Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. METHODS: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. RESULTS: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. CONCLUSIONS: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

Cholestasis is associated with a higher rate of complications in both medical and surgical necrotizing enterocolitis.

OBJECTIVE: To evaluate the relationship between cholestasis and outcomes in medical and surgical necrotizing enterocolitis (NEC). STUDY DESIGN: A retrospective analysis of prospectively collected data from 1472 infants with NEC [455 medical (mNEC) and 1017 surgical (sNEC)] from the Children's Hospital Neonatal Database. RESULTS: The prevalence of cholestasis was lower in mNEC versus sNEC (38.2% vs 70.1%, p < 0.001). In both groups, cholestasis was associated with lower birth gestational age [mNEC: OR 0.79 (95% CI 0.68-0.92); sNEC: OR 0.86 (95% CI 0.79-0.95)] and increased days of parenteral nutrition [mNEC: OR 1.08 (95% CI 1.04-1.13); sNEC: OR 1.01 (95% CI 1.01-1.02)]. For both groups, the highest direct bilirubin was associated with the composite outcome mortality or length of stay >75th percentile [mNEC: OR 1.21 (95% CI 1.06-1.38); sNEC: OR 1.06 (95% CI 1.03-1.09)]. CONCLUSION: Cholestasis with both medical NEC and surgical NEC is associated with adverse patient outcomes including increased mortality or extreme length of stay.

A quality improvement initiative standardizing the antibiotic treatment and feeding practices in patients with medical necrotizing enterocolitis.

OBJECTIVE: Evaluate the impact of a multidisciplinary guideline standardizing antibiotic duration and enteral feeding practices following medical necrotizing enterocolitis (mNEC). STUDY DESIGN: For preterm infants with Bell Stage 2 A mNEC and negative blood culture, antibiotic treatment was standardized to 7 days. Trophic feeds of unfortified human milk began 72 h after resolution of pneumatosis. Feeds were advanced by 20 cc/kg/day starting on the last day of antibiotics. Primary outcomes were antibiotic days and days to full feeds, defined as 120 cc/kg/day of enteral nutrition. Secondary outcomes included central line days and length of stay (LOS). RESULTS: Antibiotic duration decreased 23%. Time to start trophic feeds and time to full feeds decreased 33 and 16% respectively. Central line use dropped (98 to 72% of infants) and central line days were reduced by 59%. CONCLUSION: Implementation of a mNEC QI package reduced antibiotic duration, time to full feeds, central line use and CL days.

Clinical and economic impacts of a modified-observational screening approach to well-appearing infants born to mothers with chorioamnionitis.

OBJECTIVE: Term infants born to mothers with chorioamnionitis are at risk for early-onset sepsis (EOS). We aimed to measure the impact of changing from a categorical to a modified-observational EOS screening approach on NICU admission, antibiotic utilization, and hospitalization costs. STUDY DESIGN: Single-center retrospective pre-post cohort study of full-term infants born to mothers with chorioamnionitis. Primary outcomes included NICU admission, antibiotic utilization, and hospitalization costs. Outcomes were adjusted for demographic variables. Budget-impact analysis was performed using bootstrapping with replication. RESULTS: 380 term infants were included (197 categorical; 183 modified-observational). There was a significant decrease in NICU admission and antibiotic utilization (p < 0.05) in the modified-observational cohort but no significant difference in per-patient total hospitalization costs. Budget-impact analysis suggested a high probability of cost savings. CONCLUSION: A modified-observational approach to evaluating term infants of mothers with chorioamnionitis can reduce NICU admission and unnecessary antibiotic therapy, and may lead to cost-savings.

Umbilical Cord Milking Versus Delayed Cord Clamping in Infants 28 to 32 Weeks: A Randomized Trial.

