mother and her developing fetus. Iron homeostasis is influenced by 3 regulatory hormones: erythropoietin (EPO), hepcidin, and erythroferrone (ERFE). To date, normative data on ERFE across pregnancy and its relations to other hormones and iron status indicators are limited., Objectives: The objective of this study was to characterize maternal ERFE across pregnancy and at delivery and evaluate the utility of hepcidin, ERFE, and EPO in identifying women with increased iron needs., Methods: ERFE was measured in extant serum samples collected from 2 longitudinal cohorts composed of women carrying multiple fetuses (n = 79) and pregnant adolescents (n = 218) at midgestation (∼26 wk) and delivery (∼39 wk). Receiver operating characteristic curves were generated to characterize the predictive ability of serum ERFE, hepcidin, and EPO and their ratios to identify women at increased risk of iron deficiency and anemia., Results: In these pregnant women, mean ERFE was 0.48 ng/mL at both ∼25 wk of gestation and at delivery. ERFE was positively associated with EPO at midgestation (β = 0.14, P = 0.002, n = 202) and delivery (β = 0.12, P < 0.001, n = 225) but was not significantly associated with maternal hepcidin at any time point surveyed. Of all hormones measured at midgestation and delivery, EPO was best able to identify women with anemia (AUC: 0.86 and 0.75, respectively) and depleted iron stores (AUC: 0.77 and 0.84), whereas the hepcidin-to-EPO ratio was best able to identify women with iron deficiency anemia (AUC: 0.85 and 0.84)., Conclusions: Maternal ERFE was significantly associated with EPO but was not able to identify women with gestational iron deficiency. At term, the hepcidin-to-EPO ratio, an index that accounts for both iron status and erythropoietic demand, and EPO were the strongest indicators of maternal iron deficiency and anemia. This trial was registered at clinicaltrials.gov as NCT04517734 (https://clinicaltrials.gov/ct2/show/NCT04517734)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Heavy parasitic loads increase the risk of iron (Fe) deficiency anemia, which remains prevalent globally. Where parasites are common, understanding the influence of parasitic infections on Fe incorporation and erythropoiesis in toddlers is especially important., Objectives: The aim of this study was to identify the impacts of malarial and helminth infections on red blood cell (RBC) Fe incorporation and subsequent changes in RBC Fe isotope enrichment for 84 days postdosing in toddlers at high risk for parasitic infections., Methods: Fe incorporation was measured in a group of Zanzibari toddlers (n = 71; 16-25 months) using a stable Fe isotopic method. At study entry, an oral stable Fe isotope was administered. Blood was collected 14 (D14) and 84 (D84) days postdosing for the assessment of Fe status indicators and RBC isotopic enrichment. Blood and stool samples were collected and screened for malaria and helminth parasites. Factors associated with changes in RBC Fe isotope enrichment were identified using regression models., Results: Toddlers who had larger weight-for-age z-scores, lower total body Fe, and helminth infections (n = 26) exhibited higher RBC Fe incorporation. RBC Fe isotope enrichment decreased from D14 to D84 by -2.75 percentage points (P < 0.0001; n = 66). Greater loss in RBC Fe isotope enrichment from D14 to D84 was observed in those who received Fe supplementation, those with either helminths or both malarial and helminth infections, and in those with greater RBC Fe incorporation on D14., Conclusions: Toddlers who received Fe supplementation exhibited significantly greater losses of RBC Fe isotope enrichment over time. We speculate this greater loss of RBC Fe enrichment is indicative of increased erythropoiesis due to the provision of Fe among anemic or helminth-infected toddlers., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Over the past 30-years, the U.S. Dietary Guidelines for Americans have included recommendations around dairy consumption, largely based on meeting recommendations for calcium intake with the intended purpose of osteoporosis prevention. Although dairy products provide more bone-beneficial nutrients (e.g., calcium, magnesium, potassium, zinc, phosphorus, and protein) per unit of energy than any other food group, the relevance of dairy products for long-term bone health and fracture prevention has resurged as some observational studies have suggested consumption to be associated with a greater risk of fractures. Given this controversy, we sought to synthesize the evidence on dairy consumption and bone health across the lifespan. We searched the PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases for English-language publications through June 2, 2020. Case-controlled, cross-sectional, prospective cohort or nestled case-control (or case cohort), and clinical trials reporting the effect of dairy products on bone mineral density, bone mineral content, and/or fractures were included in the systematic review. Two reviewers independently performed data extractions. Data from 91 