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Abstract Background A major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations. Methods Data from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight

Abstract Using pooled vaginal microbiota data from pregnancy cohorts (N = 683 participants) in the Environmental influences on Child Health Outcomes (ECHO) Program, we analyzed 16S rRNA gene amplicon sequences to identify clinical and demographic host factors that associate with vaginal microbiota structure in pregnancy both within and across diverse cohorts. Using PERMANOVA models, we assessed factors associated with vaginal community structure in pregnancy, examined whether host factors were conserved across populations, and tested the independent and combined effects of host factors on vaginal community state types (CSTs) using multinomial logistic regression models. Demographic and social factors explained a larger amount of variation in the vaginal microbiome in pregnancy than clinical factors. After adjustment, lower education, rather than self-identified race, remained a robust predictor of L. iners dominant (CST III) and diverse (CST IV) (OR = 8.44, 95% CI = 4.06–17.6 and OR = 4.18, 95% CI = 1.88–9.26, respectively). In random forest models, we identified specific taxonomic features of host factors, particularly urogenital pathogens associated with pregnancy complications (Aerococcus christensenii and Gardnerella spp.) among other facultative anaerobes and key markers of community instability (L. iners). Sociodemographic factors were robustly associated with vaginal microbiota structure in pregnancy and should be considered as sources of variation in human microbiome studies.

Abstract Methods for collection of placental tissue at room temperature for metabolic profiling are described. Specimens were excised from the maternal side of the placenta and immediately flash frozen or fixed and stored for 1, 6, 12, 24, or 48 h in 80% methanol. Untargeted metabolic profiling was performed on both the methanol-fixed tissue and the methanol extract. Data were analyzed using Gaussian generalized estimating equations, two sample t-tests with false discovery rate (FDR) corrections, and principal components analysis. Methanol-fixed tissue samples and methanol extracts had a similar number of metabolites (p = 0.45, p = 0.21 in positive vs. negative ion mode). In positive ion mode, when compared to flash frozen tissue, both the methanol extract and methanol-fixed tissue (6 h) had a higher number of metabolites detected (146 additional metabolites, pFDR = 0.020; 149 additional metabolites, pFDR = 0.017; respectively), but these associations were not found in negative ion mode (all pFDR ≥ 0.05). Principle components analysis demonstrated separation of the metabolite features in the methanol extract, but similarity between methanol-fixed tissue and flash frozen tissue. These results show that placental tissue samples collected in 80% methanol at room temperature can yield similar metabolic data to flash frozen specimens.

Though studies in animals and humans link the gut microbiota to brain development and control of behavior, little research has examined this connection in healthy infants. This prospective study could determine associations between infant gut microbiota at 3 months, and infant temperament at 9 months, in a prospective pregnancy cohort (Michigan Archive for Research on Child Health; n = 159). Microbiota profiling with 16S rRNA gene sequencing was conducted on fecal samples obtained at 3 months of age. Based on the relative abundance of gut microbiotas, three groups were identified, and each group was characterized by different microbes. Infant temperament outcomes were reported by mothers using the Infant Behavior Questionnaire-Revised Very Short Form at a mean age of 9.4 months. Fully adjusted multivariate linear regression models showed that certain clusters were associated with higher negative emotionality scores, prominently among infants who had poor vitamin D intake. However, no associations were evident between gut microbiota clusters and temperament scales after FDR correction. After using three differential abundance tools, Firmicutes was associated with higher positive affect/surgency scores, whereas Clostridioides was associated with lower scores. An association between the gut microbiota and early infancy temperament was observed; thus, this study warrants replication, with a particular focus on vitamin D moderation.

ABSTRACT The totality of evidence favors the efficacy of convalescent plasma to treat COVID-19 when high-titer plasma is administered early in the course of disease or to immunocompromised patients. In this commentary, we frame the findings of L. A. Bartelt, A. J. Markmann, B. Nelson, J. Keys, et al. (mBio 13:e01751-22, 2022, https://doi.org/10.1128/mBio.01751-22) in the context of the normal approval process for a therapeutic product. We point out that convalescent plasma has taken all of the typical steps associated with approval for a therapeutic product. Additionally, in less than 3 years, the optimal use cases and continued utility of this product to treat COVID-19 have been defined.