OBJECTIVES: To determine whether rate of severe intraventricular hemorrhage (IVH) or death among preterm infants receiving placental transfusion with UCM is noninferior to delayed cord clamping (DCC). METHODS: Noninferiority randomized controlled trial comparing UCM versus DCC in preterm infants born 28 to 32 weeks recruited between June 2017 through September 2022 from 19 university and private medical centers in 4 countries. The primary outcome was Grade III/IV IVH or death evaluated at a 1% noninferiority margin. RESULTS: Among 1019 infants (UCM n = 511 and DCC n = 508), all completed the trial from birth through initial hospitalization (mean gestational age 31 weeks, 44% female). For the primary outcome, 7 of 511 (1.4%) infants randomized to UCM developed severe IVH or died compared to 7 of 508 (1.4%) infants randomized to DCC (rate difference 0.01%, 95% confidence interval: (-1.4% to 1.4%), P = .99). CONCLUSIONS: In this randomized controlled trial of UCM versus DCC among preterm infants born between 28 and 32 weeks' gestation, there was no difference in the rates of severe IVH or death. UCM may be a safe alternative to DCC in premature infants born at 28 to 32 weeks who require resuscitation.

Categorical Risk Stratification for Neonatal Early Onset Sepsis using Suspected Intraamniotic Infection and the Newborn Exam.

Objective: To determine test characteristics of categorical risk stratification for early onset sepsis (EOS) using maternal criteria for suspected intraamniotic infection (IAI) and/or newborn exam and compare them to the EOS calculator. Study Design: Retrospective 1:3 case-control study of late preterm/term infants with bacterial culture growth obtained <72 hours of life. For categorical approach, infants of mothers with suspected IAI or equivocal/ill appearing were presumed high-risk for EOS and blood culture obtained. For calculator, estimated probability of EOS and care recommendations were recorded from online calculator. Test characteristics were compared with McNemar's test; recommendation for blood culture was considered a "positive" test. Result: 52 cases and 172 controls were included. Compared to the calculator, the categorical approach had higher sensitivity 90%(95%CI:79-96%) vs 67% (95%CI:54-79%) but lower specificity 85%(95%CI:78-89%) vs. 92%(95%CI:87-96%). 10% of cases were not identified by either. Conclusion: A categorical approach using suspected IAI/newborn exam offers good EOS discrimination and is comparable to the calculator.

Current Patterns of Probiotic Use in U.S. Neonatal Intensive Care Units: A Multi-Institution Survey.

OBJECTIVE: Probiotic supplementation is associated with health benefits in preterm infants. The 2021 American Academy of Pediatrics (AAP) statement on probiotic use advised caution, citing heterogeneity and absence of federal regulation. We assessed the impact of the AAP statement and current institution-wide patterns of probiotic use across neonatal intensive care units (NICU) across the United States. STUDY DESIGN: A cross-sectional web-based institutional survey using REDCap was emailed to 430 Children's Hospital Neonatal Consortium (CHNC) and Pediatrix Medical Group institutions. The survey captured data on probiotic formulations, supplementation, initiation and cessation criteria, reasons for discontinuation, interest in initiating, and AAP statement's impact. RESULTS: Ninety-five (22.1%) hospitals, including 42/46 (91%) CHNC and 53/384 (14%) Pediatrix institutions, completed the survey. Thirty-seven (39%) currently use probiotics. Fourteen different probiotic formulations were reported. The common criteria for initiation were birth weight <1,500 g and gestational age <32 weeks. Parental consent or assent was obtained at only 30% of institutions. Five hospitals (11%) with prior probiotic use discontinued solely due to the AAP statement. Overall, 23 (24%) of hospitals indicated that the AAP statement significantly influenced their decision regarding probiotic use. Nineteen of 51 nonusers (37%) are considering initiation. CONCLUSION: Probiotic use in preterm infants is likely increasing in NICUs across the United States, but significant variability exists. The 2021 AAP statement had variable impact on NICUs' decision regarding probiotic use. The growing interest in adopting probiotics and the significant interhospital variability highlight the need for better regulation and consensus guidelines to ensure standardized use. KEY POINTS: · Probiotic use in preterm infants is likely increasing in U.S. NICUs, but clinical variability exists.. · The AAP statement on probiotic use in preterm infants had a modest impact on current practices.. · There's a need for better product regulation and consensus guidelines to ensure standardized use..

