Human Epidemiology and RespOnse to SARS-CoV-2 (HEROS): Objectives, Design and Enrollment Results of a 12-City Remote Observational Surveillance Study of Households with Children using Direct-to-Participant Methods.

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

Demographic characteristics, perinatal smoking patterns, and risk for neonatal health complications among pregnant smokers in the United States who begin using electronic cigarettes during pregnancy: A descriptive study using population-based surveillance data.

INTRODUCTION: Health agencies have called for research evaluating e-cigarette (EC) use in supporting prenatal smoking cessation. This study aimed to describe (a) characteristics of smokers who begin using ECs during pregnancy, (b) how frequently smokers reduce or eliminate pre- and post-natal combustible cigarette (CC) use, and (c) risk for neonatal health complications among smokers who initiate ECs during pregnancy. METHODS: Pregnant women using CCs exclusively pre-pregnancy, who participated in a U.S. surveillance study, were classified by their reported late-pregnancy smoking behavior as CC-exclusive users, EC initiators, or quitters. EC initiators were further subclassified as dual users (used both ECs and CCs) or EC replacers (used ECs exclusively). RESULTS: Of 29,505 pregnant smokers, 1.5% reported using ECs during the last 3 pregnancy months. Among them, 29.7% became EC-exclusive users. EC initiators were disproportionately non-Hispanic White. Relative to quitters, EC initiators had lower income, were less likely to be married, have intended pregnancies, receive first-trimester prenatal care, and participate in a federal assistance program. Compared to CC-exclusive users, EC initiators overall, and dual users specifically, were more likely to reduce pre- and post-natal CC usage relative to pre-pregnancy levels. EC initiators' risk for neonatal health complications fell between quitters and CC-exclusive users, though differences were not statistically significant. CONCLUSIONS: Although EC initiators reduced CC use more than CC-exclusive users, only 29.7% reported complete CC cessation, and there was insufficient evidence of reduction in neonatal health complications relative to CC-exclusive users. Currently, ECs should not be considered a viable gestational smoking cessation strategy. IMPLICATIONS: Health agencies have identified a critical need for research evaluating the use of e-cigarettes in supporting prenatal smoking cessation. Using the US Pregnancy Risk Assessment Monitoring System surveillance study data, we provide real-world evidence that prenatal e-cigarette initiation as a smoking cessation tool is used infrequently among pregnant combustible cigarettes smokers. Most using e-cigarettes in the last three months of pregnancy also used combustible cigarettes.

Personalized Infant Risk Prediction for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection Requiring Intensive Care Unit Admission.

Background: Currently, there are no available tools to identify infants at the highest risk of significant morbidity and mortality from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) who would benefit most from RSV prevention products. The objective was to develop and internally validate a personalized risk prediction tool for use among all newborns that uses readily available birth/postnatal data to predict RSV LRTI requiring intensive care unit (ICU) admission. Methods: We conducted a population-based birth cohort study of infants born from 1995 to 2007, insured by the Tennessee Medicaid Program, and who did not receive RSV immunoprophylaxis during the first year of life. The primary outcome was severe RSV LRTI requiring ICU admission during the first year of life. We built a multivariable logistic regression model including demographic and clinical variables available at or shortly after birth to predict the primary outcome. Results: In a population-based sample of 429 365 infants, 713 (0.2%) had severe RSV LRTI requiring ICU admission. The median age of admission was 66 days (interquartile range, 37-120). Our tool, including 19 variables, demonstrated good predictive accuracy (area under the curve, 0.78; 95% confidence interval, 0.77-0.80) and identified infants who did not qualify for palivizumab, based on American Academy of Pediatrics guidelines, but had higher predicted risk levels than infants who qualified (27% of noneligible infants with >0.16% predicted probabilities [lower quartile for eligible infants]). Conclusions: We developed a personalized tool that identified infants at increased risk for severe RSV LRTI requiring ICU admission, expected to benefit most from immunoprophylaxis.

Associations between Smoking and Smoking Cessation during Pregnancy and Newborn Metabolite Concentrations: Findings from PRAMS and INSPIRE Birth Cohorts.