publications, including 30 RCTs, 28 prospective cohorts, 23 cross-sectional studies, and 10 case-control studies were included in the systematic review. We assigned a "D" grade or "insufficient evidence" for the effect of dairy in infants and toddlers (0- to <36-months), children (3- to <10-years), and young adults (19- to <50-years). A "C" grade or "limited evidence" was assigned for the effect of dairy in adolescents (10- to <19-years). A "B" grade or "moderate" evidence was assigned for the effect of dairy in middle aged to older adults (≥50-years). Research on bone mass in adults between the ages of 20- to 50-years and individuals from other ethnic groups apart from Chinese females and Caucasians is greatly needed. Daily intake of low or nonfat dairy products as part of a healthy habitual dietary pattern may be associated with improved BMD of the total body and at some sites and associated with fewer fractures in older adults.

Background: Maternal iron absorption during pregnancy can be evaluated using RBC incorporation of orally administered stable iron isotope. This approach underestimates true maternal absorption of iron as it does not account for absorbed iron that is transferred to the fetus or retained within the placenta., Objective: Our objective was to re-evaluate maternal iron absorption after factoring in these losses and identify factors associated with iron partitioning between the maternal, neonatal, and placental compartments., Methods: This study utilized data from stable iron isotope studies carried out in 68 women during the third trimester of pregnancy. Iron status indicators and stable iron isotopic enrichment were measured in maternal blood, umbilical cord blood, and placental tissue when available. Factors associated with iron isotope partitioning between the maternal, neonatal, and placental compartments were identified., Results: On average, true maternal absorption of iron increased by 10% (from 19% to 21%) after accounting for absorbed iron present in the newborn (P < 0.001), and further increased by 7%, (from 39% to 42%, P < 0.001) after accounting for iron retained within the placenta. On average, 2% of recovered tracer was present in the placenta and 6% was found in the newborn. Net transfer of iron to the neonate was higher in women with lower total body iron (standardized β = -0.48, P < 0.01) and lower maternal hepcidin (standardized β = -0.66, P < 0.01). In women carrying multiple fetuses, neonatal hepcidin explained a significant amount of observed variance in net placental transfer of absorbed iron (R = 0.95, P = 0.03)., Conclusions: Maternal RBC iron incorporation of an orally ingested tracer underestimated true maternal iron absorption. The degree of underestimation was greatest in women with low body iron. Maternal hepcidin was inversely associated with maternal RBC iron utilization, whereas neonatal hepcidin explained variance in net transfer of iron to the neonatal compartment.These trials were registered at clinicaltrials.gov as NCT01019096 and NCT01582802., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Background: An adequate maternal iron supply is crucial for maternal red blood cell (RBC) expansion, placental and fetal growth, and fetal brain development. Obese women may be at risk for poor iron status in pregnancy due to proinflammatory-driven overexpression of hepcidin leading to decreased iron bioavailability., Objective: The objective of this study was to determine the impact of prepregnancy (PP) obesity on third-trimester maternal iron utilization., Design: Using the stable isotope 57Fe, we measured iron utilization in the third trimester in PP obese [BMI (in kg/m2): ≥30] and nonobese (BMI: 18.5-29.9) women. We also assessed iron status, hepcidin, inflammation, erythropoietin, dietary iron intake, and gestational weight gain. Descriptive and inferential statistical tests (e.g., Student t test, Pearson correlation) were used for data analysis., Results: Fifty pregnant women (21 PP obese, 29 PP nonobese) were included. Mean age was 27.6 ± 6.8 y and mean gestational age at time of 57Fe administration was 32.7 ± 0.7 wk. Anemia (hemoglobin <11 g/dL for non-black and <10.2 g/dL for black women) affected 38% of women (43% PP obese compared with 35% PP nonobese; P = 0.55). Women with PP obesity had significantly higher C-reactive protein (8.5 compared with 3.4 mg/L, P = 0.0007) and total body iron corrected for inflammation (6.0 compared with 4.3 mg/kg, P = 0.04) compared with the nonobese women. There was no difference in serum hepcidin or iron utilization between the PP BMI groups., Conclusion: This is the first study to assess the impact of PP obesity on maternal iron utilization. We found no difference in iron utilization in the third trimester of pregnancy in women with and without PP obesity. Despite higher frequency of anemia, women with PP obesity had less depleted body iron stores, suggesting some degree of iron sequestration. This finding should be followed up and extended to understand effects on fetal iron bioavailability., (Copyright © The Author(s) 2020.)