Antibiotic therapy and necrotizing enterocolitis.

Antibiotic therapy remains a cornerstone of treatment of both medical and surgical presentations of necrotizing enterocolitis (NEC). However, guidelines regarding the administration of antibiotics for the treatment of NEC are lacking and practices vary amongst clinicians. Although the pathogenesis of NEC is unknown, there is consensus that the infant gastrointestinal microbiome contributes to the disease. The presumed connection between dysbiosis and NEC has prompted some to study whether early prophylactic enteral antibiotics can prevent NEC. Yet others have taken an opposing approach, studying whether perinatal antibiotic exposure increases the risk of NEC by inducing a state of dysbiosis. This narrative review summarizes what is known about antibiotics and their association with the infant microbiome and NEC, current antibiotic prescribing practices for infants with medical and surgical NEC, as well as potential strategies to further optimize the use of antibiotics in this population of infants.

Efficacy of a Vibrating Crib Mattress to Reduce Pharmacologic Treatment in Opioid-Exposed Newborns: A Randomized Clinical Trial.

Importance: Pharmacologic agents are often used to treat newborns with prenatal opioid exposure (POE) despite known adverse effects on neurodevelopment. Alternative nonpharmacological interventions are needed. Objective: To examine efficacy of a vibrating crib mattress for treating newborns with POE. Design, Setting, and Participants: In this dual-site randomized clinical trial, 208 term newborns with POE, enrolled from March 9, 2017, to March 10, 2020, were studied at their bedside throughout hospitalization. Interventions: Half the cohort received treatment as usual (TAU) and half received standard care plus low-level stochastic (random) vibrotactile stimulation (SVS) using a uniquely constructed crib mattress with a 3-hour on-off cycle. Study initiated in the newborn unit where newborns were randomized to TAU or SVS within 48 hours of birth. All infants whose symptoms met clinical criteria for pharmacologic treatment received morphine in the neonatal intensive care unit per standard care. Main Outcomes and Measures: The a priori primary outcomes analyzed were pharmacotherapy (administration of morphine treatment [AMT], first-line medication at both study sites [number of infants treated], and cumulative morphine dose) and hospital length of stay. Intention-to-treat analysis was conducted. Results: Analyses were performed on 181 newborns who completed hospitalization at the study sites (mean [SD] gestational age, 39.0 [1.2] weeks; mean [SD] birth weight, 3076 (489) g; 100 [55.2%] were female). Of the 181 analyzed infants, 121 (66.9%) were discharged without medication and 60 (33.1%) were transferred to the NICU for morphine treatment (31 [51.7%] TAU and 29 [48.3%] SVS). Treatment rate was not significantly different in the 2 groups: 35.6% (31 of 87 infants who received TAU) and 30.9% (29 of 94 infants who received SVS) (P = .60). Adjusting for site, sex, birth weight, opioid exposure, and feed type, infant duration on the vibrating mattress in the newborn unit was associated with reduction in AMT (adjusted odds ratio, 0.88 hours per day; 95% CI, 0.81-0.93 hours per day). This translated to a 50% relative reduction in AMT for infants who received SVS on average 6 hours per day. Among 32 infants transferred to the neonatal intensive care unit for morphine treatment who completed treatment within 3 weeks, those assigned to SVS finished treatment nearly twice as fast (hazard ratio, 1.96; 95% CI, 1.01-3.81), resulting in 3.18 fewer treatment days (95% CI, -0.47 to -0.04 days) and receiving a mean 1.76 mg/kg less morphine (95% CI, -3.02 to -0.50 mg/kg) than the TAU cohort. No effects of condition were observed among infants treated for more than 3 weeks (n = 28). Conclusions and Relevance: The findings of this clinical trial suggest that SVS may serve as a complementary nonpharmacologic intervention for newborns with POE. Reducing pharmacotherapy with SVS has implications for reduced hospitalization stays and costs, and possibly improved infant outcomes given the known adverse effects of morphine on neurodevelopment. Trial Registration: ClinicalTrials.gov Identifier: NCT02801331.