Newborn metabolite perturbations may identify potential biomarkers or mechanisms underlying adverse, smoking-related childhood health outcomes. We assessed associations between third-trimester smoking and newborn metabolite concentrations using the Tennessee Pregnancy Risk Assessment Monitoring System (PRAMS, 2009-2019) as the discovery cohort and INSPIRE (2012-2014) as the replication cohort. Children were linked to newborn screening metabolic data (33 metabolites). Third-trimester smoking was ascertained from birth certificates (PRAMS) and questionnaires (INSPIRE). Among 8600 and 1918 mother-child dyads in PRAMS and INSPIRE cohorts, 14% and 13% of women reported third-trimester smoking, respectively. Third-trimester smoking was associated with higher median concentrations of free carnitine (C0), glycine (GLY), and leucine (LEU) at birth (PRAMS: C0: adjusted fold change 1.11 [95% confidence interval (CI) 1.08, 1.14], GLY: 1.03 [95% CI 1.01, 1.04], LEU: 1.04 [95% CI 1.03, 1.06]; INSPIRE: C0: 1.08 [95% CI 1.02, 1.14], GLY: 1.05 [95% CI 1.01, 1.09], LEU: 1.05 [95% CI 1.01, 1.09]). Smoking cessation (vs. continued smoking) during pregnancy was associated with lower median metabolite concentrations, approaching levels observed in infants of non-smoking women. Findings suggest potential pathways underlying fetal metabolic programming due to in utero smoke exposure and a potential reversible relationship of cessation.

Electronic cigarette use during pregnancy and the risk of adverse birth outcomes: A cross-sectional surveillance study of the US Pregnancy Risk Assessment Monitoring System (PRAMS) population.

BACKGROUND: Research on health effects and potential harms of electronic cigarette (EC) use during pregnancy is limited. We sought to determine the risks of pregnancy EC use on pregnancy-related adverse birth outcomes and assess whether quitting ECs reduces the risks. METHODS: Women with singleton live births who participated in the US Pregnancy Risk Assessment Monitoring System (PRAMS) survey study 2016-2020 were classified into four mutually exclusive groups, by their use of ECs and combustible cigarettes (CCs) during pregnancy: non-use, EC only use, CC only use, and dual use. We determined the risk of preterm birth, low birth weight, and small-for-gestational-age (SGA) by comparing cigarette users to non-users with a modified Poisson regression model adjusting for covariates. In a subset of women who all used ECs prior to pregnancy, we determined whether quitting EC use reduces the risk of preterm birth, low birth weight, and SGA by comparing to those who continued its use. All analyses were weighted to account for the PRAMS survey design and non-response rate. RESULTS: Of the 190,707 women (weighted N = 10,202,413) included, 92.1% reported cigarette non-use, 0.5% EC only use, 6.7% CC only use, and 0.7% dual use during pregnancy. Compared with non-use, EC only use was associated with a significantly increased risk of preterm birth (adjusted risk ratio [aRR]: 1.29, 95% confidence interval [CI]: 1.00, 1.65) and low birth weight (aRR: 1.38, 95%CI: 1.09, 1.75), but not SGA (aRR: 1.04, 95%CI: 0.76, 1.44). Among 7,877 (weighted N = 422,533) women EC users, quitting use was associated with a significantly reduced risk of low birth weight (aRR: 0.76, 95%CI: 0.62, 0.94) and SGA (aRR: 0.77, 95%CI: 0.62, 0.94) compared to those who continued to use ECs during pregnancy. CONCLUSIONS: Pregnancy EC use, by itself or dual use with CC, is associated with preterm birth and low birth weight. Quitting use reduces that risk. ECs should not be considered as a safe alternative nor a viable gestational smoking cessation strategy.

Model-estimated impacts of pediatric respiratory syncytial virus prevention programs in Mali on asthma prevalence.

Background: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) in young children and is associated with subsequent recurrent wheezing illness and asthma (wheeze/asthma). RSV prevention may therefore reduce wheeze/asthma prevalence. Objectives: We estimated the contribution of RSV LRTI and the impact of RSV prevention on recurrent wheeze/asthma in Mali. Methods: We simulated 12 consecutive monthly birth cohorts in Mali and estimated RSV LRTI cases through 2 years and recurrent wheeze/asthma prevalence at 6 years under different RSV prevention scenarios: status quo, seasonal birth-dose extended half-life mAb, and seasonal birth-dose extended half-life mAb followed by 2 doses of pediatric vaccine (mAb + vaccine). We used World Health Organization (WHO) Preferred Product Characteristics for RSV prevention, demographic and RSV epidemiologic data from Mali, regional recurrent wheeze/asthma prevalence, and relative risk of recurrent wheeze/asthma given early childhood RSV LRTI. Results: Among the simulated cohort of 778,680 live births, 10.0% had RSV LRTI by 2 years and 89.6% survived to 6 years. We estimated that 13.4% of all recurrent wheeze/asthma at 6 years was attributable to RSV LRTI. Recurrent wheeze/asthma prevalence at 6 years was 145.0 per 10,000 persons (RSV LRTI attributable) and 1084.2 per 10,000 persons (total). In mAb and mAb + vaccine scenarios, RSV LRTI cases decreased by 11.8% and 44.4%, respectively, and recurrent wheeze/asthma prevalence decreased by 11.8% and 44.4% (RSV LRTI attributable) and 1.6% and 5.9% (total). Conclusion: In Mali, RSV prevention programs may have a meaningful impact on chronic respiratory disease, strengthening the case for investment in RSV prevention.

