Development and Validation of a Novel Placental DNA Methylation Biomarker of Maternal Smoking during Pregnancy in the ECHO Program.

BACKGROUND: Maternal cigarette smoking during pregnancy (MSDP) is associated with numerous adverse health outcomes in infants and children with potential lifelong consequences. Negative effects of MSDP on placental DNA methylation (DNAm), placental structure, and function are well established. OBJECTIVE: Our aim was to develop biomarkers of MSDP using DNAm measured in placentas (N=96), collected as part of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function double-blind, placebo-controlled randomized clinical trial conducted between 2012 and 2016. We also aimed to develop a digital polymerase chain reaction (PCR) assay for the top ranking cytosine-guanine dinucleotide (CpG) so that large numbers of samples can be screened for exposure at low cost. METHODS: We compared the ability of four machine learning methods [logistic least absolute shrinkage and selection operator (LASSO) regression, logistic elastic net regression, random forest, and gradient boosting machine] to classify MSDP based on placental DNAm signatures. We developed separate models using the complete EPIC array dataset and on the subset of probes also found on the 450K array so that models exist for both platforms. For comparison, we developed a model using CpGs previously associated with MSDP in placenta. For each final model, we used model coefficients and normalized beta values to calculate placental smoking index (PSI) scores for each sample. Final models were validated in two external datasets: the Extremely Low Gestational Age Newborn observational study, N=426; and the Rhode Island Children's Health Study, N=237. RESULTS: Logistic LASSO regression demonstrated the highest performance in cross-validation testing with the lowest number of input CpGs. Accuracy was greatest in external datasets when using models developed for the same platform. PSI scores in smokers only (n=72) were moderately correlated with maternal plasma cotinine levels. One CpG (cg27402634), with the largest coefficient in two models, was measured accurately by digital PCR compared with measurement by EPIC array (R2=0.98). DISCUSSION: To our knowledge, we have developed the first placental DNAm-based biomarkers of MSDP with broad utility to studies of prenatal disease origins. https://doi.org/10.1289/EHP13838.

Presurgical pulmonary function tests in the first few days of life in neonates with congenital heart disease, a pilot study.

OBJECTIVE: To compare early pulmonary function tests (PFTs) in neonates with critical congenital heart disease (CHD) compared to a historical reference group. DESIGN: Infants ≥ 37 weeks gestation with critical CHD were studied within the first few days of life, prior to cardiac surgery, and compared to data from a published reference group of healthy term neonates without CHD, studied at the same institution. Passive respiratory resistance (Rrs) and compliance (Crs) were measured with the single breath occlusion technique following specific acceptance criteria. The study was powered for a 30% difference in Rrs. RESULTS: PFTs in 24 infants with CHD were compared to 31 historical reference infants. There was no difference in the Rrs between the groups. The infants with CHD had a significantly decreased Crs (1.02 ± 0.26 mL/cmH2O/kg versus 1.32 ± 0.36; (p < 0.05; mean ± SD)). CONCLUSIONS: Further prospective studies are required to quantify early PFTs in infants with CHD of different phenotypes.

Risk of Adverse Neonatal Outcomes After Combined Prenatal Cannabis and Nicotine Exposure.