Pregnant adolescents are at increased risk of adverse pregnancy outcomes compared to adult women, necessitating a need for early and comprehensive health care. This study aimed to evaluate the effectiveness of a social media intervention (i.e. weekly prenatal health messages) on improving diet quality, and health beliefs and knowledge. Participants (10 adolescents and 12 adults) completed pre-post intervention interviews, nutrition knowledge and health belief questionnaires, and 24-hour diet recalls. Participants entering pregnancy as overweight or obese were more likely to experience excessive GWG during the intervention. The adults had greater participation during the study despite high levels of social media access among both groups. Participants were able to identify sugar-sweetened foods and acknowledged the benefits of whole grains; however, overall knowledge of MyPlate Guidelines was limited. Social media-based education was well received by participants but did not result in large changes in dietary intake and knowledge. Although larger studies are needed, social media appears to have the potential to reach high-risk women., Competing Interests: The authors have declared that no competing interests exist.

Aims: The skeletal complications of type 1 diabetes (T1D) include low bone density, poor bone quality and fractures. Greater calcium intake, vitamin D intake, and physical activity are commonly recommended to improve bone health in patients with T1D. However, it is not clear whether these factors are affected by T1D or improve clinical outcomes., Methods: The objective of this study was to systematically review the literature for evidence of associations between calcium intake, vitamin D intake, and physical activity and skeletal outcomes in T1D. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, twenty-two studies were included in this review., Results: The prevalence of calcium deficiency was high and encompassed greater than 50% of participants in the majority of studies. Despite this finding, there was no clear association between calcium intake and bone density in any study. Calcitriol use was associated with gains in bone density in one study but was not associated with changes in bone turnover markers in a second report. No studies specifically investigated the impact of vitamin D2 or D3 supplementation on bone health. Two studies reported a beneficial effect of physical activity interventions on bone accrual in children. The findings from observational studies of physical activity were mixed., Conclusion: There are insufficient data to determine if deficient calcium intake, vitamin D intake, or physical activity contributes to the skeletal complications of T1D. Future studies specifically designed to assess the impact of these interventions on the skeleton in T1D participants are needed.

Background: It has been proposed that the fetus prioritizes iron for hemoglobin production over delivery to tissues. However, few studies have evaluated the interrelations between hemoglobin and multiple iron status biomarkers in umbilical cord blood. A full understanding is needed of how these parameters influence each other within cord blood to fully interpret iron and hematologic status at birth., Objectives: We evaluated the determinants of neonatal hemoglobin and assessed the interrelations between hemoglobin, serum iron status indicators, and serum iron regulatory hormones in healthy neonates., Methods: This was an observational study that assessed umbilical cord hemoglobin (Hb), serum ferritin (SF), erythropoietin (EPO), soluble transferrin receptor (sTfR), serum iron, hepcidin, vitamin B-12, folate, IL-6, and CRP measured in 234 neonates born to adolescents or to women carrying multiples. Correlations between these indicators were evaluated and mediation models consistent with the observed significant determinants of cord Hb concentrations were developed., Results: A highly significant inverse association was found between cord SF and Hb concentrations that was not attributable to neonatal or maternal inflammation (as measured by IL-6 and CRP). The inverse association was present in the combined cohort, as well as in the adolescent and multiples cohorts independently. Mediation analyses found that EPO and hepcidin had significant indirect effects on cord Hb, associations that are explicable by mediation through SF and sTfR., Conclusion: In contrast to observations made in older infants, a highly significant inverse association between Hb and SF, as well positive associations between Hb and both sTfR and EPO, were observed in umbilical cord blood from neonates born to adolescents or women carrying multiples. These findings, combined with review of the published literature, indicate a need for analysis of the relations between multiple parameters to assess iron and hematologic status at birth. These clinical trials were registered at clinicaltrials.gov as NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802) and NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902)., (© 2019 American Society for Nutrition.)

