BACKGROUND & AIMS:Prenatal exposure to air pollution is robustly associated with fetal growth restriction but the extent to which it is associated with postnatal growth and the risk of childhood obesity remains unknown. We examined the association of prenatal exposure to air pollution with offspring obesity related measures and evaluated the possible protective effect of maternal fruits and vegetables intake (FV). METHODS:We included 633 mother-child pairs from the Rhea pregnancy cohort in Crete, Greece. Fine particles (PM2.5 and PM10) exposure levels during pregnancy were estimated using land-use regression models. We measured weight, height and waist circumference at 4 and 6 years of age, and body composition analysis was performed at 6 years using bioimpedance. Maternal diet was evaluated by means of a semi-quantitative food frequency questionnaire in mid-pregnancy. Adjusted associations were obtained via multivariable regression analyses and multiplicative interaction was used to evaluate the potential modifying role of FV intake. RESULTS:Exposure to PMs in utero was not associated with measures of adiposity at 4 or 6 years of age. Associations at 4 years did not differ according to maternal consumption of FV. However, at 6 years, among children whose mothers reported consuming less than 5 servings of FV per day, one SD increase in PM10 during pregnancy was associated with increased BMI (beta 0.41 kg/m2, 95% CI: -0.06, 0.88, p-interaction = 0.037) and increased waist circumference (beta 0.83 cm, 95% CI: -0.38, 2.05, p-interaction = 0.043) and one SD increase in PM2.5 was associated with increased fat mass (beta 0.5 kg, 95% CI: 0.0, 0.99, p-interaction = 0.039) and increased percentage of body fat (beta 1.06%, 95% CI: -0.06, 2.17, p-interaction = 0.035). Similarly, higher prenatal PM2.5 and PM10 exposure was associated with increased risk for obesity and abdominal obesity at 6 years only in the low FV group. CONCLUSIONS:Exposure to fine particulate matter during pregnancy was not associated with obesity-related measures at 4 and 6 years. However, only among offspring of mothers who consumed inadequate FV, we observed higher obesity-related measures at 6 years. Our results indicate that mothers' diet during pregnancy may play a role in the relationship between air-pollution and childhood obesity.

BACKGROUND:Helicobacter pylori is a prevalent infection that may complicate pregnancy, but evidence remains limited, controversial and may not apply to all pregnant women. OBJECTIVE:This study aims to evaluate whether Helicobacter pylori is a risk factor for adverse pregnancy outcomes and to identify vulnerable subpopulations. STUDY DESIGN:Multiplex serology was utilized to measure blood levels of immunoglobulin G against eight Helicobacter pylori antigens in 1372 pregnant women from three European birth cohorts: BiB (United Kingdom), Rhea (Greece) and INMA (Spain). Outcomes of interest included gestational diabetes mellitus, gestational hypertension, preeclampsia, preterm birth and small for gestational age neonates, as well as prenatal anxiety and depression. Adjusted logistic regression models were used to evaluate the association between Helicobacter pylori seropositivity (overall and by antigen) and antigen specific antibody levels with the outcomes. We examined effect modification of the associations by ethnicity. RESULTS:Helicobacter pylori seropositivity was detected in 18.8% (258/1372) of pregnant women. Preeclampsia was the least common outcome (26/830). Helicobacter pylori seropositivity was associated with the development of two or more adverse pregnancy outcomes (gestational hypertension, gestational diabetes, preterm birth, small gestational age and preeclampsia) [OR:1.32 (95% CI: 1.06-1.65), p-value: 0.01], especially in women with high antibody levels to OMP antigen [OR: 2.12 (95% CI: 1.62-2.76), p-value: 0.001]. Women with high antibody levels to Helicobacter pylori antigens GroEL and NapA were more likely to develop preeclampsia [OR: 2.34 (95% CI: 1.10-8.82), p-value: 0.03; OR: 4.09 (95% CI: 1.4-11.93), p-value 0.01)]. Helicobacter pylori seropositivity increased the odds of developing any hypertensive disorder during pregnancy among women of western ethnicity (948/1372) [OR:3.35 (95% CI: 1.29-8.74), p-value 0.03]. CONCLUSION:Our study suggests that Helicobacter pylori seropositivity is a risk factor for multiple adverse pregnancy outcomes and particularly in women of western origin for hypertensive disorders during pregnancy. Moreover, pathogen specific characteristics reflected in the antibody responses against OMP, GroEL and NapA seem to determine disease associations.

