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 (ß = -.01; 95% CI -0.02, -0.01) and FPI (ß = -.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.

Cross-sectional and longitudinal associations of Iron biomarkers and cardiovascular risk factors in pre- and postmenopausal women: leveraging repeated measurements to address natural variability.

BACKGROUND: The association between iron biomarkers and cardiovascular disease risk factors (CVD-RFs) remains unclear. We aimed to (1) evaluate the cross-sectional and longitudinal associations between iron biomarkers (serum ferritin, transferrin saturation (TSAT), transferrin) and CVD-RFs among women, and (2) explore if these associations were modified by menopausal status. METHOD: Cross-sectional and longitudinal analyses including 2542 and 1482 women from CoLaus cohort, respectively. Multiple linear regression and multilevel mixed models were used to analyse the associations between Iron biomarkers and CVD-RFs. Variability of outcomes and iron markers between surveys was accessed using intraclass correlation (ICC). RESULTS: After multivariable adjustment, elevated serum ferritin levels were associated with increased insulin and glucose levels, while higher transferrin levels were linked to elevated glucose, insulin and total cholesterol, and systolic and diastolic blood pressure (p < 0.05). No association was observed between CVD-RFs and TSAT (p > 0.05). Iron biomarkers demonstrated low reliability across reproductive stages but exhibited stronger associations in the perimenopausal group. In longitudinal analysis, we found association only for transferrin with lower glucose levels [ß = - 0.59, 95% CI (- 1.10, - 0.08), p = 0.02] and lower diastolic blood pressure [ß = - 7.81, 95% CI (- 15.9, - 0.56), p = 0.04]. CONCLUSION: In cross-sectional analysis, transferrin was associated with several CVD-RFs, and the associations did not change according to menopausal status. Conversely, in the longitudinal analyses, changes in transferrin were associated only with lower glucose and diastolic blood pressure levels. These differences might stem from the substantial longitudinal variation of iron biomarkers, underscoring the need for multiple iron measurements in longitudinal analyses.

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.

Vulnerable newborn phenotypes in Peru: a population-based study of 3,841,531 births at national and subnational levels from 2012 to 2021.

Background: We aimed to examine the national and subnational prevalence of vulnerable newborn phenotypes in Peru, 2012-2021. Methods: Newborn phenotypes were defined using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight [LBW], non-LBW) using the Peruvian National Birth Registry as six (by excluding birthweight) and ten newborn phenotypes (using all three outcomes). Small phenotypes (with at least one classification of PT, SGA, or LBW) were further considered. Using individual-level data, we stratified the phenotypes by maternal educational level, maternal age, healthcare insurance, altitude of residence, and geographic region (Coast, Andes, and Amazon). Findings: The prevalence of the five vulnerable newborn phenotypes for the study period was LGA+T (15.2%), AGA+PT (5.2%), SGA+T (4.6%), LGA+PT (0.8%), and SGA+PT (0.7%). The Coast had a higher prevalence of newborns with large phenotypes (19.4%) and the Highlands a higher prevalence of newborns with small phenotypes (12.5%). Mothers with poor socioeconomic status, extreme ages and living at high altitude had a higher prevalence of newborns with small phenotypes, and mothers who were wealthier, more educated, and older had a higher prevalence of infants with large phenotypes. Interpretation: Our findings cautiously suggest that socioeconomic and geographic disparities may play a crucial role in shaping vulnerable newborn phenotypes at national and subnational level in Peru. Further studies using longitudinal data are needed to corroborate our findings and to identify individual-level risk factors. Funding: Ter Meulen Grant from the KNAW Medical Sciences Fund of the Royal Netherlands Academy of Arts and Sciences (KNAWWF/1085/TMB406, KNAWWF/1327/TMB202116), Fogarty Program (D43TW011502).

Body composition and respiratory outcomes in children: a population-based prospective cohort study.

