Childhood Atopic Disease Research Articles

Prenatal blood metals, per- and polyfluoroalkyl substances and antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion

BackgroundEvidence suggests that prenatal per- and polyfluoroalkyl substances (PFAS) and metals, two classes of chemicals found ubiquitously in human populations, influence immune system development and response. ObjectiveWe evaluated whether first trimester blood PFAS and metals were associated with antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion. MethodsWe measured six PFAS, as well as six nonessential and four essential metals, in first trimester blood from participants in the longitudinal pre-birth Project Viva cohort, recruited between 1999 and 2000 in eastern Massachusetts. We measured antigen- or mitogen-stimulated cord blood mononuclear cell proliferation responses (n = 269–314) and cytokine secretion (n = 217–302). We used covariate-adjusted least absolute shrinkage and selection operator (LASSO) for variable selection and multivariable regression to estimate associations with the immune markers. ResultsEach ng/mL of MeFOSAA was associated with a 3.6% (1.4, 5.8) higher lymphocyte proliferation response after stimulation with egg antigen, as well as 0.8 (0.7, 1.0) reduced odds of having IFN-γ detected in response to dust mite. Each ng/g increment of cesium was associated with 27.8% (−45.1, −4.9) lower IL-10 levels in response to dust mite. Each ng/g increment of mercury was associated with 12.0% (1.3, 23.8) higher IL-13 levels in response to mitogen PHA. Each ng/g increment of selenium and zinc was associated with 0.2% (0.01, 0.4) and 0.01% (0.002, 0.02) higher TNF-α in response to mitogen PHA, respectively. ConclusionsPrenatal metals and PFAS influence cord blood lymphocyte proliferation and cytokine secretion in ways that may increase risk for atopic disease in childhood.

Atopic diseases-Diagnostics, mechanisms, and exposures.

Epidemiological data suggest that atopic diseases begin in early life and that most cases present clinically during early childhood. The diseases are highly prevalent and increase as communities adopt western lifestyles. Disentangling the pathophysiological mechanisms leading to disease debut is necessary to identify beneficial/harmful exposures so that successful prevention and treatment can be generated. The objective of this review is to explore the definition of atopy and mechanisms of atopic diseases, and to investigate the importance of environmental factors in early life, prior to disease development. First, the distribution of sIgE levels in children is investigated, as this is one of the main criteria for the definition of atopy. Thereafter, it is explored how studies of parental atopic status, sensitization patterns, and early debut and severity of atopic dermatitis have substantiated the theory of an early-life window of opportunity for intervention that precedes the development of atopic diseases in childhood. Then, it is examined whether early-life exposures such as breastfeeding, dogs, cats, and house dust mites in the home perinatally constitute important influencers in this crucial time of life. Finally, it is discussed how these findings could be validated in randomized controlled trials, which might prepare the ground for improved diagnostics and prevention strategies to mitigate the current atopic pandemic.

Urinary eicosanoid levels in early life and risk of atopic disease in childhood

IntroductionEicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs) and leukotrienes (LTs) with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. We aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. MethodsWe quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (age 1 year, n=450) and VDAART (age 3 years, n=575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of Type-2 inflammation, applying FDR5% multiple testing correction. ResultsIn both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P<FDR5%) and Type-2 inflammation (p<0.05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P<FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (p<0.05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P<FDR5%). ConclusionsThis study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.

Antibiotic exposure during pregnancy increases risk for childhood atopic diseases: a nationwide cohort study