Patterns of lipid-injectable emulsion use in neonatal intensive care units across the United States: A multi-institution survey.

BACKGROUND: Lipid-injectable emulsions (ILEs) are a necessity for neonates dependent on parenteral nutrition (PN). In this manuscript, we describe the patterns of ILE use in neonatal intensive care units (NICUs) in the United States (US). METHODS: An electronic survey was sent to 488 NICUs across the US between December 2020 and March 2021. Survey fields included availability and utilization of various ILE in neonates. RESULTS: The response rate was 22% (107 out of 488). Soybean oil ILE (SO-ILE) and soybean oil, medium-chain triglycerides, olive oil, fish oil ILE (SO, MCT, OO, FO-ILE) had similar availability (87% vs 86%, respectively), and SO, MCT, OO, FO-ILE was more commonly used (SO-ILE, 71% vs SO, MCT, OO, FO-ILE, 86%). Fish oil-ILE (FO-ILE) was used by 55% of centers. SO-ILE was most frequently used with PN and needs <4 weeks without cholestasis (79%). The most common reason for SO, MCT, OO, FO-ILE use was cholestasis (71%). ILE minimization was used by 28% of SO-ILE and 22% of SO, MCT, OO, FO-ILE users; 95% of these centers restrict SO, MCT, OO, FO-ILE to doses ≤2 g/kg/day. Twenty-two percent of centers started FO-ILE at direct bilirubin of >5 mg/dl. CONCLUSION: The results of this survey reveal significant variability in ILE usage across the US. Lipid minimization with SO, MCT, OO, FO-ILE and initiation of FO-ILE for cholestasis at higher bilirubin thresholds are prevalent. Such reports are crucial for a better understanding of ILE use in the NICU and in future ILE development.

Infections in the NICU: Neonatal sepsis.

Neonatal infections remain an important cause of neonatal morbidity and mortality worldwide. Neonatal sepsis is a systemic infection that can be classified as early-onset or late-onset pending the timing of presentation. The pathophysiology and causative pathogens of neonatal sepsis vary, with early-onset sepsis being associated with a vertically transmitted infection from mother to neonate versus late onset sepsis being commonly associated with nosocomial infections. The signs and symptoms of neonatal sepsis mimic those associated with prematurity, making timely diagnosis difficult for treating clinicians. The management of neonatal sepsis is centered around obtaining adequate culture data and initiation of broad-spectrum parenteral antibiotics. Controversies surrounding the management of neonatal sepsis include the administration of empiric antibiotics, given recent clinical studies associating early antibiotic use with clinical sequelae such as late-onset sepsis, necrotizing enterocolitis, and death in the preterm, low-birthweight infant population.

Utility of Postnatal Chest X-Ray in Newborns for the Evaluation of Prenatally Suspected Congenital Pulmonary Airway Malformation: A Single-Center Experience.

