Congenital Diaphragmatic Hernia Patients with Left Heart Hypoplasia and Left Ventricular Dysfunction Have Highest Odds of Mortality.

OBJECTIVES: To describe the scope of left ventricular (LV) dysfunction and left heart hypoplasia (LHH) in infants with congenital diaphragmatic hernia (CDH), to determine associations with CDH severity, and to evaluate the odds of extracorporeal membrane oxygenation (ECMO) and death with categories of left heart disease. STUDY DESIGN: Demographic and clinical variables were collected from a single-center, retrospective cohort of CDH patients from January 2017 through May 2022. Quantitative measures of LV function and LHH were prospectively performed on initial echocardiograms. LHH was defined as ≥2 of the following: Z-score ≤ -2 of any left heart structure or LV end-diastolic volume <3 mL. LV dysfunction was defined as shortening fraction <28%, ejection fraction <60%, or global longitudinal strain <20%. The exposure was operationalized as a four-group categorical variable (LV dysfunction +/-, LHH +/-). Logistic regression models evaluated associations with ECMO and death, adjusting for CDH severity. RESULTS: One-hundred and eight-two patients (80.8% left CDH, 63.2% liver herniation, 23.6% ECMO, 12.1% mortality) were included. Twenty percent demonstrated normal LV function and no LHH (LV dysfunction-/LHH-), 37% normal LV function with LHH (LV dysfunction-/LHH+), 14% LV dysfunction without LHH (LV dysfunction+/LHH-), and 28% both LV dysfunction and LHH (LV dysfunction+/LHH+). There was a dose-response effect between increasing severity of left heart disease, ECMO use, and mortality. LV dysfunction+/LHH+ infants had the highest odds of ECMO use and death, after adjustment for CDH severity [OR (95% CI); 1.76 (1.20,2.62) for ECMO, 2.76 (1.63, 5.17) for death]. CONCLUSIONS: In our large single-center cohort, CDH patients with LV dysfunction+/LHH+ had the highest risk of ECMO use and death.

The Delivery Room Resuscitation of Infants with Congenital Diaphragmatic Hernia Treated with Fetoscopic Endoluminal Tracheal Occlusion: Beyond the Balloon.

INTRODUCTION: Randomized controlled trials found that fetoscopic endoluminal tracheal occlusion (FETO) resulted in increased fetal lung volume and improved survival for infants with isolated, severe left-sided congenital diaphragmatic hernia (CDH). The delivery room resuscitation of these infants is particularly unique, and the specific delivery room events are largely unknown. The objective of this study was to compare the delivery room resuscitation of infants treated with FETO to standard of care (SOC) and describe lessons learned. METHODS: Retrospective single-center cohort study of infants treated with FETO compared to infants who met FETO criteria during the same period but who received SOC. RESULTS: FETO infants were more likely to be born prematurely with 8/12 infants born <35 weeks gestational age compared to 3/35 SOC infants. There were 5 infants who required emergent balloon removal (2 ex utero intrapartum treatment and 3 tracheoscopic removal on placental bypass with delayed cord clamping) and 7 with prenatal balloon removal. Surfactant was administered in 6/12 FETO (50%) infants compared to 2/35 (6%) in the SOC group. Extracorporeal membrane oxygenation use was lower at 25% and survival was higher at 92% compared to 60% and 71% in the SOC infants, respectively. CONCLUSION: The delivery room resuscitation of infants treated with FETO requires thoughtful preparation with an experienced multidisciplinary team. Given increased survival, FETO should be offered to infants with severe isolated left-sided CDH, but only in high-volume centers with the experience and capability of removing the balloon, emergently if needed. The neonatal clinical team must be skilled in managing the unique postnatal physiology inherent to FETO where effective interdisciplinary teamwork is essential. Empiric and immediate surfactant administration should be considered in all FETO infants to lavage thick airway secretions, particularly those delivered <48 h after balloon removal.

The Impact of Comprehensive Fetal Care on Mortality of Children With Congenital Diaphragmatic Hernia when Delivery is Co-located in a Pediatric Hospital.

