Newborn screen metabolic panels reflect the impact of common disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero. METHODS: A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010. RESULTS: A total of 41,333 maternal-infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations. CONCLUSIONS: Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth. IMPACT: Substantial differences in newborn screen analyte profiles were present based on the presence or absence of maternal diabetes or hypertensive disorder of pregnancy and this finding was further influenced by the newborn size designation at birth. The metabolic health of the newborn can be examined using the newborn screen and is heavily impacted by the condition of the mother during pregnancy. Utilizing the newborn screen to identify newborns affected by common conditions of pregnancy may help relate an infant's underlying biological disposition with their clinical phenotype allowing for greater risk stratification and intervention.

Short-Term Outcomes following Standardized Admission of Late Preterm Infants to Family-Centered Care.

OBJECTIVE: The study compares the short-term outcomes of late preterm infants (LPI) at an academic center in San Diego, California after a change in protocol that eliminated a previously mandatory 12-hour neonatal intensive care unit (NICU) observation period after birth. STUDY DESIGN: This is a retrospective observational study examining all LPI born with gestational age 35 to 366/7 weeks between October 1, 2016 and October 31, 2017. A total of 189 infants were included in the review. Short-term outcomes were analyzed before and after the protocol change. RESULTS: Transfers to the NICU from family-centered care (FCC) were considerably higher (23.2%) following the protocol change, compared to before (8.2%). More infants were transferred to the NICU for failed car seat tests postprotocol compared to preprotocol. Length of stay before the protocol change was 5.13 days compared to 4.80 days after. CONCLUSION: LPI are vulnerable to morbidities after delivery and through discharge. We found an increase in failed car seat tests in LPI cared for in FCC after elimination of a mandatory NICU observation after birth. The transitions of care from delivery to discharge are key checkpoints in minimizing complications.

The Diagnostic Accuracy of Serum Procalcitonin for Bacteremia in Critically Ill Children.

BACKGROUND: Bacterial sepsis is frequently encountered in children admitted to the Pediatric Intensive Care Unit (PICU) and requires early recognition and treatment. Procalcitonin (PCT) is a serum biomarker with a high sensitivity to predict bacteremia in critically-ill adults. This study sought to evaluate the diagnostic accuracy of PCT for bacteremia in febrile children in the PICU. METHODS: This retrospective observational study used data from children admitted to the PICU from October 2010 to October 2012. Patients up to 21 years of age were included if they had an abnormal temperature, serum PCT and blood culture assayed, and were not receiving empiric antibiotics at the time. RESULTS: There were 202 PCT values that met inclusion criteria. The prevalence of positive blood cultures was 13.2% (27 total positive blood cultures). The area under the curve (AUC) for PCT was 0.79 (95% CI, 0.70-0.89), the AUC for lactate was 0.76 (95% CI, 0.65-0.87), and the AUC for C-reactive protein was 0.68 (95% CI, 0.57-0.80). The optimal threshold of PCT for accuracy was determined to be 2 ng/mL (sensitivity = 69.2%, specificity = 74.4%, positive predictive value = 28.6%, negative predictive value = 94.2%). The combination of an abnormal lactate (> 2.0mmol/L) increased the specificity of PCT for diagnosing bacteremia. CONCLUSIONS: PCT has a good diagnostic accuracy to rule-out bacteremia in critically-ill, febrile children. The combination of PCT and an abnormal lactate value increases the specificity and may improve the ability to diagnose bacteremia.

Peripartum thromboprophylaxis before and after implementation of a uniform heparin protocol.

AIM: The objective of this study was to assess the utilization of postpartum thromboprophylaxis with heparin in patients according to the Royal College of Obstetrics and Gynaecology Green-Top guidelines after change from an opt-in to an opt-out policy for health care providers ordering heparin thromboprophylaxis after cesarean delivery. STUDY DESIGN: The present study is a retrospective review of 500 consecutive births at one academic institution before and after implementation of a uniform thromboprophylaxis policy with heparin for all cesarean deliveries. An "opt-out" policy for ordering physicians was implemented by automatically defaulting to order heparin in the electronic order set used after cesarean delivery. RESULTS: Cesarean delivery rates were similar during both time periods. Heparin thromboprophylaxis was indicated in 99.6% of the cesarean delivery population before implementation and 94.5% after implementation. Prior to implementation only 5.7% received thromboprophylaxis compared to 96.1% after implementation, P<0.0001. CONCLUSION: An opt-out heparin thromboprophylaxis policy improves compliance with thromboprophylaxis guidelines compared to an opt-in policy. Institutions should consider opt-out heparin thromboprophylaxis policies after cesarean deliveries to improve compliance with recommendations.