The Associations of Maternal Health Characteristics, Newborn Metabolite Concentrations, and Child Body Mass Index among US Children in the ECHO Program.

We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with linked newborn screening metabolic data. Maternal health characteristics were ascertained from questionnaires, birth certificates, and medical records. Child BMI was ascertained from medical records and study visits. We used multivariate analysis of variance, followed by multivariable linear/proportional odds regression, to determine maternal health characteristic-newborn metabolite associations. Significant associations were found in discovery and replication cohorts of higher pre-pregnancy BMI with increased C0 and higher maternal age at delivery with increased C2 (C0: discovery: aß 0.05 [95% CI 0.03, 0.07]; replication: aß 0.04 [95% CI 0.006, 0.06]; C2: discovery: aß 0.04 [95% CI 0.003, 0.08]; replication: aß 0.04 [95% CI 0.02, 0.07]). Social Vulnerability Index, insurance, and residence were also associated with metabolite concentrations in a discovery cohort. Associations between metabolites associated with maternal health characteristics and child BMI were modified from 1-3 years (interaction: p < 0.05). These findings may provide insights on potential biologic pathways through which maternal health characteristics may impact fetal metabolic programming and child growth patterns.

Changes in Body Mass Index Among School-Aged Youths Following Implementation of the Healthy, Hunger-Free Kids Act of 2010.

Importance: The prevalence of obesity among youths 2 to 19 years of age in the US from 2017 to 2018 was 19.3%; previous studies suggested that school lunch consumption was associated with increased obesity. The Healthy, Hunger-Free Kids Act of 2010 (HHFKA) strengthened nutritional standards of school-based meals. Objective: To evaluate the association between the HHFKA and youth body mass index (BMI). Design, Setting, and Participants: This cohort study was conducted using data from the Environmental Influences on Child Health Outcomes program, a nationwide consortium of child cohort studies, between January 2005 and March 2020. Cohorts in the US of youths aged 5 to 18 years with reported height and weight measurements were included. Exposures: Full implementation of the HHFKA. Main Outcomes and Measures: The main outcome was annual BMI z-score (BMIz) trends before (January 2005 to August 2016) and after (September 2016 to March 2020) implementation of the HHFKA, adjusted for self-reported race, ethnicity, maternal education, and cohort group. An interrupted time-series analysis design was used to fit generalized estimating equation regression models. Results: A total of 14 121 school-aged youths (7237 [51.3%] male; mean [SD] age at first measurement, 8.8 [3.6] years) contributing 26 205 BMI measurements were included in the study. Overall, a significant decrease was observed in the annual BMIz in the period following implementation of the HHFKA compared with prior to implementation (-0.041; 95% CI, -0.066 to -0.016). In interaction models to evaluate subgroup associations, similar trends were observed among youths 12 to 18 years of age (-0.045; 95% CI, -0.071 to -0.018) and among youths living in households with a lower annual income (-0.038; 95% CI, -0.063 to -0.013). Conclusions and Relevance: In this cohort study, HHFKA implementation was associated with a significant decrease in BMIz among school-aged youths in the US. The findings suggest that school meal programs represent a key opportunity for interventions to combat the childhood obesity epidemic given the high rates of program participation and the proportion of total calories consumed through school-based meals.

Association of citrulline concentration at birth with lower respiratory tract infection in infancy: Findings from a multi-site birth cohort study.