BACKGROUND: We evaluated the impact of delivery at a comprehensive fetal care center co-located in a pediatric hospital on extracorporeal membrane oxygenation (ECMO) exposure and survivorship of children with CDH. METHODS: This retrospective study includes maternal-fetal dyads with a prenatal diagnosis of isolated CDH who received any prenatal care at a single fetal center between February 2006 and March 2021. The principal variables included: (1) delivery setting (children born in the pediatric hospital ["inborn"] vs. children who were delivered elsewhere ["outborn"]), (2) exposure to ECMO (yes vs. no), and (3) survival-at-discharge from birth hospitalization (yes vs. no). Multivariable logistic regression was used to evaluate the association between delivery setting and ECMO cannulation, and whether delivery setting moderates the association between exposure to ECMO and survival-at-discharge. RESULTS: Among 418 maternal-fetal dyads, 77.0% of children were inborn and 32.0% of children were exposed to ECMO during their index hospitalization. Inborn children had more severe prenatal prognostic indicators but had a 57% lower odds of extracorporeal than outborn children. In multivariable logistic regression, delivery setting moderated the association between exposure to ECMO and survival-at-discharge. Although there was no statistically significant difference in mortality between inborn and outborn children who were not exposed to ECMO, inborn children exposed to ECMO had a 6.86 (1.98, 23.74) increased odds of death and outborn children exposed to ECMO had a 17.71 (4.69, 66.87) increased odds of death when both were compared to non-cannulated outborn children. CONCLUSIONS: Comprehensive fetal care with delivery co-located in a pediatric hospital was associated with decreased exposure to ECMO and a survivorship advantage among children with CDH who required extracorporeal support. LEVEL OF EVIDENCE: Level III.

Prevalence and patterns of executive function, adaptive function, and behavioral outcomes in preschool and school age children with congenital diaphragmatic hernia.

BACKGROUND: Executive function, adaptive function, and behavioral outcomes in congenital diaphragmatic hernia (CDH) survivors have not been well studied. AIM: To evaluate executive and neurobehavioral dysfunction in preschool and early school-aged children with CDH. STUDY DESIGN: Retrospective cohort study. SUBJECTS: All eligible CDH survivors ages 3 to 7 years enrolled in our follow-up program between February 2020 and February 2021. OUTCOME MEASURES: The Behavior Rating Inventory of Executive Function (BRIEF), the Adaptive Behavior Assessment System, 2nd Edition (ABAS-II), and the Child Behavior Checklist (CBCL) were used to assess functional and behavioral outcomes. Summary scores were compared to standard population norms. RESULTS: A total of 100 patients were enrolled during the study period. Of those, 73 parents completed at least one of the questionnaires, resulting in completion of the BRIEF, ABAS-II, and CBCL for 63, 68, and 63 patients, respectively. Preschool children had normal executive function (BRIEF-P) while global executive composite (P = 0.012) and the emotional regulation index (P = 0.010) for school age patients (BRIEF-2) were worse. CDH survivors had favorable adaptive functioning (ABAS-II). Mean CBCL scores for preschool attention problems (P = 0.018), school age attention problems (P = 0.001), and attention deficits hyperactivity problems (P = 0.027) were significantly worse. Prematurity, surrogate markers of disease severity, non-white race, and public insurance status were associated with worse neurobehavioral dysfunction in bivariable analysis. CONCLUSIONS: The majority of preschool and school age CDH survivors have age-appropriate executive, adaptive and behavioral functioning. CDH survivors, however, have lower executive function and attention scores compared with the general population.

Association of Asthma With Patients Diagnosed With Metabolic Syndrome: A Cohort Study in a Tertiary Care Hospital.

