Maternal hemoglobin and iron status in early pregnancy and risk of respiratory tract infections in childhood:A population-based prospective cohort study

Background: Maternal hemoglobin and iron status measures during pregnancy might affect the developing fetal respiratory system leading to adverse respiratory conditions. Our aim was to assess the associations of maternal hemoglobin and iron status measures during pregnancy with the risk of respiratory tract infections in children until 10 years of age. Methods:In a population-based cohort study among 5134 mother–child pairs, maternal hemoglobin and iron status including ferritin, transferrin, and transferrin saturation were measured during early pregnancy. In children, physician-attended respiratory tract infections from age 6 months until 10 years were assessed by questionnaires. Confounder-adjusted generalized estimating equation modeling was applied. Results: After taking multiple testing into account, high maternal ferritin concentrations and low maternal transferrin saturation during pregnancy were associated with an overall increased risk of upper, not lower, respiratory tract infections until age 10 years of the child [OR (95% CI: 1.23 (1.10, 1.38) and 1.28 (1.12, 1.47), respectively)]. High maternal transferrin saturation during pregnancy was associated with a decreased and increased risk of upper respiratory tract infections at 1 and 6 years, respectively, [OR (95% CI: 0.60 (0.44, 0.83) and 1.54 (1.17, 2.02))]. Observed associations were suggested to be U-shaped (p-values for non-linearity ≤.001). Maternal hemoglobin and iron status measures during pregnancy were not consistently associated with child's gastroenteritis and urinary tract infections, as proxies for general infection effects. Conclusion: High maternal ferritin and low transferrin saturation concentrations during early pregnancy were most consistently associated with an overall increased risk of child's upper, not lower, respiratory tract infections.</p

A comprehensive analysis of cardiovascular mortality trends in Peru from 2017 to 2022:Insights from 183,386 deaths of the national death registry

Background/objectives: Cardiovascular diseases are the leading cause of global mortality. Systematic studies on cardiovascular-related mortality at national and subnational levels in Peru are lacking. We aimed to describe the trends in cardiovascular-related mortality between 2017 and 2022 in Peru at national and subnational levels and by socioeconomic indicators. Subjects/methods: We used data from the Peruvian death registry 2017–2022. Using ICD-10 codes, mortality was categorized into: hypertensive-, coronary-, and cerebrovascular- related deaths. We estimated age-standardized cardiovascular-related mortality rates by sex at national and regional levels, and by natural regions (Coast, Highlands, Amazon). We estimated the change in mortality rates between 2017–2019 and 2020–2022 and explored factors that contributed to such a change. We explored ecological relationships between mortality rates and socioeconomic indicators.Findings: Overall 183,386 cardiovascular-related deaths were identified. Coronary-related deaths (37.2 %) were followed by hypertensive-related (25.1 %) and cerebrovascular-related deaths (22.6 %). Peru showed a marked increasing trend in cardiovascular-related mortality in 2020–2022 (77.8 %). The increase clustered in the Coast and Highlands, with the highest change observed in Lima (132.1 %). Mortality was highest in subjects with lower education and subjects with public health insurance. Gini coefficient was associated with lower mortality rates while unemployment was associated with higher mortality rates.Interpretation: There was a notable rise in cardiovascular-related mortality in Peru, particularly during the Covid-19 pandemic with a slight decrease in 2022. Gaining a comprehensive understanding of the factors that contribute to the increase in cardiovascular deaths in Peru will facilitate the development of precise interventions at both the national and regional levels.</p

Ethnic differences in adverse iron status in early pregnancy: a cross-sectional population-based study