Background: Evidence regarding child iodine intake and neurodevelopment is scarce. Methods: We aimed to assess the impact of child iodine intake at 4 years of age on cognitive and motor development at 4 and 6 years among 304 children from the Rhea cohort on Crete, Greece. Child iodine intake was assessed via urinary iodine concentrations (UIC) measured using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and adjusted for specific gravity. Child cognitive and motor development was assessed using the McCarthy Scales of Children's Abilities (MSCA) at 4 years of age and Raven's Coloured Progressive Matrices (RCPM), Finger Tapping Test (FTT), and Trail Making Test (TMT) at 6 years. Associations were explored using multivariable-adjusted linear regression analyses with UIC categorized according to WHO criteria [insufficient intake <100 g/L, adequate 100-299 mu g/L (reference group), excessive >= 300 mu g/L]. Results: The children's median UIC was 249 mu g/L (25-75th percentile: 181-344 mu g/L). Children with UIC <100 mu g/L had lower scores in the motor scale at 4 years (MSCA-motor scale: B=-10.3; 95 %CI -19.9, -0.6; n=10) and in intelligence at 6 years (RCPM-total score: B=-3.6, 95 %CI -6.8, -0.5; n=9) than children in the reference group. No associations were found with the general cognitive scale at 4 years or with TMT and FTT scales at 6 years. Children with UIC >= 300 mu g/L had lower cognitive scores both at 4 (MSCA; B= -3.5; 95 %CI -6.9, -0.1; n =101) and 6 years of age (RCPM-total score; B= -1.2; 95 %CI -2.3, -0.0; n =98) than children in the reference group. No associations were observed with the motor scale at 4 years or with TMT and FTT scales at 6 years. Conclusion: Our findings indicate that both low and excessive iodine intake at preschool age may adversely affect child cognitive abilities. Additionally, low iodine intake may also impact motor abilities.

BACKGROUND:Growing evidence suggests that cardiovascular disease develops over the lifetime, often beginning in childhood. Metal exposures have been associated with cardiovascular disease and important risk factors, including dyslipidemia, but prior studies have largely focused on adult populations and single metal exposures. OBJECTIVE:To investigate the individual and joint impacts of multiple metal exposures on lipid levels during childhood. METHODS:This cross-sectional study included 291 4-year-old children from the Rhea Cohort Study in Heraklion, Greece. Seven metals (manganese, cobalt, selenium, molybdenum, cadmium, mercury, and lead) were measured in whole blood using inductively coupled plasma mass spectrometry. Serum lipid levels included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. To determine the joint and individual impacts of child metal exposures (log2-transformed) on lipid levels, Bayesian kernel machine regression (BKMR) was employed as the primary multi-pollutant approach. Potential effect modification by child sex and childhood environmental tobacco smoke exposure was also evaluated. RESULTS:BKMR identified a positive association between the metal mixture and both total and LDL cholesterol. Of the seven metals examined, selenium (median 90.6 [IQR = 83.6, 96.5] µg/L) was assigned the highest posterior inclusion probability for both total and LDL cholesterol. A difference in LDL cholesterol of 8.22 mg/dL (95% CI = 1.85, 14.59) was observed when blood selenium was set to its 75th versus 25th percentile, holding all other metals at their median values. In stratified analyses, the positive association between selenium and LDL cholesterol was only observed among boys or among children exposed to environmental tobacco smoke during childhood. IMPACT STATEMENT:Growing evidence indicates that cardiovascular events in adulthood are the consequence of the lifelong atherosclerotic process that begins in childhood. Therefore, public health interventions targeting childhood cardiovascular risk factors may have a particularly profound impact on reducing the burden of cardiovascular disease. Although growing evidence supports that both essential and nonessential metals contribute to cardiovascular disease and risk factors, such as dyslipidemia, prior studies have mainly focused on single metal exposures in adult populations. To address this research gap, the current study investigated the joint impacts of multiple metal exposures on lipid concentrations in early childhood.