Introduction Asthma is defined as a chronic inflammatory airway disease. The prevalence of both asthma and obesity has been rising simultaneously, demonstrating a parallel trend. Obesity is a significant factor in metabolic syndrome, and numerous studies have indicated a connection between metabolic syndrome and bronchial asthma. Aims and objectives The aim of this paper is to evaluate the association of asthma with patients diagnosed with metabolic syndrome. The main objectives were to analyze the clinical profile and spirometric indices in patients with metabolic syndrome and to assess asthmatic patients among them with spirometry and clinical parameters at a tertiary care hospital in Chennai. Materials and methods This hospital-based cohort study was conducted on 73 patients attending the outpatient department who had a known case of metabolic syndrome and were evaluated for asthma through history, physical examination, and a pulmonary function test. A history of cough, expectoration, shortness of breath, wheezing, chest tightness, allergy, seasonal variation, and smoking habits was asked, and a thorough physical examination was performed. Bronchial asthma was confirmed with airflow reversibility by spirometry as per the Global Initiative for Asthma Guidelines. Metabolic and spirometry parameters were examined, such as body mass index (BMI), waist circumference, waist-hip ratio, fasting blood sugar (FBS), postprandial blood sugar, hemoglobin A1C (HbA1C), serum insulin, lipid profile, C-reactive protein (CRP), forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC pre- and post-reversibility (baseline vs. six months). Results and discussion The average BMI of all participants was 29.6511 ±2.64564. The waist-hip ratio was 0.5512 ±0.43855, which decreased during the follow-ups, demonstrating a decline in the risk of obesity in study participants. The level of HbA1C showed a drop from 6.1% to 5.9% at the first follow-up. This exhibited a further reduction at the six-month follow-up in addition to a positive reflection in insulin sensitivity, indicating successful control of diabetes among study participants. It was discovered that this was statistically significant (p<0.001). At the third and sixth months of follow-up, the FEV1/FVC ratio increased by 38% and 37%, respectively, when metabolic syndrome was under control. The results show that controlling diabetes, hypertension, obesity, and triglyceride values improved asthmatic symptoms, and this was determined to be statistically significant (p<0.001). Conclusion The results of the current study demonstrated that the regulation and maintenance of metabolic parameters such as BMI, diabetes, hyperlipidemia, and hypertension aid in improving asthma control.

Quantitative Measures of Right Ventricular Size and Function by Echocardiogram Correlate with Cardiac Catheterization Hemodynamics in Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate associations between cardiac catheterization (cath) hemodynamics, quantitative measures of right ventricular (RV) function by echocardiogram, and survival in patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN: This single-center retrospective cohort study enrolled patients with CDH who underwent index cath from 2003 to 2022. Tricuspid annular plane systolic excursion z score, RV fractional area change, RV free wall and global longitudinal strain, left ventricular (LV) eccentricity index, RV/LV ratio, and pulmonary artery acceleration time were measured from preprocedure echocardiograms. Associations between hemodynamic values, echocardiographic measures, and survival were evaluated by Spearman correlation and Wilcoxon rank sum test, respectively. RESULTS: Fifty-three patients (68% left-sided, 74% liver herniation, 57% extracorporeal membrane oxygenation, 93% survival) underwent cath (39 during index hospitalization, 14 later) including device closure of a patent ductus arteriosus in 5. Most patients (n = 31, 58%) were on pulmonary hypertension treatment at cath, most commonly sildenafil (n = 24, 45%) and/or intravenous treprostinil (n = 16, 30%). Overall, hemodynamics were consistent with precapillary pulmonary hypertension. Pulmonary capillary wedge pressure was >15 mm Hg in 2 patients (4%). Lower fractional area change and worse ventricular strain were associated with higher pulmonary artery pressure while higher LV eccentricity index and higher RV/LV ratio were associated with both higher pulmonary artery pressure and higher pulmonary vascular resistance. Hemodynamics did not differ based on survival status. CONCLUSIONS: Worse RV dilation and dysfunction by echocardiogram correlate with higher pulmonary artery pressure and pulmonary vascular resistance on cath in this CDH cohort. These measures may represent novel, noninvasive clinical trial targets in this population.

Extracorporeal Membrane Oxygenation for Neonates With Congenital Diaphragmatic Hernia: Prevalence of Seizures and Outcomes.

