Environmental Phenols and Growth in Infancy: The Infant Feeding and Early Development Study.

CONTEXT: Higher mean and rapid increases in body mass index (BMI) during infancy are associated with subsequent obesity and may be influenced by exposure to endocrine-disrupting chemicals such as phenols. OBJECTIVE: In a prospective US-based cohort conducted 2010-2014, we investigated associations between environmental phenol exposures and BMI in 199 infants. METHODS: We measured seven urinary phenols at ages 6-8 and 12 weeks and assessed BMI z-score at up to 12 study visits between birth and 36 weeks. We examined individual and joint associations of averaged early infancy phenols with level of BMI z-score using mean differences (ß [95% confidence intervals (CI)]) and with BMI z-score trajectories using relative risk ratios (RR [95% CI]). RESULTS: Benzophenone-3, methyl and propyl paraben, and all phenols jointly were positively associated with higher mean BMI z-score (0.07 [-0.05, 0.18], 0.10 [-0.08, 0.27], 0.08 [-0.09, 0.25], 0.17 [-0.08, 0.43], respectively). Relative to a Stable trajectory, benzophenone-3, 2,4-dichlorophenol, 2,5-dichlorophenol, and all phenols jointly were positively associated with risk of a Rapid Increase trajectory (1.46 [0.89, 2.39], 1.33 [0.88, 2.01], 1.66 [1.03, 2.68], 1.41 [0.71, 2.84], respectively). CONCLUSION: Early phenol exposure was associated with a higher mean and rapid increase in BMI z-score across infancy, signaling potential long-term cardiometabolic consequences of exposure.

Environmental phenol exposures in 6- to 12-week-old infants: The Infant Feeding and Early Development (IFED) study.

BACKGROUND: Exposure to phenols, endocrine-disrupting chemicals used in personal care and consumer products, is widespread. Data on infant exposures are limited despite heightened sensitivity to endocrine disruption during this developmental period. We aimed to describe distributions and predictors of urinary phenol concentrations among U.S. infants ages 6-12 weeks. METHODS: The Infant Feeding and Early Development (IFED) study is a prospective cohort study of healthy term infants enrolled during 2010-2013 in the Philadelphia region. We measured concentrations of seven phenols in 352 urine samples collected during the 6- or 8- and/or 12-week study visits from 199 infants. We used linear mixed models to estimate associations of maternal, sociodemographic, infant, and sample characteristics with natural-log transformed, creatinine-standardized phenol concentrations and present results as mean percent change from the reference level. RESULTS: Median concentrations (µg/L) were 311 for methylparaben, 10.3 for propylparaben, 3.6 for benzophenone-3, 2.1 for triclosan, 1.0 for 2,5-dichlorophenol, 0.7 for BPA, and 0.3 for 2,4-dichlorophenol. Geometric mean methylparaben concentrations were approximately 10 times higher than published estimates for U.S. children ages 3-5 and 6-11 years, while propylparaben concentrations were 3-4 times higher. Infants of Black mothers had higher concentrations of BPA (83%), methylparaben (121%), propylparaben (218%), and 2,5-dichorophenol (287%) and lower concentrations of benzophenone-3 (-77%) and triclosan (-53%) than infants of White mothers. Triclosan concentrations were higher in breastfed infants (176%) and lower in infants whose mothers had a high school education or less (-62%). Phenol concentrations were generally higher in summer samples. CONCLUSIONS: Widespread exposure to select environmental phenols among this cohort of healthy U.S. infants, including much higher paraben concentrations compared to those reported for U.S. children, supports the importance of expanding population-based biomonitoring programs to infants and toddlers. Future investigation of exposure sources is warranted to identify opportunities to minimize exposures during these sensitive periods of development.

Natural variation of immune epitopes reveals intrabacterial antagonism.

Plants and animals detect biomolecules termed microbe-associated molecular patterns (MAMPs) and induce immunity. Agricultural production is severely impacted by pathogens which can be controlled by transferring immune receptors. However, most studies use a single MAMP epitope and the impact of diverse multicopy MAMPs on immune induction is unknown. Here, we characterized the epitope landscape from five proteinaceous MAMPs across 4,228 plant-associated bacterial genomes. Despite the diversity sampled, natural variation was constrained and experimentally testable. Immune perception in both Arabidopsis and tomato depended on both epitope sequence and copy number variation. For example, Elongation Factor Tu is predominantly single copy, and 92% of its epitopes are immunogenic. Conversely, 99.9% of bacterial genomes contain multiple cold shock proteins, and 46% carry a nonimmunogenic form. We uncovered a mechanism for immune evasion, intrabacterial antagonism, where a nonimmunogenic cold shock protein blocks perception of immunogenic forms encoded in the same genome. These data will lay the foundation for immune receptor deployment and engineering based on natural variation.

