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.).

Variable Association of Physiologic Changes With Electrographic Seizure-Like Events in Infants Born Preterm.

OBJECTIVES: To determine the incidence of seizure-like events in a cohort of infants born preterm as well as the prevalence of associated vital sign changes (heart rate [HR], respiratory rate, and pulse oximetry [SpO2]). STUDY DESIGN: We performed prospective conventional video electroencephalogram monitoring on infants born at 23-30 weeks of gestational age during the first 4 postnatal days. For detected seizure-like events, simultaneously captured vital sign data were analyzed during the pre-event baseline and during the event. Significant vital sign changes were defined as HR or respiratory rate >±2 SD from the infant's own baseline physiologic mean, derived from a 10-minute interval before the seizure-like event. Significant change in SpO2 was defined as oxygen desaturation during the event with a mean SpO2 <88%. RESULTS: Our sample included 48 infants with median gestational age of 28 weeks (IQR 26-29) and birth weight of 1125 g (IQR 963-1265). Twelve (25%) infants had seizure-like discharges with a total of 201 events; 83% (10/12) of infants had vital sign changes during these events, and 50% (6/12) had significant vital sign changes during the majority of the seizure-like events. Concurrent HR changes occurred the most frequently. CONCLUSIONS: Individual infant variability was observed in the prevalence of concurrent vital sign changes with electroencephalographic seizure-like events. Physiologic changes associated with preterm electrographic seizure-like events should be investigated further as a potential biomarker to assess the clinical significance of such events in the preterm population.

How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

Mild hypoxic-ischemic encephalopathy (HIE): timing and pattern of MRI brain injury.

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a risk factor for neonatal brain injury. We examined the timing and pattern of brain injury in mild HIE. METHODS: This retrospective cohort study includes infants with mild HIE treated at 9 hospitals. Neonatal brain MRIs were scored by 2 reviewers using a validated classification system, with discrepancies resolved by consensus. Severity and timing of MRI brain injury (i.e., acute, subacute, chronic) was scored on the subset of MRIs that were performed at or before 8 days of age. RESULTS: Of 142 infants with mild HIE, 87 (61%) had injury on MRI at median age 5 (IQR 4-6) days. Watershed (23%), deep gray (20%) and punctate white matter (18%) injury were most common. Among the 125 (88%) infants who received a brain MRI at ≤8 days, mild (44%) injury was more common than moderate (11%) or severe (4%) injury. Subacute (37%) lesions were more commonly observed than acute (32%) or chronic lesions (1%). CONCLUSION: Subacute brain injury is common in newborn infants with mild HIE. Novel neuroprotective treatments for mild HIE will ideally target both subacute and acute injury mechanisms. IMPACT: Almost two-thirds of infants with mild HIE have evidence of brain injury on MRI obtained in the early neonatal period. Subacute brain injury was seen in 37% of infants with mild HIE. Neuroprotective treatments for mild HIE will ideally target both acute and subacute injury mechanisms.

An Amplitude-Integrated EEG Evaluation of Neonatal Opioid Withdrawal Syndrome.

OBJECTIVE: Infants with neonatal opioid withdrawal syndrome (NOWS) have disrupted neurobehavior that requires hospitalization and treatment. This article aimed to evaluate electroencephalography (EEG) abnormalities using amplitude-integrated EEG (aEEG) in NOWS. STUDY DESIGN: Eighteen term born infants with NOWS were recruited prospectively for an observational pilot study. aEEG monitoring was started within 24 hours of recruitment and twice weekly through discharge. aEEG data were analyzed for background and seizures. Severity of withdrawal was monitored using the modified Finnegan scoring (MFS) system. RESULTS: Fifteen neonates had complete datasets. Thirteen (87%) had continuous aEEG background in all recordings. None had sleep-wake cyclicity (SWC) at initial recording. Brief seizures were noted in 9 of 15 (60%) infants. Lack of SWC was associated with higher MFS scores. At discharge, 8 of 15 (53%) had absent or emerging SWC. CONCLUSION: aEEG abnormalities (absent SWC) are frequent and persist despite treatment at the time of discharge in the majority of patients with NOWS. Brief electrographic seizures are common. Neonates with persistent aEEG abnormalities at discharge warrant close follow-up. KEY POINTS: · EEG abnormalities are common and persist after clinical signs resolve in patients with NOWS.. · Short subclinical seizures may be seen.. · aEEG may identify neonates who need follow-up..

Low Variability of Blood Pressure Predicts Abnormal Electroencephalogram in Infants with Hypoxic Ischemic Encephalopathy.