OBJECTIVES: We aimed to determine the prevalence of electrographic seizures and associated odds of adverse outcomes of electrographic seizures in neonates with congenital diaphragmatic hernia (CDH) receiving extracorporeal membrane oxygenation (ECMO). DESIGN: Retrospective, descriptive case series. SETTING: Neonatal ICU (NICU) in a quaternary care institution. PATIENTS: All neonates with CDH receiving ECMO undergoing continuous electroencephalographic monitoring (CEEG) and follow-up between January 2012 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All eligible neonates with CDH receiving ECMO underwent CEEG (n = 75). Electrographic seizures occurred in 14 of 75 (19%): they were exclusively electrographic-only in nine of 14, both electrographic-only and electroclinical in three of 14, and electroclinical only in two of 14. Two neonates developed status epilepticus. We identified an association between presence of seizures, rather than not, and longer duration of initial session of CEEG monitoring (55.7 hr [48.2-87.3 hr] vs 48.0 hr [43.0-48.3 hr]; p = 0.001). We also found an association between presence of seizures, rather than not, and greater odds of use of a second CEEG monitoring (12/14 vs 21/61; odds ratio [OR], 11.43 [95% CI, 2.34-55.90; p = 0.0026). Most neonates with seizures (10/14), experienced their onset of seizures more than 96 hours after the start of ECMO. Overall, the presence of electrographic seizures, compared with not, was associated with lower odds of survival to NICU discharge (4/14 vs 49/61; OR 0.10 [95% CI 0.03 to 0.37], p = 0.0006). Also, the presence of seizures-rather than not-was associated with greater odds of a composite of death and all abnormal outcomes on follow-up (13/14 vs 26/61; OR, 17.5; 95% CI, 2.15-142.39; p = 0.0074). CONCLUSIONS: Nearly one in five neonates with CDH receiving ECMO developed seizures during the ECMO course. Seizures were predominantly electrographic-only and when present were associated with great odds of adverse outcomes. The current study provides evidence to support standardized CEEG in this population.

Treprostinil in Neonates with Congenital Diaphragmatic Hernia-Related Pulmonary Hypertension.

OBJECTIVE: To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH). STUDY DESIGN: A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores. RESULTS: Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded. CONCLUSIONS: In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.

Respiratory function after birth in infants with congenital diaphragmatic hernia.

OBJECTIVE: To characterise the transitional pulmonary physiology of infants with congenital diaphragmatic hernia (CDH) using measures of expiratory tidal volume (TV) and end-tidal carbon dioxide (ETCO2). DESIGN: Prospective single-centre observational study. SETTING: Quaternary neonatal intensive care unit. PATIENTS: Infants with an antenatal diagnosis of CDH born at the Children's Hospital of Philadelphia. INTERVENTIONS: TV and ETCO2 were simultaneously recorded using a respiratory function monitor (RFM) during invasive positive pressure ventilation immediately after birth. MAIN OUTCOME MEASURES: TV per birth weight and ETCO2 values were summarised for each minute after birth. Subgroups of interest were defined by liver position (thoracic vs abdominal) and extracorporeal membrane oxygenation (ECMO) treatment. RESULTS: RFM data were available for 50 infants from intubation until a median (IQR) of 9 (7-14) min after birth. TV and ETCO2 values increased for the first 10 min after birth, but intersubject values were heterogeneous. TVs were overall lower and ETCO2 values higher in infants with an intrathoracic liver and infants who were ultimately treated with ECMO. On hospital discharge, survival was 88% (n=43) and 34% (n=17) of infants were treated with ECMO. CONCLUSION: Respiratory function immediately after birth is heterogeneous for infants with CDH. Lung aeration, as evidenced by expired TV and ETCO2, appears to be ongoing throughout the first 10 min after birth during invasive positive pressure ventilation. Close attention to expired TV and ETCO2 levels by 10 min after birth may provide an opportunity to optimise and individualise ventilatory support for this high-risk population.

The associations between prenatal phthalate exposure measured in child meconium and cognitive functioning of 12-month-old children in two cohorts at elevated risk for adverse neurodevelopment.