OBJECTIVE: The aim of the study is to assess the necessity of chest X-ray (CXR) during the newborn hospitalization for all patients with prenatally suspected congenital pulmonary airway malformation (CPAM). STUDY DESIGN: This is a retrospective chart review of all infants delivered with prenatally suspected CPAM at our high-risk delivery hospital from January 2013 through April 2020 (n = 44). Nonparametric tests assessed the association between postnatal CXR findings, prescribed follow-up timeline, and neonatal outcomes. RESULTS: Mean follow-up period recommended was 6.4 weeks regardless of CXR findings in the neonatal period (p = 0.81). Additionally, patients who required respiratory support at or after birth were not more likely to have a lesion identified on chest X-ray (odds ratio [OR] = 0.72, 95% confidence interval [CI], 0.18-2.64, p = 0.71). CONCLUSION: Neonatal hospital course and future follow-up plan of patients with prenatally suspected CPAM were not altered by information from the CXR obtained in the immediate neonatal period, suggesting that this CXR may not be necessary in the asymptomatic patient. KEY POINTS: · Immediate postnatal X-ray of prenatally diagnosed CPAM does not alter planned follow-up interval.. · Immediate postnatal X-ray does not alter surgical plan for CPAM.. · Postnatal X-ray is not absolutely required for asymptomatic newborns with CPAM..

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Variability in antibiotic duration for necrotizing enterocolitis and outcomes in a large multicenter cohort.

OBJECTIVES: To evaluate variability in antibiotic duration for necrotizing enterocolitis (NEC) and associated clinical outcomes. STUDY DESIGN: Five-hundred ninety-one infants with NEC (315 medical; 276 surgical) were included from 22 centers participating in Children's Hospitals Neonatal Consortium (CHNC). Multivariable analyses were used to determine predictors of variability in time to full feeds (TFF) and length of stay (LOS). RESULTS: Median (IQR) antibiotic duration was 12 (9, 17) days for medical and 17 (14, 21) days for surgical NEC. Wide variability in antibiotic use existed both within and among centers. Duration of antibiotic therapy was associated with longer TFF in both medical (OR 1.04, 95% CI [1.01, 1.05], p < 0.001) and surgical NEC (OR 1.02 [1, 1.03] p = 0.046); and with longer LOS in medical (OR 1.03 [1.02, 1.04], p < 0.001) and surgical NEC (OR 1.01 [1.01, 1.02], p = 0.002). CONCLUSION: Antibiotic duration for both medical and surgical NEC remains variable within and among high level NICUs.

Opioid exposure during therapeutic hypothermia and short-term outcomes in neonatal encephalopathy.

OBJECTIVE: To assess the association between opioid exposure during therapeutic hypothermia (TH) for perinatal hypoxic-ischemic encephalopathy (HIE) and in-hospital outcomes. STUDY DESIGN: In this retrospective cohort study, linked data were accessed on infants ≥36 weeks gestation, who underwent TH for HIE, born from 2010-2016 in 23 Neonatal Intensive Care Units participating in Children's Hospitals Neonatal Consortium and Pediatric Health Information Systems. We excluded infants who received opioids for >5 days. RESULTS: The cohort (n = 1484) was categorized as No opioid [240(16.2%)], Low opioid (1-2 days) [574 (38.7%)] and High opioid group (HOG, 3-5 days) [670 (45.2%)]. After adjusting for HIE severity, opioids were not associated with abnormal MRI, but were associated with decreased likelihood of complete oral feeds at discharge. HOG had increased likelihood of prolonged hospital stay and ventilation. CONCLUSION: Opioid exposure during TH was not associated with abnormal MRI; its association with adverse short-term outcomes suggests need for cautious empiric use.

Perinatal Outcomes of Subjects Enrolled in a Multicenter Trial with a Waiver of Antenatal Consent.