Personal care product use patterns in association with phthalate and replacement biomarkers across pregnancy.

BACKGROUND: Humans are exposed to phthalates, a class of non-persistent chemicals, through multiple products, including personal care and cosmetics. Associations between specific phthalates and product use have been inconsistent. However, determining these connections could provide avenues for exposure reduction. OBJECTIVE: Examine the association between patterns of personal care product use and associations with phthalate and replacement biomarkers. METHODS: In the Human Placenta and Phthalates Study, 303 women were enrolled in early pregnancy and followed for up to 8 visits across gestation. At each visit, women completed a questionnaire about product use in the prior 24 hours and contributed urine samples, subsequently analyzed for 18 phthalate and replacement metabolites. At early, mid-, and late pregnancy, questionnaire responses were condensed and repeated metabolite concentrations were averaged. Latent class analysis (LCA) was used to determine groups of women with similar use patterns, and weighted associations between group membership and biomarker concentrations were assessed. RESULTS: LCA sorted women into groups which largely corresponded to: (1) low fragranced product use (16-23% of women); (2) fragranced product and low body wash use (22-26%); 3) fragranced product and low bar soap use (26-51%); and (4) low product use (7-34%). Monoethyl phthalate (MEP) urinary concentrations were 7-10% lower and concentrations of summed di(2-ethylhexyl) terephthalate metabolites were 15-21% lower among women in the "low fragranced product use" group compared to the population mean. Few other consistent associations between group and biomarker concentrations were noted. IMPACT STATEMENT: Personal care products and cosmetics are a known exposure source for phthalates and potentially represent one of the most accessible intervention targets for exposure reduction. However, in this analysis accounting for concurrent use and fragranced status of products, we did not find any use patterns that corresponded to universally lower levels.

Natural variation of immune epitopes reveals intrabacterial antagonism.

Plants and animals detect biomolecules termed Microbe-Associated Molecular Patterns (MAMPs) and induce immunity. Agricultural production is severely impacted by pathogens which can be controlled by transferring immune receptors. However, most studies use a single MAMP epitope and the impact of diverse multi-copy MAMPs on immune induction is unknown. Here we characterized the epitope landscape from five proteinaceous MAMPs across 4,228 plant-associated bacterial genomes. Despite the diversity sampled, natural variation was constrained and experimentally testable. Immune perception in both Arabidopsis and tomato depended on both epitope sequence and copy number variation. For example, Elongation Factor Tu is predominantly single copy and 92% of its epitopes are immunogenic. Conversely, 99.9% of bacterial genomes contain multiple Cold Shock Proteins and 46% carry a non-immunogenic form. We uncovered a new mechanism for immune evasion, intrabacterial antagonism, where a non-immunogenic Cold Shock Protein blocks perception of immunogenic forms encoded in the same genome. These data will lay the foundation for immune receptor deployment and engineering based on natural variation.

Midpregnancy Phthalate and Phenol Biomarkers in Relation to Infant Body Composition: The Healthy Start Prospective Cohort.

BACKGROUND: Gestational phthalate and phenol exposure disrupts adipogenesis, contributing to obesity in mice. Whether gestational phthalate or phenol exposure is associated with infant body composition has not been investigated in humans. OBJECTIVE: We examined associations between biomarkers of phthalate and phenol exposure in midpregnancy and infant size and body composition at birth and at 5 months of age. METHODS: Analyses were conducted among 438 infants from the Healthy Start prospective pregnancy cohort. Sixteen phthalate and phenol biomarkers were quantified in spot urine samples collected at 24-28 wk of gestation. Infant outcomes measured at birth and at 5 months of age included size [weight (in grams)] and body composition [fat and lean masses (in grams); percentage fat mass]. Single- (linear) and multipollutant (quantile g-computation) models were used to estimate associations of phthalate and phenol biomarkers with infant outcomes at birth and at 5 months of age. Models were adjusted for sociodemographics, sample collection timing, and lifestyle factors and used to examine for effect modification by infant sex. RESULTS: In single-pollutant models, mono-benzyl phthalate and di-n-butyl phthalate were inversely associated with percentage fat mass [ß: -0.49 (95% CI: -0.91, -0.08) and -0.51 (95% CI: -1.02, 0.01), respectively] in male but not female infants at birth. Similar, but less precise, associations were observed at 5 months of age. In multipollutant models, a 1-quartile increase in the phthalate and phenol biomarker mixture was inversely associated with percentage fat mass at birth [-1.06 (95% CI: -2.21, 0.1)] and at 5 months of age [-2.14 (95% CI: -3.88, -0.39)] among males, but associations were null among females [0.48 (95% CI: -0.78, 1.75) and -0.64 (95% CI: -2.68, 1.41), respectively]. Similar associations were observed with infant weight. CONCLUSION: In this U.S.-based prospective cohort, gestational phthalate and phenol biomarkers were inversely associated with infant weight and fat mass, particularly in males. https://doi.org/10.1289/EHP12500.