Background: As obesity rates continue to rise, it is increasingly important to understand factors that can influence body weight and growth, especially from an early age. The infant gut microbiota has broad effects on a variety of bodily processes, but its relation to infant growth is not yet fully characterized. Since the infant gut microbiota is closely related to breastfeeding practices and maternal health, understanding the relationship between these factors and infant growth may provide insight into the origins of childhood obesity. Objectives: Identify the relationship between human milk exposure, maternal pre-pregnancy body mass index (BMI), the infant gut microbiota, and 12-month-old BMI-for-age z-scores (12M BAZ) to identify key factors that shape infant growth. Methods: Two Michigan cohorts (ARCHGUT and BABYGUT) comprised of a total of 33 mother-infant dyads provided infant fecal samples at 12M. After DNA extraction, amplification, and sequencing of the V4 16S rRNA region using Illumina MiSeq v2 Chemistry, gut bacterial diversity metrics were analyzed in relation to human milk exposure, maternal pre-pregnancy BMI, and infant growth parameters. Results: Recent human milk exposure was inversely related to maternal pre-pregnancy BMI and most strongly associated with infant gut bacterial community membership and individual gut microbiota richness differences. Maternal pre-pregnancy BMI was not associated with the infant gut microbiota after adjusting for human milk exposure. However, maternal pre-pregnancy BMI was the only factor significantly associated with 12M BAZ. Conclusions: Human milk exposure is one of the central influences on the infant gut microbiota at 12M of age. However, the lack of association between the infant gut microbiota and 12M-old infant BAZ suggests that genetic, physiological, dietary, and other environmental factors may play a more direct role than the gut microbiota in determining infant BAZ at 12M.

[This corrects the article DOI: 10.1371/journal.pone.0245064.].

Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age Results: The analytic cohort consisted of 11,762 infants, 10% of whom had bronchiolitis hospitalization. Overall, 15% subsequently developed asthma. In the Cox proportional hazards model adjusting for 10 patient-level factors, compared with the no-bronchiolitis hospitalization group, the bronchiolitis hospitalization group had a significantly higher rate of asthma (14% vs. 24%, HR = 2.77, 95%CI = 2.24–3.43, p < 0.001). There was significant heterogeneity by race and ethnicity (Pinteraction = 0.02). The magnitude of the association was greater in non-Hispanic White (HR = 3.77, 95%CI = 2.74–5.18, p < 0.001) and non-Hispanic Black (HR = 2.39, 95%CI = 1.60–3.56; p < 0.001) infants, compared with Hispanic infants (HR = 1.51, 95%CI = 0.77–2.95, p = 0.23). Conclusions: According to the nationwide cohort data, infants hospitalized with bronchiolitis are at a higher risk for asthma, with quantitative heterogeneity in different racial and ethnic groups.

Background: The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA. Methods: We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data. Results: CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = −0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021. Conclusions: A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths. Funding: There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.

Background and purpose: Stigma hinders care for patients with neurologic illness. Layered stigma due to comorbid disease is common yet poorly characterized due to lack of instruments. Epilepsy and HIV are prototypical stigmatized conditions widespread in sub-Saharan Africa. Methods: We assessed layered stigma among people with HIV and epilepsy (n=21), epilepsy only (n=88), and HIV only (n=40) in Zambia. Epilepsy-associated stigma was assessed using the Stigma Scale of Epilepsy and Jacoby's Stigma Scale. HIV-related stigma was assessed using the HIV/AIDS Stigma Instrument-People Living with HIV/AIDS and Jacoby's Stigma Scale. Stigma was compared across groups using χ2 tests. Results: 55% (60/109) with epilepsy reported some epilepsy-associated stigma and 20% (12/61) with HIV reported HIV self-stigmatization. Those with HIV and epilepsy were more likely to associate seizures with fear (OR 6.1 [95% CI: 1.3–27.9]) and epilepsy with dependence (OR 4.6 [1.1–19.6]), controlling for age, gender, marital status, and employment. Those with comorbid disease were more likely to report they were “no longer a person” and felt “blamed” for their HIV. Controlling for age and gender, the difference in depersonalization remained (OR: 6.4 [1.1–36.1]). Conclusion: Individuals carrying the burden of one stigmatized condition may be more vulnerable to stigma from a comorbid disease. Keywords: Intersectional stigma, Double stigma, Resource-limited setting, Sub-Saharan Africa, Vulnerable populations