Importance: The prevalence of cannabis use in pregnancy is rising and is associated with adverse perinatal outcomes. In parallel, combined prenatal use of cannabis and nicotine is also increasing, but little is known about the combined impact of both substances on pregnancy and offspring outcomes compared with each substance alone. Objective: To assess the perinatal outcomes associated with combined cannabis and nicotine exposure compared with each substance alone during pregnancy. Design, Setting, and Participants: This retrospective population-based cohort study included linked hospital discharge data (obtained from the California Department of Health Care Access and Information) and vital statistics (obtained from the California Department of Public Health) from January 1, 2012, through December 31, 2019. Pregnant individuals with singleton gestations and gestational ages of 23 to 42 weeks were included. Data were analyzed from October 14, 2023, to March 4, 2024. Exposures: Cannabis-related diagnosis and prenatal nicotine product use were captured using codes from International Classification of Diseases, Ninth Revision, Clinical Modification, and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification. Main Outcome and Measures: The main outcomes were infant and neonatal death, infants small for gestational age, and preterm delivery. Results were analyzed by multivariable Poisson regression models. Results: A total of 3 129 259 pregnant individuals were included (mean [SD] maternal age 29.3 [6.0] years), of whom 23 007 (0.7%) had a cannabis-related diagnosis, 56 811 (1.8%) had a nicotine-use diagnosis, and 10 312 (0.3%) had both in pregnancy. Compared with nonusers, those with cannabis or nicotine use diagnoses alone had increased rates of infant (0.7% for both) and neonatal (0.3% for both) death, small for gestational age (14.3% and 13.7%, respectively), and preterm delivery (<37 weeks) (12.2% and 12.0%, respectively). Moreover, risks in those with both cannabis and nicotine use were higher for infant death (1.2%; adjusted risk ratio [ARR], 2.18 [95% CI, 1.82-2.62]), neonatal death (0.6%; ARR, 1.76 [95% CI, 1.36-2.28]), small for gestational age (18.0%; ARR, 1.94 [95% CI, 1.86-2.02]), and preterm delivery (17.5%; ARR, 1.83 [95% CI, 1.75-1.91]). Conclusions and Relevance: These findings suggest that co-occurring maternal use of cannabis and nicotine products in pregnancy is associated with an increased risk of infant and neonatal death and maternal and neonatal morbidity compared with use of either substance alone. Given the increasing prevalence of combined cannabis and nicotine use in pregnancy, these findings can help guide health care practitioners with preconception and prenatal counseling, especially regarding the benefits of cessation.

Vitamin C Supplementation Among Pregnant Smokers and Airway Function Trajectory in Offspring: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial analyzes the association of vitamin C supplementation in women who smoked during pregnancy with airway function trajectory in their offspring at 4 to 6 years of age.

Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age.

BACKGROUND: We previously reported in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers is associated with improved respiratory outcomes that persist through 5 years of age. The objective of this study was to assess whether buccal cell DNA methylation (DNAm), as a surrogate for airway epithelium, is associated with vitamin C supplementation, improved lung function, and decreased occurrence of wheeze. METHODS: We conducted epigenome-wide association studies (EWAS) using Infinium MethylationEPIC arrays and buccal DNAm from 158 subjects (80 placebo; 78 vitamin C) with pulmonary function testing (PFT) performed at the 5-year visit. EWAS were performed on (1) vitamin C treatment, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25-75), and (3) offspring wheeze. Models were adjusted for sex, race, study site, gestational age at randomization (≤ OR > 18 weeks), proportion of epithelial cells, and latent covariates in addition to child length at PFT in EWAS for FEF25-75. We considered FDR p < 0.05 as genome-wide significant and nominal p < 0.001 as candidates for downstream analyses. Buccal DNAm measured in a subset of subjects at birth and near 1 year of age was used to determine whether DNAm signatures originated in utero, or emerged with age. RESULTS: Vitamin C treatment was associated with 457 FDR significant (q < 0.05) differentially methylated CpGs (DMCs; 236 hypermethylated; 221 hypomethylated) and 53 differentially methylated regions (DMRs; 26 hyper; 27 hypo) at 5 years of age. FEF25-75 was associated with one FDR significant DMC (cg05814800), 1,468 candidate DMCs (p < 0.001), and 44 DMRs. Current wheeze was associated with 0 FDR-DMCs, 782 candidate DMCs, and 19 DMRs (p < 0.001). In 365/457 vitamin C FDR significant DMCs at 5 years of age, there was no significant interaction between time and treatment. CONCLUSIONS: Vitamin C supplementation to pregnant smokers is associated with buccal DNA methylation in offspring at 5 years of age, and most methylation signatures appear to be persistent from the prenatal period. Buccal methylation at 5 years was also associated with current lung function and occurrence of wheeze, and these functionally associated loci are enriched for vitamin C associated loci. Clinical trial registration ClinicalTrials.gov, NCT01723696 and NCT03203603.

The Role of Lung Function in Determining Which Children Develop Asthma.

Longitudinal studies have demonstrated that altered indices of airway function, assessed shortly after birth, are a risk factor for the subsequent development of wheezing illnesses and asthma, and that these indices predict airway size and airway wall thickness in adult life. Pre- and postnatal factors that directly alter early airway function, such as extreme prematurity and cigarette smoke, may continue to affect airway function and, hence, the risks for wheeze and asthma. Early airway function and an associated asthma risk may also be indirectly influenced by immune system responses, respiratory viruses, the airway microbiome, genetics, and epigenetics, especially if they affect airway epithelial dysfunction. Few if any interventions, apart from smoking avoidance, have been proven to alter the risks of developing asthma, but vitamin C supplementation to pregnant smokers may help decrease the effects of in utero smoke on offspring lung function. We conclude that airway size and the factors influencing this play an important role in determining the risk for asthma across the lifetime. Progress in asthma prevention is long overdue and this may benefit from carefully designed interventions in well-phenotyped longitudinal birth cohorts with early airway function assessments monitored through to adulthood.