PurposeThe prevalence of atopic diseases has increased in recent decades. A possible link between antibiotic use during pregnancy and childhood atopic disease has been proposed. The aim of this study is to explore the association of antibiotic exposure during pregnancy with childhood atopic diseases from a nationwide, population-based perspective.MethodsThis was a nationwide population-based cohort study. Taiwan’s National Health Insurance Research Database was the main source of data. The pairing of mothers and children was achieved by linking the NHIRD with the Taiwan Maternal and Child Health Database. This study enrolled the first-time pregnancies from 2004 to 2010. Infants of multiple delivery, preterm delivery, and death before 5 years old were excluded. All participants were followed up at least for 5 years. Antenatal antibiotics prescribed to mothers during the pregnancy period were reviewed. Children with more than two outpatient visits, or one admission, with a main diagnosis of asthma, allergic rhinitis, or atopic dermatitis were regarded as having an atopic disease.ResultsA total of 900,584 children were enrolled in this study. The adjusted hazard ratios of antibiotic exposure during pregnancy to childhood atopic diseases were 1.12 for atopic dermatitis, 1.06 for asthma, and 1.08 for allergic rhinitis, all of which reached statistical significance. The trimester effect was not significant. There was a trend showing the higher the number of times a child was prenatally exposed to antibiotics, the higher the hazard ratio was for childhood atopic diseases.ConclusionsPrenatal antibiotic exposure might increase the risk of childhood atopic diseases in a dose-dependent manner.

Atopic dermatitis phenotype affects expression of atopic diseases despite similar mononuclear cell cytokine response

BackgroundThe atopic march refers to the co-expression and progression of atopic diseases in childhood, often beginning with atopic dermatitis, although children may not “progress” through each atopic disease. ObjectiveWe hypothesized that future atopic disease expression is modified by atopic dermatitis phenotype, and that these differences result from underlying dysregulation of cytokine signaling. MethodsChildren (n=285) were enrolled into the Childhood Origins of ASThma birth cohort and followed prospectively. Rates of atopic dermatitis, food allergy, allergic rhinitis, and asthma were assessed longitudinally from birth to 18 years of age. Associations between atopic dermatitis phenotype and food allergy, allergic rhinitis, asthma, allergic sensitization, exhaled nitric oxide, and lung function were determined. Peripheral blood mononuclear cell responses (IL-5, IL-10, IL-13, IFN-γ) to dust mite, phytohemagglutinin, Staphylococcus aureus Cowan I, and tetanus toxoid were compared among atopic dermatitis phenotypes. ResultsAtopic dermatitis at year 1 was associated with an increased risk of food allergy (p=0.004). Both persistent and late-onset atopic dermatitis were associated with an increased risk of asthma (p=<0.001), rhinitis (p<0.001), elevated total IgE (p=<0.001), percentage of aeroallergens with detectable IgE (p<0.001), and elevated exhaled nitric oxide (p=0.002). Longitudinal analyses did not reveal consistent differences in PBMC responses among dermatitis phenotypes. ConclusionAtopic dermatitis phenotype is associated with differential expression of other atopic diseases. Our findings suggest peripheral blood cytokine dysregulation is not a mechanism underlying this process, and immune dysregulation may be mediated at mucosal surfaces or in secondary lymphoid organs.

Does having siblings really protect against childhood atopic diseases? A total population and within-family analysis

The association between having older siblings and decreased risk for atopic symptoms is well-established. This has been interpreted as evidence for the microbiota hypothesis, i.e. that increased early-childhood microbial exposure caused by siblings protects from immune hypersensitivities. However, possible confounders of the association have received little attention. We used register data on Finnish cohorts born in 1995–2004 (N = 559,077) to assess medication purchases for atopic diseases: antihistamines, eczema medication, asthma medication and Epinephrine. We modelled the probability of atopic medication purchases at ages 0–15 by birth order controlling for important observed confounders and all unobserved genetic and environmental characteristics shared by siblings in a within-family fixed effects model. We further studied medication purchases among first-borns according to the age difference with younger siblings to assess whether having younger siblings in early childhood is beneficial. Having older siblings was associated with a lower probability of atopic medication purchases. Compared to first-borns, the probability was 10–20% lower among second-borns, 20–40% lower among third-borns, and 30–70% lower among subsequent children, depending on medication type. Confounding accounted for up to 75% of these differences, particularly for asthma and eczema medication, but significant differences by birth order remained across all medication types. Among first-borns, a smaller age difference with younger siblings was related to a lower likelihood of atopic medication use. Our results, based on designs that account for unobserved confounding, show that exposure to siblings in early childhood, protects from atopic diseases, and thus strongly support the microbiota hypothesis.