Background: During the Pregnancy and Birth to 24 Months Project, the US Departments of Agriculture and Health and Human Services initiated a review of evidence on diet and health in these populations., Objectives: The aim of these systematic reviews was to examine the relation of 1) never versus ever feeding human milk, 2) shorter versus longer durations of any human milk feeding, 3) shorter versus longer durations of exclusive human milk feeding, and 4) feeding a lower versus higher intensity of human milk to mixed-fed infants with type 1 and type 2 diabetes in offspring., Methods: The Nutrition Evidence Systematic Review team conducted systematic reviews with external experts. We searched CINAHL, Cochrane, Embase, and PubMed for articles published January 1980-March 2016, dual-screened the results according to predetermined criteria, extracted data from and assessed the risk of bias for each included study, qualitatively synthesized the evidence, developed conclusion statements, and graded the strength of the evidence., Results: The 4 systematic reviews included 21, 37, 18, and 1 articles, respectively. Observational evidence suggests that never versus ever feeding human milk (limited evidence) and shorter versus longer durations of any (moderate evidence) and exclusive (limited evidence) human milk feeding are associated with higher type 1 diabetes risk. Insufficient evidence examined type 2 diabetes. Limited evidence suggests that the durations of any and exclusive human milk feeding are not associated with intermediate outcomes (e.g., fasting glucose, insulin resistance) during childhood., Conclusions: Limited to moderate evidence suggests that feeding less or no human milk is associated with higher risk of type 1 diabetes in offspring. Limited evidence suggests no associations between the durations of any and exclusive human milk feeding and intermediate diabetes outcomes in children. Additional research is needed on infant milk-feeding practices and type 2 diabetes and intermediate outcomes in US populations, which may have distinct metabolic risk., (© American Society for Nutrition 2019.)

Skeletal mineralization is initiated in utero and continues throughout childhood and adolescence. During these key periods of the life cycle, calcium retention must increase significantly to provide sufficient mineral for bone deposition and skeletal growth. Stable calcium isotopes have served as a fundamental tool to non-invasively characterize the dynamic changes in calcium physiology that occur from infancy through adolescence. These approaches have helped define the dynamics of calcium absorption and utilization in healthy children and in children with chronic diseases. As data in this area have accumulated, new areas of emphasis are beginning to characterize the determinants of variability in mineral retention, the genetic determinants of bone turnover and calcium flux and the impact of the gut microbiome on whole body and niche specific calcium dynamics. Advances in these areas will help define calcium utilization in paediatric populations and provide information that may be useful in maximizing bone acquisition across this critical phase of the life cycle., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Background: During the Pregnancy and Birth to 24 Months Project, the USDA and US Department of Health and Human Services initiated an evidence review on diet and health in these populations., Objective: The aim of these systematic reviews was to examine the relationships of never versus ever feeding human milk, shorter versus longer durations of any and exclusive human milk feeding, and feeding a lower versus a higher intensity of human milk to mixed-fed infants with diagnosed celiac disease and inflammatory bowel disease (IBD)., Methods: The Nutrition Evidence Systematic Review team (formerly called the Nutrition Evidence Library) conducted systematic reviews with external experts. We searched CINAHL, Cochrane, Embase, and PubMed for articles published January, 1980 to March, 2016, dual-screened the results using predetermined criteria, extracted data from and assessed risk of bias for each included study, qualitatively synthesized the evidence, developed conclusion statements, and graded the strength of the evidence., Results: We included 9 celiac disease and 17 IBD articles. Limited case-control evidence suggests never versus ever being fed human milk is associated with higher risk of celiac disease, but concerns about reverse causality precluded a conclusion about the relationship of shorter versus longer durations of any human milk feeding with celiac disease. Evidence examining never versus ever feeding human milk and IBD was inconclusive, and limited, but consistent, case-control evidence suggests that, among infants fed human milk, shorter versus longer durations of any human milk feeding are associated with higher risk of IBD. For both outcomes, evidence examining the duration of exclusive human milk feeding was scant and no articles examined the intensity of human milk fed to mixed-fed infants., Conclusion: Limited case-control evidence suggests that feeding human milk for short durations or not at all associates with higher risk of diagnosed IBD and celiac disease, respectively. The small number of studies and concern about reverse causality and recall bias prevent stronger conclusions., (© American Society for Nutrition 2019.)