BACKGROUND: Body composition might influence lung function and asthma in children, but its longitudinal relations are unclear. We aimed to identify critical periods for body composition changes during childhood and adolescence in relation to respiratory outcomes in adolescents. METHODS: In a population-based prospective cohort study, we measured body mass index, fat mass index (FMI), lean mass index (LMI) and the ratio of android fat mass divided by gynoid fat mass (A/G ratio) by dual-energy X-ray absorptiometry at 6, 10 and 13 years. At 13 years, lung function was measured by spirometry, and current asthma was assessed by questionnaire. RESULTS: Most prominently and consistently, higher FMI and A/G ratio at age 13 years were associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and forced expiratory flow after exhaling 75% of FVC (FEF75) (range Z-score difference -0.13 (95% CI -0.16 to -0.10) to -0.08 (95% CI -0.11 to -0.05) per SD score increase), and higher LMI at all ages was associated with higher FEF75 (range Z-score difference 0.05 (95% CI 0.01 to 0.08) to 0.09 (95% CI 0.06 to 0.13)). Between the ages of 6 and 13 years, normal to high FMI and A/G ratio were associated with lower FEV1/FVC and FEF75 (range Z-score difference -0.20 (95% CI -0.30 to -0.10) to -0.17 (95% CI -0.28 to -0.06)) and high to high LMI with higher FEF75 (range Z-score difference0.32 (95% CI 0.23 to 0.41)). Body composition changes were not associated with asthma. CONCLUSION: Adolescents with higher total and abdominal fat indices may have impaired lung function, while those with a higher lean mass during childhood and adolescence may have better small airway function. Public health measures should focus on a healthy body composition in adolescents to minimise respiratory morbidity.

Long-Term Bowel Vaginoplasty With a Single Yang-Monti Tube.

INTRODUCTION: The bowel remains the favored tissue for neo-vaginoplasty (NeoVP) in pediatric patients with vaginal agenesis. In 2001, the first description of NeoVP using the Yang-Monti technique with a sigmoid double tubular flap was published. We present our experience of NeoVP with a single Yang-Monti tube (SYMT) flap and report on the use of different segments of colon. METHODS: We conducted a retrospective review of patients who underwent NeoVP using a bowel SYMT between 2009 and 2021. The procedure was performed under open abdominal surgery by isolating 8 to 12 cm from the rectosigmoid, cecum, or ascending colon. Subsequently, this segment was detubularized near the mesenteric border, folded, and retubularized transversally, leaving the mesentery in a cephalic position. A channel was dissected in the pelvis to accommodate the NeoVP. RESULTS: Seventeen patients were identified. The median age was 16 years old. The principal diagnosis was Mayer-Rokitansky's syndrome (47.1%). The median follow-up was 50 months. The mean harvested bowel length was 9 cm, and the sigmoid was the preferred site (65%). The cecum-ascending colon was used in 3 (17.6%) patients. Complications were recorded in 6 patients (35%). Of these 6 patients, 4 had introital stenosis. There was 1 case of urethrovaginal fistula and another of left hematometrocolpos. Satisfactory sexual function has been reported in sexually active individuals. CONCLUSIONS: We described our experience in NeoVP using a large bowel SYMT as a safe and effective technique. It allows decreased tension on the vascular pedicle and the use of shorter colon segments.

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.

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.

Maternal iron status in early pregnancy and childhood body fat measures and cardiometabolic risk factors: A population-based prospective cohort.

BACKGROUND: Whether maternal iron status during pregnancy is associated with cardiometabolic health in the offspring is poorly known. OBJECTIVES: We aimed to assess the associations of maternal iron status during early pregnancy with body fat measures and cardiometabolic risk factors in children aged 10 y. METHODS: In a population-based cohort study among 3718 mother-child pairs, we measured ferritin, transferrin, and transferrin saturation during early pregnancy. We obtained child BMI, fat mass index, and android/gynoid fat mass ratio by DXA, subcutaneous fat index, visceral fat index, pericardial fat index, and liver fat fraction by magnetic resonance imaging and assessed systolic and diastolic blood pressure, serum lipids, glucose, insulin, and CRP at 10 y. RESULTS: A one-standard deviation score (SDS) higher maternal ferritin was associated with lower fat mass index [difference -0.05 (95% CI: -0.08, -0.02) SDS] and subcutaneous fat index [difference -0.06 (95% CI: -0.10, -0.02) SDS] in children. One-SDS higher maternal transferrin was associated with higher fat mass index [difference 0.04 (95% CI: 0.01, 0.07) SDS], android/gynoid fat mass ratio [difference 0.05 (95% CI: 0.02, 0.08) SDS], and subcutaneous fat index [difference 0.06 (95% CI: 0.02, 0.10) SDS] in children. Iron status during pregnancy was not consistently associated with organ fat and cardiometabolic risk factors at 10 y. CONCLUSIONS: Maternal lower ferritin and higher transferrin in early pregnancy are associated with body fat accumulation and distribution but are not associated with cardiometabolic risk factors in childhood. Underlying mechanisms and long-term consequences warrant further study.