Associations between diet diversity during infancy and atopic disease in later life: Systematic review

The incidence of allergic disease remains high, and many studies have focused on the association between food diversity in infancy and allergic disease later in life, but their conclusions are still controversial. We aimed to synthesize the literature on the association between childhood diet diversity and atopic disease. We searched the PubMed, Cochrane Library, Embase, Scopus, VPCS, and Wanfang databases for studies about food diversity and atopic disease. Seventeen high-quality studies, 14 cohort studies, and 1 case-control study were included from 5244 studies with sample sizes ranging from 100 to 5225. All high-quality cohort studies showed that increasing food diversity in infancy can effectively prevent the occurrence of food allergies (5/5). Moderate evidence showed that increased food diversity reduced the risk of asthma (4/6), food sensitization (3/5), and atopic dermatitis (3/5). However, its effect on eczema (5), allergic rhinitis (4), and other diseases remains controversial. Increasing food diversity during infancy is a potential method for preventing food allergy, asthma, atopic dermatitis, and food sensitization later in life. There is little or no comparative evidence about the protective effect of food diversity on other atopic diseases.

No associations between type 1 diabetes and atopic dermatitis, allergic rhinitis, or asthma in childhood: a nationwide Danish case-cohort study

Studies examining the association between type 1 diabetes (T1D) and atopic diseases, i.e., atopic dermatitis, allergic rhinitis and asthma have yielded conflicting results due to different algorithms for classification, sample size issues and risk of referral bias of exposed cohorts with frequent contact to health care professionals. Using Danish national registries and well-established disease algorithms, we examined the bidirectional association between T1D and atopic diseases in childhood and adolescence using Cox Proportional Hazard regression compared to two different unexposed cohorts from a population of 1.5 million Danish children born from 1997 to 2018. We found no associations between T1D and atopic dermatitis, allergic rhinitis, or asthma (defined after age five). However, in multivariable analysis we found an increased risk of persistent wheezing (defined as asthma medication before age five) after T1D with an adjusted hazard ratio (aHR) of 1.70 [1.17–2.45]. We also identified an increased risk of developing T1D after persistent wheezing with aHR of 1.24 [1.13–1.36]. This study highlights similar risks of atopic diseases in children with T1D and of T1D in children with atopic disease after age of five years versus healthy controls. However, more research is needed to understand the possible early immunological effects of the link between persistent wheezing and T1D.

Twinship and childhood atopic disease: understanding early-life factors among discordant twins

Twinship and childhood atopic disease: understanding early-life factors among discordant twins

Longitudinal analysis of the impact of smoking exposure on atopic indices and allergies in early childhood

BackgroundExposure to smoking is recognized as a health hazard; however, a longitudinal analysis of the impact of smoking exposure in families on the allergic reactions related to childhood atopic diseases has not been well addressed. MethodsChildren who completed a three-year follow-up period from the birth cohort were included in this study. The history of smoking exposure was recorded, and the urine cotinine levels were measured at 1 and 6 months, and 1, 2, and 3 years of age. Specific IgE levels against food and mite allergens were measured at age 6 months, and 1, 2, and 3 years. Their relevance to family smoking exposure and the subsequent development of atopic diseases was also analyzed. This study was approved by the Ethics Committee of Chang Gung Memorial Hospital (No. 102-1842C) ResultsA total of 198 infants were enrolled in this study. The prevalence of passive smoking exposure among these children was as high as 45%. The urine cotinine levels were significantly higher in children with history of smoking exposure (P < 0.001). At 6 months of age, the food-specific IgE levels and the prevalence of eczema were significantly higher in children with smoking exposure than in those without smoking exposure (P < 0.05). By contrast, the urine cotinine levels were significantly higher in children with IgE sensitization (>100 kU/L, P < 0.05) at 3 years of age, which was also significantly associated with a higher prevalence of allergic rhinitis and development of asthma (P < 0.01). ConclusionFamily smoking exposure appears to be strongly associated with food sensitization in infancy and with IgE production in later childhood. This could potentially increase the susceptibility of developing infantile eczema and subsequent childhood airway allergies.