Fetal Organophosphate Pesticide Exposure and Child Adiposity Measures at 10 Years of Age in the General Dutch Population.

BACKGROUND: Fetal exposure to organophosphate (OP) pesticides might lead to fetal metabolic adaptations, predisposing individuals to adverse metabolic profiles in later life. OBJECTIVE: We examined the association of maternal urinary OP pesticide metabolite concentrations in pregnancy with offspring body mass index (BMI) and fat measures at 10 years of age. METHODS: Between 2002 and 2006, we included 642 mother-child pairs from the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. We measured maternal urinary concentrations of OP pesticide metabolites, namely, dialkyl phosphates, including three dimethyl and three diethyl phosphates in early-, mid- and late-pregnancy. At 10 years of age, child total and regional body fat and lean mass were measured through dual energy X-ray absorptiometry, and abdominal and organ fat through magnetic resonance imaging. RESULTS: Higher maternal urinary pregnancy-average or trimester-specific dialkyl, dimethyl, or diethyl phosphate concentrations were not associated with childhood BMI and the risk of overweight. In addition, we did not observe any association of dialkyl, dimethyl, or diethyl phosphate concentrations with total and regional body fat, abdominal visceral fat, liver fat, or pericardial fat at child age of 10 y. CONCLUSION: We observed no associations of maternal urinary dialkyl concentrations during pregnancy with childhood adiposity measures at 10 years of age. Whether these associations develop at older ages should be further studied. https://doi.org/10.1289/EHP12267.

Variability and Longitudinal Trajectories of Phthalate and Replacement Biomarkers across Pregnancy in the Human Placenta and Phthalates Study.

Human exposure to phthalates is widespread, but assessment of variability across pregnancy has been hampered by short half-lives of phthalate biomarkers and a few repeated measures in prior studies. We aimed to characterize the variability and longitudinal profiles of phthalate and replacement biomarkers across pregnancy. Within the Human Placenta and Phthalates Study, 303 pregnant women provided urine samples at up to 8 visits across gestation. Concentrations of 14 metabolites of phthalates and 4 metabolites of replacements were quantified in each sample, and subject-specific averages within each trimester were calculated. We examined variability in individual biomarker concentrations across the 8 visits, within trimesters, and across trimester-specific averages using intraclass correlation coefficients (ICCs). To explore longitudinal exposure biomarker profiles, we applied group-based trajectory modeling to trimester-specific averages over pregnancy. Pooling multiple visits into trimester-specific averages improved the ICCs for all biomarkers. Most biomarkers generally showed stable concentrations across gestation, i.e., high-, medium-, and low-concentration profiles, with small proportions of participants falling into the "high"-exposure groups. Variability over pregnancy is likely attributable to random fluctuations around a baseline exposure rather than true changes in concentrations over time.

Maternal asthma in relation to infant size and body composition.

Background: Asthma affects 10% of pregnancies and may influence offspring health, including infant size and body composition, through hypoxic and inflammatory pathways. Objective: We sought to determine associations between maternal asthma and asthma phenotypes during pregnancy and infant size and body composition. Methods: The B-WELL-Mom study (2015-19) is a prospective cohort of 418 pregnant persons with and without asthma recruited in the first trimester of pregnancy from 2 US obstetric clinics. Exposures were maternal self-reported active asthma (n = 311) or no asthma (n = 107), and asthma phenotypes were classified on the bases of atopy, onset, exercise induced, control, severity, symptomology, and exacerbations. Outcomes were infant weight, length, head circumference, and skinfold measurements at birth and postnatal follow-up, as well as fat and lean mass assessed by air displacement plethysmography at birth. Adjusted multivariable linear regression examined associations of maternal asthma and asthma phenotypes with infant outcomes. Results: Offspring were born at a mean ± SD of 38 ± 2.3 weeks' gestation and were 18 ± 2.2 weeks of age at postnatal follow-up. Infants of participants with asthma had a mean ± SD fat mass of 11.0 ± 4.2%, birth weight of 3045.8 ± 604.3 g, and postnatal follow-up weight of 6696.4 ± 964.2 g, which were not different from infants of participants without asthma (respectively, ß [95% confidence interval]: -0.1 [-1.4, 1.3], -26.7 [-156.9, 103.4], and 107.5 [-117.3, 332.3]). Few associations were observed between asthma or asthma phenotypes and infant size or body composition. Conclusions: In a current obstetric cohort, maternal asthma during pregnancy was not associated with differential infant size or body composition.