Extremely short cervix in the second trimester: bed rest or modified Shirodkar cerclage?

OBJECTIVE: The objective of this study was to compare modified Shirodkar cerclage to bed rest for treatment of the midtrimester extremely short cervix. METHODS: This study used a concurrent retrospective cohort design at two institutions over the same period, 2000-2010. Patients were included at both institutions when midtrimester endovaginal ultrasound cervical length was ≤ 15 mm and had modified Shirodkar cerclage (cerclage group) at New York Hospital Queens and bed rest (control group) at Weill Cornell Medical Center. Cerclage was placed as high on the cervix as possible. Indomethacin and antibiotics were used perioperatively. RESULTS: The cerclage group included 112 patients and the control group included 55 patients. Median postoperative cervical length in the cerclage group was 3.3 cm (interquartile range 3.0-3.6). Cerclage patients were less likely to deliver preterm at 37, 35, 32, and 28 weeks (P=0.0066, 0.0004, 0.0023, and 0.03 respectively) and had longer latency (median 120 vs. 94 days P<0.0001). Kaplan-Meier survival curve showed a significant benefit in favor of cerclage (P=0.0043). CONCLUSIONS: Our data suggest that modified Shirodkar cerclage as high as possible on the cervix with perioperative indomethacin and antibiotics is superior to bed rest for treatment of the midtrimester extremely short cervix (≤15 mm). We propose a randomized trial of this specific technique.

Data-driven longitudinal characterization of neonatal health and morbidity.

Although prematurity is the single largest cause of death in children under 5 years of age, the current definition of prematurity, based on gestational age, lacks the precision needed for guiding care decisions. Here, we propose a longitudinal risk assessment for adverse neonatal outcomes in newborns based on a deep learning model that uses electronic health records (EHRs) to predict a wide range of outcomes over a period starting shortly before conception and ending months after birth. By linking the EHRs of the Lucile Packard Children's Hospital and the Stanford Healthcare Adult Hospital, we developed a cohort of 22,104 mother-newborn dyads delivered between 2014 and 2018. Maternal and newborn EHRs were extracted and used to train a multi-input multitask deep learning model, featuring a long short-term memory neural network, to predict 24 different neonatal outcomes. An additional cohort of 10,250 mother-newborn dyads delivered at the same Stanford Hospitals from 2019 to September 2020 was used to validate the model. Areas under the receiver operating characteristic curve at delivery exceeded 0.9 for 10 of the 24 neonatal outcomes considered and were between 0.8 and 0.9 for 7 additional outcomes. Moreover, comprehensive association analysis identified multiple known associations between various maternal and neonatal features and specific neonatal outcomes. This study used linked EHRs from more than 30,000 mother-newborn dyads and would serve as a resource for the investigation and prediction of neonatal outcomes. An interactive website is available for independent investigators to leverage this unique dataset: https://maternal-child-health-associations.shinyapps.io/shiny_app/.

Progressive Metabolic Abnormalities Associated with the Development of Neonatal Bronchopulmonary Dysplasia.