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate's degree, vocational or technical training [reference category]; bachelor's degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor's degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor's degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

Perinatal factors can shape fecal microbiome patterns among pregnant women and their infants. However, there is scarce information about the effect of maternal demographics and perinatal exposures on antibiotic resistance genes (ARG) and mobile genetic element (MGE) patterns in pregnant women and infants. We examined fecal samples from pregnant women during their third trimester of pregnancy (n = 51) and 6-month-old infants (n = 40). Of the 91 participants, 72 represented 36 maternal-infant dyads, 15 were additional pregnant women, and 4 were additional infants. We assessed the effects of demographics, pre-pregnancy BMI, smoking and parity in the pregnancy resistome and the effects of demographics, delivery mode, feeding habits and prenatal antibiotic treatment on the infancy resistome. ARG and MGE richness and abundance were assessed using a SmartChip qPCR-array. Alpha diversity (Shannon and Inverse Simpson index) and beta diversity (Sorensen and Bray-Curtis index) were calculated. The Wilcoxon and the Kruskal non-parametric test were used for comparisons. There is a high variability in shared resistome patterns between pregnant women and their infants. An average of 29% of ARG and 24% of MGE were shared within dyads. Infants had significantly greater abundance and higher diversity of ARG and MGE compared to pregnant women. Pregnancy and infancy samples differed in ARG and MGE gene composition and structure. Composition of the fecal resistome was significantly associated with race in pregnant women, with non-white women having different patterns than white women, and, in infants, with extent of solid food consumption. Our data showed that the pregnancy and infancy resistome had different structure and composition patterns, with maternal race and infant solid food consumption as possible contributors to ARG. By characterizing resistome patterns, our results can inform the mechanism of antibiotic resistome development in pregnant women and their infants.

Breastfeeding and introduction of solid food are the two major components of infant feeding practices that influence gut microbiota composition in early infancy. However, it is unclear whether additional factors influence the microbiota of infants either exclusively breastfed or not breastfed. We obtained 194 fecal samples from infants at 3–9 months of age, extracted DNA, and sequenced the V4 region of the 16S rRNA gene. Feeding practices and clinical information were collected by questionnaire and abstraction of birth certificates. The gut microbiota of infants who were exclusively breastfed displayed significantly lower Shannon diversity (p-adjust < 0.001) and different gut microbiota composition compared to infants who were not breastfed (p-value = 0.001). Among the exclusively breastfed infants, recipients of vitamin D supplements displayed significantly lower Shannon diversity (p-adjust = 0.007), and different gut microbiota composition structure than non-supplemented, breastfed infants (p-value = 0.02). MaAslin analysis identified microbial taxa that associated with breastfeeding and vitamin D supplementation. Breastfeeding and infant vitamin D supplement intake play an important role in shaping infant gut microbiota.

Abstract Background Cerebral palsy is the most frequent motor disability in childhood, but little is known about its etiology. It has been suggested that cerebral palsy risk may be increased by prenatal thyroid hormone disturbances. The objective of this study was to investigate whether maternal thyroid disorder is associated with increased risk of cerebral palsy. Methods A population-based cohort study using two study populations. 1) 1,270,079 children born in Denmark 1979–2007 identified in nationwide registers, and 2) 192,918 children born 1996–2009 recruited into the Danish National Birth Cohort and The Norwegian Mother and Child Cohort study, combined in the MOthers and BAbies in Norway and Denmark (MOBAND) collaboration cohort. Register-based and self-reported information on maternal thyroid disorder was studied in relation to risk of cerebral palsy and its unilateral and bilateral spastic subtypes using multiple logistic regression. Children were followed from the age of 1 year to the age of 6 years, and cerebral palsy was identified in nationwide registers with verified diagnoses. Results In register data, hypothyroidism was recognized in 12,929 (1.0%), hyperthyroidism in 9943 (0.8%), and unclassifiable thyroid disorder in 753 (

