Placental Iron Content is Lower than Previously Estimated and is Associated with Maternal Iron Status in Women at Greater Risk for Gestational Iron Deficiency and Anemia

Background Based on limited data, it is estimated that the placenta retains 90 mg of iron (Fe). Little is known about determinants of placental Fe content. Animal data indicate that the placenta prioritizes Fe for its own needs, but this hypothesis has not been evaluated in humans. Objectives To characterize placental Fe content and placental Fe concentration (p[Fe]) in pregnant women at risk of Fe insufficiency and identify determinants of p[Fe]. Methods Placentae 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 Fe status indicators (hemoglobin, SF, sTfR, serum Fe, TBI) and hormones (erythropoietin, hepcidin) were measured. P[Fe] was measured using ICP-MS. Correlation analyses and mixed-effects models were constructed to identify determinants of p[Fe]. Results Mean placental Fe content was 23 mg per placenta [95%CI 15–33] in the multiples and 40 mg [95%CI 31–51] in the teens (P = 0.03). Mean p[Fe] did not differ between the cohorts. P[Fe] was higher in anemic (175 [95%CI 120–254] μg/g) compared to non-anemic (46 [95%CI 26–82] μg/g) women carrying multiples (P = 0.009), but did not differ between anemic (62 [95%CI 40–102] μg/g) and non-anemic (73 [95%CI 56–97] μg/g) teens. In women carrying multiples, low maternal Fe status [lower SF (P = 0.002) and lower TBI (P = 0.01)] was associated with higher p[Fe], while in teens, improved Fe status [lower sTfR (P = 0.03) and higher TBI (P = 0.03)] was associated with higher p[Fe]. Conclusions Placental Fe content was ∼50% lower than previously estimated. P[Fe] is significantly associated with maternal Fe status. In women carrying multiples, poor maternal Fe status was associated with higher p[Fe], while in teens, improved Fe status was associated with higher p[Fe]. More data are needed to understand determinants of p[Fe] and the variable Fe partitioning in teens compared to mature women. Clinical Trial Registry: These clinical trials were registered at clinicaltrials.gov as NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902) and NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802).

A descriptive study of New Zealand midwives' primary care management of iron status in pregnancy and the postpartum period

<p>Background: Globally there is no consensus on haemoglobin (Hb) parameters that define maternal anaemia. Therefore it is difficult to distinguish physiological anaemia of pregnancy from anaemia associated with pathology. Low maternal iron status is associated with adverse outcomes, although the evidence is difficult to interpret. Non-anaemic iron deficiency requires prevention and treatment, before end stage iron deficiency anaemia. Increases in serum ferritin (SF) secondary to inflammation, gives misleading results of iron stores if not tested with C-reactive protein (CRP). Given the complexities, how do Lead Maternity Carer (LMC) midwives in New Zealand manage anaemia and iron deficiency, without a clinical guideline? Methods: In this descriptive study, quantitative data was retrospectively collected from September-December 2013, from LMC midwives (n=21) and women (n=189), in one New Zealand area. Main outcomes assessed were women’s iron status. Anaemia was defined as Hb <110g/L in the first trimester, <105g/L in subsequent trimesters, and <100g/L postnatally. Iron deficiency was defined as SF <20 μg/L, if CRP<5mg/L. A secondary analysis of iron status and body mass index (BMI) was undertaken. Results: Of the 186 women who had Hb testing at booking, 46% did not have ferritin tested concurrently. Of the 385 ferritin tests undertaken, 86% were not tested with CRP. Despite midwives prescribing iron for 48.7%, and recommending iron for 16.9% of second trimester women, 47.1% had low iron status before birth. Only 22.8% had Hb testing postpartum, including 65.1% (of 38) with blood loss >500mls. Results of a secondary analysis showed a significant difference (p=.05) between third trimester ferritin levels in women with BMI ≥ 25 (Md SF 14 μg/L) and BMI < 25 (Md SF 18 μg/L). Conclusions: Inconsistent testing of ferritin made it difficult to assess maternal iron status, especially without concurrent testing of CRP. Midwives may not understand and recognise the progression from iron sufficiency to end-stage iron deficiency anaemia. Even without further research this small study may indicate the need for improved education for midwives, and a clinical guideline. More complex studies on the prevalence in New Zealand, BMI and iron status, and maternal outcomes especially in the postpartum period, are warranted.</p>