Objective: To assess the longitudinal metabolic patterns during the evolution of bronchopulmonary dysplasia (BPD) development. Methods: A case-control dataset of preterm infants (<32-week gestation) was obtained from a multicenter database, including 355 BPD cases and 395 controls. A total of 72 amino acid (AA) and acylcarnitine (AC) variables, along with infants' calorie intake and growth outcomes, were measured on day of life 1, 7, 28, and 42. Logistic regression, clustering methods, and random forest statistical modeling were utilized to identify metabolic variables significantly associated with BPD development and to investigate their longitudinal patterns that are associated with BPD development. Results: A panel of 27 metabolic variables were observed to be longitudinally associated with BPD development. The involved metabolites increased from 1 predominant different AC by day 7 to 19 associated AA and AC compounds by day 28 and 16 metabolic features by day 42. Citrulline, alanine, glutamate, tyrosine, propionylcarnitine, free carnitine, acetylcarnitine, hydroxybutyrylcarnitine, and most median-chain ACs (C5:C10) were the most associated metabolites down-regulated in BPD babies over the early days of life, whereas phenylalanine, methionine, and hydroxypalmitoylcarnitine were observed to be up-regulated in BPD babies. Most calorie intake and growth outcomes revealed similar longitudinal patterns between BPD cases and controls over the first 6 weeks of life, after gestational adjustment. When combining with birth weight, the derived metabolic-based discriminative model observed some differences between those with and without BPD development, with c-statistics of 0.869 and 0.841 at day 7 and 28 of life on the test data. Conclusions: The metabolic panel we describe identified some metabolic differences in the blood associated with BPD pathogenesis. Further work is needed to determine whether these compounds could facilitate the monitoring and/or investigation of early-life metabolic status in the lung and other tissues for the prevention and management of BPD.

Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations.

Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.

Single-Cell Analysis of the Neonatal Immune System Across the Gestational Age Continuum.

Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8+CD161+ T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections.

Outcomes of Infants with Mild Hypoxic Ischemic Encephalopathy Who Did Not Receive Therapeutic Hypothermia.

INTRODUCTION: Accurately diagnosing and treating infants with mild forms of hypoxic ischemic encephalopathy (HIE) is important, as the majority of neonates with signs and symptoms of HIE after birth do not meet clinical criteria for moderate or severe disease. Emerging evidence, however, suggests that infants with mild HIE (mHIE) have an increased risk for neurodevelopmental impairment (NDI). METHODS: This retrospective descriptive study examined all inborn infants ≥35 week's gestational age at a single, level III neonatal intensive care unit (NICU) in California between January 1, 2012, and December 31, 2015. International Classification of Diseases codes were used as a proxy to identify neonates with mHIE but who did not receive therapeutic hypothermia (TH). Short- and long-term neurodevelopmental outcomes were documented, including abnormal (1) brain magnetic resonance imaging within 10 days of birth suggestive of HIE, (2) electroencephalogram with electrographic seizures, (3) neurologic discharge examination, or (4) NDI following NICU discharge. RESULTS: Over the 4-year study period, 25 infants met inclusion criteria. Eight of 25 (32%) infants demonstrated neurologic impairment, defined by an abnormality in at least one of the four categories. The remaining 17 infants were without documented evidence for adverse outcomes. CONCLUSION: Our results indicate that children with mHIE are at significant risk for neurologic injury and may benefit from more aggressive interventions. Further prospective studies should be completed to determine the efficacy of TH in this specific patient population.

Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry.

INTRODUCTION: Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database. METHODS: The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed. RESULTS: A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection. CONCLUSIONS: The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

Long-term follow up of rates of secondary malignancy and late relapse of two trials using radioimmunotherapy consolidation following induction chemotherapy for previously untreated indolent lymphoma.

Existing data suggest that myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) peak in incidence 5-10 years following exposure to ionizing radiation, while most publications report less than 5 years of follow-up after radioimmunotherapy (RIT). We report the rate of secondary MDS/AML among 60 patients treated with two front-line sequential chemotherapy-RIT trials with over 11 years of follow-up. Among 35 patients evaluated after fludarabine-RIT and 25 patients evaluated after CVP (cyclophosphamide, vincristine, prednisone)-RIT treatment, the crude, cumulative and Kaplan-Meier rates of MDS/AML at 11 years of follow-up from the combined trials were 0.12/person, 0.010/person-year and 14% (95% confidence interval [CI] 5-24%), respectively. Additionally, we found that patients treated with RIT consolidation appear to have durable remissions but that relapses after 10 years do occur. Studies of efficacy and secondary MDS/AML that report fewer than 10 years of follow-up likely underestimate risk.