Prenatal bisphenol A and S exposure and atopic disease phenotypes at age 6

BackgroundAtopic disease may be influenced by prenatal and early life exposure to endocrine disrupting chemicals, including bisphenols, but results from epidemiological studies have been mixed. This study aimed to extend the epidemiological literature, hypothesizing that children with higher prenatal bisphenol exposure are more likely to have childhood atopic disease. MethodsUrinary bisphenol A (BPA) and S (BPS) concentrations were measured in each trimester from 501 pregnant women in a multi-center, prospective pregnancy cohort. Ever asthma, current asthma, wheeze, and food allergy) were assessed at age six via standardized ISAAC questionnaire. We constructed generalized estimating equations to examine BPA and BPS exposure jointly at each trimester for each atopy phenotype. BPA was modeled as a log-transformed continuous variable, whereas BPS was modeled as detected versus not detected. We also modeled pregnancy-averaged BPA values and a categorical indicator for number of detectable BPS values over pregnancy (0–3) in logistic regression models. ResultsFirst trimester BPA was associated with inverse odds of food allergy among the entire study sample (OR = 0.78, 95% CI = 0.64–0.95, p = 0.01) and females only (OR = 0.69, 95% CI = 0.52–0.90, p = 0.006). The inverse relationship persisted in pregnancy-averaged models of BPA among females (OR = 0.56, 95% CI = 0.35–0.90, p = 0.006). Second trimester BPA was associated with greater odds of food allergy in the entire sample (OR = 1.27, 95% CI = 1.02–1.58, p = 0.03) and among males only (OR = 1.48, 95% CI = 1.02–2.14, p = 0.04). Odds of current asthma increased among males in the pregnancy-averaged BPS models (OR = 1.65, 95% CI = 1.01–2.69, p = 0.045). ConclusionWe saw opposite effects of BPA on food allergy that were trimester- and sex-specific. These divergent associations warrant further investigation. There is some evidence to suggest that prenatal BPS is associated with asthma among males, but further research is required in cohorts with a greater proportion of prenatal urine samples with detectable BPS to validate these results.

Study on the relationship between nephrotic syndrome and atopic diseases in childhood.

ObjectiveThe present study aimed to explore the relationship between nephrotic syndrome and atopic diseases in childhood.MethodsFrom 2018 to 2019, 234 children with first-onset primary nephrotic syndrome (PNS) were selected for observation and long-term follow-up, and the clinical and laboratory data. To compare the levels of total serum IgE, histamine and bradykinin of the same children at the time of first onset, remission and relapse of PNS. The extent of podocyte foot process effacement was compared between the urinary protein negative-conversion group and the proteinuric group with the NS range. The correlation between the urine protein quantification and the extent of foot process effacement was also observed.Results(1) The mean age of 234 children with first-onset PNS was 4.82 ± 3.63 years, with a male to female ratio of 162/72. (2) There were 109 cases (46.58%) with concomitant atopic diseases (AD) and 151 cases (64.53%) with elevated levels of total serum IgE. There were 136 cases with recurrence during the follow-up, of which recurrence due to allergy-related factors was greater than that due to infection-related factors. (3) The total IgE and bradykinin serum levels were significantly higher in children with first-onset PNS and recurrent PNS compared with those in remission, and the differences were statistically significant (P < 0.05). The level of histamine in children with first-onset PNS was higher than that in children with remission (P < 0.05), and there was no significant difference in the level of histamine between children in the recurrence group and those in the remission group (P > 0.05). (4) There was no significant difference in the extent of foot process effacement between the urinary protein negative-conversion group and the proteinuric group with the NS range. There was no significant correlation between the proteinuria quantification and the extent of foot process effacement.ConclusionThere existed a high co-morbidity with AD in children with PNS, and allergy-related factors might be an important recurrence factor in children with PNS. The injury to the filtration barrier in MCD might not only be correlated with podocyte lesions but also with some serum permeability factors. Serum IgE, histamine, and bradykinin might be the plasma permeability factors in children with PNS.

