Placental Erythroferrone and Erythropoietin mRNA Expression is not Associated with Maternal or Neonatal Iron Status in Adolescents Carrying Singletons and Adult Women Carrying Multiples.

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).

Fetal iron uptake from recent maternal diet and the maternal RBC iron pool.

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.

Umbilical Cord Erythroferrone Is Inversely Associated with Hepcidin, but Does Not Capture the Most Variability in Iron Status of Neonates Born to Teens Carrying Singletons and Women Carrying Multiples.

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 (ß: 1.17, P < 0.001), ferritin (ß: -0.27, P < 0.01), and hemoglobin (Hb) (ß: 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.

Child Pain Intensity and Parental Attitudes toward Complementary and Alternative Medicine Predict Post-Tonsillectomy Analgesic Use.

Parental attitudes regarding pain interventions and perceptions of their child's pain intensity likely influence the decision to administer postoperative analgesics. Our study examined the impact of daily fluctuations in child pain intensity and parental attitudes regarding complementary and alternative medicine (CAM) on analgesic administration following pediatric tonsillectomy. Parents of children undergoing tonsillectomy (n = 33) completed a survey assessing CAM attitudes and a 7-day postoperative electronic daily diary to record their child's daily pain intensity and analgesic medications (acetaminophen, ibuprofen, or oxycodone). Generalized linear mixed models with Poisson distributions evaluated the effects of within-person (child's daily pain intensity) and between-person (average postoperative pain, parental CAM attitudes) components on the number of medication doses administered. Higher daily pain intensity was associated with more oxycodone doses administered on a given day, but not acetaminophen or ibuprofen. Positive parental CAM attitudes were associated with less oxycodone use, beyond the variations accounted for by the child's daily pain intensity and average postoperative pain. Both parental CAM attitudes and their child's daily pain intensity were independently associated with parental decisions to administer opioids following tonsillectomy. Understanding factors influencing individual variability in analgesic use could help optimize children's postoperative pain management.

Iron absorption during pregnancy is underestimated when iron utilization by the placenta and fetus is ignored.

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 ß = -0.48, P < 0.01) and lower maternal hepcidin (standardized ß = -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.

Tissue remodeling gene expression in a murine model of chronic rhinosinusitis.

OBJECTIVE/HYPOTHESIS: The matrix metalloproteinase (MMP), fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) families regulate tissue remodeling in many normal and pathophysiologic processes. We hypothesize that induction of chronic sinonasal inflammation will be associated with changes in regulation of these tissue remodeling cytokines. METHODS: Balb/c mice aged 8 to 12 weeks were sensitized and treated with intranasal Aspergillus fumigatis (AF) three times per week for 1 week, 3 weeks, 2 months, and 3 months (n = 8 each time point). Sinonasal tissues were evaluated for changes in MMP, FGF, and BMP regulation using standard RT-PCR techniques. Additional snouts were processed for histology and immunohistochemistry. Untreated mouse snouts of identical age were used as controls. RESULTS: Significant upregulation of MMP8 was observed at 2 months, and MMP1a, MMP7, MMP8, and MMP12 were all significantly upregulated at 3 months. FGF3 was significantly upregulated at 3 weeks and 3 months, and FGF5, FGF6, and FGF8 were all significantly upregulated at 3 months. BMP8b and BMP9 were significantly upregulated at 3 months. Histologic analysis revealed mucosal, stromal, and mucin gland hypertrophy, increased mucin production, and metaplasia with loss of cilia. Antibody staining was strongly positive in the AF-treated group. CONCLUSIONS: Induction of CRS is associated with time-dependent changes in tissue remodeling cytokine expression occurring in conjuction with inflammatory tissue changes. Antibody staining for upregulated cytokines suggests local production within the sinonasal mucosa. Further study is required to better understand the association between BMP, FGF, and MMP regulation and tissue remodeling changes resulting from chronic inflammation.