Background: During the Pregnancy and Birth to 24 Months Project, the US Departments of Agriculture and Health and Human Services initiated a review of evidence on diet and health in these populations., Objectives: The aim of these systematic reviews was to examine the relation of 1) never versus ever feeding human milk, 2) shorter versus longer durations of any human milk feeding, 3) shorter versus longer durations of exclusive human milk feeding, and 4) feeding a lower versus higher intensity of human milk to mixed-fed infants with acute childhood leukemia, generally, and acute lymphoblastic leukemia, specifically., Methods: The Nutrition Evidence Systematic Review team conducted systematic reviews with external experts. We searched CINAHL, Cochrane, Embase, and PubMed for articles published January 1980 to March 2016, dual-screened the results using predetermined criteria, extracted data from and assessed risk of bias for each included study, qualitatively synthesized the evidence, developed conclusion statements, and graded the strength of the evidence., Results: We included 24 articles from case-control or retrospective studies. Limited evidence suggests that never feeding human milk versus 1) ever feeding human milk and 2) feeding human milk for durations ≥6 mo are associated with a slightly higher risk of acute childhood leukemia, whereas evidence comparing never feeding human milk with feeding human milk for durations <6 mo is mixed. Limited evidence suggests that, among infants fed human milk, a shorter versus longer duration of human milk feeding is associated with a slightly higher risk of acute childhood leukemia. None of the included articles examined exclusive human milk feeding or the intensity of human milk fed to mixed-fed infants., Conclusions: Feeding human milk for short durations or not at all may be associated with slightly higher acute childhood leukemia risk. The evidence could be strengthened with access to broadly generalizable prospective samples; therefore, we recommend linking surveillance systems that collect infant feeding and childhood cancer data., (© American Society for Nutrition 2019.)

Background: During the Pregnancy and Birth to 24 Months Project, the US Departments of Agriculture and Health and Human Services initiated a review of evidence on diet and health in these populations., Objectives: The aim of these systematic reviews was to examine the relation of 1) never versus ever feeding human milk, 2) shorter versus longer durations of any human milk feeding, 3) shorter versus longer durations of exclusive human milk feeding, and 4) lower versus higher intensities of human milk fed to mixed-fed infants with intermediate and endpoint cardiovascular disease (CVD) outcomes in offspring., Methods: The Nutrition Evidence Systematic Review team conducted systematic reviews with external experts. We searched CINAHL, Cochrane, Embase, and PubMed for articles published January 1980-March 2016, dual-screened the results using predetermined criteria, extracted data from and assessed the risk of bias for each included study, qualitatively synthesized the evidence, developed conclusion statements, and graded the strength of the evidence., Results: The 4 systematic reviews included 13, 24, 6, and 0 articles, respectively. The evidence was insufficient to draw conclusions about endpoint CVD outcomes across all 4 systematic reviews. Limited evidence suggests that never versus ever being fed human milk is associated with higher blood pressure within a normal range at 6-7 y of age. Moderate evidence suggests there is no association between the duration of any human milk feeding and childhood blood pressure. Limited evidence suggests there is no association between the duration of exclusive human milk feeding and blood pressure or metabolic syndrome in childhood. Additional evidence about intermediate outcomes for the 4 systematic reviews was scant or inconclusive., Conclusions: There is insufficient evidence to draw conclusions about the relationships between infant milk-feeding practices and endpoint CVD outcomes; however, some evidence suggests that feeding less or no human milk is not associated with childhood hypertension., (© American Society for Nutrition 2019.)