OBJECTIVE: This study aimed to determine whether outcomes differed between infants enrolled in the PREMOD2 trial and those otherwise eligible but not enrolled, and whether the use of waiver effected these differences. STUDY DESIGN: The multicenter PREMOD2 (PREmature infants receiving Milking Or Delayed cord clamping) trial was approved for waiver of antenatal consent by six of the nine sites institutional review boards, while three sites exclusively used antenatal consent. Every randomized subject delivered at a site with a waiver of consent was approached for postnatal consent to allow for data collection. Four of those six sites IRBs required the study team to attempt antenatal consent when possible. Three sites exclusively used antenatal consent. RESULTS: Enrolled subjects had higher Apgar scores, less use of positive pressure ventilation, a lower rate of bronchopulmonary dysplasia, and a less frequent occurrence of the combined outcome of severe intraventricular hemorrhage or death. A significantly greater number of infants were enrolled at sites with an option of waiver of consent (66 vs. 26%, risk ratio = 2.54, p < 0.001). At sites with an option of either approaching families before delivery or after delivery with a waiver of antenatal consent, those approached prior to delivery refused consent 40% (range 15-74% across six sites) of the time. CONCLUSION: PREMOD2 trial demonstrated analytical validity limitations because of the variable mix of antenatal consent and waiver of consent. A waiver of antenatal consent for minimal risk interventional trials conducted during the intrapartum period will be more successful in enrolling a representative sample of low and high-risk infants if investigators are able to enroll all eligible subjects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03019367. KEY POINTS: · Waiver of consent is when informed consent cannot be obtained prior to delivery.. · Cord milking is a procedure in which blood is pushed (stripped) two to four times towards the newborn.. · Delayed clamping means the umbilical cord is not clamped immediately after birth..

Utilization of Therapeutic Hypothermia and Neurological Injury in Neonates with Mild Hypoxic-Ischemic Encephalopathy: A Report from Children's Hospital Neonatal Consortium.

OBJECTIVE: This study was aimed to describe utilization of therapeutic hypothermia (TH) in neonates presenting with mild hypoxic-ischemic encephalopathy (HIE) and associated neurological injury on magnetic resonance imaging (MRI) scans in these infants. STUDY DESIGN: Neonates ≥ 36 weeks' gestation with mild HIE and available MRI scans were identified. Mild HIE status was assigned to hyper alert infants with an exaggerated response to arousal and mild HIE as the highest grade of encephalopathy recorded. MRI scans were dichotomized as "injury" versus "no injury." RESULTS: A total of 94.5% (257/272) neonates with mild HIE, referred for evaluation, received TH. MRI injury occurred in 38.2% (104/272) neonates and affected predominantly the white matter (49.0%, n = 51). Injury to the deep nuclear gray matter was identified in (10.1%) 20 infants, and to the cortex in 13.4% (n = 14 infants). In regression analyses (odds ratio [OR]; 95% confidence interval [CI]), history of fetal distress (OR = 0.52; 95% CI: 0.28-0.99) and delivery by caesarian section (OR = 0.54; 95% CI: 0.31-0.92) were associated with lower odds, whereas medical comorbidities during and after cooling were associated with higher odds of brain injury (OR = 2.31; 95% CI: 1.37-3.89). CONCLUSION: Majority of neonates with mild HIE referred for evaluation are being treated with TH. Odds of neurological injury are over two-fold higher in those with comorbidities during and after cooling. Brain injury predominantly involved the white matter. KEY POINTS: · Increasingly, neonates with mild HIE are being referred for consideration for hypothermia therapy.. · Drift in clinical practice shows growing number of neonates treated with hypothermia as having mild HIE.. · MRI data show that 38% of neonates with mild HIE have brain injury, predominantly in the white matter..

Feasibility and Safety of Contrast-Enhanced Ultrasound of the Neonatal Brain: A Prospective Study Using MRI as the Reference Standard.

