Associations of prenatal exposure to a mixture of persistent organic pollutants with social traits and cognitive and adaptive function in early childhood: Findings from the EARLI study.

BACKGROUND: Literature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits. OBJECTIVE: To evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study. METHODS: Maternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs. RESULTS: Higher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (ß = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p'-DDE was associated with lower social deficits (ß = -8.34, 95% CI: -15.32, -1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (ß = 5.68, 95% CI: 0.18, 11.17; ß = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p'-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores. CONCLUSIONS: We observed independent effects of PCB180, PCB187, PBDE47, and p,p' DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.

Maternal post-traumatic stress and depression symptoms and outcomes after NICU discharge in a low-income sample: a cross-sectional study.

BACKGROUND: Having a preterm newborn and the experience of staying in the neonatal intensive care unit (NICU) has the potential to impact a mother's mental health and overall quality of life. However, currently there are few studies that have examined the association of acute post-traumatic stress (PTS) and depression symptoms and infant and maternal outcomes in low-income populations. DESIGN/ METHODS: In a cross-sectional study, we examined adjusted associations between positive screens for PTS and depression using the Perinatal Post-traumatic stress Questionnaire (PPQ) and the Patient Health-Questionnaire 2 (PHQ-2) with outcomes using unconditional logistic and linear regression models. RESULTS: One hundred sixty-nine parents answered the questionnaire with 150 complete responses. The majority of our sample was Hispanic (68%), non-English speaking (67%) and reported an annual income of <$20,000 (58%). 33% of the participants had a positive PPQ screen and 34% a positive PHQ-2 screen. After adjusting for confounders, we identified that a positive PHQ-2 depression score was associated with a negative unit (95% CI) change on the infant's Vineland Adaptive Behavior Scales, second edition of - 9.08 (- 15.6, - 2.6) (p < 0.01). There were no significant associations between maternal stress and depression scores and infant Bayley Scales of Infant Development III scores or re-hospitalizations or emergency room visits. However, positive PPQ and screening score were associated with a negative unit (95% CI) unit change on the maternal Multicultural Quality of Life Index score of - 8.1 (- 12, - 3.9)(p < 0.01) and - 7.7 (- 12, - 3) (p = 0.01) respectively. CONCLUSIONS: More than one-third of the mothers in this sample screened positively for PTS and depression symptoms. Screening scores positive for stress and depression symptoms were associated with a negative change in some infant development scores and maternal quality of life scores. Thoughtful screening programs for maternal stress and depression symptoms should be instituted.

The association of care transitions measure-15 score and outcomes after discharge from the NICU.

BACKGROUND: Our objectives were (1) to describe Care Transitions Measure (CTM) scores among caregivers of preterm infants after discharge from the neonatal intensive care unit (NICU) and (2) to describe the association of CTM scores with readmissions, enrollment in public assistance programs, and caregiver quality of life scores. METHODS: The study design was a cross-sectional study. We estimated adjusted associations between CTM scores (validated measure of transition) with outcomes using unconditional logistic and linear regression models and completed an E-value analysis on readmissions to quantify the minimum amount of unmeasured confounding. RESULTS: One hundred sixty-nine parents answered the questionnaire (85% response rate). The majority of our sample was Hispanic (72.5%), non-English speaking (67.1%) and reported an annual income of <$20,000 (58%). Nearly 28% of the infants discharged from the NICU were readmitted within a year from discharge. After adjusting for confounders, we identified that a positive 10-point change of CTM score was associated with an odds ratio (95% CI) of 0.74 (0.58, 0.98) for readmission (p = 0.01), 1.02 (1, 1.05) for enrollment in early intervention, 1.03 (1, 1.05) for enrollment in food assistance programs, and a unit change (95% CI) 0.41 (0.27, 0.56) in the Multicultural Quality of Life Index score (p < 0.0001). The associated E-value for readmissions was 1.6 (CI 1.1) suggesting moderate confounding. CONCLUSION: The CTM may be a useful screening tool to predict certain outcomes for infants and their families after NICU discharge. However, further work must be done to identify unobserved confounding factors such as parenting confidence, problem-solving and patient activation.

Proportion of Retinopathy of Prematurity That Was Treated across Regions in the United States.