Background: During the Pregnancy and Birth to 24 Months Project, the USDA and Department of Health and Human Services initiated a review of evidence on diet and health in these populations., Objectives: The aim of these systematic reviews was to examine the relation of 1) never versus ever feeding human milk, 2) shorter versus longer durations of any human milk feeding, 3) shorter versus longer durations of exclusive human milk feeding prior to infant formula introduction, 4) feeding a lower versus higher intensity of human milk to mixed-fed infants, and 5) feeding a higher intensity of human milk by bottle versus breast with food allergies, allergic rhinitis, atopic dermatitis, and asthma., Methods: The Nutrition Evidence Systematic Review team conducted systematic reviews with external experts. We searched CINAHL, Cochrane, Embase, and PubMed for articles published between January 1980 and March 2016, dual-screened the results according to predetermined criteria, extracted data from and assessed the risk of bias for each included study, qualitatively synthesized the evidence, developed conclusion statements, and graded the strength of the evidence., Results: The systematic reviews numbered 1-5 above included 44, 35, 1, 0, and 0 articles, respectively. Moderate, mostly observational, evidence suggests that 1) never versus ever being fed human milk is associated with higher risk of childhood asthma, and 2) among children and adolescents who were fed human milk as infants, shorter versus longer durations of any human milk feeding are associated with higher risk of asthma. Limited evidence does not suggest associations between 1) never versus ever being fed human milk and atopic dermatitis in childhood or 2) the duration of any human milk feeding and allergic rhinitis and atopic dermatitis in childhood., Conclusions: Moderate evidence suggests that feeding human milk for short durations or not at all is associated with higher childhood asthma risk. Evidence on food allergies, allergic rhinitis, and atopic dermatitis is limited., (© American Society for Nutrition 2019.)

Vitamin B 12 deficiency has been associated with increased risk of adverse pregnancy outcomes. Few prospective studies have investigated the burden or determinants of vitamin B 12 deficiency early in life, particularly among pregnant adolescents and their children. The objectives of this study were to determine the prevalence of vitamin B 12 deficiency and to examine associations between maternal and neonatal vitamin B 12 status in a cohort study of healthy pregnant adolescents. Serum vitamin B 12 and folate concentrations were measured in adolescents at mid-gestation ( n = 124; 26.4 ± 3.5 weeks) and delivery ( n = 131; 40.0 ± 1.3 weeks), and in neonates at birth using cord blood. Linear regression was used to examine associations between maternal and neonatal vitamin B 12 status. Although the prevalence of vitamin B 12 deficiency (<148.0 pmol/L; 1.6%) in adolescents was low during pregnancy, 22.6% of adolescents were vitamin B 12 insufficient (<221.0 pmol/L; 22.6%) at mid-gestation. Maternal vitamin B 12 concentrations significantly decreased from mid-gestation to delivery ( p < 0.0001), and 53.4% had insufficient vitamin B 12 status at delivery. Maternal vitamin B 12 concentrations ( p < 0.001) and vitamin B 12 deficiency ( p = 0.002) at delivery were significantly associated with infant vitamin B 12 concentrations in multivariate analyses, adjusting for gestational age, maternal age, parity, smoking status, relationship status, prenatal supplement use, pre-pregnancy body mass index, race, and intake of vitamin B 12 and folate. Maternal vitamin B 12 concentrations significantly decreased during pregnancy and predicted neonatal vitamin B 12 status in a cohort of healthy pregnant adolescents.

Study Objective: Regular physical activity (PA) during pregnancy decreases the risk of gestational hypertension and preeclampsia. Currently, little is known about the PA of pregnant adolescents. Our intent was to characterize the PA behaviors of a group of racially diverse, low-income pregnant teens and to identify potential determinants of PA., Design, Setting, Participants, and Interventions: A cohort of 157 racially diverse pregnant adolescents (13-18 years of age) completed up to 3 previous day PA recalls as part of a larger prospective longitudinal study on determinants of maternal and fetal bone health. Subjects self-reported activities from 7 AM to 11:30 PM, choosing from a list of 37 activities including a category for "other." Subjects recorded activities in 30-minute intervals., Main Outcome Measures: Estimated metabolic equivalent task (MET) values were assigned to each activity and summed for a measure of total daily PA in MET min/d. Determinants of PA were evaluated using a stepwise linear mixed effect model., Results: The average calculated MET min/d was 1478 ± 130. Significant determinants of MET min/d included race (P = .007), maternal age at conception (P = .042), gestational age (P = .002), and attending school (P < .001). Black teens were less physically active than white teens, and older teens were more active than younger teens; activity decreased throughout gestation, and teens currently attending school were more active., Conclusion: PA is low across gestation and pregnant teens spent more than half of their monitored time in sedentary activities. Targeted interventions are needed to achieve current PA goals in this pediatric obstetric population., (Copyright © 2018 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Serum free 25-hydroxyvitamin D (25(OH)D) rather than total 25(OH)D may better indicate vitamin D status during pregnancy given the pregnancy-associated increase in serum vitamin D binding protein (DBP) concentration. Our aims were to assess changes in DBP and free 25(OH)D across gestation and to determine whether free compared with total 25(OH)D more strongly correlates with markers of vitamin D and calcium metabolism during pregnancy. This ancillary study included 58 pregnant adolescents (53% African American, 47% White) who completed a vitamin D 3 supplementation study in Rochester, NY. Blood was collected at entry, mid-study, and delivery (median 17, 29, and 40 weeks' gestation). Mixed-effects regression was used to test for differences in DBP, directly measured free 25(OH)D, and other serum markers by study visit and race. Free and total 25(OH)D were evaluated in relation to serum PTH, 1,25(OH) 2 D, 24,25(OH) 2 D, and calcium. The mean DBP concentration was above nonpregnant reference values at entry and increased across gestation (P < 0.0001). Total 25(OH)D explained most of the variance in free 25(OH)D (r ≥ 0.67; P < 0.0001). Holding total 25(OH)D constant, each 100 mg/L increase in DBP was associated with a 0.4 pg/mL decrease in free 25(OH)D (P < 0.01). The percent free 25(OH)D was inversely related to both DBP and total 25(OH)D at each visit. Regardless of race or visit, total 25(OH)D was a stronger correlate of PTH, 1,25(OH) 2 D, and 24,25(OH) 2 D, and neither total nor free 25(OH)D was related to serum calcium. African Americans had lower total 25(OH)D (P <  0.0001), but free 25(OH)D did not significantly differ by race (P =  0.2). In pregnant adolescents, DBP concentration was elevated and inversely associated with percent free 25(OH)D, but measured free 25(OH)D provided no advantage over total 25(OH)D as a predictor of PTH, 1,25(OH) 2 D, 24,25(OH) 2 D, or calcium. The clinical relevance of the small racial difference in percent free 25(OH)D requires further investigation., (Copyright © 2018. Published by Elsevier Ltd.)

Abnormal umbilical cord coiling has been associated with adverse neonatal outcomes, but the etiology of these findings remains poorly characterized. This study was undertaken to examine associations between cord coiling and maternal iron (Fe) status and to identify potential determinants of hypo- and hypercoiling in 2 higher risk obstetric groups: pregnant adolescents (≤18 years, n = 92) and adult women carrying twins (n = 49), triplets (n = 11), or quadruplets (n = 1). Umbilical cords were classified as hypo-, normo-, or hypercoiled using digital photographs to assess gross appearance. Hypocoiling and hypercoiling were observed in 44% (n = 86/195) and 13% (n = 26/195) of the combined study population. The prevalence of hypocoiling among women carrying multiples was over 3-fold higher than the prevalence in singleton pregnancies based on the published data. Within the entire study population, hypocoiling was associated with a lower gestational age at birth when compared to normocoiling and hypercoiling (36.3 ± 3.6 weeks [n = 86] vs 37.8 ± 2.7 [n = 83], P < .01, and 38.2 ± 2.6 [n = 26], P < .01, respectively), whereas hypercoiling was associated with significantly lower serum ferritin when compared to normocoiling ( P < .01) and hypocoiling ( P < .001). In the multiples cohort only, hypercoiling was significantly associated with multiparity ( P < .01) and lower birth weight ( P < .05). Further studies are needed to identify the determinants and consequences of cord coiling.

Background: Hepcidin is a systemic regulator of iron homeostasis. Little is known about the relative role of maternal compared with cord hepcidin on neonatal iron homeostasis., Objective: This study was undertaken to evaluate inter- and intrauterine variance in neonatal iron status, vitamin B-12, folate, and inflammatory markers in a cohort of twins (n = 50), triplets (n = 14), and quadruplets (n = 1) born to 65 women., Methods: Umbilical cord blood was obtained from 144 neonates born at 34.8 ± 2.7 wk of gestation with a mean birth weight of 2236 ± 551 g (means ± SDs). Cord hemoglobin and cord serum measures of ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, erythropoietin (EPO), iron, vitamin B-12, folate, interleukin 6, and C-reactive protein were evaluated., Results: Intraclass correlation coefficient (ICC) analyses were used to examine inter- and intrauterine variance in neonatal iron indicators. A greater variability in cord hepcidin (ICC = 0.39) was found between siblings. Cord hepcidin had the greatest association with cord iron indicators because cord hepcidin alone captured 63.8%, 48.4%, 44.4%, and 31.3% of the intrauterine variance in cord hemoglobin, SF, sTfR, and EPO, respectively, whereas maternal hepcidin had no effect on cord iron indicators. Significantly greater differences in cord SF (P = 0.03), sTfR (P = 0.03), hepcidin (P = 0.0003), and EPO (P = 0.03) were found between di- and trichorionic siblings than between monochorionic siblings. In contrast, cord folate (ICC = 0.79) and vitamin B-12 (ICC = 0.74) exhibited a greater variability between unrelated neonates., Conclusions: In summary, fetally derived hepcidin might have more control on intrauterine variance in iron indicators than maternal hepcidin and appears to be capable of regulating fetal iron status independently of maternal hepcidin. The use of a multiple-birth model provides a unique way to identify factors that may contribute to placental nutrient transport and iron stores at birth.

Background: Iron (Fe) status of neonates born to women carrying multiple fetuses might be compromised as a consequence of the high prevalence of maternal Fe deficiency and anemia coupled with an increased risk of preterm birth. This study aimed to characterize and identify determinants of anemia in this neonatal population., Methods: Umbilical cord blood obtained from 183 neonates was utilized to assess hemoglobin (Hb), ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, serum Fe, erythropoietin, folate, vitamin B-12, C-reactive protein, and interleukin-6. Associations with maternal Fe status were explored., Results: Cord Hb or SF did not change significantly as a function of gestational age at birth (25-38 wks). Neonates born to women who were obese prior to pregnancy or smoked cigarettes during pregnancy had a 4-5-fold greater odds of anemia at birth. Cord sTfR was the strongest indicator of cord Hb (P < 0.0001), and it was significantly associated with maternal sTfR at mid-gestation (P = 0.01) and delivery (P = 0.002). Cord Fe indicators were significantly associated with cord hepcidin, but not maternal hepcidin., Conclusion: Screening for Fe status in neonates born to women carrying multiple fetuses is warranted, especially for those born to smokers or to women who are obese at entry into pregnancy.