The association between prenatal F2-isoprostanes and child wheeze/asthma and modification by maternal race

BackgroundChildhood wheeze, asthma, and allergic rhinitis are common and likely have prenatal origins. Oxidative stress is associated with respiratory disease, but the association of oxidative stress during the prenatal period with development of respiratory and atopic disease in childhood, particularly beyond the infancy period, is unknown. This study aims to investigate associations between prenatal oxidative stress, measured by maternal urinary F2-isoprostanes, and child respiratory outcomes, including effect modification by maternal race. MethodsWe prospectively studied Black (n = 717) and White (n = 363) mother-child dyads. We measured F2-isoprostanes in 2nd-trimester urine (ng/mg-creatinine). At approximately age 4, we obtained parent report of provider-diagnosed asthma (ever), current wheeze, current asthma (diagnosis, symptoms and/or medication), and current allergic rhinitis (current defined as previous 12 months). We used multivariable logistic regression to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) per interquartile range (IQR) increase in F2-isoprostane concentration, controlling for confounders. We examined modification by maternal race using interaction terms. ResultsThe prevalence of provider-diagnosed asthma and current wheeze, asthma and allergic rhinitis was 14%, 19%, 15%, and 24%, respectively. Median (IQR) F2-isoprostane levels were 2.1 (1.6, 2.9) ng/mg-creatinine. Associations between prenatal F2-isoprostanes and provider-diagnosed asthma, current wheeze, and current asthma were modified by maternal race. Results were strongest for current wheeze (aOR [95%CI]: 1.55 [1.16, 2.06] for White; 0.98 [0.78, 1.22] for Black; p-interaction = 0.01). We observed no association between F2-isoprostanes and allergic rhinitis. ConclusionPrenatal urinary F2-isoprostanes may be a marker associated with childhood wheeze/asthma in certain populations. Research is needed to understand underlying mechanisms and racial differences.

Atopic heredity modifies the association between maternal vitamin D status in pregnancy and the risk of atopic disease in childhood: an observational study

BackgroundThe relationship between maternal vitamin D status in pregnancy and the development of atopic diseases in the offspring has been frequently studied, but with contradictory results. Previous studies have found an inverse relation between maternal vitamin D in pregnancy and the risk of atopic diseases in the child. In contrast, others have found a higher maternal 25OHD to be related to a higher risk of atopic diseases. Thus, the aim was to investigate the associations between maternal vitamin D status and intake in pregnancy with asthma, eczema and food allergies in the children up to 5 years. In addition, effect modification by reported atopic heredity was studied.MethodsParticipants in the GraviD study had 25-hydroxyvitamin D (25OHD) analyzed in serum in early (T1) and late (T3) pregnancy. Maternal dietary vitamin D intake was estimated from a short food frequency questionnaire and supplement use by questionnaires. At 5 years of age the child´s history of asthma, eczema and food allergy, including atopic heredity, was reported by questionnaire. Multivariable logistic regression was used.ResultsThe cumulative incidence of asthma was 13%, eczema 22%, and food allergy 18%. Only among children without reported atopic heredity, maternal 25OHD of 50–75 nmol/L in T1 was associated with lower odds of asthma (OR 0.271, 95% CI 0.127–0.580), compared to maternal 25OHD > 75 nmol/L. Additionally in these children, maternal 25OHD in T3 (continuous) was associated with asthma (OR 1.014, 95% CI 1.002–1.009), and dietary vitamin D intake with eczema (OR 1.141, 95% CI 1.011–1.288).ConclusionsAmong children without reported atopic heredity, higher maternal vitamin D status and intake during pregnancy was associated with increased risk of reported atopic disease.