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.

COVID-19 and drivers of excess death rate in Peru: A longitudinal ecological study.

Background: Peru has experienced unprecedented mortality and economic toll due to the COVID-19 (Coronavirus disease 2019) pandemic in 2020. We aimed to assess the association between socioeconomic factors and excess death rate, and to explore the relative contribution of these factors to the differences in excess death rate during January-December 2020. Methods: Different national secondary data sources were used to describe excess death rates and different determinants, from distal to proximal. A confounding-adjusted multilevel mixed-effects linear regression was used to assess the association between these variables and excess death rates. Their relative contributions to the differences in excess death rate between the periods with the highest and lowest excess death rates were analyzed through regression-based Oaxaca-Blinder decomposition methods. Findings: The excess death rate showed an increasing trend in all regions, with different slopes. The confounding-adjusted multilevel analysis showed that higher healthcare access was associated with lower excess death rates (difference (95%CI) -0.004 (-0.005, -0.002)), whereas COVID-19 incidence was associated with higher excess death rates (difference (95%CI) 0.052 (0.042, 0.063)). The decomposition analysis showed COVID-19 incidence (41.9%), per capita income (19.4%) and unemployment rate (14.6%) as the main risk factors, while the main protective factors included per capita health expenditure (44.7%), healthcare access (33.2%) and health insurance (12.1%). Interpretation: Our study suggests that the excess death rate during the COVID-19 pandemic in Peru may have been influenced by other factors besides COVID-19 incidence, from distal to proximal drivers, including socioeconomic determinants, factors outside and within the health sector, and susceptibility factors. Further studies at individual level are needed to corroborate our findings.

Flat trend of high caesarean section rates in Peru: A pooled analysis of 3,376,062 births from the national birth registry, 2012 to 2020.

Background: National and subnational C-section rates are seldom available in low- and middle-income countries to guide policies and interventions. We aimed to describe the C-section rates at the national and subnational levels in Peru (2012-2020). Methods: Based on the Peruvian national birth registry, we quantified C-section rates at the national, regional and province levels; also, by natural regions (Coast, Highlands, and Amazon). Using individual-level data from the mother, we stratified the C-section rates by educational level, healthcare insurance and provider. Ecologically, we studied the correlations between C-section rates and human development index (HDI), altitude above sea level, proportion of the population living in poverty and proportion of rural population. Findings: C-section rate in Peru decreased slightly from 2012 (39·7%) to 2020 (38·0%). A widening gap of C-section rates was observed through the study years among the Coast that showed higher rates and the other natural regions that showed lower rates. The rates in most of the 25 regions showed a flat trend, particularly in the last four years and some provinces showed a very low rate. The rates were highest in mothers with higher education and in users of private health insurance. Higher HDI, health facility located at lower altitude, lower poverty and urbanization were positively correlated with higher C-section rates. Interpretation: C-section rates in Peru are above the international recommendations. Large differences by natural region, provinces and women socioeconomic status were found. Further efforts are needed to achieve the recommended C-section rates. Funding: Academy Ter Meulen grant of the Academy Medical Sciences Fund of the Royal Netherlands Academy of Arts & Sciences (KNAWWF/1327/TMB202116), Wellcome Trust (214185/Z/18/Z), Fogarty (D43TW011502).

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.

Maternal Iron Status in Early Pregnancy and Blood Pressure Throughout Pregnancy, Placental Hemodynamics, and the Risk of Gestational Hypertensive Disorders.

