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Background: The function of the gestational sac (GS) and the placenta in the closely related processes of embryogenesis and teratogenicity in the first trimester has been minimally described. The prevailing assumption is that direct teratogenic effects are mediated by the critical extraembryonic organ, the placenta, which either blocks or transfers exposures to the foetus. Placental transfer is a dominant mechanism, but there are other paradigms by which the placenta can mediate teratogenic effects. Knowledge of these paradigms and first trimester human developmental biology can be useful to the epidemiologist in the conduct of biomarker-based studies of both maternal and child health.Objective and Rationale: Our aim is to provide a causal framework for modelling the teratogenic effects of first trimester exposures on child health outcomes mediated by the GS and placenta using biomarker data collected in the first trimester. We initially present first trimester human developmental biology for the sake of informing and strengthening epidemiologic approaches. We then propose analytic approaches of modelling placental mechanisms by way of causal diagrams using classical non-embryolethal teratogens (diethylstilboestrol [DES], folic acid deficiency and cytomegalovirus [CMV]) as illustrative examples. We extend this framework to two chronic exposures of particular current interest, phthalates and maternal adiposity.Search Methods: Information on teratogens was identified by a non-systematic, narrative review. For each teratogen, we included papers that answered the five following questions: (i) why were these exposures declared teratogens? (ii) is there a consensus on biologic mechanism? (iii) is there reported evidence of a placental mechanism? (iv) can we construct a theoretical model of a placental mechanism? and (v) can this knowledge inform future work on measurement and modelling of placental-foetal teratogenesis? We prioritized literature specific to human development, the organogenesis window in the first trimester and non-embryolethal mechanisms.Outcomes: As a result of our review of the literature on five exposures considered harmful in the first trimester, we developed four analytic strategies to address first trimester placental mechanisms in birth cohort studies: placental transfer and direct effects on the foetus (DES and maternal adiposity), indirect effects through targeted placental molecular pathways (DES and phthalates), pre-placental effects through disruptions in embryonic and extraembryonic tissue layer differentiation (folic acid deficiency), and multi-step mechanisms that involve maternal, placental and foetal immune function and inflammation (DES and CMV).Wider Implications: The significance of this review is to offer a causal approach to classify the large number of potentially harmful exposures in pregnancy when the exposure occurs in the first trimester. Our review will facilitate future research by advancing knowledge of the first trimester mechanisms necessary for researchers to effectively associate environmental exposures with child health outcomes. [ABSTRACT FROM AUTHOR]

Background: The risks and benefits of pharmacologic treatment and operative closure of patent ductus arteriosus (O-PDA) in premature infants remain controversial. Recent series have demonstrated the feasibility of transcatheter PDA closure (TC-PDA) in increasingly small infants. The effect of this change on practice has not been evaluated.Methods: A multicenter observational study of infants treated in neonatal intensive care units in hospitals contributing data to the Pediatric Health Information Systems Database from January 2007 to December 2017 was performed to study trends in the propensities for (1) mechanical closure of PDA and (2) TC-PDA versus O-PDA, as well as interhospital variation in practice.Results: A total of 6,214 subjects at 44 hospitals were studied (5% TC-PDA). Subject median gestational age was 25 weeks (interquartile range: 24-27 weeks). Median age at closure was 24 days (interquartile range: 14-36 days). The proportion of all neonatal intensive care unit patients undergoing either O-PDA or TC-PDA decreased (3.1% in 2007 and 0.7% in 2017, P < .001), whereas the proportion in which TC-PDA was used increased significantly (0.1% in 2007 to 29.0% in 2017). Case-mix-adjusted multivariable models similarly demonstrated increasing propensity to pursue TC-PDA (odds ratio [OR] 1.66 per year, P < .001) with acceleration of the trend after 2014 (OR 2.46 per year, P < .001) as well as significant practice variation (P < .001, median OR 4.6) across the study period.Conclusions: In the face of decreasing closure of PDA, the use of TC-PDA increased dramatically with significant practice variability. This demonstrates that there is equipoise for potential clinical trials. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the association between the method of procedural sedation and outcomes for congenital cardiac catheterization procedures. The safety of operator-directed sedation (ODS) in the pediatric/congenital cardiac catheterization laboratory has been questioned. To our knowledge, the relative safety of ODS versus general anesthesia (GA) in these cases has not to date been critically evaluated. A single-center retrospective cohort study was performed to compare the relative safety, cost, and times of catheterization procedures performed with ODS and those performed with GA from a cardiac anesthesiologist. The risk of adverse outcomes was compared using propensity-score-adjusted models. Using the same propensity score, procedure times and relative charges were also compared. Over the study period, 4,424 procedures in 2,547 patients were studied. Of these, 27% of cases were performed with ODS. ODS procedures were 70% diagnostic procedures, 17% device closure of patent ductus arteriosus, 5% balloon pulmonary valvuloplasty, and 3% pulmonary artery angioplasty. The risk of adverse event in adjusted models for ODS cases was significantly lower than in GA cases (odds ratio: 0.66; 95% confidence interval: 0.45 to 0.95; p = 0.03). Total room time and case time were also significantly shorter (p < 0.001). Professional (charge ratio: 0.88; p < 0.001) and hospital (charge ratio: 0.84; p < 0.001) charges for ODS cases were also lower than those for GA cases. This study demonstrates that clinical judgment can identify subjects in whom ODS is not associated with increased risk of adverse events. The use of ODS was associated with reduced case times and charges. In combination, these findings suggest that the selective use of ODS can allow for greater efficiency and higher value care without sacrificing safety. [ABSTRACT FROM AUTHOR]

Background: Many effects of statins on non-cardiovascular disease (non-CVD) outcomes have been reported.Purpose: To evaluate the quantity, validity, and credibility of evidence regarding associations between statins and non-CVD outcomes and the effects of statins on these outcomes.Data Sources: MEDLINE and EMBASE (English terms only, inception to 28 May 2018).Study Selection: Meta-analyses (published in English) of observational studies and of randomized controlled trials (RCTs) that examined non-CVD outcomes of statin intake.Data Extraction: Two investigators extracted data from meta-analyses and individual studies. Credibility assessments based on summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance, and credibility ceilings were devised to classify evidence.Data Synthesis: This review explored 278 unique non-CVD outcomes from 112 meta-analyses of observational studies and 144 meta-analyses of RCTs. For observational studies, no convincing (class I) evidence, 2 highly suggestive (class II) associations (decreased cancer mortality in patients with cancer and decreased exacerbation in patients with chronic obstructive pulmonary disease), 21 suggestive (class III) associations, and 42 weak (class IV) associations were identified. One outcome from the RCTs (decreased all-cause mortality in patients with chronic kidney disease) attained a sufficient amount of evidence with no hints of bias. For adverse events, observational studies showed suggestive evidence that statins increase the risk for diabetes and myopathy. Among the RCTs, no statistically significant effects were found on myopathy, myalgia, or rhabdomyolysis.Limitations: Studies with relevant data and outcomes not included in the meta-analyses may have been missed. Credibility assessments relied on several assumptions and arbitrary thresholds.Conclusion: The absence of convincing evidence of an association between statins and non-CVD outcomes supports leaving the current recommendations unchanged.Primary Funding Source: None. [ABSTRACT FROM AUTHOR]

Background Prenatal exposure to organophosphate insecticides may be associated with autism spectrum disorders and related behaviors. This association may be modified by single nucleotide polymorphisms in the paraoxonase ( PON1 ) enzyme. Objective We examined the relationship of prenatal organophosphate insecticide biomarkers with reciprocal social, repetitive, and stereotypic behaviors in 8-year old children, and modification of this relationship by child PON1 polymorphisms. Methods Among 224 pregnant women, we quantified concentrations of six nonspecific dialkyl phosphate (DAP) metabolites of organophosphate insecticides in two urine samples collected at ~16 and ~26 weeks gestation. When children were eight years old, we administered the Social Responsiveness Scale (SRS), a continuous measure of various dimensions of interpersonal behavior, communication, and repetitive/stereotypic behaviors. We estimated the association between a 10-fold increase in the sum of six DAP concentrations (ΣDAP) and SRS scores. We examined whether child PON1 192 and PON1 –108 genotypes modified this association. Results After covariate adjustment, ΣDAP concentrations were not associated with SRS scores [β=–1.2; 95% confidence interval (CI): –4.0, 1.6]. Among children with the PON1 –108TT genotype, ΣDAP concentrations were associated with 2.5-point higher (95% CI: −4.9, 9.8) SRS scores; however, the association was not different from the 1.8-point decrease (95% CI: −5.8, 2.2) among children with PON1 –108CT/CC genotypes (ΣDAP × PON1 –108 p-value =0.54). The association between ΣDAP concentrations and SRS scores was not modified by PON1 192 (ΣDAP × PON1 192 p-value =0.89). Conclusions In this cohort, prenatal urinary DAP concentrations were not associated with children's social behaviors; these associations were not modified by child PON1 genotype. [ABSTRACT FROM AUTHOR]