Quantitative glycoproteomics of human milk and association with atopic disease.

The prevalence of allergic diseases and asthma is increasing rapidly worldwide, with environmental and lifestyle behaviors implicated as a reason. Epidemiological studies have shown that children who grow up on farms are at lower risk of developing childhood atopic disease, indicating the presence of a protective "farm effect". The Old Order Mennonite (OOM) community in Upstate New York have traditional, agrarian lifestyles, a low rate of atopic disease, and long periods of exclusive breastfeeding. Human milk proteins are heavily glycosylated, although there is a paucity of studies investigating the milk glycoproteome. In this study, we have used quantitative glycoproteomics to compare the N-glycoprotein profiles of 54 milk samples from Rochester urban/suburban and OOM mothers, two populations with different lifestyles, exposures, and risk of atopic disease. We also compared N-glycoprotein profiles according to the presence or absence of atopic disease in the mothers and, separately, the children. We identified 79 N-glycopeptides from 15 different proteins and found that proteins including immunoglobulin A1, polymeric immunoglobulin receptor, and lactotransferrin displayed significant glycan heterogeneity. We found that the abundances of 38 glycopeptides differed significantly between Rochester and OOM mothers and also identified four glycopeptides with significantly different abundances between all comparisons. These four glycopeptides may be associated with the development of atopic disease. The findings of this study suggest that the differential glycosylation of milk proteins could be linked to atopic disease.

The correlation between middle schoolchildren allergic symptoms and airborne particle season: A cross-sectional study.

Limited studies correlate allergic symptoms and associated outdoor biological particle exposure among schoolchildren globally.This study aimed to investigate the relationship between the seasonality of symptoms of allergic diseases among middle schoolchildren and the annual variation of airborne pollen and fungal spore in a hot and humid geographical region (Qatar).During November 2017 to January 2018, a self-reported study of middle schoolchildren living in the Doha capital city of Qatar was conducted, and data gathered were evaluated in relation to the collected monthly pollen and fungal spores. Participants’ data were collected by conducting a survey based on a modified questionnaire adopted from the International Study of Asthma and Allergy in Childhood (ISAAC). The airborne pollen and fungal spore in Doha's atmosphere were extracted from the Doha aerobiology project (2017–2020).Among the 1000 distributed questionnaires, 100 were excluded due to significant missing data and 644 middle schoolchildren living in Doha city responded and were included in the final analysis. The symptoms of allergic rhinitis (AR) pattern among the responders with positive symptoms were strongly linked with the higher airborne fungal spore incidence during the month of November. Out of 331 students with positive symptoms, the prevalence of AR, lifetime wheeze, and eczema was 62.8%, 28.1%, and 26.6%, respectively. Asthma was significantly higher in Qatari (39.8%) compared to non-Qatari (26.7%) middle schoolchildren (P = .02).Outdoor aeroallergen may be a contributing factor in addition to other environmental and genetic predisposing factors for childhood atopic diseases in the prevalence rate of allergic symptoms among middle schoolchildren in the peninsula of Qatar.