BACKGROUND: Phthalate metabolites in gestational-maternal urine represents short-term maternal exposure, but meconium, the newborn's first stool may better capture cumulative fetal exposure. We quantified phthalate metabolites in meconium from two cohorts of children at higher risk of adverse neurodevelopment and evaluated associations with their cognitive function at 12 months. METHODS: Meconium phthalate metabolites were quantified in the Safe Passage Study (SPS), N = 720, a pregnancy cohort with high community-levels of prenatal alcohol use, and the Early Autism Risk Longitudinal Investigation (EARLI), N = 236, a high familial autism risk pregnancy cohort. EARLI also had second and third trimester (T2/T3) maternal urine for exposure assessment. Molar sum of di (2-ethylhexyl) (∑DEHP) metabolites and an anti-androgenic score (AAS) using mono-isobutyl, mono-n-butyl, monobenzyl (MBZP), and DEHP metabolites were computed. Cognitive function was assessed at 12 months using the Mullen Scales of Early Learning-Composite (ELC). Multivariable linear regression assessed associations between loge-transformed metabolites and ELC. Quadratic terms explored nonlinearity and interaction terms of metabolite by child's sex examined effect modification. RESULTS: In SPS, MBzP (ßLinear = -6.73; 95% CI: 12.04, -1.42; ßquadratic = 1.95; 0.27, 3.62) and mono (2-ethyl-5-carboxypentyl), (ßLinear = -3.81; -7.53, -0.27; ßquadratic = 0.93; 0.09, 1.77) had U-shaped associations with ELC. In EARLI, T2 urine mono-carboxyisononyl was associated with linear decrease in ELC, indicating lower cognitive function. Interaction with sex was suggested (P < 0.2) for several urine metabolites, mostly indicating negative association between phthalates and ELC among girls but reversed among boys. Only mono-isononyl phthalate and ∑DEHP had consistent main effect associations across matrixes and cohorts, but similar interaction with sex was observed for meconium-measured ∑DEHP, AAS, MBzP, and mono (2-ethylhexyl) in both cohorts. CONCLUSIONS: Few phthalate metabolites were consistently associated with children's cognitive function, but a similar set of meconium metabolites from both cohorts displayed sex-specific associations. Gestational phthalate exposure may have sexually-dimorphic associations with early cognitive function in children at higher risk for adverse neurodevelopment.

Prenatal phthalate exposure measurement: A comparison of metabolites quantified in prenatal maternal urine and newborn's meconium.

Phthalates are chemicals suspected to adversely affect fetal neurodevelopment, but quantifying the fetal exposure is challenging. While prenatal phthalate exposure is commonly quantified in maternal urine, the newborn's meconium may better capture cumulative prenatal exposure. Currently, data on phthalates measured in meconium is sparse. We measured phthalate metabolites in 183 maternal second and 140 third trimester (T2, T3) urine, and in 190 meconium samples collected in an autism enriched-risk pregnancy cohort of 236 mothers. Eleven and eight metabolites were detected in over 90% of urine and meconium samples, respectively. Hydrophilic and hydrophobic metabolites were detected in both biosamples. Most urine phthalate metabolite distributions were similar between T2 and T3. Among metabolites detected in both biosamples, those of di(2-ethylhexyl) phthalate displayed a similar pattern in magnitude across metabolite type. Specifically, T2 creatinine adjusted distribution [median (25%, 75%)] of urine measured mono(2-ethylhexyl-carboxypentyl) (MECPP), mono(2-ethyl-5-hydroxyhexyl) (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) were 18.8(11.9, 31.4), 11.8(7.2, 19.1), and 8.9(6.2, 14.2) ng/mg. In meconium these were 16.6(10.9, 23.7), 2.5(1.5, 3.8), and 1.3(0.8, 2.3) ng/g, respectively. Metabolite-to-metabolite correlations were lower in meconium than urine, but patterns were similar. For example, correlation (95% CI) between mono(2-ethylhexyl) phthalate and MECPP was 0.73 (0.66, 0.78), and between MEOHP and MEHHP was 0.96 (0.95, 0.97) in urine as compared to 0.10 (-0.04, 0.24) and 0.31 (0.18, 0.43) respectively in meconium. Correlations between same metabolites measured in urine and meconium were low and differed by metabolite and trimester. Correlation between MEHHP in urine and meconium, for example, was 0.20 (0.008, 0.37) at T3, but 0.05 (-0.12, 0.21) at T2. Our study provides evidence of general population-level prenatal phthalate exposure in a population at high risk for neurodevelopmental disorders and supports the utility of meconium to measure prenatal phthalate exposure but provides little evidence of correlation with exposure measured in prenatal maternal urine.

Cytokine profiling: variation in immune modulation with preterm birth vs. uncomplicated term birth identifies pivotal signals in pathogenesis of preterm birth.