Prenatal exposure to perceived stress, maternal asthma, and placental size.

INTRODUCTION: Prenatal exposure to stress has been associated with poor pregnancy outcomes, yet evidence linking stress and placental size is limited. Asthma is associated with worse pregnancy outcomes and women with asthma may be more susceptible to stress. Using the asthma-enriched B-WELL-Mom cohort, we examined the association between perceived stress and placental size. METHODS: Placental measures of weight, length, width, and thickness were available for 345 women (262 with asthma) via placental pathology report. Perceived Stress Scale (PSS) scores were obtained in each trimester of pregnancy and categorized into quartiles (low quartile as reference). For associations between PSS and placental size, generalized estimating equations adjusted for maternal and infant factors were used to estimate regression coefficients (ß) and 95% confidence intervals (95% CI). Full models and models stratified by asthma status were run. RESULTS: Compared to Quartile 1, high levels of stress (Quartile 4) were associated with smaller placental weight (-20.63 95% CI: -37.01,-4.26) and length (-0.55 95% CI: -0.96,-0.15), but not width or thickness. Results by asthma status show a stronger association between perceived stress and shorter placental length in those with asthma and a stronger association between perceived stress and smaller placental thickness in those without asthma. Findings were robust to sensitivity analyses DISCUSSION: Higher levels of perceived stress were associated with smaller placental size. Additional research is warranted to understand the relationship between stress and placental size.

Variation in microbial feature perception in the Rutaceae family with immune receptor conservation in citrus.

Although much is known about the responses of model plants to microbial features, we still lack an understanding of the extent of variation in immune perception across members of a plant family. In this work, we analyzed immune responses in Citrus and wild relatives, surveying 86 Rutaceae genotypes with differing leaf morphologies and disease resistances. We found that responses to microbial features vary both within and between members. Species in 2 subtribes, the Balsamocitrinae and Clauseninae, can recognize flagellin (flg22), cold shock protein (csp22), and chitin, including 1 feature from Candidatus Liberibacter species (csp22CLas), the bacterium associated with Huanglongbing. We investigated differences at the receptor level for the flagellin receptor FLAGELLIN SENSING 2 (FLS2) and the chitin receptor LYSIN MOTIF RECEPTOR KINASE 5 (LYK5) in citrus genotypes. We characterized 2 genetically linked FLS2 homologs from "Frost Lisbon" lemon (Citrus ×limon, responsive) and "Washington navel" orange (Citrus ×aurantium, nonresponsive). Surprisingly, FLS2 homologs from responsive and nonresponsive genotypes were expressed in Citrus and functional when transferred to a heterologous system. "Washington navel" orange weakly responded to chitin, whereas "Tango" mandarin (C. ×aurantium) exhibited a robust response. LYK5 alleles were identical or nearly identical between the 2 genotypes and complemented the Arabidopsis (Arabidopsis thaliana) lyk4/lyk5-2 mutant with respect to chitin perception. Collectively, our data indicate that differences in chitin and flg22 perception in these citrus genotypes are not the results of sequence polymorphisms at the receptor level. These findings shed light on the diversity of perception of microbial features and highlight genotypes capable of recognizing polymorphic pathogen features.

The Association of Periconception Asthma Medication Discontinuation with Adverse Obstetric Outcomes.