Foetal Exposure to Heavy Metals and Risk of Atopic Diseases in Early Childhood

Early-life exposures to heavy metals have been associated with many adverse health outcomes in children. The purpose of this study was to investigate the association of fetal exposure to lead, cadmium, and manganese with the risk of developing asthma, allergic rhinitis, eczema, and food allergy in early childhood.In the study, researchers included 651 children who were part of a longitudinal birth cohort living in France.A total of 2002 mothers were recruited for the birth cohort in early pregnancy. They underwent an initial clinical examination and survey assessing their lifestyle and health between 24 and 28 weeks' gestation. Pregnancy, birth, and newborn characteristics were collected through standardized questionnaires and obstetric records. Measurements of lead, cadmium, and manganese were performed from the first consecutive 915 mother–children pairs from peripheral blood samples of mothers between 24 and 28 weeks' gestation as well as from cord blood at the time of delivery. A standardized parental-administered questionnaire used to assess the child’s health and environment was administered every 4 months for the first year, followed by every year until the age of 5 years and then, finally, at the age of 8 years. Asthma, allergic rhinitis, eczema, and food allergy were defined as positive responses for corresponding questions by using the International Study on Asthma and Allergies in Childhood questionnaire.A total of 915 children were enrolled for laboratory assessment of heavy metal exposure, and 845 completed this. Of these, 651 children had follow-up between 3 and 8 years of age and were included in this study. A total of 60% completed the final assessment at 8 years, and 52% were male. In this group, there was a lifetime prevalence of 17% for asthma, 22% for allergic rhinitis, 43% for eczema, and 11% for food allergy. There was a weak correlation between the concentrations of metals measured in maternal midpregnancy and cord blood samples. Comparing the quartiles of subjects with the lowest and highest exposure, there was a significant association between cord blood cadmium and food allergy (hazard ratio (HR): 3.17 [1.36–7.38]), cord blood cadmium and eczema (HR: 1.60 [1.09–2.35]), and maternal blood manganese and eczema (HR: 1.55 [1.05–2.28]), adjusted for sex, BMI, maternal education, parental history of atopy, maternal smoking in pregnancy, birth weight, gestational age, and type of delivery.In a prospective birth cohort, there was an association between fetal exposure to cadmium and manganese and the development of eczema and food allergy by 8 years of age.This may be the first prospective study in which researchers suggest an association between in utero exposure to heavy metals and risk for developing atopic diseases, although limited by parental report of these conditions. Further studies are needed to not only confirm this association but, also, to evaluate the effect of timing of in utero heavy metal exposure on the risk of developing atopic diseases in childhood, given the weak correlation between heavy metal concentrations in maternal midpregnancy and cord blood samples.

Traditional Farming Lifestyle in Old Older Mennonites Modulates Human Milk Composition.

BackgroundIn addition to farming exposures in childhood, maternal farming exposures provide strong protection against allergic disease in their children; however, the effect of farming lifestyle on human milk (HM) composition is unknown.ObjectiveThis study aims to characterize the maternal immune effects of Old Order Mennonite (OOM) traditional farming lifestyle when compared with Rochester (ROC) families at higher risk for asthma and allergic diseases using HM as a proxy.MethodsHM samples collected at median 2 months of lactation from 52 OOM and 29 ROC mothers were assayed for IgA1 and IgA2 antibodies, cytokines, endotoxin, HM oligosaccharides (HMOs), and targeted fatty acid (FA) metabolites. Development of early childhood atopic diseases in children by 3 years of age was assessed. In addition to group comparisons, systems level network analysis was performed to identify communities of multiple HM factors in ROC and OOM lifestyle.ResultsHM contains IgA1 and IgA2 antibodies broadly recognizing food, inhalant, and bacterial antigens. OOM HM has significantly higher levels of IgA to peanut, ovalbumin, dust mites, and Streptococcus equii as well TGF-β2, and IFN-λ3. A strong correlation occurred between maternal antibiotic use and levels of several HMOs. Path-based analysis of HMOs shows lower activity in the path involving lactoneohexaose (LNH) in the OOM as well as higher levels of lacto-N-neotetraose (LNnT) and two long-chain FAs C-18OH (stearic acid) and C-23OH (tricosanoic acid) compared with Rochester HM. OOM and Rochester milk formed five different clusters, e.g., butyrate production was associated with Prevotellaceae, Veillonellaceae, and Micrococcaceae cluster. Development of atopic disease in early childhood was more common in Rochester and associated with lower levels of total IgA, IgA2 to dust mite, as well as of TSLP.ConclusionTraditional, agrarian lifestyle, and antibiotic use are strong regulators of maternally derived immune and metabolic factors, which may have downstream implications for postnatal developmental programming of infant’s gut microbiome and immune system.