OBJECTIVES: Retinopathy of prematurity (ROP) is the leading preventable cause of blindness in children worldwide. Major eye and visual problems are strongly linked to ROP requiring treatment. Objectives of the study are to: (1) evaluate the trends and regional differences in the proportion of treated ROP, (2) describe risk factors, and (3) examine if treated ROP predicts mortality. STUDY DESIGN: Retrospective data analysis was conducted using the Kids' Inpatient Database from 1997 to 2012. ROP was categorized into treated ROP (requiring laser photocoagulation or surgical intervention) and nontreated ROP. Bivariate and multivariate logistic regression analyses were performed. RESULTS: Out of 21,955,949 infants ≤ 12 months old, we identified 70,541 cases of ROP and 7,167 (10.2%) were treated. Over time, the proportion of treated ROP decreased (p = < 0.001). While extremely low birth weight infants cared for in the Midwest was associated with treated ROP (adjusted odds ratio [aOR] = 29.05; 95% confidence interval [CI]: 10.64-79.34), black race (aOR = 0.57; 95% CI: 0.51-0.64) care for in the birth hospital (aOR = 0.44; 95% CI: 0.41-0.48) was protective. Treated ROP was not associated with mortality. CONCLUSION: The proportion of ROP that is surgically treated has decreased in the United States; however, there is variability among the different regions. Demographics and clinical practice may have contributed for this variability.

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.

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.

Comprehensive meta-analysis reveals association between multiple imprinting disorders and conception by assisted reproductive technology.

PURPOSE: To determine whether a history of conception by assisted reproductive technology (ART) is associated with occurrence of one or more imprinting disorders of either maternal or paternal origin. METHODS: We implemented a systematic review of scholarly literature followed by comprehensive meta-analysis to quantitatively synthesize data from reports relating to use of ART to occurrence of any imprinting disorder of humans, including Beckwith-Wiedemann (BWS), Angelman (AS), Prader-Willi (PWS), and Silver-Russell (SRS) syndromes, as well as transient neonatal diabetes mellitus (TNDB) and sporadic retinoblasoma (RB). RESULTS: The systematic review identified 13 reports presenting unique data from 23 studies that related conception following ART to occurrence of imprinting disorders. Multiple studies of four disorder were identified, for which meta-analysis yielded the following summary estimates of associations with a history of ART: AS, summary odds ratio (sOR) = 4.7 (95% confidence interval (CI) 2.6-8.5, 4 studies); BWS, sOR = 5.8 (95% CI 3.1-11.1, 8 studies); PWS, sOR = 2.2 (95% CI 1.6-3.0, 6 studies); SRS, sOR = 11.3 (95% CI 4.5-28.5, 3 studies). Only one study reported on each of TNDB and RB. CONCLUSION: Published data reveal positive associations between history of ART conception and each of four imprinting disorders. Reasons for these associations warrant further investigation.

Costs and outcomes associated with the administration of Intravenous Acetaminophen in neonates after esophageal atresia and tracheoesophageal fistula repair.

BACKGROUND: Over the last decade, the intravenous (IV) formulation of acetaminophen (APAP) has gained popularity as a safe and effective first-line analgesic in the neonatal intensive care unit and it is especially useful in peri-operative settings where oral agents are contraindicated. The primary objective was to examine the outcomes and costs associated with the use of IV APAP in combination with opioids versus opioids alone as a pain management strategy after neonatal esophageal atresia (EA) and tracheoesophageal fistula (TEF) repair. METHODS: Data from the Pediatric Health Information System was used to examine 1137 hospitalizations for EA/TEF repair from October 2015 to September 2018. Neonates administered opioids only, or IV APAP in combination with opioids as pain management, were included. RESULTS: Neonates receiving IV APAP experienced a longer median LOS, but a significantly lower mortality rate, a decreased mean daily cost, and reduced opioid use compared to neonates given only opioids. The two groups had no significant differences in pharmacy and total costs. CONCLUSION: Our findings suggest that the use of IV APAP alongside opioids in EA/TEF repair is associated with reduced mortality and opioid use, as well as longer LOS.

Prenatal air pollution and children's autism traits score: Examination of joint associations with maternal intake of vitamin D, methyl donors, and polyunsaturated fatty acids using mixture methods.