OBJECTIVE: This study aimed to investigate asthma medication reduction in the periconceptional period as it relates to asthma status and adverse outcomes in pregnancy. STUDY DESIGN: In a prospective cohort study, self-reported current and past asthma medications were collected and analyzes compared measures of asthma status in women who discontinued asthma medication in the 6 months prior to enrollment ("step-down") versus those who did not ("no change"). Evaluation of asthma was done at three study visits (one per trimester) and by daily diaries, including measures of lung function (percent predicted forced expiratory volume in 1 and 6 s [%FEV1, %FEV6], peak expiratory flow [%PEF], forced vital capacity [%FVC], FEV1 to FVC ratio [FEV1/FVC]), lung inflammation (fractional exhaled nitric oxide [FeNO], ppb), rate of asthma symptoms (activity limitation, night symptoms, rescue inhaler use, wheeze, shortness of breath, cough, chest tightness, chest pain), and rate of asthma exacerbations. Adverse pregnancy outcomes were also evaluated. Adjusted regression analyses examined whether adverse outcomes differed by periconceptional asthma medication changes. RESULTS: Of 279 participants included in analyses, 135 (48.4%) did not change asthma medication in the periconceptional period, whereas 144 (51.6%) reported a step down in medication. Those in the step-down group were more likely to have milder disease (88 [61.1%] in the step-down vs. 74 [54.8%] in the no change group), exhibited less activity limitation (rate ratio [RR]: 0.68, 95% confidence interval [CI]: 0.47-0.98), and experienced fewer asthma attacks (RR: 0.53, 95% CI: 0.34-0.84) during pregnancy. The step-down group had a nonsignificant increase in overall odds of experiencing an adverse pregnancy outcome (odds ratio: 1.62, 95% CI: 0.97-2.72). CONCLUSION: Over half of women with asthma reduce asthma medication in the periconceptional period. Although these women typically have milder disease, a step down in medication may be associated with an increased risk of adverse pregnancy outcomes. KEY POINTS: · Many women reduce their asthma medication in pregnancy.. · Reduction is more common among those with mild disease.. · Medication reduction may lead to adverse pregnancy outcomes..

Early pregnancy phthalates and replacements in relation to fetal growth: The human placenta and phthalates study.

BACKGROUND: Pregnant persons are exposed ubiquitously to phthalates and increasingly to chemicals introduced to replace phthalates. In early pregnancy, exposure to these chemicals may disrupt fetal formation and development, manifesting adverse fetal growth. Previous studies examining the consequences of early pregnancy exposure relied on single spot urine measures and did not investigate replacement chemicals. OBJECTIVE: Characterize associations between urinary phthalate and replacement biomarkers in early pregnancy and fetal growth outcomes. METHODS: Analyses were conducted among 254 pregnancies in the Human Placenta and Phthalates Study, a prospective cohort with recruitment 2017-2020. Exposures were geometric mean concentrations of phthalate and replacement biomarkers quantified in two spot urine samples collected around 12- and 14-weeks of gestation. Outcomes were fetal ultrasound biometry (head and abdominal circumferences, femur length, estimated fetal weight) collected in each trimester and converted to z-scores. Adjusted linear mixed effects (single-pollutant) and quantile g-computation (mixture) models with participant-specific random effects estimated the difference, on average, in longitudinal fetal growth for a one-interquartile range (IQR) increase in individual (single-pollutant) or all (mixture) early pregnancy phthalate and replacement biomarkers. RESULTS: Mono carboxyisononyl phthalate and the sums of metabolites of di-n-butyl, di-iso-butyl, and di-2-ethylhexyl phthalate were inversely associated with fetal head and abdominal circumference z-scores. A one-IQR increase in the phthalate and replacement biomarker mixture was inversely associated with fetal head circumference (ß: -0.36 [95% confidence interval: -0.56, -0.15]) and abdominal circumference (-0.31 [-0.49, -0.12]) z-scores. This association was mainly driven by phthalate biomarkers. CONCLUSIONS: Urine concentrations of phthalate biomarkers, but not replacement biomarkers, in early pregnancy were associated with reductions in fetal growth. Though the clinical implications of these differences are unclear, reduced fetal growth contributes to excess morbidity and mortality across the lifecourse. Given widespread global exposure to phthalates, findings suggest a substantial population health burden resulting from early pregnancy phthalate exposure.

12th Japan-US Seminar in Plant Pathology Meeting Report.

The 12th iteration of the Japan-US Seminar in Plant Pathology was held in Ithaca, New York at Cornell University in the fall of 2022. Presentations covered a range of topics under the theme "Remodeling of the Plant-Microbe Environment During Disease, Defense, and Mutualism," and the meeting included a panel discussion of best practices in science communication. This report presents highlights of the meeting, from the perspective of early career participants of the seminar. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Overlapping Local and Systemic Defense Induced by an Oomycete Fatty Acid MAMP and Brown Seaweed Extract in Tomato.