Introduction: Life-threatening events (LTE) in patients with Wolff-Parkinson-White Syndrome (WPW) are rare, with considerable variation in published rates. Existing data on LTE incidence represent selected populations or tertiary referral-based cohorts. Access to large observational datasets allows, for the first time, measurement of the risk of LTE in an unselected, contemporary WPW population. Methods: A retrospective cohort study was conducted using administrative claims from Truven Health Analytics (MarketScan®) to identify all WPW patients (aged ≤18 years) from both inpatient and outpatient encounters between January 2013 and December 2016. Prevalence of WPW was measured. A composite outcome, LTE, was defined as an episode that included ventricular fibrillation or cardiac arrest. Secondary outcomes included diagnoses of atrial fibrillation (AF) and supraventricular tachycardia (SVT). Factors associated with LTE were evaluated by creating multivariable models. Results: The prevalence of WPW in the study population was 0.025% (4,717/18,884,579). Subjects with WPW were 57% male, had a median age of 13 yrs (IQR 7-16 yrs), with coincident Ebstein's anomaly in 1.9%, other congenital heart disease (CHD) in 12%, and cardiomyopathy (CM) in 2%. Over the study period, SVT was reported in 20.3% (n=957/4,717), and AF in 1.3% (n=61/4,717) of subjects. Patients with AF were 79% male (n=48/61), with median age 16 yrs (IQR 14-17 yrs), with CHD in 25% (n=15/61) and CM in 7% (n=4/61). LTE occurred in 23 subjects: 70% male (n=16/23), at median age 16 yrs (IQR 7-17 yrs), with CHD in 9% (n=2/23) and CM in 13% (n=3/23); AF was reported in 3 patients with LTE. The incidence of LTE was 1.4 events per 1000 person years of follow up (23/16,514). In a multivariate model including age, gender, CHD, and CM, the only independent predictor of LTE was CM (OR 10.2, 95% CI 2.4-31.1, p<0.001). Conclusions: Use of a large claims dataset allowed for evaluation of LTE risk in an unselected pediatric WPW population. This WPW-related LTE estimate of 1.4/1000 person years can serve as a benchmark for assessment of risk reduction interventions on a population level. Incidence of LTE in this unselected contemporary cohort is consistent with observed rates in prior reports from selected populations. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to assess contemporary use of operator directed sedation (ODS) and anesthesiologist care (AC) in the pediatric/congenital cardiac catheterization laboratory (PCCL), specifically evaluating whether the use of operator-directed sedation was associated with increased risk of major adverse events., Background: The safety of ODS relative to AC during PCCL procedures has been questioned., Methods: A multicenter, retrospective cohort study was performed studying procedures habitually performed with ODS or AC at IMPACT (Improving Adult and Congenital Treatment) registry hospitals using ODS for ≥5% of cases. The risks for major adverse events (MAE) for ODS and AC cases were compared, adjusted for case mix. Current recommendations were evaluated by comparing the ratio of observed to expected MAE for cases in which ODS was inappropriate (inconsistent with those guidelines) with those for similar risk AC cases, as well as those in which ODS or AC was appropriate., Results: Of the hospitals submitting data to IMPACT, 28 of 101 met inclusion criteria. Of the 7,042 cases performed using ODS at these centers, 88% would be inappropriate. Use of ODS was associated with lower likelihood of MAE both in observed results (p < 0.0001) and after adjusting for case-mix (odds ratio: 0.81; p = 0.006). Use of AC was also associated with longer adjusted fluoroscopy and procedure times (p < 0.0001 for both). The observed/expected ratio for ODS cases with high pre-procedural risk (inappropriate for ODS) was significantly lower than that for AC cases with comparable pre-procedural risk. Across a range of pre-procedural risks, there was no stratum in which risk for MAE was lower for AC than ODS., Conclusions: Across a range of hospitals, ODS was used safely and with improved efficiency. Clinical judgment better identified cases in which ODS could be used than pre-procedural risk score. This should inform future guidelines for the use of ODS and AC in the catheterization laboratory., Competing Interests: Funding Support and Author Disclosures Dr. O’Byrne has received research support from the National Institutes of Health/National Heart, Lung, and Blood Institute (grant K23 HL130420-01). Dr. Hill has received research support from the National Centers for Advancing Translational Sciences (grant U01TR-001803-01). Dr. Chamberlain is supported by the National Institute of General Medical Sciences and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (grant T32GM086330). The specific study was supported by the American College of Cardiology Foundation. It was reviewed by the IMPACT registry research and publications committee during its planning, as was the resulting manuscript. However, the funding agencies had no role in the planning or execution of the study, nor did they edit the paper as presented. The paper represents the opinions of the authors alone. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)