OBJECTIVES: To assess deviations in longitudinally measured cytokines with preterm birth (PTB). METHODS: Prospective longitudinal study targeting 80 subjects. Phlebotomy specimens for broad panel of cytokine analysis were obtained at three time (T) intervals: first trimester (T1: 8-14 weeks' gestation), second trimester (T2: 18-22 weeks' gestation), and third trimester (T3: 28-32 weeks' gestation). Important demographics and outcomes were tracked. Data were stratified and the target groups were analyzed as follows: "Uncomplicated" (delivered ≥37 weeks) or "Preterm Birth" (<37 weeks). Generalized Linear Modeling determined rate of change T1-T3 by outcome. RESULTS: Complete data replete with phlebotomy at all three visits were obtained on 80 women. Birth outcomes were as follows: 11 Uncomplicated Term Birth (UTB), 28 PTB, 4 low birth weight (LBW), 16 OB complications (OBC), 11 current infections (IFN), and 10 mixed complications (MC=2 or more of the above). 28 PTB were compared to 11 uncomplicated term deliveries. In both groups, T helper type 1 (TH1) cytokine (IL-1ß), pleiotrophic pro-inflammatory cytokine (IL-6), and counter-regulatory cytokine (IL-10) responses decreased over gestation, but rates of change in IL-1ß, IL-6, and IL-10 were significantly different. Stratification of women by smoking status additionally demonstrated significant variance in immune status over the course of pregnancy. CONCLUSIONS: Women delivering PTB demonstrated significant differences in cytokine trajectory over pregnancy; these data further validate key role played by immune regulation in directing pregnancy outcome. Likewise, smoking impacts longitudinal trajectory of cytokines over pregnancy.

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort.

BACKGROUND: Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results. METHODS: To provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS. RESULTS: Separate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63). Limitations Since we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium. CONCLUSIONS: This study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.

Variation in C-reactive protein at 1 month post-partum by etiology of preterm birth: selective identification of those at risk for both poor pregnancy outcome and future health complications.

Objective To assess post-partum inflammation for patients delivering prior to 34 6/7 weeks by birth etiology. Methods This was an observational study of early preterm birth (PTB) occurring between 20 0/7 and 34 6/7 weeks of gestation. Serum C-reactive protein (CRP) levels were measured 1 month post-partum. CRP measurements were compared by birth etiology. Results A total of 399 women were analyzed. Distribution of birth etiology was 35% (n = 138) preterm labor (PTL), 28% (n = 115) preterm premature rupture of membranes (pPROM), and 37% (n = 141) indicated preterm birth (IPTB). Serum CRP varied by birth etiology (P = 0.036). Women with pPROM had elevated median CRP levels compared to women with PTL (P = 0.037). IPTB demonstrated elevated CRP levels when compared to PTL (P = 0.019). Pre-eclamptic/eclamptic subjects exhibited increased median CRP levels compared to PTL (P = 0.04). Conclusion Post-partum inflammation varies by birth etiology. Such variation may serve as identification of subjects whose future pregnancies and, ultimately, overall health status may benefit from inter-pregnancy interventions aimed at reducing inflammatory-associated risk factors.

Perceptions of Infection Risk With Immunomodulatory Medications.

OBJECTIVES: Physicians of many specialties encounter patients treated with immunomodulatory medications and must weigh the risk of infection when making medical decisions. We explored how physician perceptions of the infection risk of immunomodulatory medications differ by specialty and level of experience. METHODS: A survey was distributed to physicians from the internal medicine, family medicine, emergency medicine, rheumatology, dermatology, and infectious disease departments at 1 tertiary care institution. Physicians scored their level of concern for the risk of infection of 15 commonly used immunomodulatory medications hypothetically taken for 1 year. RESULTS: The survey was distributed to 634 people; 197 physicians completed the survey. Opinion of the risk of infection differed significantly by specialty for 8 of 15 medications. Experienced providers rated risk of infection differently from less experienced providers for prednisone 10 to 20 mg (P = 0.046), hydroxychloroquine (P = 0.013), dapsone (P = 0.029), and anti-tumor necrosis factor (TNF) therapy (P = 0.027). Most experienced physicians regarded dapsone (95%) and hydroxychloroquine (93%) as low risk, whereas many less experienced physicians scored them as medium- or high-risk medications. In contrast, experienced physicians were more likely to rate prednisone 10 to 20 mg as medium or high risk. Most less experienced physicians (55%) identified anti-TNF therapy as high risk, whereas experienced physicians were split evenly among low, medium, and high risk. CONCLUSIONS: There is substantial variability in physician perception of the risk of infection of many immunomodulatory medications. Experienced physicians are more concerned than peers about the risk of infection of intermediate doses of prednisone. Opinions regarding anti-TNF therapy range broadly even among experienced providers.

First Trimester Maternal Glycated Hemoglobin and Sex Hormone-Binding Globulin Do Not Predict Third Trimester Glucose Intolerance of Pregnancy.