Effect of Vitamin C Supplementation for Pregnant Smokers on Offspring Airway Function and Wheeze at Age 5 Years: Follow-up of a Randomized Clinical Trial.

Importance: Vitamin C supplementation (500 mg/d) for pregnant smokers has been reported to increase offspring airway function as measured by forced expiratory flow (FEF) through age 12 months; however, its effects on airway function at age 5 years remain to be assessed. Objective: To assess whether vitamin C supplementation in pregnant smokers is associated with increased and/or improved airway function in their offspring at age 5 years and whether vitamin C decreases the occurrence of wheeze. Design, Setting, and Participants: This study followed up the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) double-blind, placebo-controlled randomized clinical trial conducted at 3 centers in the US (in Oregon, Washington, and Indiana) between 2012 and 2016. Investigators and participants remain unaware of the treatment assignments. Forced expiratory flow measurements at age 5 years were completed from 2018 to 2021. Interventions: Pregnant smokers were randomized to vitamin C (500 mg/d) or placebo treatment. Main Outcomes and Measures: The primary outcome was the prespecified measurement of FEF between 25% and 75% expired volume (FEF25-75) by spirometry at age 5 years. Secondary outcomes included FEF measurements at 50% and 75% of expiration (FEF50 and FEF75), forced expiratory volume in 1 second (FEV1), and occurrence of wheeze. Results: Of the 251 pregnant smokers included in this study, 125 (49.8%) were randomized to vitamin C and 126 (50.2%) were randomized to placebo. Of 213 children from the VCSIP trial who were reconsented into this follow-up study, 192 (90.1%) had successful FEF measurements at age 5 years; 212 (99.5%) were included in the analysis of wheeze. Analysis of covariance demonstrated that offspring of pregnant smokers allocated to vitamin C compared with placebo had 17.2% significantly higher mean (SE) measurements of FEF25-75 at age 5 years (1.45 [0.04] vs 1.24 [0.04] L/s; adjusted mean difference, 0.21 [95% CI, 0.13-0.30]; P < .001). Mean (SE) measurements were also significantly increased by 14.1% for FEF50 (1.59 [0.04] vs 1.39 [0.04] L/s; adjusted mean difference, 0.20 [95% CI, 0.11-0.30]; P < .001), 25.9% for FEF75 (0.79 [0.02] vs 0.63 [0.02] L/s; 0.16 [95% CI, 0.11-0.22]; P < .001), and 4.4% for FEV1 (1.13 [0.02] vs 1.09 [0.02] L; 0.05 [95% CI, 0.01-0.09]; P = .02). In addition, offspring of pregnant smokers randomized to vitamin C had significantly decreased wheeze (28.3% vs 47.2%; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003). Conclusions and Relevance: In this follow-up study of offspring of pregnant smokers randomized to vitamin C vs placebo, vitamin C supplementation during pregnancy resulted in significantly increased airway function of offspring at age 5 years and significantly decreased the occurrence of wheeze. These findings suggest that vitamin C supplementation for pregnant smokers may decrease the effects of smoking in pregnancy on childhood airway function and respiratory health. Trial Registration: ClinicalTrials.gov Identifier: NCT03203603.

Characteristics of Individuals in the United States Who Used Opioids During Pregnancy.