Assessing the association of the newborn metabolic state with severity of subsequent respiratory tract infection may provide important insights on infection pathogenesis. In this multi-site birth cohort study, we identified newborn metabolites associated with lower respiratory tract infection (LRTI) in the first year of life in a discovery cohort and assessed for replication in two independent cohorts. Increased citrulline concentration was associated with decreased odds of LRTI (discovery cohort: aOR 0.83 [95% CI 0.70-0.99], p = 0.04; replication cohorts: aOR 0.58 [95% CI 0.28-1.22], p = 0.15). While our findings require further replication and investigation of mechanisms of action, they identify a novel target for LRTI prevention and treatment.

Human Epidemiology and RespOnse to SARS-CoV-2 (HEROS): Objectives, Design and Enrollment Results of a 12-City Remote Observational Surveillance Study of Households with Children using Direct-to-Participant Methods.

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

Exclusive breast-feeding, the early-life microbiome and immune response, and common childhood respiratory illnesses.

BACKGROUND: The impact of breast-feeding on certain childhood respiratory illnesses remains controversial. OBJECTIVE: We sought to examine the effect of exclusive breast-feeding on the early-life upper respiratory tract (URT) and gut microbiome, the URT immune response in infancy, and the risk of common pediatric respiratory diseases. METHODS: We analyzed data from a birth cohort of healthy infants with prospective ascertainment of breast-feeding patterns and common pediatric pulmonary and atopic outcomes. In a subset of infants, we also characterized the URT and gut microbiome using 16S ribosomal RNA sequencing and measured 9 URT cytokines using magnetic bead-based assays. RESULTS: Of the 1949 infants enrolled, 1495 (76.71%) had 4-year data. In adjusted analyses, exclusive breast-feeding (1) had an inverse dose-response on the ⍺-diversity of the early-life URT and gut microbiome, (2) was positively associated with the URT levels of IFN-α, IFN-γ, and IL-17A in infancy, and (3) had a protective dose-response on the development of a lower respiratory tract infection in infancy, 4-year current asthma, and 4-year ever allergic rhinitis (odds ratio [95% CI] for each 4 weeks of exclusive breast-feeding, 0.95 [0.91-0.99], 0.95 [0.90-0.99], and 0.95 [0.92-0.99], respectively). In exploratory analyses, we also found that the protective association of exclusive breast-feeding on 4-year current asthma was mediated through its impact on the gut microbiome (P = .03). CONCLUSIONS: Our results support a protective causal role of exclusive breast-feeding in the risk of developing a lower respiratory tract infection in infancy and asthma and allergic rhinitis in childhood. They also shed light on potential mechanisms of these associations, including the effect of exclusive breast-feeding on the gut microbiome.

Validation of International Classification of Diseases criteria to identify severe influenza hospitalizations.

In this cohort study of hospitalized patients with linked medical record data, we developed International Classification of Diseases (ICD) criteria that accurately identified laboratory-confirmed, severe influenza hospitalizations (positive predictive value [PPV] 80%, 95% confidence interval [CI] 71-87%), which we validated through medical record documentation. These criteria identify patients with clinically important influenza illness outcomes to inform evaluation of preventive and therapeutic interventions and public health policy recommendations.

Cellular and systemic energy metabolic dysregulation in asthma development-a hypothesis-generating approach.

BACKGROUND: The roles of systemic and airway-specific epithelial energy metabolism in altering the developmental programming of airway epithelial cells (AECs) in early life are poorly understood. OBJECTIVE: Our aim was to assess carbohydrate metabolism in developing AECs among children with and without wheeze and test the association of infant plasma energy biomarkers with subsequent recurrent wheeze and asthma outcomes. METHODS: We measured cellular carbohydrate metabolism in live nasal AECs collected at age 2 years from 15 male subjects with and without a history of wheeze and performed a principal component analysis to visually assess clustering of data on AEC metabolism of glycolitic metabolites and simple sugars. Among 237 children with available year 1 plasma samples, we tested the associations of year 1 plasma energy biomarkers and recurrent wheeze and asthma by using generalized estimating equations and logistic regression. RESULTS: Children with a history of wheeze had lower utilization of glucose in their nasal AECs than did children with no wheeze. Systemically, a higher plasma glucose concentration at year 1 (within the normal range) was associated with decreased odds of asthma at age 5 years (adjusted odds ratio = 0.56; 95% CI = 0.35-0.90). Insulin concentration, glucose-to-insulin ratio, C-peptide concentration, and leptin concentration at year 1 were associated with recurrent wheeze from age 2 years to age 5 years. CONCLUSION: These results suggest that there is significant energy metabolism dysregulation in early life, which likely affects AEC development. These pertubations of epithelial cell metabolism in infancy may have lasting effects on lung development that could render the airway more susceptible to allergic sensitization.