Background: In Greece, influenza vaccination is currently recommended for children with high-risk conditions. There are limited data on influenza vaccination uptake among Greek children with and without high-risk conditions. We aim to describe the annual influenza vaccination uptake until the age of ten in a population-based mother–child cohort and identify the factors influencing vaccination rates. Methods: Immunization data from the child’s health cards at 4 and 10 years were available for 830 and 298 children participating in the Rhea cohort (2008–2019). We calculated vaccination coverage by age, winter season and among children with asthma and obesity for whom the vaccine is indicated. Univariable and multivariable stepwise logistic regression models were utilized to identify the association between several sociodemographic, lifestyle and health-related variables and vaccine uptake by age four. Results: By the ages of four and ten, 37% and 40% of the children, respectively, had received at least one influenza vaccination. Only 2% of the children were vaccinated for all winter seasons during their first four years of life. The vaccination rate was highest at the age of two and during the 2009–2010 season. Vaccination rates for children with asthma and obesity were 18.2% and 13.3% at age four and 8.3% and 2.9% at age ten. About 10% of all vaccines were administered after December and 24% of the children received only one dose upon initial vaccination. Children with younger siblings and those who had experienced more respiratory infections were more likely to be vaccinated by the age of four, while children exposed to smoking were less likely to be vaccinated. Conclusions: Children in our study were more likely to be vaccinated against influenza at an early age with the peak occurring at the age of two. Nonetheless, annual vaccination uptake was uncommon. Vaccination rates of children with asthma and obesity were well below the national target of 75% for individuals with chronic conditions. Certain groups may merit increased attention in future vaccination campaigns such as children raised in families with unfavourable health behaviours.

Accumulating evidence suggests that in utero exposures can influence the development of the immune system. Few studies have investigated whether prenatal exposure to persistent organic pollutants (POPs) is associated with allergy-related phenotypes in childhood, nor explored sex differences. We examined the association between prenatal exposure to POPs and offspring allergic outcomes in early and mid-childhood. We included 682 mother-child pairs from the prospective birth cohort Rhea. We measured dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and 6 polychlorinated biphenyl (PCB) congeners in maternal first trimester serum. Parents completed the questionnaires adapted from the International Study on Asthma and Allergy in Childhood (ISAAC) for allergy-related phenotypes when their children were 4 and 6 years old. We used Poisson regression models to estimate Risk Ratios. Prenatal HCB was associated with increased risk for rhinoconjunctivitis at 6 years (RR (95% CI): 2.5; (1.3, 4.8) for a doubling in the exposure). Among girls, prenatal DDE was associated with increased risk for current wheeze, current asthma and current rhinoconjunctivitis at 4 years (RR (95%CI): 1.4 (0.8, 2.6), 1.6 (1.1, 2.4) and 1.8 (1.0, 3.3) and p-interaction = 0.035, 0.027 and 0.059, respectively), with increased risk for current rhinoconjunctivitis at 6 years (RR (95%CI): 1.7 (0.7, 3.8) and p-interaction = 0.028) and total PCBs were associated with increased risk for current eczema at 4 years (RR (95%CI): 2.1 (1.1, 4.2) and p-interaction = 0.028). In boys, prenatal DDE was associated with decreased risk for current wheeze and current asthma at 4 years. Our findings suggest that even low levels of exposure to POPs prenatally may affect the development of childhood allergy-related outcomes in a sex and age-specific manner.