Background: Maternal nutrient intake may moderate associations between environmental exposures and children's neurodevelopmental outcomes, but few studies have assessed joint effects. We aimed to evaluate whether prenatal nutrient intake influences the association between air pollutants and autism-related trait scores. Methods: We included 126 participants from the EARLI (Early Autism Risk Longitudinal Investigation, 2009-2012) cohort, which followed US pregnant mothers who previously had a child with autism. Bayesian kernel machine regression and traditional regression models were used to examine joint associations of prenatal nutrient intake (vitamins D, B12, and B6; folate, choline, and betaine; and total omega 3 and 6 polyunsaturated fatty acids, reported via food frequency questionnaire), air pollutant exposure (particulate matter <2.5 µm [PM2.5], nitrogen dioxide [NO2], and ozone [O3], estimated at the address level), and children's autism-related traits (measured by the Social Responsiveness Scale [SRS] at 36 months). Results: Most participants had nutrient intakes and air pollutant exposures that met US standards. Bayesian kernel machine regression mixture models and traditional regression models provided little evidence of individual or joint associations of nutrients and air pollutants with SRS scores or of an association between the overall mixture and SRS scores. Conclusion: In this cohort with a high familial likelihood of autism, we did not observe evidence of joint associations between air pollution exposures and nutrient intake with autism-related traits. Future work should examine the use of these methods in larger, more diverse samples, as our results may have been influenced by familial liability and/or relatively high nutrient intakes and low air pollutant exposures.

Accelerated epigenetic age at birth and child emotional and behavioura development in early childhood: a meta-analysis of four prospective cohort studies in ECHO.

Background: 'Epigenetic clocks' have been developed to accurately predict chronologic gestational age and have been associated with child health outcomes in prior work.Methods: We meta-analysed results from four prospective U.S cohorts investigating the association between epigenetic age acceleration estimated using blood DNA methylation collected at birth and preschool age Childhood Behavior Checklist (CBCL) scores.Results: Epigenetic ageing was not significantly associated with CBCL total problem scores (ß = 0.33, 95% CI: -0.95, 0.28) and DSM-oriented pervasive development problem scores (ß = -0.23, 95% CI: -0.61, 0.15). No associations were observed for other DSM-oriented subscales.Conclusions: The meta-analysis results suggest that epigenetic gestational age acceleration is not associated with child emotional and behavioural functioning for preschool age group. These findings may relate to our study population, which includes two cohorts enriched for ASD and one preterm birth cohort.; future work should address the role of epigenetic age in child health in other study populations.Abbreviations: DNAm: DNA methylation; CBCL: Child Behavioral Checklist; ECHO: Environmental Influences on Child Health Outcomes; EARLI: Early Autism Risk Longitudinal Investigation; MARBLES: Markers of Autism Risk in Babies - Learning Early Signs; ELGAN: Extremely Low Gestational Age Newborns; ASD: autism spectrum disorder; BMI: body mass index; DSM: Diagnostic and Statistical Manual of Mental Disorders.

Opioid and Methadone Use for Infants With Surgically Treated Necrotizing Enterocolitis.

Importance: Necrotizing enterocolitis (NEC) requiring surgical intervention is the most common reason for surgical procedures in preterm neonates. Opioids are used to manage postoperative pain, with some infants requiring methadone to treat physiologic opioid dependence or wean from nonmethadone opioid treatment during recovery. Objective: To describe postoperative opioid use and methadone treatment for infants with surgically treated NEC and evaluate postoperative outcomes. Design, Setting, and Participants: A cohort study of infants with surgically treated NEC admitted from January 1, 2013, to December 31, 2022, to 48 Children's Hospital Association hospitals contributing data to the Pediatric Health Information System (PHIS) was performed. Infants who received methadone preoperatively, were aged 14 days or less at the time of the operation, had a congenital heart disease-related operation, or died within 90 days of the operation were excluded. Mixed-effects multivariable logistic regression was used to evaluate thresholds for duration of opioid use after the operation associated with methadone treatment and clinical outcomes associated with methadone use were enumerated. Exposure: Postoperative administration of nonmethadone opioids. Main Outcomes and Measures: Methadone use and postoperative length of stay, ventilator days, and total parenteral nutrition (TPN) days. Results: Of the 2037 infants with surgically treated NEC identified, the median birth weight was 920 (IQR, 700.0-1479.5) g; 1204 were male (59.1%), 911 were White (44.7%), and 343 were Hispanic (16.8%). Infants received nonmethadone opioids for a median of 15 (IQR, 6-30) days after the operation and 231 received methadone (11.3%). The median first day of methadone use was postoperative day 18 (IQR, days 9-64) and continued for 28 days (IQR, 14-73). Compared with infants who received nonmethadone opioids for 1 to 5 days, infants receiving 16 to 21 days of opioids were most likely to receive methadone treatment (odds ratio, 11.45; 95% CI, 6.31-20.77). Methadone use was associated with 21.41 (95% CI, 10.81-32.02) more days of postoperative length of stay, 10.80 (95% CI, 3.63-17.98) more ventilator days, and 16.21 (95% CI, 6.34-26.10) more TPN days. Conclusions and Relevance: In this cohort study of infants with surgically treated NEC, prolonged use of nonmethadone opioids after the operation was associated with an increased likelihood of methadone treatment and increased postoperative length of stay, ventilation, and TPN use. Optimizing postoperative pain management for infants requiring an operation may decrease the need for methadone treatment and improve health care use.