Early pregnancy prediction of third trimester glucose intolerance may identify a population of women whose trajectory toward gestational diabetes mellitus (GDM) is modifiable. We assessed whether first trimester glycated hemoglobin (HbA1c) and sex hormone-binding globulin (SHBG), markers of insulin resistance, predicted third trimester glucose intolerance. Nondiabetic women with singleton pregnancies enrolled in a prospective observational study, 11 0/7 to 14 6/7 weeks. At enrollment, maternal characteristics, medical history, and blood samples were collected for HbA1c and SHBG. Two-step GDM screening was performed, 22 0/7 to 33 6/7 weeks. A 50 g oral glucose tolerance test ≥130 mg/dL defined screen positive, or glucose intolerance. Carpenter-Coustan criteria diagnosed GDM. Means HbA1c and SHBG were compared between glucose-intolerant versus normoglycemic women, and GDM versus no GDM women. We report unadjusted and adjusted odds ratios (OR; 95% confidence interval [CI]) of regression analyses. Adjusted models include race, enrollment body mass index, and history of GDM. Among 250 women, 29% were glucose intolerant and 6% had GDM. Among glucose-intolerant women, HbA1c was higher (5.3 ± 0.3 vs. 5.1 ± 0.3, P = .01) and associated with glucose intolerance in unadjusted, but not adjusted, models (OR: 2.9, 95% CI: 1.2-7.1; adjusted odds ratio [aOR]: 2.0, 95% CI: 0.7-5.4). Among GDM women, HbA1c was higher (5.4 ± 0.4 vs 5.2 ± 0.3, P = .002) and SHBG was lower (228 ± 72 vs 288 ± 93 mmol/L, P = .02). The HbA1c predicted GDM in unadjusted (OR: 13.2, 95% CI: 2.6-68.0) but not adjusted (aOR: 6.7, 95% CI: 0.8-55.2) models. Although metabolic alterations may well precede third trimester glucose intolerance, neither HbA1c of SHBG remained an independent predictor of glucose intolerance or GDM in adjusted models.

Parent and Adolescent Interest in Receiving Adolescent Health Communication Information From Primary Care Clinicians.

PURPOSE: Patient-centered health care recognizes that adolescents and parents are stakeholders in adolescent health. We investigate adolescent and parent interest in receiving information about health topics and parent-teen communication from clinicians. METHODS: Ninety-one parent-adolescent dyads in one practice completed individual interviews. Items assessed levels of interest in receiving health and health communication information from the adolescent's doctor about 18 topics, including routine, mental health, sexual health, substance use, and injury prevention issues. Analyses tested differences between parents and adolescents, within-dyad correlations, and associations with adolescent gender and age. RESULTS: Most parents were female (84%). Adolescents were evenly divided by gender; 36 were aged 12-13 years, 35 were aged 14-15 years, and 20 were aged 16-17 years. Adolescent race reflected the practice population (60% black; 35% white). The vast majority of parents and adolescents reported moderate or high levels of interest in receiving information about all 18 health issues and information to increase parent-teen communication about these topics. Parents' interest in receiving information varied by adolescent age when the expected salience of topics varied by age (e.g., acne, driving safety), whereas adolescents reported similar interest regardless of age. Adolescent gender influenced parent and adolescent interest. Level of interest in receiving information from doctors within adolescent-parent pairs was not significantly correlated for one-half of topics. CONCLUSIONS: Parents and adolescents want health care professionals to help them learn and talk about a wide range of adolescent health topics. Feasible primary care interventions that effectively improve parent-teen health communication, and specific adolescent health outcomes are needed.

Lessons learned from the Philadelphia Collaborative Preterm Prevention Project: the prevalence of risk factors and program participation rates among women in the intervention group.