Background and aims: Early fetal exposure to tobacco smoke has been associated with several adverse effects on offspring reproductive development possibly due to the suspected endocrine disrupting action of toxic compounds contained in cigarettes. We investigated the association of prenatal exposure to tobacco smoke with anogenital distance measures in young children and reproductive-related hormones in pre-adolescents from the Rhea birth cohort in Greece. Methods: Information regarding tobacco smoke exposure was obtained from maternal questionnaires throughout pregnancy. Anogenital distances - sexually dimorphic, longer in males than females- [(AGD; anus to upper penis), anoscrotal distance (ASD; anus to scrotum), anoclitoral (ACD; anus to clitoris) and anofourchetal distance (AFD; anus to fourchette)] were measured in 350 boys and 350 girls at the age of 2 years. At 10-11 years of age, we measured dehydroepiandrosterone sulfate (DHEA-S), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in 242 children (132 boys and 110 girls). Adjusted associations were obtained via multivariable regression analyses. Results: Maternal active smoking before and during pregnancy was associated with increased ACD in girls (adjusted β= 1.9 mm; 95% CI: 0.6, 3.3, β= 1.7 mm; 95% CI: 0.1, 3.3 respectively). Moreover, maternal exposure to passive smoking -via paternal active smoking- was associated with decreased LH in girls (adjusted β=-0.7 mUI/mL; 95% CI: -1.4, 0.0). In boys, maternal smoking in early pregnancy was associated with increased FSH (adjusted β= 0.5 mUI/mL; 95% CI: 0.1, 0.8) and the same association was observed for maternal smoking during any trimester of gestation(adjusted β= 0.4 mUI/mL; 95% CI: 0.1, 0.7). Conclusions: In utero exposure to tobacco smoke was associated with increased anogenital distances in girls and altered hormonal levels in both sexes. Further research is needed to understand whether these findings may indicate long-term adverse effects on the reproductive health. Keywords: smoking during pregnancy, anogenital distance, reproductive hormones

BACKGROUND AND AIM: Puberty is a period of major hormonal changes and prenatal exposure to endocrine disruptors such as organochlorine compounds (OCs) might impair normal development. However, only a few studies have investigated relationships between OCs and pubertal development with mixed findings. The aim of the current study was to examine the role of in utero exposure to OCs on pubertal development in 11-years old children (n=137 boys and n=107 girls) from the Rhea birth cohort in Greece. METHODS: Concentrations of 6 polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethene (DDE), and hexachlorobenzene (HCB) were determined in 1st trimester maternal serum. At 11 years of age, we measured dehydroepiandrosterone sulfate (DHEA-S), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Associations between OCs and puberty-related hormones were assessed using multivariable linear regression separately in boys and girls. Further, the hierarchical version of Bayesian Kernel Machine Regression (BKMR) was employed to investigate exposure mixtures as well as possible interactions between exposures. RESULTS: In boys, the sum of prenatal PCBs was positively associated with DHEA-S (for a doubling of exposure, β= 25.5 μg/mL, 95% CI: 1.5, 48.5) and HCB was positively associated with FSH (β= 0.2 mUI/mL, 95% CI: 0.1, 0.5). In BKMR the OCs mixture showed a trend for a positive association with DHEA-S and the PCBs ranked higher according to their group Posterior Inclusion Probabilities (PIPs) with PCB-170 and PCB-180 ranking higher according to their conditional PIPs. Also, the OCs mixture showed a positive association with FSH with HCB ranking higher according to the conditional PIPs. No sign for an interaction between compounds was detected. Among girls the associations were null. CONCLUSION: Prenatal exposure to OCs was associated with puberty-related hormones in boys but not in girls. The implications on future reproductive function in puberty and adulthood should be determined. KEYWORDS: endocrine disruptors, puberty, prenatal