Maternal and early life exposures and their potential to influence development of the microbiome

At the dawn of the twentieth century, the medical care of mothers and children was largely relegated to family members and informally trained birth attendants. As the industrial era progressed, early and key public health observations among women and children linked the persistence of adverse health outcomes to poverty and poor nutrition. In the time hence, numerous studies connecting genetics (“nature”) to public health and epidemiologic data on the role of the environment (“nurture”) have yielded insights into the importance of early life exposures in relation to the occurrence of common diseases, such as diabetes, allergic and atopic disease, cardiovascular disease, and obesity. As a result of these parallel efforts in science, medicine, and public health, the developing brain, immune system, and metabolic physiology are now recognized as being particularly vulnerable to poor nutrition and stressful environments from the start of pregnancy to 3 years of age. In particular, compelling evidence arising from a diverse array of studies across mammalian lineages suggest that modifications to our metagenome and/or microbiome occur following certain environmental exposures during pregnancy and lactation, which in turn render risk of childhood and adult diseases. In this review, we will consider the evidence suggesting that development of the offspring microbiome may be vulnerable to maternal exposures, including an analysis of the data regarding the presence or absence of a low-biomass intrauterine microbiome.

Early life factors as predictors of age-associated deficit accumulation across 17 years from midlife into old age

Background Early life exposures have been associated with the risk of frailty in old age. We investigated whether early life exposures predict the level and rate of change in a frailty index (FI) from midlife into old age. Methods A linear mixed model analysis was performed using data from three measurement occasions over 17 years in participants from the Helsinki Birth Cohort Study (n=2000) aged 57-84 years. A 41-item FI was calculated on each occasion. Information on birth size, maternal body mass index (BMI), growth in infancy and childhood, childhood socioeconomic status (SES), and early life stress (wartime separation from both parents), was obtained from registers and healthcare records. Results At age 57 years the mean FI level was 0.186 and the FI levels increased by 0.34 percent/year from midlife into old age. Larger body size at birth associated with a slower increase in FI levels from midlife into old age. Per 1kg greater birth weight the increase in FI levels per year was -0.087 percentage points slower (95% CI=-0.163, -0.011; p=0.026). Higher maternal BMI was associated with a higher offspring FI level in midlife and a slower increase in FI levels into old age. Larger size, faster growth from infancy to childhood, and low SES in childhood were all associated with a lower FI level in midlife but not with its rate of change. Conclusions Early life factors seem to contribute to disparities in frailty from midlife into old age. Early life factors may identify groups that could benefit from frailty prevention, optimally initiated early in life.

Childhood Disadvantage and Adult Functional Status: Do Early-Life Exposures Jeopardize Healthy Aging?

Objectives To examine whether childhood disadvantage is associated with later-life functional status and identify mediating factors. Methods Unique and additive effects of five childhood domains on functional status were assessed at baseline (2006) and over time (2006–2016) in a sample of 13,894 adults from the Health and Retirement Study (>50 years). Adult health behaviors and socioeconomic status (SES) were tested as mediators. Results Respondents exposed to multiple childhood disadvantages (OR = .694) as well as low childhood SES (OR = .615), chronic diseases (OR = .694), impairments (OR = .599), and risky adolescent behaviors (OR = .608) were less likely to be free of functional disability by baseline. Over time, these unique and additive effects of childhood disadvantage increased the hazard odds of eventually developing functional disability (e.g., additive effect: hOR = 1.261). Adult health behaviors and SES mediated some of these effects. Discussion Given the enduring effects of childhood disadvantage, policies to promote healthy aging should reduce exposure to childhood disadvantage.

Season of Birth and Cardiovascular Mortality in Atrial Fibrillation: A Population-Based Cohort Study

Background: The fetal origins hypothesis have associated early life exposures with the development of adverse health outcomes in adulthood. Season of birth has been shown to be associated with overall and cardiovascular mortality. Methods: We performed a retrospective database study to explore the association between season of birth and mortality in patients with atrial fibrillation. Results: A total of 8962 patients with AF were identified in the database with 1253 deaths recorded. AF patients born in spring and summer had a higher mortality rate when compared to those born in autumn and winter (hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.01–1.26, p = 0.03). This effect was consistent in the male subgroup (HR 1.25, 95% CI 1.03–1.51, p = 0.02 for males born in spring; HR 1.24, 95% CI 1.03–1.51, p = 0.03 for males born in summer when compared to winter as the reference) but not in females (HR 1.02, 95% CI 0.79–1.31, p = 0.88 for females born in spring; HR 1.11, 95% CI 0.87–1.42, p = 0.39 for females born in summer when compared to winter as the reference). Results persisted after adjustment for baseline characteristics and clinical risk profile. A similar pattern was observed with cardiovascular mortality. Conclusion: Birth in spring or summer is associated with a higher risk of cardiovascular mortality in male AF patients, but not in females. This could be related to the underlying differences in rates of major adverse clinical events between genders. Further studies should aim at clarifying the mechanisms behind this association, which may help us understand the higher level of risk in female patients with AF.

Early-life exposures and age at thelarche in the Sister Study cohort

Background Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974. Methods Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11–13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood. Results Early thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09–1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04–1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13–1.27), young maternal age (OR 1.30, 95% CI 1.16–1.47 for < 20 vs. 25–29 years), and being firstborn (OR = 1.25, 95% CI 1.17–1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche. Conclusions Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.

Life Course Stressors and Functional Limitations in Later Life Among White, Black, and Hispanic Adults

Although striking racial and ethnic disparities in health are manifest during later life, they may be rooted in early-life exposures. Drawing from cumulative inequality theory, we investigate whether experiencing life course stressors increases the risk of later-life functional limitations and whether this relationship differs by race and ethnicity. This study utilizes longitudinal data from the Health and Retirement Study to test whether six indicators of child stressors and eleven indicators of adult stressors predict trajectories of the onset and severity of functional limitations in later life among a diverse sample of adults. We find that child and adult stressors are associated with earlier onset and greater severity of functional limitations during later life. Mediation analyses reveal the indirect influence of child stressors via adult stressors on onset and severity of functional limitations; however, the indirect effects are slightly stronger for Black and Hispanic adults than their White counterparts (i.e., moderated mediation). In sum, child stressors, in and of themselves, do not increase functional limitations among Black and Hispanic people but are associated with greater adult stress exposure, leading to more functional limitations in later life. Disparities in functional limitations are also partly due to lower education and less wealth among Black and Hispanic adults.

Childhood asthma- pathogenesis and phenotypes

In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility, and environmental exposures (such as farmyard environment, air pollution, tobacco smoke exposure) influence the development of wheezing illness and the risk for progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy resistant asthma, and it is to be expected that more personalized treatment options may become available.