BACKGROUND: Women who deliver preterm infants are at a much greater risk for repeating a preterm birth (PTB), compared to women without a history of PTB. However, little is known about the prevalence of the risk factors which account for this markedly increased risk. Moreover, little or nothing is known about the feasibility of providing treatments and services to these women, outside of the context of prenatal care, during the inter-conception period, which provides the best opportunity for successful risk-reduction interventions. METHODS: The Philadelphia Collaborative Preterm Prevention Project (PCPPP), a large randomized control trial designed to identify and reduce six major risk factors for a repeat preterm birth among women immediately following the delivering of a preterm infant. For the women assigned to the PCPPP treatment group, we calculated the prevalence of the six risk factors in question, the percentages of women who agreed to receive high quality risk-appropriate treatments or services, and the of rates of participation among those who were offered and eligible for these treatments or services. RESULTS: Urogenital tract infections were identified in 57% of the women, while 59% were found to have periodontal disease. More than 39% were active smokers, and 17% were assessed with clinical depression. Low literacy, and housing instability were identified in, 22 and 83% of the study sample, respectively. Among women eligible for intervention, the percentages who accepted and at least minimally participated in treatment ranged from a low of 28% for smoking, to a high of 85% for urogenital tract infection. Most PCPPP enrollees (57%) had three or more major risk factors. Participation rates associated with the PCPPP treatments or services varied markedly, and were quite low in some cases, despite considerable efforts to reduce the barriers to receiving care. CONCLUSION: The efficacy of individual level risk-reduction efforts designed to prevent preterm/repeat preterm in the pre- or inter-conception period may be limited if participation rates associated with interventions to reduce major risk factors for PTB are low. Achieving adequate participation may require identifying, better understanding, and eliminating barriers to access, beyond those associated with cost, transportation, childcare, and service location or hours of operation. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01117922 ).

Pregnancy intention and contraceptive use at six months postpartum among women with recent preterm delivery.

OBJECTIVE: To describe pregnancy intention and contraceptive use among women with a recent delivery that occurred at 35 weeks gestation or fewer and who were enrolled in a large-scale randomized control trial. DESIGN: In this descriptive study we used data from assessments conducted at 6 months postpartum as part of a randomized controlled clinical trial, the Philadelphia Collaborative Preterm Prevention Project (PCPPP). PARTICIPANTS AND SETTING: Participants were recruited following a preterm birth (PTB) in one of the 12 urban birth hospitals. All women enrolled in PCPPP, who completed their 6-month postpartum assessment, and who were sexually active at the time of that assessment (n = 566), were included in the analysis. METHODS: Data were collected during face-to-face interviews. Study questionnaires included questions about participants' plans for the timing of subsequent pregnancies, contraceptive behaviors, and other health variables. RESULTS: Nearly all of the participants (90.1%, n = 509) reported they did not want to get pregnant within one year of the index PTB. However, more than one half of these women (54.6%) reported contraceptive practices of low or moderate effectiveness. Most predictive of intending another pregnancy within the year was the death of the index PTB infant (odds ratio [OR]= 18.2,95% confidence interval [CI] [8.9, 37.0]). CONCLUSIONS: Discordant pregnancy intention and contraceptive use were reported among this group of mothers of PTB infants who are at particularly high risk for a poor outcome of any subsequent pregnancy. The findings highlight the need for further investigation of the causes, correlates, and consequences of discordant pregnancy intentions and contraceptive practices.

Small-for-gestational-age births in pregnant women with HIV, due to severity of HIV disease, not antiretroviral therapy.

OBJECTIVES: To determine rate and factors associated with small-for-gestational-age (SGA) births to women with HIV. METHODS: Prospective data were collected from 183 pregnant women with HIV in an urban HIV prenatal clinic, 2000-2011. An SGA birth was defined as less than the 10th or 3rd percentile of birth weight distribution based upon cut points developed using national vital record data. Bivariate analysis utilized chi-squared and t-tests, and multiple logistic regression analyses were used. RESULTS: The prevalence of SGA was 31.2% at the 10th and 12.6% at the 3rd percentile. SGA at the 10th (OR 2.77; 95% CI, 1.28-5.97) and 3rd (OR 3.64; 95% CI, 1.12-11.76) percentiles was associated with cigarette smoking. Women with CD4 count>200 cells/mm3 at the first prenatal visit were less likely to have an SGA birth at the 3rd percentile (OR 0.29; 95% CI, 0.10-0.86). Women taking NNRTI were less likely to have an SGA infant at the 10th (OR 0.28; 95% CI, 0.10-0.75) and 3rd (OR 0.16; 95% CI, 0.03-0.91) percentiles compared to those women on PIs. CONCLUSIONS: In this cohort with high rates of SGA, severity of HIV disease, not ART, was associated with SGA births after adjusting for sociodemographic, medication, and disease severity.