Background: Opioid use has disproportionally impacted pregnant people and their fetuses. Previous studies describing opioid use among pregnant people are limited by geographic location, type of medical coverage, and small sample size. We described characteristics of a large, diverse group of pregnant people who were enrolled in the Environmental Influences on Child Health Outcomes (ECHO) Program, and determined which characteristics were associated with opioid use during pregnancy. Materials and Methods: Cross-sectional data obtained from 21,905 pregnancies of individuals across the United States enrolled in the ECHO between 1990 and 2021 were analyzed. Medical records, laboratory testing, and self-report were used to determine opioid-exposed pregnancies. Multiple imputation methods using fully conditional specification with a discriminant function accounted for missing characteristics data. Results: Opioid use was present in 2.8% (n = 591) of pregnancies. The majority of people who used opioids in pregnancy were non-Hispanic White (67%) and had at least some college education (69%). Those who used opioids reported high rates of alcohol use (32%) and tobacco use (39%) during the pregnancy; although data were incomplete, only 5% reported heroin use and 86% of opioid use originated from a prescription. After adjustment, non-Hispanic White race, pregnancy during the years 2010-2012, higher parity, tobacco use, and use of illegal drugs during pregnancy were each significantly associated with opioid use during pregnancy. In addition, maternal depression was associated with increased odds of opioid use during pregnancy by more than two-fold (adjusted odds ratio 2.42, 95% confidence interval: 1.95-3.01). Conclusions: In this large study of pregnancies from across the United States, we found several factors that were associated with opioid use among pregnant people. Further studies examining screening for depression and polysubstance use may be useful for targeted interventions to prevent detrimental opioid use during pregnancy, while further elucidation of the reasons for use of prescription opioids during pregnancy should be further explored.

Perioperative Improvement in Pulmonary Function in Infants with Congenital Diaphragmatic Hernia.

OBJECTIVE: The objective of this study was to compare serial changes in pulmonary function in contemporary infants with congenital diaphragmatic hernia managed with a gentle ventilation approach. STUDY DESIGN: Observational cohort, single-center study of infants ≥350/7 weeks gestation at delivery with congenital diaphragmatic hernia. Functional residual capacity (FRC), passive respiratory compliance, and passive respiratory resistance were measured presurgical and postsurgical repair and within 2 weeks of discharge. A 1-way analysis of variance for repeated measures was used to evaluate the change in FRC, passive respiratory compliance, and passive respiratory resistance over these repeated measures. RESULTS: Twenty-eight infants were included in the analysis with a mean gestational age of 38.3 weeks and birth weight of 3139 g. We found a significant increase in FRC across the 3 time points (mean in mL/kg [SD]: 10.9 [3.6] to 18.5 [5.2] to 24.2 [4.4]; P < .0001). There was also a significant increase in passive respiratory compliance and decrease in passive respiratory resistance. In contrast to a previous report, there were survivors in the current cohort with a preoperative FRC of <9 mL/kg. The mean FRC measured at discharge was in the range considered within normal limits. Sixteen infants had prenatal measurements of the lung-to-head ratio, but there was no relationship between the lung-to-head ratio and preoperative or postoperative FRC measurements. CONCLUSIONS: Infants with congenital diaphragmatic hernia demonstrate significant increases in FRC and improvements in respiratory mechanics measured preoperatively and postoperatively and at discharge. We speculate these improvements are due to the surgical resolution of the mechanical obstruction to lung recruitment and that after achieving preoperative stability, repair should not be delayed given these demonstrable postoperative improvements.

Sleep and Executive Functioning in Pediatric Traumatic Brain Injury Survivors after Critical Care.

Over 50,000 children are hospitalized annually for traumatic brain injury (TBI) and face long-term cognitive morbidity. Over 50% develop sleep/wake disturbances (SWDs) that can affect brain development and healing. We hypothesized SWDs would portend worse executive function outcomes in children aged 3−18 years with TBI 1−3 months after hospital discharge. SWDs were defined using the Sleep Disturbances Scale for Children (t-scores ≥ 60). Outcomes included the Global Executive Composite (GEC, t-score) from the Behavior Rating Inventory of Executive Function, Second and Preschool Editions, and multiple objective executive function assessments combined through Principal Components Analysis into a Neurocognitive Index (NCI, z-score). Multiple linear regression evaluated associations between SWDs and executive function outcomes, controlling for covariates. Among 131 children, 68% had clinically significant SWDs, which were associated with significantly worse median scores on the GEC (56 vs. 45) and NCI (−0.02 vs. 0.42; both p < 0.05). When controlling for baseline characteristics and injury severity in multivariable analyses, SWDs were associated with worse GEC (ß-coefficient = 7.8; 95% Confidence Interval = 2.5, 13.1), and worse NCI (ß-coefficient = −0.4; 95% Confidence Interval = −0.8, −0.04). SWDs in children with TBI are associated with worse executive function outcomes after hospital discharge, and may serve as modifiable targets to improve outcomes.

Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes.

BACKGROUND: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes. RESULTS: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers. CONCLUSIONS: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696 .

Pulmonary Function Tests in Very Low Birth Weight Infants Screened for Pulmonary Hypertension: A Pilot Study.

OBJECTIVE: To compare pulmonary function tests (PFTs), specifically respiratory system resistance (Rrs) and compliance (Crs), in very low birth weight (VLBW) infants with and without pulmonary hypertension. STUDY DESIGN: Infants were included who underwent PFTs at 34-38 weeks postmenstrual age (PMA) as part of our pulmonary hypertension screening guidelines for infants born at ≤1500 g requiring respiratory support at ≥34 weeks PMA. One pediatric cardiologist reviewed and estimated right ventricular or pulmonary arterial pressure and defined pulmonary hypertension as an estimated pulmonary arterial pressure or right ventricular pressure greater than one-half the systemic pressure. Rrs and Crs were measured with the single breath occlusion technique and functional residual capacity with the nitrogen washout method according to standardized criteria. RESULTS: Twelve VLBW infants with pulmonary hypertension and 39 without pulmonary hypertension were studied. Those with pulmonary hypertension had significantly lower birth weight and a trend toward a lower gestational age. There were no other demographic differences between the groups. The infants with pulmonary hypertension had significantly higher Rrs (119 vs 78 cmH2O/L/s; adjusted P = .012) and significantly lower Crs/kg (0.71 vs 0.92 mL/cmH2O/kg; P = .04). CONCLUSIONS: In this pilot study of VLBW infants screened for pulmonary hypertension at 34-38 weeks PMA, those with pulmonary hypertension had significantly increased Rrs and decreased Crs compared with those without pulmonary hypertension. Additional studies are needed to further phenotype infants with evolving BPD and pulmonary hypertension.

Maternal Prenatal Hair Cortisol Is Associated with Child Wheeze among Mothers and Infants with Tobacco Smoke Exposure and Who Face High Socioeconomic Adversity.

The association of co-occurring prenatal stress and tobacco exposures on childhood wheezing and asthma are not well established. In this study, we compared maternal prenatal hair cortisol concentration (HCC) to the maternal report of infant wheezing (y/n) in the first year of life among mother-infant dyads exposed to tobacco smoke and socioeconomic adversity. Data were obtained from the Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function study. Maternal adversity was defined by the level of education, household income, and health insurance provider. Hair was collected at delivery, representing average circulating third-trimester cortisol levels. HCC was log transformed and dichotomized into high/low cortisol groups that were placed into a multivariate model predicting wheeze. Subjects (n = 132) were primarily White with ≤high school education and receiving government-provided health insurance. Forty-five percent of infants wheezed. Average HCC was 3.39 pg/mg hair. Women with HCC > 3.55 pg/mg were more than twice as likely to report having a child who wheezed (odds ratio 2.56, 95% confidence interval 1.22-5.40; p = 0.01), adjusting for insurance provider and maternal asthma. Among this sample of dyads with prenatal smoke exposure, elevated maternal HCC was associated with child wheeze that was not diminished after consideration of covariates.

Hair and nail nicotine levels of mothers and their infants as valid biomarkers of exposure to intrauterine tobacco smoke.

INTRODUCTION: Tobacco use remains the single most modifiable cause of adverse pregnancy outcomes. It is crucial to be able to accurately quantify the burden of tobacco exposure on both the mother and fetus to have better measures of efficacy with interventions being studied. METHODS: This is a descriptive and exploratory study conducted within a randomized controlled trial. Pregnant smoking and non-smoking women were followed from ≤22 weeks' gestation through delivery with monthly maternal smoking questionnaires, urine cotinine levels, and collection of maternal and infant hair and nail samples, at delivery. Nicotine was extracted and measured (ng/mg) using high-performance liquid chromatography with electrochemical detection. RESULTS: Forty-six mother-infant dyads (34 pregnant smokers and 12 pregnant non-smokers) had successful completion of maternal and infant hair and nails samples. The median hair nicotine levels of the smoking mothers and their infants was significantly higher than those of the non-smokers (1.015 vs 0.037 ng/ mg, p<0.05 for the mothers; 0.445 vs 0.080 ng/mg, p<0.01 for the infants). Similarly, the median nail nicotine levels for smoking mothers and their infants were significantly higher than the non-smokers (2.130 vs 0.056 ng/mg, p<0.01 for the mothers; 0.594 vs 0.132 ng/mg, p<0.05 for the infants). We found a moderate but significant correlation between maternal hair and nail nicotine (r=0.64, p<0.001), infant hair and nail nicotine (r=0.64; p<0.001), maternal and infant hair nicotine (r=0.61, p<0.001), and maternal and infant nail nicotine levels (r=0.58, p<0.001). CONCLUSIONS: Our study shows that both infant hair and nail nicotine levels are valid biomarkers of intrauterine tobacco smoke exposure, and can be used to identify prenatal smoke exposure, correlating well with the level of maternal nicotine exposure.

Prenatal and Childhood Tobacco Smoke Exposure Are Associated With Sleep-Disordered Breathing Throughout Early Childhood.

OBJECTIVE: To determine whether prenatal and childhood tobacco smoke exposure (TSE) are each independently associated with mild sleep-disordered breathing (SDB) symptoms throughout early childhood, and whether the association between childhood TSE and SDB differs according to the level of prenatal exposure. METHODS: Longitudinal cohort study, using data from the Avon Longitudinal Study of Parents and Children, a population-based birth cohort from the United Kingdom. Primary exposures were repeated measures of mother-reported prenatal and childhood TSE through age 7 years. Outcomes were mother-reported measures of mild SDB symptoms, including snoring, mouth breathing, and witnessed apnea, repeated annually through age 7 years. RESULTS: A total of 12,030 children were followed for a median duration of 7 years. About 24.2% were exposed to prenatal tobacco smoke, 46.2% were exposed at least once in childhood, and 20.6% were exposed during both periods. Both prenatal and childhood TSE were associated with SDB symptoms throughout early childhood (adjusted OR [aOR] for any prenatal TSE 1.23; 95% confidence interval [CI] 1.08, 1.40; aOR for any childhood TSE 1.17; 95% CI 1.06, 1.29). We observed a dose-response effect between TSE and SBD symptoms, and found evidence of effect modification for those exposed during both time periods (combined high level exposure both prenatally and during childhood: aOR snoring 2.43 [95% CI 1.50, 3.93], aOR apnea 2.65 [95% CI 1.46, 4.82]). CONCLUSIONS: Prenatal and childhood TSE were both independently associated with mild SDB symptoms throughout early childhood in a dose-dependent manner, further supporting the critical importance of maintaining a tobacco-free environment throughout gestation and childhood.

Pulmonary function in extremely low birth weight infants with bronchopulmonary dysplasia before hospital discharge.

OBJECTIVE: To compare pulmonary function in extremely low birth weight (ELBW) infants with bronchopulmonary dysplasia (BPD) studied at 34-36 weeks postmenstrual age (PMA) with a reference group of "healthy" infants born at 34-36 weeks. We hypothesized that ELBW infants have decreased functional residual capacity (FRC) and respiratory compliance (Crs). STUDY DESIGN: Pulmonary function testing was performed at 34-36 weeks PMA in infants with BPD and within 96 h of age in infants delivered at 34-36 weeks. RESULTS: Twenty BPD patients and 20 healthy infants were studied. FRC (18.9 versus 26.2 mL/kg; adjusted 95% CI 5.0, 10.9; P < 0.001) and Crs (0.80 versus 1.29-mL/cm H2O/kg; 95% CI 0.31, 0.71; P < 0.001) were decreased in BPD patients. Respiratory resistance was increased in BPD patients. CONCLUSIONS: ELBW infants with BPD have decreased pulmonary function compared to healthy infants delivered at 34-36 weeks. This suggests that infants with BPD have smaller lung volumes.

Trajectories of Lung Function in Infants and Children: Setting a Course for Lifelong Lung Health.

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.

Vitamin C to Pregnant Smokers Persistently Improves Infant Airway Function to 12†Months of Age: A Randomised Trial.

BACKGROUND: Vitamin C (500 mg·day-1) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported. OBJECTIVE: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age. METHODS: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day-1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance. RESULTS: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec-1 for FEF75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec-1 for FEF50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec-1 for FEF25-75 (95% CI, 9.7 to 100.5; p=0.013). CONCLUSIONS: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway.

Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE).

BACKGROUND: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown. METHODS: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3-14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF). RESULTS: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls. CONCLUSIONS: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.