A descriptive study of New Zealand midwives' primary care management of iron status in pregnancy and the postpartum period

<p>Background: Globally there is no consensus on haemoglobin (Hb) parameters that define maternal anaemia. Therefore it is difficult to distinguish physiological anaemia of pregnancy from anaemia associated with pathology. Low maternal iron status is associated with adverse outcomes, although the evidence is difficult to interpret. Non-anaemic iron deficiency requires prevention and treatment, before end stage iron deficiency anaemia. Increases in serum ferritin (SF) secondary to inflammation, gives misleading results of iron stores if not tested with C-reactive protein (CRP). Given the complexities, how do Lead Maternity Carer (LMC) midwives in New Zealand manage anaemia and iron deficiency, without a clinical guideline? Methods: In this descriptive study, quantitative data was retrospectively collected from September-December 2013, from LMC midwives (n=21) and women (n=189), in one New Zealand area. Main outcomes assessed were women’s iron status. Anaemia was defined as Hb <110g/L in the first trimester, <105g/L in subsequent trimesters, and <100g/L postnatally. Iron deficiency was defined as SF <20 μg/L, if CRP<5mg/L. A secondary analysis of iron status and body mass index (BMI) was undertaken. Results: Of the 186 women who had Hb testing at booking, 46% did not have ferritin tested concurrently. Of the 385 ferritin tests undertaken, 86% were not tested with CRP. Despite midwives prescribing iron for 48.7%, and recommending iron for 16.9% of second trimester women, 47.1% had low iron status before birth. Only 22.8% had Hb testing postpartum, including 65.1% (of 38) with blood loss >500mls. Results of a secondary analysis showed a significant difference (p=.05) between third trimester ferritin levels in women with BMI ≥ 25 (Md SF 14 μg/L) and BMI < 25 (Md SF 18 μg/L). Conclusions: Inconsistent testing of ferritin made it difficult to assess maternal iron status, especially without concurrent testing of CRP. Midwives may not understand and recognise the progression from iron sufficiency to end-stage iron deficiency anaemia. Even without further research this small study may indicate the need for improved education for midwives, and a clinical guideline. More complex studies on the prevalence in New Zealand, BMI and iron status, and maternal outcomes especially in the postpartum period, are warranted.</p>