BACKGROUND: In nonpregnant populations, higher serum ferritin, which reflects high iron stores, is associated with an increased risk of hypertension. We hypothesized that a dysregulated maternal iron status in early pregnancy may lead to impaired gestational hemodynamic adaptations, leading to an increased risk of gestational hypertensive disorders. OBJECTIVES: We examined the associations of maternal iron status with maternal blood pressure, placental hemodynamic parameters, and the risks of gestational hypertensive disorders. METHODS: In a population-based prospective cohort study among 5983 pregnant women, we measured maternal serum ferritin, transferrin saturation, serum iron, and transferrin concentrations at a median of 13.2 weeks gestation (95% range, 9.6-17.6). Maternal blood pressure was measured in early pregnancy, mid pregnancy, and late pregnancy, and placental hemodynamic parameters in mid pregnancy and late pregnancy were measured by ultrasound. Information on gestational hypertensive disorders was collected from medical records. We examined the associations of maternal early pregnancy iron status with maternal systolic and diastolic blood pressure, placental hemodynamic parameters, and the risks of gestational hypertensive disorders using linear and logistic regression models. RESULTS: Higher maternal early pregnancy serum ferritin concentrations were associated with higher systolic and diastolic blood pressure throughout pregnancy in the basic models (P values < 0.05). After adjustment for maternal inflammation, sociodemographic and lifestyle factors, higher maternal early pregnancy serum ferritin concentrations were only associated with a higher early pregnancy diastolic blood pressure [0.27 (95% CI, 0.03-0.51) mmHg per SD score increase in serum ferritin] and with a higher mid pregnancy umbilical artery pulsatility index (P < 0.05). No associations with the risk of gestational hypertensive disorders were present. CONCLUSIONS: No consistent associations were present of maternal iron status in early pregnancy with gestational hemodynamic adaptations or the risks of gestational hypertensive disorders. Further studies are needed to examine the potential role of iron metabolism in the development of gestational hypertensive disorders within higher-risk populations.

National and subnational trends of birthweight in Peru: Pooled analysis of 2,927,761 births between 2012 and 2019 from the national birth registry.

BACKGROUND: National and subnational characterization of birthweight profiles lacks in low- and middle-income countries, yet these are needed for monitoring the progress of national and global nutritional targets. We aimed to describe birthweight indicators at the national and subnational levels in Peru (2012-2019), and by selected correlates. METHODS: We studied mean birthweight (g), low birthweight (<2,500 g) and small for gestational age (according to international growth curves) prevalences. We analysed the national birth registry and summarized the three birthweight indicators at the national, regional, and province level, also by geographic area (Coast, Highlands, and Amazon). With individual-level data from the mother, we described the birthweight indicators by age, educational level and healthcare provider. Following an ecological approach (province level), we described the birthweight indicators by human development index (HDI), altitude above sea level, proportion of the population living in poverty and proportion of rural population. FINDINGS: Mean birthweight was always the lowest in the Highlands (2,954 g in 2019) yet the highest in the Coast (3,516 g in 2019). The same was observed for low birthweight and small for gestational age. In regions with Coast and Highlands, the birthweight indicators worsen from the Coast to the Highlands; the largest absolute difference in mean birthweight between Coast and Highlands in the same region was 367 g. All birthweight indicators were the worst in mothers with none/initial education, while they improved with higher HDI. INTERPRETATION: This analysis suggests that interventions are needed at the province level, given the large differences observed between Coast and Highlands even in the same region. FUNDING: Wellcome Trust (214185/Z/18/Z).

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.

Maternal iron status during early pregnancy and school-age, lung function, asthma, and allergy: The Generation R Study.

BACKGROUND: Iron deficiency during early life could affect the developing lung and immune system, and influence child's respiratory or allergy outcomes in later life. OBJECTIVE: To examine the associations of maternal iron status during early pregnancy with child's lung function, asthma, inhalant allergic sensitization, and physician-diagnosed inhalant allergy at school-age. METHODS: In a population-based cohort study, among 3825 mother-child pairs, ferritin, transferrin concentrations, and transferrin saturation were measured from maternal venous blood samples during early pregnancy. In children at the age of 10 years, spirometry was used to determine child's lung function, current asthma and physician-diagnosed inhalant allergy were assessed by questionnaires, and inhalant allergic sensitization was measured by skin prick tests. We used multivariable regression models to examine the associations. RESULTS: After adjustment for gestational age at maternal iron status measurement and sociodemographic or lifestyle-related confounders, a higher maternal transferrin concentration was associated with a higher risk of physician-diagnosed inhalant allergy (odds ratio [95% confidence interval]: 1.13 [1.01 to1.26]), but not with lung function, asthma, or inhalant allergic sensitization. This association did not attenuate after further adjustment for maternal hemoglobin levels or early growth factors. We observed no consistent association of maternal ferritin concentrations or transferrin saturation with child's respiratory or allergy outcomes. CONCLUSION: Higher maternal transferrin concentrations during pregnancy, reflecting lower serum iron levels, were associated with an increased risk of child's physician-diagnosed inhalant allergy but not lung outcomes. Underlying mechanisms and clinical implications need to be explored.