Eicosapolyenoic fatty acids are integral components of oomycete pathogens that can act as microbe-associated molecular patterns to induce disease resistance in plants. Defense-inducing eicosapolyenoic fatty acids include arachidonic acid (AA) and eicosapentaenoic acid and are strong elicitors in solanaceous plants, with bioactivity in other plant families. Similarly, extracts of a brown seaweed, Ascophyllum nodosum, used in sustainable agriculture as a biostimulant of plant growth, may also induce disease resistance. A. nodosum, similar to other macroalgae, is rich in eicosapolyenoic fatty acids, which comprise as much as 25% of total fatty acid composition. We investigated the response of roots and leaves from AA or a commercial A. nodosum extract (ANE) on root-treated tomatoes via RNA sequencing, phytohormone profiling, and disease assays. AA and ANE significantly altered transcriptional profiles relative to control plants, inducing numerous defense-related genes with both substantial overlap and differences in gene expression patterns. Root treatment with AA and, to a lesser extent, ANE also altered both salicylic acid and jasmonic acid levels while inducing local and systemic resistance to oomycete and bacterial pathogen challenge. Thus, our study highlights overlap in both local and systemic defense induced by AA and ANE, with potential for inducing broad-spectrum resistance against pathogens. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Asthma Medication Regimens in Pregnancy: Longitudinal Changes in Asthma Status.

OBJECTIVE: This study aimed to assess the impact of common asthma medication regimens on asthma symptoms, exacerbations, lung function, and inflammation during pregnancy. STUDY DESIGN: A total of 311 women with asthma were enrolled in a prospective pregnancy cohort. Asthma medication regimen was categorized into short-acting ß agonist (SABA) alone, SABA + inhaled corticosteroid (ICS), SABA + ICS + long-acting ß agonist (LABA), and no asthma medications (reference). We evaluated asthma control at enrollment (< 15 weeks' gestation) and its change into trimesters 2 and 3, including per cent predicted forced expiratory volume in 1 second (%FEV1) and peak expiratory flow (%PEF), pulse oximetry, fractional exhaled nitric oxide (FeNO), asthma symptoms (asthma attacks/month, night symptoms/week), and severe exacerbations. Linear mixed models adjusted for site, age, race, annual income, gestational age, body mass index, and smoking, and propensity scores accounted for asthma control status at baseline. RESULTS: Women taking SABA + ICS and SABA + ICS + LABA had better first trimester %PEF (83.5% [75.7-91.3] and 84.6% [76.9-92.3], respectively) compared with women taking no asthma medications (72.7% [66.0-79.3]). Women taking SABA + ICS + LABA also experienced improvements in %FEV1 (+11.1%, p < 0.01) in the third trimester and FeNO in the second (-12.3 parts per billion [ppb], p < 0.01) and third (-11.0 ppb, p < 0.01) trimesters as compared with the trajectory of women taking no medications. SABA + ICS use was associated with increased odds of severe exacerbations in the first (odds ratio [OR]: 2.22 [1.10-4.46]) and second (OR: 3.15 [1.11-8.96]) trimesters, and SABA + ICS + LABA use in the second trimester (OR: 7.89 [2.75-21.47]). Women taking SABA alone were similar to those taking no medication. CONCLUSION: Pregnant women taking SABA + ICS and SABA + ICS + LABA had better lung function in the first trimester. SABA + ICS + LABA was associated with improvements in lung function and inflammation across gestation. However, both the SABA + ICS and SABA + ICS + LABA groups had a higher risk of severe exacerbation during early to mid-pregnancy. KEY POINTS: · Medication regimens may affect perinatal asthma control.. · Intensive regimens improved lung function/inflammation.. · Women on intensive regimens had more acute asthma events..

Fetal growth trajectories of babies born large-for-gestational age in the LIFECODES Fetal Growth Study.