Analysis of Pregnancy Complications and Epigenetic Gestational Age of Newborns.

Importance: Preeclampsia, gestational hypertension, and gestational diabetes, the most common pregnancy complications, are associated with substantial morbidity and mortality in mothers and children. Little is known about the biological processes that link the occurrence of these pregnancy complications with adverse child outcomes; altered biological aging of the growing fetus up to birth is one molecular pathway of increasing interest. Objective: To evaluate whether exposure to each of these 3 pregnancy complications (gestational diabetes, gestational hypertension, and preeclampsia) is associated with accelerated or decelerated gestational biological age in children at birth. Design, Setting, and Participants: Children included in these analyses were born between 1998 and 2018 and spanned multiple geographic areas of the US. Pregnancy complication information was obtained from maternal self-report and/or medical record data. DNA methylation measures were obtained from blood biospecimens collected from offspring at birth. The study used data from the national Environmental Influences on Child Health Outcomes (ECHO) multisite cohort study collected and recorded as of the August 31, 2021, data lock date. Data analysis was performed from September 2021 to December 2022. Exposures: Three pregnancy conditions were examined: gestational hypertension, preeclampsia, and gestational diabetes. Main Outcomes and Measures: Accelerated or decelerated biological gestational age at birth, estimated using existing epigenetic gestational age clock algorithms. Results: A total of 1801 child participants (880 male [48.9%]; median [range] chronological gestational age at birth, 39 [30-43] weeks) from 12 ECHO cohorts met the analytic inclusion criteria. Reported races included Asian (49 participants [2.7%]), Black (390 participants [21.7%]), White (1026 participants [57.0%]), and other races (92 participants [5.1%]) (ie, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple races, and other race not specified). In total, 524 participants (29.0%) reported Hispanic ethnicity. Maternal ages ranged from 16 to 45 years of age with a median of 29 in the analytic sample. A range of maternal education levels, from less than high school (260 participants [14.4%]) to Bachelor's degree and above (629 participants [34.9%]), were reported. In adjusted regression models, prenatal exposure to maternal gestational diabetes (ß, -0.423; 95% CI, -0.709 to -0.138) and preeclampsia (ß, -0.513; 95% CI, -0.857 to -0.170), but not gestational hypertension (ß, 0.003; 95% CI, -0.338 to 0.344), were associated with decelerated epigenetic aging among exposed neonates vs those who were unexposed. Modification of these associations, by sex, was observed with exposure to preeclampsia (ß, -0.700; 95% CI, -1.189 to -0.210) and gestational diabetes (ß, -0.636; 95% CI, -1.070 to -0.200), with associations observed among female but not male participants. Conclusions and Relevance: This US cohort study of neonate biological changes related to exposure to maternal pregnancy conditions found evidence that preeclampsia and gestational diabetes delay biological maturity, especially in female offspring.

Epigenetics as a Biomarker for Early-Life Environmental Exposure.