BACKGROUND. MRI is the reference standard for neonatal brain imaging, but it is expensive, time-consuming, potentially limited by availability and accessibility, and contraindicated in some patients. Transfontanelle neonatal head ultrasound is an excellent alternative but may be less sensitive and specific than MRI. Contrast-enhanced ultrasound (CEUS) has the potential to improve the capabilities of ultrasound. OBJECTIVE. The purpose of this study is to prospectively evaluate the feasibility, safety, and diagnostic performance of transfontanelle neonatal brain CEUS, with MRI used as the reference standard. METHODS. Neonates in the institutional neonatal ICU who were undergoing MRI as part of their clinical care were prospectively recruited to undergo portable brain ultrasound and CEUS for research purposes. Brain ultrasound and CEUS were performed portably without moving the patient from the isolette or crib in the neonatal ICU. Adverse events were recorded. Two radiologists independently evaluated ultrasound and CEUS images for abnormalities and then reached consensus regarding discrepancies. A separate radiologist reviewed MRI examinations. Sensitivity, specificity, and interreader agreement were evaluated, with MRI used as the reference. Qualitative post hoc image review was performed. RESULTS. Twenty-six neonates (nine boys and 17 girls; mean [± SD] age, 15.2 ± 14.0 days) were included. No significant alteration in patient vital signs or adverse reaction to the ultrasound contrast agent (UCA) occurred. The mean duration of the examination was significantly shorter for combined ultrasound and CEUS than for MRI (21.1 ± 4.7 vs 74.2 ± 34.8 minutes; p < .001). Interrater agreement for any abnormality was almost perfect for both ultrasound and CEUS (κ = 0.92 and 0.85, respectively). Sensitivity for any abnormality was 86.7% for ultrasound and 93.3% for CEUS; specificity was 100.0% for both. CEUS had sensitivity of 87.5% for acute or subacute ischemia and 100.0% for chronic ischemia; its specificity was 100.0% for acute or subacute ischemia and chronic ischemia. For both ultrasound and CEUS, sensitivity for subdural and intraparenchymal hemorrhage was poor (22.2-50.0%). On CEUS but not on MRI, post hoc review showed a case of postischemic hyperperfusion, which was confirmed by subsequently performed contrast-enhanced CT. CONCLUSION. The use of portable brain CEUS in neonates is feasible, safe, and more rapid than MRI. CLINICAL IMPACT. The potential diagnostic utility of brain neonatal CEUS relative to conventional ultrasound, particularly for ischemia, warrants further investigation.

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. STUDY DESIGN: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. RESULTS: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. CONCLUSIONS: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02811263.

Study design and rationale for a randomized controlled trial to assess effectiveness of stochastic vibrotactile mattress stimulation versus standard non-oscillating crib mattress for treating hospitalized opioid-exposed newborns.

The incidence of Neonatal Abstinence Syndrome (NAS) continues to rise and there remains a critical need to develop non-pharmacological interventions for managing opioid withdrawal in newborns. Objective physiologic markers of opioid withdrawal in the newborn remain elusive. Optimal treatment strategies for improving short-term clinical outcomes and promoting healthy neurobehavioral development have yet to be defined. This dual-site randomized controlled trial (NCT02801331) is designed to evaluate the therapeutic efficacy of stochastic vibrotactile stimulation (SVS) for reducing withdrawal symptoms, pharmacological treatment, and length of hospitalization, and for improving developmental outcomes in opioid-exposed neonates. Hospitalized newborns (n = 230) receiving standard clinical care for prenatal opioid exposure will be randomly assigned within 48-hours of birth to a crib with either: 1) Intervention (SVS) mattress: specially-constructed SVS crib mattress that delivers gentle vibrations (30-60 Hz, ~12 µm RMS surface displacement) at 3-hr intervals; or 2) Control mattress (treatment as usual; TAU): non-oscillating hospital-crib mattress. Infants will be studied throughout their hospitalization and post discharge to 14-months of age. The study will compare clinical measures (i.e., withdrawal scores, cumulative dose and duration of medications, velocity of weight gain) and characteristic progression of physiologic activity (i.e., limb movement, cardio-respiratory, temperature, blood-oxygenation) throughout hospitalization between opioid-exposed infants who receive SVS and those who receive TAU. Developmental outcomes (i.e., physical, social, emotional and cognitive) within the first year of life will be evaluated between the two study groups. Findings from this randomized controlled trial will determine whether SVS reduces in-hospital severity of NAS, improves physiologic function, and promotes healthy development.