BACKGROUND: Babies born large-for-gestational age have an increased risk of adverse health outcomes, including birth injuries, childhood obesity, and cardiometabolic disorders. However, little work has been done to characterize patterns of fetal growth among large-for-gestational age births, which may further elucidate high- and low-risk subgroups. OBJECTIVE: This study aimed to identify subgroups of large-for-gestational age births based on trajectories of fetal growth derived from prenatal ultrasound measurements and explore differences in sociodemographic, pregnancy, and birth outcome characteristics across subgroups. STUDY DESIGN: This study identified and described trajectories of fetal growth among large-for-gestational age births (n=235) in the LIFECODES Fetal Growth Study. Ultrasound measurements of fetal growth in middle to late pregnancy were abstracted from health records. Group-based multi-trajectory modeling was applied to measurements of head circumference, abdominal circumference, and femur length z-scores to identify multivariate trajectories of fetal growth. Moreover, sociodemographic variables, pregnancy characteristics, and birth outcomes based on trajectory membership were summarized. RESULTS: This study identified 4 multivariate trajectories of fetal growth among large-for-gestational age births: catch-up growth (n=28), proportional abdominal circumference-to-femur length growth (n=67), disproportional abdominal circumference-to-femur length growth (n=96), and consistently large (n=44). Fetuses in the "catch-up growth" group exhibited small relative sizes in midpregnancy (ie, below average head circumference, abdominal circumference, and femur length z-scores) and large relative sizes in late pregnancy. Growth among these births was driven by increases in relative abdominal circumference and head circumference sizes. Participants who delivered births assigned to this group were less likely to have normal glucose control (40% vs 65%-75%) and more likely to have pregestational diabetes mellitus (36% vs 10%-17%) than other large-for-gestational age subgroups. In addition, the babies in this trajectory group were more likely to have macrosomia (86% vs 67%-73%) and to be admitted to the neonatal intensive care unit (32% vs 14%-21%) than other large-for-gestational age subgroups. In contrast, babies in the "consistently large" group had the largest relative size for all growth parameters throughout gestation and experienced a lower risk of adverse birth outcomes than other large-for-gestational age subgroups. CONCLUSION: This study characterized several trajectories of fetal growth among large-for-gestational age births, which were related to different pregnancy characteristics and the distribution of adverse birth outcomes. Although the number of individuals within some trajectories was small, a subgroup that exhibited a catch-up growth phenotype during gestation was identified, which may be uniquely associated with exposure to pregestational diabetes mellitus and a higher risk of admission to the neonatal intensive care unit. These results have highlighted that the risk of adverse outcomes may not be evenly distributed across all large-for-gestational age births.

An application of group-based trajectory modeling to define fetal growth phenotypes among small-for-gestational-age births in the LIFECODES Fetal Growth Study.

BACKGROUND: Reductions in fetal growth are associated with adverse outcomes at birth and later in life. However, identifying fetuses with pathologically small growth remains challenging. Definitions of small-for-gestational age are often used as a proxy to identify those experiencing pathologic growth (ie, fetal growth restriction). However, this approach is subject to limitation as most newborns labeled small-for-gestational age are constitutionally, not pathologically, small. Incorporating repeated ultrasound measures to examine fetal growth trajectories may help distinguish pathologic deviations in growth from normal variability, beyond a simple definition of small-for-gestational age. OBJECTIVE: This study aimed to characterize phenotypes of growth using ultrasound trajectories of fetal growth among small-for-gestational-age births. STUDY DESIGN: This study identified and described trajectories of fetal growth among small-for-gestational-age births (<10th percentile weight for gestational age; n=245) in the LIFECODES Fetal Growth Study using univariate and multivariate trajectory modeling approaches. Available ultrasound measures of fetal growth (estimated fetal weight, head circumference, abdominal circumference, and femur length) from health records were abstracted. First, univariate group-based trajectory modeling was used to define trajectories of estimated fetal weight z scores during gestation. Second, group-based multi-trajectory modeling was used to identify trajectories based on concurrent measures of head circumference, abdominal circumference, and femur length z scores. Last, how these trajectories were related to patient demographics, pregnancy characteristics, and birth outcomes compared with those observed among appropriate-for-gestational-age controls was described. RESULTS: Of note, 3 univariate trajectories of estimated fetal weight and 4 multivariate trajectories of fetal growth among small-for-gestational-age births were identified. In our univariate approach, infants with the smallest estimated fetal weight trajectory throughout pregnancy had poorer outcomes, including the highest risk of neonatal intensive care unit admission. The remaining univariate trajectory groups did not have an elevated risk of adverse birth outcomes relative to appropriate-for-gestational-age controls. In our multivariate approach, 2 groups at increased or moderately increased risk of neonatal intensive care unit admission were identified, including infants that remained extremely small for all parameters throughout pregnancy and those who had disproportionately smaller femur length and abdominal circumference compared with head circumference. The remaining multivariate trajectory groups did not have an elevated risk of adverse birth outcome relative to appropriate-for-gestational-age controls. CONCLUSION: Latent class group-based trajectory modeling applied to ultrasound measures of fetal growth may help distinguish pathologic vs constitutional growth profiles among newborns born small-for-gestational age. Although trajectories cannot be fully characterized until delivery, limiting the direct clinical application of these methods, they may still contribute to the development of approaches for separating growth restriction from constitutional smallness.