PURPOSE OF REVIEW: There is interest in evaluating the developmental origins of health and disease (DOHaD) which emphasizes the role of prenatal and early-life environments on non-communicable health outcomes throughout the life course. The ability to rigorously assess and identify early-life risk factors for later health outcomes, including those with childhood onset, in large population samples is often limited due to measurement challenges such as impractical costs associated with prospective studies with a long follow-up duration, short half-lives for some environmental toxicants, and lack of biomarkers that capture inter-individual differences in biologic response to external environments. RECENT FINDINGS: Epigenomic patterns, and DNA methylation in particular, have emerged as a potential objective biomarker to address some of these study design and exposure measurement challenges. In this article, we summarize the literature to date on epigenetic changes associated with specific prenatal and early-life exposure domains as well as exposure mixtures in human observational studies and their biomarker potential. Additionally, we highlight evidence for other types of epigenetic patterns to serve as exposure biomarkers. Evidence strongly supports epigenomic biomarkers of exposure that are detectable across the lifespan and across a range of exposure domains. Current and future areas of research in this field seek to expand these lines of evidence to other environmental exposures, to determine their specificity, and to develop predictive algorithms and methylation scores that can be used to evaluate early-life risk factors for health outcomes across the life span.

The financial burden experienced by families of preterm infants after NICU discharge.

BACKGROUND AND OBJECTIVES: Describe the financial burden and worry that families of preterm infants experience after discharge from the neonatal intensive care unit (NICU). METHODS: We surveyed 365 parents of preterm infants in a cross-sectional study regarding socio-demographics, supplemental security income (SSI), and financial worry. We completed a multivariable logistic regression model to examine the adjusted association of financial worry with modifiable factors. RESULTS: We found that 53% of participants worried about healthcare costs after NICU discharge. After adjusting for socio-demographic and infant characteristics, we identified that, aOR (95% CI), out-of-pocket costs from the NICU index hospitalization, 3.51 (1.7, 7.26) and durable medical equipment use, 2.41 (1.11, 5.23) was associated with increased financial worry while enrollment in SSI, 0.38 (0.19, 0.76) was associated with decreased financial worry. CONCLUSIONS: We identified factors that could contribute to financial burden after NICU discharge that may advise future work to target financial support systems.

Neonates with mild hypoxic-ischaemic encephalopathy receiving supportive care versus therapeutic hypothermia in California.

OBJECTIVE: The use of therapeutic hypothermia (TH) for mild hypoxic-ischaemic encephalopathy (HIE) remains controversial and inconsistent. We analysed trends in TH and maternal and infant characteristics associated with short-term outcomes of infants with mild HIE. DESIGN: Retrospective cohort analysis of the California Perinatal Quality Care Collaborative database 2010-2018. E-value analysis was conducted to determine the potential impact of unmeasured confounding. SETTING: California neonatal intensive care units. PATIENTS: 1364 neonates with mild HIE. INTERVENTIONS: Supportive care versus TH. MAIN OUTCOME MEASURES: Factors associated with TH and mortality. RESULTS: The proportion of infants receiving TH increased from 46% in 2010 to 79% in 2018. TH was more likely in the setting of singleton birth (OR 2.69, 95% CI 1.21 to 5.39), no major birth defects (OR 2.18, 95% CI 1.42 to 3.30), operative vaginal delivery (OR 3.04, 95% CI 1.80 to 5.10) and 5-minute Apgar score ≤5 (OR 3.17, 95% CI 2.43 to 4.13). Mortality was associated with small for gestational age (OR 5.79, 95% CI 1.90 to 18.48), <38 weeks' gestation (OR 7.31 95% CI 2.39 to 24.93), major birth defects (OR 11.62, 95% CI 3.97 to 38.00), inhaled nitric oxide (OR 12.73, 95% CI 4.00 to 44.53) and nosocomial infection (OR 7.98, 95% CI 1.15 to 47.03). E-value analyses suggest that unmeasured confounding may have contributed to some of the observed effects. CONCLUSIONS: Variation in management of mild HIE persists, but therapeutic drift has become more prevalent over time. Further studies are needed to assess long-term outcomes alongside resource utilisation to inform evidence-based practice.

Prenatal exposure to pesticide residues in the diet in association with child autism-related traits: Results from the EARLI study.