Erythroferrone Modulates Iron Distribution for Fetal Erythropoiesis

Erythroferrone (ERFE) is an erythroblast-derived regulator of iron metabolism, and its production increases during stress erythropoiesis. ERFE decreases expression of the iron-regulatory hormone hepcidin to enhance iron availability for erythropoiesis 1. Pregnancy requires a substantial increase in iron availability to sustain a dramatic increase in maternal RBC volume and support fetal development. Whether maternal or fetal ERFE plays a role in regulating iron homeostasis during pregnancy is unknown. In humans, maternal ERFE concentrations were elevated in anemic pregnancies at mid gestation and delivery 2. To define the role of ERFE during iron-replete or iron-deficient pregnancy, we utilized Erfe transgenic (ETg) 3 and Erfe knockout (EKO) 1 mice. Maternal iron status of ETg, WT and EKO mice was altered by placing animals on adequate iron (100ppm) or low iron (4ppm) diet 2 weeks prior to and throughout pregnancy. ETg and WT dams were mated with WT sires to generate ETg and WT embryos while EKO dams were mated with EKO sires to generate EKO embryos. Analysis was performed at embryonic day 18.5. To examine the effect of pregnancy on ERFE expression, we compared non-pregnant females to WT dams at E18.5. Serum ERFE was mildly elevated from 0.01 to 0.2 ng/mL in iron-replete dams, but substantially elevated from 0.01 to 3.1 ng/mL in iron-deficient dams, similarly to human pregnancy 2. We next assessed iron and hematological parameters in pregnant dams with different Erfe genotypes. Under iron-replete conditions, all three groups had similar serum hepcidin, serum iron and hemoglobin concentrations, but ETg dams had 3-fold higher liver iron than WT and EKO dams, presumably because they are mildly iron-overloaded before pregnancy. On iron-deficient diet, maternal hepcidin was decreased in all three genotypes but more so in ETg dams; however, all three Erfe genotypes had similarly depleted liver iron stores, hypoferremia and anemia. MCV was the only parameter that was decreased in EKO compared to WT dams under both iron conditions. Overall, maternal ERFE played a minor role in regulation of maternal erythropoiesis and iron homeostasis, with the lack of ERFE resulting in smaller RBCs but not anemia. Among embryos, we observed a significant effect of Erfe genotype on embryo hepcidin. ETg embryos had significantly lower liver hepcidin compared to WT embryos under both iron-replete and iron-deficient conditions. Conversely, Erfe KO embryos had higher hepcidin compared to WTs under iron-deficient conditions, indicating that embryo ERFE regulates embryo hepcidin during pregnancy. Under iron-replete conditions however, all three embryo genotypes had similar hematologic parameters, and embryo liver iron was dependent on maternal iron levels, with both ETg and WT embryos from ETg dams having increased liver iron concentrations, indicating that embryo ERFE does not regulate placental iron transfer. Under iron-deficient conditions, there was no difference between ETg and WT embryos in hematological or iron parameters, and both genotypes developed iron deficiency and anemia. However, Erfe KO embryos, which had elevated hepcidin, had maldistribution of iron and worse anemia. EKO embryo liver iron concentrations were 6-fold higher compared to WT iron-deficient embryos, whereas hemoglobin was significantly decreased compared to WT iron-deficient embryos. These findings indicate that under iron-limiting conditions, embryo ERFE is important for the suppression of embryo hepcidin to ensure iron redistribution for embryo erythropoiesis. In summary, during iron replete pregnancy, ERFE plays a minor role in maternal and fetal iron homeostasis and erythropoiesis. However, in response to iron-deficiency anemia during pregnancy, ERFE is important for the redistribution of iron within the embryo to support embryo erythropoiesis. 1Kautz L et al, Nat Genet, 2014 2Delaney K et al, Curr Dev Nutr, 2020 3Coffey R et al, Blood, 2020 Disclosures Ganz: Ambys: Consultancy; Sierra Oncology: Consultancy, Research Funding; Rockwell: Consultancy; Pharmacosmos: Consultancy; Ionis: Consultancy; Protagonist: Consultancy; Intrinsic LifeSciences: Consultancy; RallyBio: Consultancy; Silence Therapeutics: Consultancy; Silarus Pharma: Consultancy; Alnylam: Consultancy; American Regent: Consultancy; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenecaFibrogen: Consultancy; Global Blood Therapeutics: Consultancy; Gossamer Bio: Consultancy; Akebia: Consultancy, Honoraria. Nemeth: Silarus Pharma: Consultancy; Intrinsic LifeSciences: Consultancy; Protagonist: Consultancy; Vifor: Consultancy; Ionis: Consultancy.

Maternal iron deficiency alters trophoblast differentiation and placental development in rat pregnancy

Iron deficiency occurs when iron demands chronically exceed intake, and is prevalent in pregnant women. Iron deficiency during pregnancy poses major risks for the baby, including fetal growth restriction and long-term health complications. The placenta serves as the interface between a pregnant mother and her baby, and ensures adequate nutrient provisions for the fetus. Thus, maternal iron deficiency may impact fetal growth and development by altering placental function. We used a rat model of diet-induced iron deficiency to investigate changes in placental growth and development. Pregnant Sprague-Dawley rats were fed either a low-iron or iron-replete diet starting two weeks before mating. Compared to controls, both maternal and fetal hemoglobin were reduced in dams fed low-iron diets. Iron deficiency decreased fetal liver and body weight, but not brain, heart or kidney weight. Placental weight was increased in iron deficiency, due primarily to expansion of the placental junctional zone. The stimulatory effect of iron deficiency on junctional zone development was recapitulated in vitro, as exposure of rat trophoblast stem cells to the iron chelator deferoxamine increased differentiation toward junctional zone trophoblast subtypes. Gene expression analysis revealed 464 transcripts changed at least 1.5-fold (P&lt;0.05) in placentas from iron-deficient dams, including altered expression of genes associated with oxygen transport and lipoprotein metabolism. Expression of genes associated with iron homeostasis was unchanged despite differences in levels of their encoded proteins. Our findings reveal robust changes in placentation during maternal iron deficiency, which could contribute to the increased risk of fetal distress in these pregnancies.