Recreational physical activity before and during pregnancy and placental DNA methylation-an epigenome-wide association study.

BACKGROUND: Physical activity (PA) prior to and during pregnancy may have intergenerational effects on offspring health through placental epigenetic modifications. We are unaware of epidemiologic studies on longitudinal PA and placental DNA methylation. OBJECTIVES: We evaluated the association between PA before and during pregnancy and placental DNA methylation. METHODS: Placental tissues were obtained at delivery and methylation was measured using HumanMethylation450 Beadchips for participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons among 298 participants. Using the Pregnancy Physical Activity Questionnaire, women recalled periconception PA (past 12 mo) at 8-13 wk of gestation and PA since last visit at 4 follow-up visits at 16-22, 24-29, 30-33, and 34-37 wk. We conducted linear regression for associations of PA at each visit with methylation controlling for false discovery rate (FDR). Top 100 CpGs were queried for enrichment of functional pathways using Ingenuity Pathway Analysis. RESULTS: Periconception PA was significantly associated with 1 CpG site. PA since last visit for visits 1-4 was associated with 2, 2, 8, and 0 CpGs (log fold changes ranging from -0.0319 to 0.0080, after controlling for FDR). The largest change in methylation occurred at a site in TIMP2 , which is known to encode a protein critical for vasodilation, placentation, and uterine expansion during pregnancy (log fold change: -0.05; 95% CI: -0.06, -0.03 per metabolic equivalent of task-h/wk at 30-33 wk). Most significantly enriched pathways include cardiac hypertrophy signaling, B-cell receptor signaling, and netrin signaling. Significant CpGs and enriched pathways varied by visit. CONCLUSIONS: Recreational PA in the year prior and during pregnancy was associated with placental DNA methylation. The associated CpG sites varied based on timing of PA. If replicated, the findings may inform the mechanisms underlying the impacts of PA on placenta health. This study was registered at clinicaltrials.gov as NCT00912132.

Infertility treatment associated with childhood asthma and atopy.

STUDY QUESTION: Are children who were conceived with infertility treatment at an increased risk of developing asthma and atopic conditions? SUMMARY ANSWER: Infertility treatment is associated with an elevated risk of asthma and atopic conditions in early and middle childhood, even after adjustment for parental asthma and atopy. WHAT IS KNOWN ALREADY: Asthma and atopic conditions are prevalent in childhood. The development of these conditions may be linked to early life exposures, including the use of infertility treatments. STUDY DESIGN, SIZE, DURATION: Upstate KIDS is a prospective cohort study of singletons and multiples born between 2008 and 2010. A total of 5034 mothers and 6171 children were enrolled and followed up until 2019, and 2056 children participated in the middle childhood follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women reported the fertility agents used to become pregnant on a baseline questionnaire. Treatment was categorized as ART (∼22%) use, ovulation induction via oral/injectable medications with or without IUI (OI/IUI, ∼20%), or no treatment (∼58%). Outcomes were assessed by maternal report on questionnaires in early (up to age 3 years, prevalence 9-28%) and middle (7-9 years, prevalence 10-16%) childhood. Weighted Poisson regression models with robust standard errors were used to analyze the risk of atopic outcomes in relation to infertility treatment exposure. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to children conceived without treatment, children conceived with any infertility treatment were at an increased risk of persistent wheeze by age 3 years (relative risk (RR): 1.66; 95% CI: 1.17, 2.33) with adjustments for parental atopy among other risk factors. Around 7-9 years, children conceived with treatment were more likely to have current asthma (RR: 1.30; 95% CI: 0.98, 1.71), eczema (RR: 1.77; 95% CI: 1.25, 2.49) or be prescribed allergy-related medications (RR: 1.45; 95% CI: 1.06, 1.99). Similar effect sizes were found when examining associations by treatment type (i.e. ART versus OI/IUI). LIMITATIONS, REASONS FOR CAUTION: Childhood outcomes were based on maternal report and are subject to potential misclassification. There was attrition in this study, which limits the precision of our measures of association. WIDER IMPLICATIONS OF THE FINDINGS: Though future research is needed to clarify the mechanisms involved, our findings support that both ART and OI/IUI influences the development of asthma and atopic conditions in the offspring from an early age. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health's Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C, #HHSN275201400013C, #HHSN275201300026I/27500004, #HHSN275201300023I/27500017). The authors have no relevant conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.