Association between asthma status and prenatal antibiotic prescription fills among women in a Medicaid population.

OBJECTIVE: Pregnant women with asthma have increased frequency of respiratory viral infections and exacerbations. Because of these risks, women with asthma may be subject to increased surveillance during pregnancy and may, therefore, be at increased risk of antibiotic receipt. The objective of this study was to assess the relationship between maternal asthma and outpatient prenatal antibiotic prescription fills to inform antibiotic stewardship. METHODS: We included women who delivered a singleton, term, non-low birthweight, and otherwise healthy infant enrolled in the Tennessee Medicaid Program. Maternal asthma and prenatal antibiotic fills were ascertained from healthcare encounters and outpatient pharmacy claims. We examined the association between maternal asthma and prenatal antibiotic fills using modified Poisson regression. RESULTS: Our study population included 168354 pregnant women, 4% of whom had asthma. Women with asthma had an increased risk of filling at least one prenatal antibiotic prescription (adjusted risk ratio [aRR] 1.27, 95% confidence interval [CI] 1.25-1.28) and had an increased number of fills during pregnancy (aRR 1.54, 95% CI 1.51-1.57) compared to women without asthma. Among those who filled at least one antibiotic prescription, women with asthma had earlier first prenatal antibiotic prescription fill and increased likelihood of filling at least one course of broad-spectrum antibiotics during pregnancy (versus narrow-spectrum). CONCLUSIONS: Pregnant women with asthma had more outpatient antibiotic prescription fills than pregnant women without asthma. These findings highlight that pregnant women with asthma disproportionately fill more antibiotic prescriptions during pregnancy, providing data that may inform antibiotic stewardship.

Clinical and laboratory features of patients with focal lymphocytic sialadenitis on minor salivary gland biopsy for sicca symptoms: A single-center experience.

ABSTRACT: Minor salivary gland biopsy (MSGB) is often used in patients lacking specific autoantibodies (seronegative patients) to confirm the presence of focal lymphocytic sialadenitis (FLS), which would suggest a diagnosis of Sjogren syndrome. There are no current guidelines indicating when to refer patients for MSGB. The objective of our study was to ascertain distinguishing clinical and laboratory features among individuals with sicca symptoms based on their serologic and histopathologic status, and to identify factors associated with FLS.Using a cross-sectional study design, patients ages 18 years or older with sicca symptoms who had MSGB performed at the University of Iowa from January 2000 to December 2016 were selected for chart reviews. The clinical and laboratory features of patients with and without FLS were analyzed using exact univariate and multivariable logistic regression, with Bonferroni correction for multiple comparisons.We identified 177 patients who had MSGB performed and available clinical data. A total of 133 patients had FLS, 37 (27.8%) were seropositive (positive-anti-Sjogren syndrome type A [SSA] and/or anti-Sjogren syndrome type B) and 96 (72.2%) were seronegative. Dry eyes (unadjusted odds ratio [OR]: 5.17, 95% confidence interval [CI]: 1.16-26.30; adjusted odds ratio [aOR]: 12.58, 95% CI: 1.70-167.77) and the presence of anti-SSA (OR: 7.16, 95% CI: 1.70-64.24; aOR: 8.82, 95% CI: 1.73-93.93) were associated with FLS. Smoking (aOR 0.27, 95% CI: 0.11-0.63) and antihistamine use (aOR 0.23, 95% CI: 0.08-0.63) were associated with lower odds of FLS.Our study suggests that dry eyes and anti-SSA positivity are associated with FLS. Smoking and antihistamine use were associated with lower odds of FLS. In the appropriate clinical context, seronegative patients with sicca symptoms and no smoking history could be considered for MSGB. A thorough medication and smoking history should be performed in all patients before referral for MSGB.

Assessing the strength of evidence for a causal effect of respiratory syncytial virus lower respiratory tract infections on subsequent wheezing illness: a systematic review and meta-analysis.