Prior work has suggested associations between prenatal exposure to several classes of pesticides and child autism spectrum disorder (ASD). We examined a previously developed pesticide residue burden score (PRBS) and intake of high pesticide residue foods in association with ASD-related traits. Participants were drawn from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 256), a cohort following mothers who previously had a child with ASD through a subsequent pregnancy and that child's development. ASD-related traits were captured according to total Social Responsiveness Scale (SRS) scores at age 3 (mean raw total SRS score = 35.8). Dietary intake was assessed through a food frequency questionnaire collected during pregnancy. We also incorporated organic intake and fatty foods in modified versions of the PRBS. Associations between high-residue fruit and vegetable intake, the overall PRBS and modified versions of it, and SRS scores were assessed using multivariable linear regression. Overall, we did not observe associations between pesticide residues in foods and ASD-related outcomes, and modified versions of the PRBS yielded similar findings. However, reductions in ASD-related traits were observed with higher overall fruit and vegetable intake (adjusted estimates for Q4 vs. Q1: ß -12.76, 95%CI -27.8, 2.3). Thus, findings from this high familial probability cohort did not suggest relationships between pesticide residues in the diet according to the PRBS and ASD-related traits. Beneficial effects of fruit and vegetable intake may influence these relationships. Future work should consider fruit and vegetable intake in association with ASD-related outcomes. LAY SUMMARY: Diet is the main source of exposure to most pesticides in use today. In this study, we examined the relationship between pesticide exposure from residues in the diet during pregnancy and child autism-related traits. We found that these pesticide residues from the diet were not related to child autism-related outcomes at age three. However, higher prenatal fruit and vegetable intake was associated with reductions in child autism-related traits.

Associations between accelerated parental biologic age, autism spectrum disorder, social traits, and developmental and cognitive outcomes in their children.

Parental age is a known risk factor for autism spectrum disorder (ASD), however, studies to identify the biologic changes underpinning this association are limited. In recent years, "epigenetic clock" algorithms have been developed to estimate biologic age and to evaluate how the epigenetic aging impacts health and disease. In this study, we examined the relationship between parental epigenetic aging and their child's prospective risk of ASD and autism related quantitative traits in the Early Autism Risk Longitudinal Investigation study. Estimates of epigenetic age were computed using three robust clock algorithms and DNA methylation measures from the Infinium HumanMethylation450k platform for maternal blood and paternal blood specimens collected during pregnancy. Epigenetic age acceleration was defined as the residual of regressing chronological age on epigenetic age while accounting for cell type proportions. Multinomial logistic regression and linear regression models were completed adjusting for potential confounders for both maternal epigenetic age acceleration (n = 163) and paternal epigenetic age acceleration (n = 80). We found accelerated epigenetic aging in mothers estimated by Hannum's clock was significantly associated with lower cognitive ability and function in offspring at 12 months, as measured by Mullen Scales of Early Learning scores (ß = -1.66, 95% CI: -3.28, -0.04 for a one-unit increase). We also observed a marginal association between accelerated maternal epigenetic aging by Horvath's clock and increased odds of ASD in offspring at 36 months of age (aOR = 1.12, 95% CI: 0.99, 1.26). By contrast, fathers accelerated aging was marginally associated with decreased ASD risk in their offspring (aOR = 0.83, 95% CI: 0.68, 1.01). Our findings suggest epigenetic aging could play a role in parental age risks on child brain development.

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.

Association of WIC Participation and Growth and Developmental Outcomes in High-Risk Infants.

The objective of this study was to describe the association of enrollment in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC), the Supplemental Nutrition Assistance Program (SNAP), and infant growth and neurodevelopmental outcomes. Z scores and Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) and Vineland Adaptive/Behavior Scale-II (VABS-II) scores represented primary outcomes. We conducted bivariate analyses and linear regression. Children who were enrolled in WIC or WIC/SNAP had weight z scores U (95% confidence interval [CI]) that were 1.32 (0.42-2.21) or 1.19 (0.16-2.23) units higher. Enrollment in WIC or WIC/SNAP was associated with a higher score (95% CI) of 11.7 U (1.2-22.2 U) or 11.5 (0.1-22.9) for Bayley-III cognitive score and 10.1 U (1.9-19.1 U) or 10.3 (0.9-19.7) for the VABS-II composite score. These findings support increased advocacy for participation in WIC or WIC/SNAP for families with high-risk infants.