Predictors of mortality among newborns admitted with perinatal asphyxia at public hospitals in Ethiopia: a prospective cohort study

Introduction Perinatal asphyxia is a complicated newborn health problem and applies a high contribution to the increased proportion of newborn mortality. It occurs in newborns due to altered breathing or inadequate inhalation and exhalation resulting in reduced oxygen perfusion to certain body tissues and organs. Irrespective of the increased progress in health care towards newborns and implementations in reductions in under-five, infant, and neonatal mortality in the past 10 years, perinatal asphyxia remained as the most common severe newborn health challenge that causes a high number of morbidity and mortality. Methods A prospective cohort longitudinal study was implemented among 573 newborns admitted with perinatal asphyxia at public hospitals in Southern Ethiopia from 1st March 2018 to 28th February 2020. The perinatal survival time was determined using Kaplan Meier survival curve together with a log-rank test. The dependent variable was time to death and the independent variables were classified as socio-demographic factors, obstetrics related factors, newborn related factors and maternal medical related factors. The study subjects were entered in to the cohort during admission with perinatal asphyxia in the hospital and followed until 7 days of life. Results The cumulative proportion of survival among the newborns admitted with perinatal asphyxia was 95.21% (95%CI:91.00,97.48), 92.82% (95%CI:87.95,95.77), 92.02%(95%CI:86.84,95.22) and 90.78%(95%CI:84.82,94.48) at the end of first, second, third and fourth follow-up days respectively. The mean survival date was 6.55(95%CI: 6.33, 6.77) and cord prolapse (AHR:6.5;95%CI:1.18,36.01), pregnancy induced hypertension (AHR:25.4;95%CI:3.68,175.0), maternal iron deficiency anemia (AHR:5.9;95%CI:1.19,29.5) and having convulsion of the newborn (AHR:10.23;95%CI:2.24,46.54) were statistically significant in multivariable cox proportional hazard model. Conclusion The survival status among newborns with perinatal asphyxia was low during the early follow-up periods after admission to the hospital and the survival status increased after fourth follow up days. In addition, cord prolapse, history of PIH, maternal iron deficiency anemia and newborns history of convulsion were the independent predictors of mortality.

Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

Iron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and may overestimate iron stores during inflammation or infection. In this study, we use mouse models to determine whether maternal iron loading, inflammation, or their interaction cause poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, causes embryo malformations and demise. Maternal iron excess potentiates embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction depends on TNFα signaling, causes apoptosis of placental and embryo endothelium, and is prevented by anti-TNFα or antioxidant treatment. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy.

Maternal Iron Status in Pregnancy and Child Health Outcomes after Birth: A Systematic Review and Meta-Analysis

In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother–child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.

Association between Iron Supplementation, Dietary Iron Intake and Risk of Moderate Preterm Birth: A Birth Cohort Study in China

Background: To evaluate the independent and collective effects of maternal iron supplementation and dietary iron intake upon the risk of moderate preterm birth and its subtypes. Methods: In this birth cohort study, 1019 pregnant women with moderate preterm birth and 9160 women with term birth were recruited at Gansu Provincial Maternity and Child Care Hospital from 2010-2012 in China. Unconditional logistic regression models were utilized to evaluate the association between maternal iron supplementation, dietary iron intake, and the risk of moderate preterm birth and its subtypes. Results: Compared with non-users, iron supplement users exerted a protective effect upon the overall (OR=0.54, 95%CI=0.40-0.72) and spontaneous moderate preterm birth (OR=0.39, 95%CI=0.33-0.83). Compared with the 25th quartiles of dietary iron intake, either before or during pregnancy, it exerted a significantly protective effect upon those who had the highest quartiles of dietary iron intake (OR=0.87, 95%CI=0.82-0.95 for the highest quartiles of dietary iron intake before pregnancy OR=0.85, 95%CI=0.79-0.91). Positive association was observed between the additive scale and multiplicative scale for preterm birth, spontaneous preterm rather than medically indicated preterm. Conclusion: Iron supplements (60 mg/day) and high-iron intake (>25.86 mg/day before pregnancy, >30.46 mg/day during pregnancy) reduced the risk of moderate preterm birth. Positive correlation is found between the additive scale and multiplicative scale for preterm birth, spontaneous preterm birth.

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.