We studied ethnic differences in terms of iron status during pregnancy between Dutch women and other ethnicities and explore to what extent these differences can be explained by environmental factors. This cross-sectional population-based study (2002–2006) was embedded in the Generation R study and included a total of 4737 pregnant women from seven ethnic groups (Dutch, Turkish, Moroccan, Cape Verdean, Surinamese-Hindustani, Surinamese-Creole and Antillean). Ethnicity was defined according to the Dutch classification of ethnic background. Ferritin, iron and transferrin were measured in early pregnancy. The overall prevalence of iron deficiency was 7 %, ranging from 4 % in both Dutch and Surinamese-Creoles, to 18 % in Turkish, Moroccan and Surinamese-Hindustani women. Iron overload was most prevalent in Surinamese-Creole (11 %) and Dutch (9 %) women. Socioeconomic factors accounted for 5–36 % of the differences. Income was the strongest socioeconomic factor in the Cape Verdean and Surinamese-Hindustani groups and parity for the Turkish and Moroccan groups. Lifestyle determinants accounted for 8–14 % of the differences. In all groups, the strongest lifestyle factor was folic acid use, being associated with higher iron status. In conclusion, in our population, both iron deficiency and iron overload were common in early pregnancy. Our data suggest that ethnic differences in terms of socioeconomic and lifestyle factors only partly drive the large ethnic differences in iron status. Our data support the development of more specific prevention programmes based on further exploration of socioeconomic inequities, modifiable risk and genetic factors in specific ethnic subgroups, as well as the need for individual screening of iron status before supplementation

The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes

Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD.</p

The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes

Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD.</p

Utility of iron biomarkers in differentiating menopausal status: Findings from CoLaus and PREVEND.

AIM To examine the association of iron biomarkers with menopausal status and assess whether these biomarkers can help differentiate menopausal status beyond age. METHODS In this cross-sectional study we included 1679 women from the CoLaus and 2133 from the PREVEND cohorts, with CoLaus used as primary cohort and PREVEND for replication. Ferritin, transferrin, iron, and transferrin saturation (TSAT) were used to assess iron status. Hepcidin and soluble transferrin receptor were assessed only in PREVEND. Menopausal status was self-reported and defined as menopausal or non-menopausal. Logistic regressions were used to explore the association of these iron biomarkers with menopause status. Sensitivity, specificity, area under the receiver operating characteristic curves (AUC), positive and negative predictive values as well as cut-off points for the iron biomarkers were calculated. The model with the highest AUC was defined as the best. RESULTS In the CoLaus and PREVEND cohorts, respectively, 513 (30.6 %) and 988 (46.3 %) women were postmenopausal. Ferritin (OR, 2.20; 95 % CI 1.72-2.90), transferrin (OR, 0.03; 95 % CI 0.01-0.10), and TSAT (OR, 1.28; 95 % CI 1.06-1.54) were significantly associated with menopausal status in CoLaus, with the findings replicated in PREVEND. AUC of age alone was 0.971. The best model resulted from combining age, ferritin, and transferrin, with an AUC of 0.976, and sensitivity and specificity of 87.1 % and 96.5 %, respectively. Adding transferrin and ferritin to a model with age improved menopause classification by up to 7.5 %. In PREVEND, a model with age and hepcidin outperformed a model with age, ferritin, and transferrin. CONCLUSION Iron biomarkers were consistently associated with menopausal status in both cohorts, and modestly improved a model with age alone for differentiating menopause status. Our findings on hepcidin need replication

Potential Mediating Role of Iron Biomarkers in the Association of Sex With Glucose, Insulin, and Type 2 Diabetes

Context: Sex-specific prevalence and incidence of type 2 diabetes (T2D) have been reported, but the underlying mechanisms are uncertain. Objective: In this study, we aimed to investigate whether iron biomarkers mediate the association between biological sex and glucose metabolism and the incidence of T2D. Methods: We used data from the general population enrolled in the prospective Prevention of REnal and Vascular ENd-stage Disease study in Groningen, The Netherlands. We measured ferritin, transferrin saturation (TSAT), hepcidin, soluble transferrin receptor (sTfR), fasting plasma glucose (FPG), fasting plasma insulin (FPI) levels, and incidence of T2D. We used multivariable regression and mediation analyses to investigate our hypothesis. All iron biomarkers, FPG, and FPI were log-transformed. Results: The mean (SD) age of the 5312 (51.3% female) individuals was 52.2 (11.6) years. Compared with males, females had lower FPG (β = -.01; 95% CI -0.02, -0.01) and FPI (β = -.03; 95% CI -0.05, -0.02) levels. Ferritin, hepcidin, and sTfR showed potential mediating effects on the association between sex and FPG, 21%, 5%, and 7.1%, respectively. Furthermore, these variables mediated 48.6%, 5.7%, and 3.1% of the association between sex and FPI, respectively. Alternatively, TSAT had a suppressive mediating role in the association of sex with FPG and FPI. The incidence of T2D was lower in females than in males (hazard ratio 0.58; 95% CI 0.44, 0.77), with 19.2% of this difference being mediated by ferritin. Conclusion: Iron biomarkers may partially mediate the association between sex and glucose homeostasis. Future studies addressing the causality of our findings are needed.</p

