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).

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.

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.

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.

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.

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.

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.

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.

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.

BACKGROUND: The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut-allergic individuals undergoing oral desensitization immunotherapy with AR101. METHODS: Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T-cell reactivity to peanut. RESULTS: The absence of clinical reactivity to the entry double-blinded placebo-controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T-cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut-reactive TH2A cells were observed in many but not all peanut-allergic patients and their level in peripheral blood correlates with T-cell reactivity to peanut and with serum peanut-specific IgE and IgG4 levels. POIT reshaped circulating peanut-reactive T-cell responses in a subset-dependent manner. Changes in basophil and T-cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut-reactive Treg cell frequency was observed between groups. CONCLUSION: Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut-reactive T effector cell responses supporting its potential as an immunomodulatory therapy.