BACKGROUND: Although a positive association has been established, it is unclear whether lower respiratory tract infections (LRTIs) with respiratory syncytial virus (RSV) cause chronic wheezing illnesses. If RSV-LRTI were causal, we would expect RSV-LRTI prevention to reduce the incidence of chronic wheezing illnesses in addition to reducing acute disease. We aimed to evaluate the strength of evidence for a causal effect of RSV-LRTI on subsequent chronic wheezing illness to inform public health expectations for RSV vaccines. METHODS: We did a systematic review and meta-analysis of observational studies evaluating the association between RSV-LRTI and subsequent wheezing illness (exposure studies) and studies evaluating the association between RSV immunoprophylaxis and subsequent wheezing illness (immunoprophylaxis studies). Exposure studies were included if the exposure group members had an LRTI with laboratory-confirmed RSV and if the exposure ascertainment period began before 2 years of age and ended before 5 years of age. We required a wash-out period of more than 30 days between the index RSV-LRTI and the outcome measurement to allow for resolution of the acute illness. Comparisons between RSV-LRTI and non-RSV-LRTI were not included. Immunoprophylaxis studies were included if they measured the association with subsequent wheezing illness relative to a control group, either in a randomised controlled trial (RCT) or an observational design. For the immunoprophylaxis drugs in question, we required evidence of efficacy in targeting RSV-LRTI from at least one RCT to ensure biological plausibility. All variations of wheezing illness were combined into a single outcome that refers broadly to asthma or any other respiratory illness with wheezing symptoms. Ovid MEDLINE and Embase databases were searched from inception up to Aug 28, 2018. We evaluated whether data from exposure studies could provide evidence against the most viable non-causal theory that RSV-LRTI is a marker of respiratory illness susceptibility rather than a causal factor. Additionally, we tested whether RSV immunoprophylaxis reduces the odds of subsequent wheezing illnesses. We used a random-effects modelling framework and, to accommodate studies providing multiple correlated estimates, robust variance estimation meta-regressions. Meta-regression coefficients (b) quantify differences between exposure and comparator groups on the loge odds ratio (loge OR) scale. FINDINGS: From 14 235 records we identified 57 eligible articles that described 42 studies and provided 153 effect estimates. 35 studies estimated the direct effect of RSV-LRTI on wheezing illnesses (exposure studies) and eight evaluated the effect of RSV immunoprophylaxis (immunoprophylaxis studies). Exposure studies that adjusted for genetic influences yielded a smaller mean adjusted OR estimate (aOR+ 2·45, 95% CI 1·23-4·88) compared with those that did not (4·17, 2·36-7·37), a significant difference (b 0·53, 95% CI 0·04-1·02). Infants who were not protected with RSV immunoprophylaxis tended to have higher odds of subsequent wheezing illness, as we would expect if RSV-LRTI were causal, but the effect was not significant (OR+ 1·21, 95% CI 0·73-1·99). There was generally a high threat of confounding bias in the observational studies. Additionally, in both the observational studies and immunoprophylaxis RCTs, there was high risk of bias due to missing outcome data. INTERPRETATION: Our findings, limited to exposure and immunoprophylaxis studies, do not support basing policy decisions on an assumption that prevention of RSV-LRTI will reduce recurrent chronic wheezing illnesses. FUNDING: Bill & Melinda Gates Foundation.

Early pregnancy prediction of gestational diabetes mellitus risk using prenatal screening biomarkers in nulliparous women.

AIMS: To evaluate the clinical utility of first and second trimester prenatal screening biomarkers for early pregnancy prediction of gestational diabetes mellitus (GDM) risk in nulliparous women. METHODS: We conducted a population-based cohort study of nulliparous women participating in the California Prenatal Screening Program from 2009 to 2011 (n = 105,379). GDM was ascertained from hospital discharge records or birth certificates. Models including maternal characteristics and prenatal screening biomarkers were developed and validated. Risk stratification and reclassification were performed to assess clinical utility of the biomarkers. RESULTS: Decreased levels of first trimester pregnancy-associated plasma protein A (PAPP-A) and increased levels of second trimester unconjugated estriol (uE3) and dimeric inhibin A (INH) were associated with GDM. The addition of PAPP-A only and PAPP-A, uE3, and INH to maternal characteristics resulted in small, yet significant, increases in area under the receiver operating characteristic curve (AUC) (maternal characteristics only: AUC 0.714 (95% CI 0.703-0.724), maternal characteristics + PAPP-A: AUC 0.718 (95% CI 0.707-0.728), maternal characteristics + PAPP-A, uE3, and INH: AUC 0.722 (0.712-0.733)); however, no net improvement in classification was observed. CONCLUSIONS: PAPP-A, uE3, and INH have limited clinical utility for prediction of GDM risk in nulliparous women. Utility of other readily accessible clinical biomarkers in predicting GDM risk warrants further investigation.