Utility of iron biomarkers in differentiating menopausal status: Findings from CoLaus and PREVEND

Aim: To examine the association of iron biomarkers with menopausal status and assess whether these biomarkers can help differentiate menopausal status beyond age. Methods: In this cross-sectional study we included 1679 women from the CoLaus and 2133 from the PREVEND cohorts, with CoLaus used as primary cohort and PREVEND for replication. Ferritin, transferrin, iron, and transferrin saturation (TSAT) were used to assess iron status. Hepcidin and soluble transferrin receptor were assessed only in PREVEND. Menopausal status was self-reported and defined as menopausal or non-menopausal. Logistic regressions were used to explore the association of these iron biomarkers with menopause status. Sensitivity, specificity, area under the receiver operating characteristic curves (AUC), positive and negative predictive values as well as cut-off points for the iron biomarkers were calculated. The model with the highest AUC was defined as the best. Results: In the CoLaus and PREVEND cohorts, respectively, 513 (30.6 %) and 988 (46.3 %) women were postmenopausal. Ferritin (OR, 2.20; 95 % CI 1.72–2.90), transferrin (OR, 0.03; 95 % CI 0.01–0.10), and TSAT (OR, 1.28; 95 % CI 1.06–1.54) were significantly associated with menopausal status in CoLaus, with the findings replicated in PREVEND. AUC of age alone was 0.971. The best model resulted from combining age, ferritin, and transferrin, with an AUC of 0.976, and sensitivity and specificity of 87.1 % and 96.5 %, respectively. Adding transferrin and ferritin to a model with age improved menopause classification by up to 7.5 %. In PREVEND, a model with age and hepcidin outperformed a model with age, ferritin, and transferrin. Conclusion: Iron biomarkers were consistently associated with menopausal status in both cohorts, and modestly improved a model with age alone for differentiating menopause status. Our findings on hepcidin need replication

Potential Mediating Role of Iron Biomarkers in the Association of Sex With Glucose, Insulin, and Type 2 Diabetes

Context: Sex-specific prevalence and incidence of type 2 diabetes (T2D) have been reported, but the underlying mechanisms are uncertain. Objective: In this study, we aimed to investigate whether iron biomarkers mediate the association between biological sex and glucose metabolism and the incidence of T2D. Methods: We used data from the general population enrolled in the prospective Prevention of REnal and Vascular ENd-stage Disease study in Groningen, The Netherlands. We measured ferritin, transferrin saturation (TSAT), hepcidin, soluble transferrin receptor (sTfR), fasting plasma glucose (FPG), fasting plasma insulin (FPI) levels, and incidence of T2D. We used multivariable regression and mediation analyses to investigate our hypothesis. All iron biomarkers, FPG, and FPI were log-transformed. Results: The mean (SD) age of the 5312 (51.3% female) individuals was 52.2 (11.6) years. Compared with males, females had lower FPG (β = -.01; 95% CI -0.02, -0.01) and FPI (β = -.03; 95% CI -0.05, -0.02) levels. Ferritin, hepcidin, and sTfR showed potential mediating effects on the association between sex and FPG, 21%, 5%, and 7.1%, respectively. Furthermore, these variables mediated 48.6%, 5.7%, and 3.1% of the association between sex and FPI, respectively. Alternatively, TSAT had a suppressive mediating role in the association of sex with FPG and FPI. The incidence of T2D was lower in females than in males (hazard ratio 0.58; 95% CI 0.44, 0.77), with 19.2% of this difference being mediated by ferritin. Conclusion: Iron biomarkers may partially mediate the association between sex and glucose homeostasis. Future studies addressing the causality of our findings are needed

Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways