Prenatal Exposure to Ambient Air Pollution and Epigenetic Aging at Birth in Newborns.

In utero air pollution exposure has been associated with adverse birth outcomes, yet effects of air pollutants on regulatory mechanisms in fetal growth and critical windows of vulnerability during pregnancy are not well understood. There is evidence that epigenetic alterations may contribute to these effects. DNA methylation (DNAm) based age estimators have been developed and studied extensively with health outcomes in recent years. Growing literature suggests environmental factors, such as air pollution and smoking, can influence epigenetic aging. However, little is known about the effect of prenatal air pollution exposure on epigenetic aging. In this study, we leveraged existing data on prenatal air pollution exposure and cord blood DNAm from 332 mother-child pairs in the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), two pregnancy cohorts enrolling women who had a previous child diagnosed with autism spectrum disorder, to assess the relationship of prenatal exposure to air pollution and epigenetic aging at birth. DNAm age was computed using existing epigenetic clock algorithms for cord blood tissue-Knight and Bohlin. Epigenetic age acceleration was defined as the residual of regressing chronological gestational age on DNAm age, accounting for cell type proportions. Multivariable linear regression models and distributed lag models (DLMs), adjusting for child sex, maternal race/ethnicity, study sites, year of birth, maternal education, were completed. In the single-pollutant analysis, we observed exposure to PM2.5, PM10, and O3 during preconception period and pregnancy period were associated with decelerated epigenetic aging at birth. For example, pregnancy average PM10 exposure (per 10 unit increase) was associated with epigenetic age deceleration at birth (weeks) for both Knight and Bohlin clocks (ß = -0.62, 95% CI: -1.17, -0.06; ß = -0.32, 95% CI: -0.63, -0.01, respectively). Weekly DLMs revealed that increasing PM2.5 during the first trimester and second trimester were associated with decelerated epigenetic aging and that increasing PM10 during the preconception period was associated with decelerated epigenetic aging, using the Bohlin clock estimate. Prenatal ambient air pollution exposure, particularly in early and mid-pregnancy, was associated with decelerated epigenetic aging at birth.

The association of inborn status and resource utilization among neonates who received extracorporeal membrane oxygenation.

BACKGROUND: Many studies have established that extracorporeal membrane oxygenation (ECMO) can be a cost-effective treatment in some populations, but limited data exist on which factors are associated with length of stay (LOS) and total hospital costs. This study aimed to determine if inborn (i.e., cared for in their birth hospitals) neonates who receive ECMO have different resource utilization and outcomes compared to outborn (i.e., not cared for in their birth hospitals) neonates who receive ECMO. METHODS: A retrospective cohort study was conducted using the Healthcare Cost and Utilization Project's Kids' Inpatient Database from 1997-2012. Neonates (infants, <28 days) placed on ECMO were categorized as either inborn or outborn. Salient clinical characteristics were compared between groups. A multivariable analysis was performed to identify the factors associated with length of stay (LOS), total hospital costs, and mortality in these two patient populations. RESULTS: Of 5,152 neonates receiving ECMO, 800 were inborn and 4,352 were outborn. Inborn neonates were more frequently diagnosed with cardiac-related diagnoses (70.5% vs 62.1%, p < 0.001). After adjusting for demographics and hospital-level factors, inborn neonates had longer hospital LOS (13.2 days, 95% CI, 8.7-18.7; p < 0.001), higher total encounter costs ($62,000, 95% CI, 40,000-85,000; p < 0.001) and higher mortality (OR 2.4, 95% CI 1.9-2.9; p < 0.001) compared to outborn neonates. CONCLUSIONS: Inborn neonates placed on ECMO were more frequently diagnosed with cardiac-related diseases or congenital diaphragmatic hernia, had longer LOS, higher total encounter costs, and higher mortality rates relative to their outborn counterparts, and likely represent a higher risk population. These two populations of infants may be inherently different and their differences should be further explored to inform decision making about optimal site of delivery.

Postoperative Opioid Analgesia Impacts Resource Utilization in Infants Undergoing Pyloromyotomy.

BACKGROUND: Opioid analgesia is often avoided in infants undergoing pyloromyotomy. Previous studies highlight an association between opioid use and prolonged hospitalization after pyloromyotomy. However, the impact of opioid use on healthcare resource utilization and cost is unknown. We hypothesized that use of opioids after pyloromyotomy is associated with increased resource utilization and costs. METHODS: A retrospective cohort study was conducted identifying healthy infants aged <6 mo with a diagnosis of pyloric stenosis who underwent pyloromyotomy from 2005 to 2015 among 47 children's hospitals using the Pediatric Health Information System database. Time of opioid exposure was categorized as day of surgery (DOS) alone, postoperative use alone, or combined DOS and postoperative use. Primary outcomes were the standardized unit cost, a proxy for resource utilization, billed charges to the patient/insurer, and hospital costs. A multivariable log-linear mixed-effects model was used to adjust for patient and hospital level factors. RESULTS: Overall, 11,008 infants underwent pyloromyotomy with 2842 (26%) receiving perioperative opioids. Most opioid use was confined to the DOS alone (n = 2,158, 19.6%). Infants who received opioids on DOS and postoperatively exhibited 13% (95% confidence interval [CI]: 7%-20%, P-value <0.001) higher total resource utilization compared with infants who did not receive any opioids. Billed charges were 3% higher (95% CI: 0%-5%, P-value = 0.034) for infants receiving opioids isolated to the postoperative period alone and 6% higher (95% CI: 2%-11%, P-value = 0.004) for infants receiving opioids on the DOS and postoperatively. CONCLUSIONS: Postoperative opioid use among infants who underwent pyloromyotomy was associated with increased resource utilization and costs.

Incident testicular cancer in relation to using marijuana and smoking tobacco: A systematic review and meta-analysis of epidemiologic studies.

BACKGROUND: Recent epidemiologic studies identified credible associations between marijuana smoking and risk of nonseminomatous testicular germ cell tumors (TGCTs), but did not distinguish exposure to cannabinoid compounds from exposure to other constituents of smoke. METHODS: We implemented a systematic review of scholarly literature followed by random effects meta-analysis to quantitatively synthesize published data relating incident TGCT to each of 2 exposure histories: ever using marijuana, and ever smoking tobacco. RESULTS: We identified four epidemiologic studies of marijuana use and 12 of tobacco smoking. Summary data concur with earlier reports of a specific association of marijuana use with nonseminoma, summary odds ratio [sOR] = 1.71 (95% confidence interval [CI] 1.12-2.60), and identify a positive association, sOR = 1.18 (95% CI 1.05-1.33), between tobacco smoking and all TGCT. CONCLUSIONS: Available data accord with positive associations between incident TGCT and each exposure, implicating both cannabinoid compounds and other constituents of smoke. Etiologic interpretation awaits epidemiologic studies that assess associations between tobacco smoking and nonseminomatous TGCT, investigating not only these exposures but also both co-use of tobacco and marijuana and smoke-free sources of cannabinoids, while adequately evaluating potential confounding among all of these exposures.

Impact of Confounding on Cost, Survival, and Length-of-Stay Outcomes for Neonates with Hypoplastic Left Heart Syndrome Undergoing Stage 1 Palliation Surgery.

The objective of this analysis was to update trends in LOS and costs by survivorship and ECMO use among neonates with hypoplastic left heart syndrome (HLHS) undergoing stage 1 palliation surgery using 2016 data from the Healthcare Cost and Utilization Project Kids' Inpatient Database. We identified neonates ≤ 28 days old with HLHS undergoing Stage 1 surgery, defined as a Norwood procedure with modified Blalock-Taussig (BT) shunt, Sano modification, or both. Multivariable regression with year random effects was used to compare LOS and costs by hospital region, case volume, survivorship, and ECMO vs. no ECMO. An E-value analysis, an approach for conducting sensitivity analysis for unmeasured confounding, was performed to determine if unmeasured confounding contributed to the observed effects. Significant differences in total costs, LOS, and mortality were noted by hospital region, ECMO use, and sub-analyses of case volume. However, other than ECMO use and mortality, the maximum E-value confidence interval bound was 1.71, suggesting that these differences would disappear with an unmeasured confounder 1.71 times more associated with both the outcome and exposure (e.g., socioeconomic factors, environment, etc.) Our findings confirm previous literature demonstrating significant resource utilization among Norwood patients, particularly those undergoing ECMO use. Based on our E-value analysis, differences by hospital region and case volume can be explained by moderate unobserved confounding, rather than a reflection of the quality of care provided. Future analyses on surgical quality must account for unobserved factors to provide meaningful information for quality improvement.

The Association Between Opioid Use and Outcomes in Infants Undergoing Pyloromyotomy.

PURPOSE: The purpose of this study was to describe the frequency and variation of opioid use across hospitals in infants undergoing pyloromyotomy and to determine the impact of opioid use on postoperative outcomes. METHODS: A retrospective cohort study (2005-2015) was conducted by using the Pediatric Health Information System (PHIS) database, including infants (aged <6 months) with pyloric stenosis who underwent pyloromyotomy. Infants with significant comorbidities were excluded. Opioid use was classified as a patient receiving at least 1 opioid medication during his or her hospital stay and categorized as preoperative, day of surgery, or postoperative (≥1 day after surgery). Outcomes included prolonged hospital length of stay (LOS; ≥3 days) and readmission within 30 days. FINDINGS: Overall, 25,724 infants who underwent pyloromyotomy were analyzed. Opioids were administered to 6865 (26.7%) infants, with 1385 (5.4%) receiving opioids postoperatively. In 2015, there was significant variation in frequency of opioid use by hospital, with 0%-81% of infants within an individual hospital receiving opioids (P < 0.001). Infants only receiving opioids on the day of surgery exhibited decreased odds of prolonged hospital LOS (odds ratio [OR], 0.85; 95% CI, 0.78-0.92). Infants who received an opioid on both the day of surgery and postoperatively exhibited increased odds of a prolonged hospital LOS (OR, 1.71; 95% CI, 1.33-2.20). Thirty-day readmission was not associated with opioid use (OR, 1.03; 95% CI, 0.93-1.14). IMPLICATIONS: There is national variability in opioid use for infants undergoing pyloromyotomy, and postoperative opioid use is associated with prolonged hospital stay. Nonopioid analgesic protocols may warrant future investigation.

Utilization patterns of extracorporeal membrane oxygenation in neonates in the United States 1997-2012.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) remains one of the most intensive therapies for newborns in the United States. However, there is limited information on resource utilization for neonates receiving ECMO. METHODS: We conducted a retrospective data analysis of the Kids' Inpatient Database from 1997 to 2012. Bivariate and multivariate analysis was completed to identify predictors of LOS, hospital costs and mortality. Cardiac and non-cardiac diagnoses of neonates receiving ECMO were also included in the bivariate and multivariable analysis. RESULTS: Of the 5151 ECMO cases, survival to discharge was 62%. 22% had a principal cardiac diagnosis. After adjusting for covariates, increased mortality was associated with treatment in the midwest compared to the northeast region (aOR=2.0, p<0.01) and decreased among neonates with a non-cardiac diagnosis (aOR=0.4, p<0.01). Living in midwest was associated with longer LOS by 13days and increased hospital costs by 63,000 dollars (p<0.01). When stratified by non-cardiac diagnoses, infants with a diagnosis of congenital diaphragmatic hernia was associated with increased mortality (2.3, p<0.01) and longer LOS (25, p<0.01) and increased costs (11,100, p<0.01). CONCLUSION: Neonates who received ECMO in certain regions of the United States were associated with poorer survival outcomes as well as increased LOS and hospital costs. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level III.