Are prenatal anxiety or depression symptoms associated with asthma or atopic diseases throughout the offspring\u2019s childhood? An updated systematic review and meta-analysis

BackgroundAsthma is the most common respiratory disease among children, while atopic diseases such as atopic dermatitis affect about 20% of infants under 2 years of age. Studies suggested that these conditions might be related to prenatal depression or anxiety. This study aimed to explore the association between prenatal mental disorders and childhood asthma or atopic disease in a systematic review and meta-analysis.MethodsPubMed, Embase, and the Cochrane Library were searched up to May 2020. The primary outcome was childhood asthma and childhood atopic dermatitis. Random-effects models were used because of high heterogeneity indicated by I2 > 50% and Q-test P < 0.10.ResultsA total of 598 studies were initially identified, but nine studies met the inclusion criteria. Prenatal mental disorder was associated with childhood asthma (n = 6 studies; ES = 1.146, 95%CI: 1.054–1.245, P = 0.001; I2 = 93.5%, Pheterogeneity < 0.001) whereas no significant association was found for childhood atopic dermatitis (n = 4 studies; ES = 1.211, 95%CI: 0.982–1.494, P = 0.073; I2 = 78.5%, Pheterogeneity < 0.001). Childhood asthma seems to be related more to depression (n = 1 study; ES = 1.170, 95%CI: 1.061–1.291, P = 0.002) and anxiety/depression (n = 4 studies; ES = 1.157, 95%CI: 1.050–1.275, P = 0.073; I2 = 95.3%, Pheterogeneity < 0.001).ConclusionThis meta-analysis demonstrated that prenatal mental disorders increase the risk of childhood asthma. We limited the included samples to pregnant women to investigate the association between prenatal psychological factors and offspring’s physical health. Future studies should include large high-quality cohort studies to investigate the behavioral, environmental, and genetic causes for this association.

Maternal Biomarkers of Nutritional Status Prior to Pregnancy and Newborn Epigenetic Aging

ObjectivesMaternal diet prior to and during pregnancy has been related to child health across the lifespan; however, mechanisms remain unclear. Gestational age acceleration (GAA), a measure of epigenetic aging relative to clinically estimated gestational age (GA), has emerged as a potential biomarker predictive of childhood BMI and atopic diseases. Few studies have evaluated the associations of maternal nutrient biomarkers, including methyl donors and fatty acids (FA), with GAA. MethodsWe evaluated associations among 391 mother-child dyads in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. Women were randomized to low-dose aspirin (LDA) or placebo, both containing 400 μg folic acid, prior to and through 36 weeks pregnancy. Maternal folate, homocysteine, vitamin B-12, vitamin D, carotenoids, tocopherols, and plasma FAs were quantified from blood samples obtained ≤6 months prior to conception and at 8 weeks gestation. DNA methylation was measured with the Infinium MethylationEPIC BeadChip using cord blood DNA. Epigenetic GA was calculated using the Knight and Bohlin clocks. GAA was defined as the residual from a model regressing GA on epigenetic GA. We assessed associations between nutritional biomarkers and GAA using robust linear regression, controlling for maternal age, race, education, employment status, total cholesterol, and child sex. A false discovery rate (FDR) correction was applied to account for multiple comparisons using the Benjamini-Hochberg method. ResultsMean (SD, range) clinically estimated GA at delivery was 38.9 (1.5, 31.1–44.9) weeks and was positively correlated with epigenetic age (Knight clock r = 0.51, Bohlin clock r = 0.76). Being female was positively related to GAAKnight. Maternal age was positively associated with GAABohlin. In multivariable regression models, preconception folate was inversely related to GAABohlin (β = –0.004, 95% CI: –0.007–0.000, P = 0.04); however, this was not significant after adjustment for multiple comparisons (FDR P = 0.82). Other nutritional biomarkers and LDA were not related to GAA. ConclusionsMaternal nutritional biomarkers prior to conception and during early pregnancy were not related to newborn epigenetic age acceleration in predominantly term deliveries among women supplemented with folic acid. Funding SourcesSupported by the Intramural Research Program of the NICHD.