The gut microbiota undergoes rapid changes during infancy in response to early-life exposures. We have investigated how the infant gut bacterial community matures over time and how exposures such as human milk and antibiotic treatment alter gut microbiota development. We used the LonGP program to create predictive models to determine the contribution of exposures on infant gut bacterial abundances from one month to two years of age. These models indicate that infant antibiotic use, human milk intake, maternal pre-pregnancy BMI, and sample shipping time were associated with changes in gut microbiome composition. In most infants, Bacteroides, Lachnospiraceae unclassified, Faecalibacterium, Akkermansia, and Phascolarctobacterium abundance increased rapidly after 6 months, while Escherichia, Bifidobacterium, Veillonella, and Streptococcus decreased in abundance over time. Individual, time-varying, random effects explained most of the variation in the LonGP models. Multivariate association with linear models (MaAsLin) displayed partial agreement with LonGP in the predicted trajectories over time and in relation to significant factors such as human milk intake. Multiple factors influence the dynamic changes in bacterial composition of the infant gut. Within-individual differences dominate the temporal variations in the infant gut microbiome, suggesting individual temporal variability is an important feature to consider in studies with a longitudinal sampling design.

BACKGROUND:About 25% of women in the United States are obese prior to becoming pregnant. Although there is some knowledge about the relationship between the gastrointestinal microbiota and obesity, little is known about the relationship between pre-pregnancy obesity and the gastrointestinal microbiota in pregnancy or its impact on infant gut microbiota. However, the composition of the gut microbiota early in life may influence childhood health. Thus, the objective of this research was to identify associations between maternal pre-pregnancy obesity and the pregnancy (n = 39) or early infancy (n = 39) microbiotas. RESULTS:Fecal bacterial communities from overweight women had lower microbiota diversity (Chao1: p = 0.02; inverse Simpson: p = 0.05; Shannon: p = 0.02) than communities from normal weight or obese women. The within-group microbiota composition of overweight women differed from those of normal and obese women at the genus and phylum levels (p = 0.003 and p = 0.02, respectively). Pre-pregnancy overweight women had higher abundances of Bacteroides and lower Phascolarctobacterium than women who were normal weight or obese prior to becoming pregnant. Normal weight women had lower abundances of Acidaminococcus and Dialister than overweight and obese women. Infant community composition tended to differ in membership (Sorensen index) by maternal pre-pregnancy BMI category, and significantly differed by delivery mode and breastfeeding exclusivity (p = 0.06, p = 0.001, p = 0.008, respectively). Infants from normal weight women had lower abundances of Megasphaera than infants from overweight or obese women. Streptococcus was lowest in infants from overweight women, and Staphylococcus was lowest in infants from obese women. CONCLUSION:Maternal and infant microbiotas are associated with and might be affected by maternal pre-pregnancy BMI. Future work should determine if there are also functional differences in the infant microbiome, if those functional differences are related to maternal pre-pregnancy BMI, and whether differences in composition or traits persist over time.

Screening newborns for treatable serious conditions is mandated in all US states and many other countries. After screening, Guthrie cards with residual blood (whole spots or portions of spots) are typically stored at ambient temperature in many facilities. The potential of archived dried blood spots (DBS) for at-birth molecular studies in epidemiological and clinical research is substantial. However, it is also challenging as analytes from DBS may be degraded due to preparation and storage conditions. We previously reported an improved assay for obtaining global RNA gene expression from blood spots. Here, we evaluated sex-specific gene expression and its preservation in DBS using oligonucleotide microarray technology. We found X inactivation-specific transcript (XIST), lysine-specific demethylase 5D (KDM5D) (also known as selected cDNA on Y, homolog of mouse (SMCY)), uncharacterized LOC729444 (LOC729444), and testis-specific transcript, Y-linked 21 (TTTY21) to be differentially-expressed by sex of the newborn. Our finding that trait-specific RNA gene expression is preserved in unfrozen DBS, demonstrates the technical feasibility of performing molecular genetic profiling using such samples. With millions of DBS potentially available for research, we see new opportunities in using newborn molecular gene expression to better understand molecular pathogenesis of perinatal diseases.

BackgroundWe sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI).MethodsProtein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.ResultsNewborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.ConclusionhyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.