OBJECTIVE: This study aimed to evaluate the role of an objective physiologic biomarker, arterial blood pressure variability, for the early identification of adverse short-term electroencephalogram (EEG) outcomes in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: In this multicenter observational study, we analyzed blood pressure of infants meeting these criteria: (1) neonatal encephalopathy determined by modified Sarnat exam, (2) continuous mean arterial blood pressure (MABP) data between 18 and 27 hours after birth, and (3) continuous EEG performed for at least 48 hours. Adverse outcome was defined as moderate-severe grade EEG at 48 hours. Standardized signal preprocessing was used; the power spectral density was computed without interpolation. Multivariate binary logistic regression was used to identify which MABP time and frequency domain metrics provided improved predictive power for adverse outcomes compared with standard clinical predictors (5-minute Apgar score and cord pH) using receiver operator characteristic analysis. RESULTS: Ninety-one infants met inclusion criteria. The mean gestational age was 38.4 ± 1.8 weeks, the mean birth weight was 3,260 ± 591 g, 52/91 (57%) of infants were males, the mean cord pH was 6.95 ± 0.21, and 10/91 (11%) of infants died. At 48 hours, 58% of infants had normal or mildly abnormal EEG background and 42% had moderate or severe EEG backgrounds. Clinical predictor variables (10-minute Apgar score, Sarnat stage, and cord pH) were modestly predictive of 48 hours EEG outcome with area under curve (AUC) of 0.66 to 0.68. A composite model of clinical and optimal time- and frequency-domain blood pressure variability had a substantially improved AUC of 0.86. CONCLUSION: Time- and frequency-domain blood pressure variability biomarkers offer a substantial improvement in prediction of later adverse EEG outcomes over perinatal clinical variables in a two-center cohort of infants with HIE. KEY POINTS: · Early outcome prediction in HIE is suboptimal.. · Patterns in blood pressure physiology may be predictive of short-term outcomes.. · Early time- and frequency-domain measures of blood pressure variability predict short-term EEG outcomes in HIE infants better than perinatal factors alone..

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..

Parental Enrollment Decision-Making for a Neonatal Clinical Trial.

OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

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.

The hidden consequence of intraventricular hemorrhage: persistent cerebral desaturation after IVH in preterm infants.

BACKGROUND: Previous studies describe a short-term decrease in cerebral oxygen saturation (StO2) after intraventricular hemorrhage (IVH) in premature infants; little is known about long-term implications. METHODS: Infants born <30 weeks gestational age (GA) were included. Clinical characteristics, hemoglobin measurements, the highest grade of IVH, and white matter injury (WMI) were noted. NIRS monitoring occurred daily or every other day for 4 weeks; weekly through 36 weeks GA. Recordings were error-corrected before calculation of mean StO2 and fractional tissue oxygen extraction (FTOE). Mean StO2 and FTOE were plotted by postnatal age and injury group (IVH/no IVH; WMI/no WMI). Non-linear regression by locally estimated scatterplot smoothing was used to generate the best-fit line and CI. RESULTS: A total of 1237 recordings from 185 infants were included; mean length = 6.5 h; mean GA = 26.3 w; mean BW = 951 g; overall/severe IVH incidence was 29/8%, WMI incidence was 16%. IVH was independently associated with an acute drop in StO2, which remained lower for 68 d. Severe IVH was associated with lower StO2 values than mild IVH. WMI was associated with early and persistent elevation of FTOE. CONCLUSION: IVH of any grade is associated with a prolonged cerebral desaturation and WMI is associated with prolonged elevation of FTOE. This finding is exacerbated for infants with severe IVH. IMPACT: The longitudinal impact of IVH on cerebral oxygenation has not been previously studied. IVH is associated with persistent cerebral desaturation, months in length, and is independent of anemia. More severe IVH is associated with worsened cerebral hypoxia. Infants later diagnosed with white matter injury have an early and persistent elevation of cerebral oxygen extraction (cFTOE). This cerebral desaturation, below previously identified normative ranges, may provide insight into the mechanistic link between IVH and white matter injury.

Blood pressure extremes and severe IVH in preterm infants.

BACKGROUND: The optimal upper and lower limits of blood pressure in preterm infants are not known. Exceeding these thresholds may contribute to intraventricular hemorrhage (IVH). METHODS: Preterm infants born ≤30 weeks GA were identified. Infants had continuous measurement of mean arterial blood pressure (MABP) for 7 days and cranial ultrasound imaging. IVH was classified as severe IVH (grade 3/4), no severe IVH (no IVH; grade 1/2), or no IVH. Mean ± SEM MABP values from hours 1-168 were calculated and sorted into bins 2 mm Hg wide. The normalized proportion of each recording spent in each bin was then calculated. Candidate limits were identified by comparison of MABP distribution in those with severe IVH vs. those without severe IVH. RESULTS: Eighty-five million measurements were made from 157 infants. Mean EGA was 25.2 weeks; mean BW was 749 g; 65/157 female; inotrope use in 59/157; grade 3/4 IVH in 29/157. Infants with severe IVH spent significantly more time with extreme MABP measurements (<23 mm Hg or >46 mm Hg) compared to those without severe IVH (12% vs. 8% of recording, p = 0.02). CONCLUSIONS: Infants who developed severe IVH had substantially more unstable MABP and spent a significantly greater period of time with MABP outside of the optimal range.

Placental pathology and neonatal brain MRI in a randomized trial of erythropoietin for hypoxic-ischemic encephalopathy.

BACKGROUND: Newborns with hypoxic-ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities correlate with MRI brain injury and with response to treatment. METHODS: Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system. RESULTS: Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality. CONCLUSION: Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE.

Practice variation in anti-epileptic drug use for neonatal hypoxic-ischemic encephalopathy among regional NICUs.

BACKGROUND: While intercenter variation (ICV) in anti-epileptic drug (AED) use in neonates with seizures has been previously reported, variation in AED practices across regional NICUs has not been specifically and systematically evaluated. This is important as these centers typically have multidisciplinary neonatal neurocritical care teams and protocolized approaches to treating conditions such as hypoxic ischemic encephalopathy (HIE), a population at high risk for neonatal seizures. To identify opportunities for quality improvement (QI), we evaluated ICV in AED utilization for neonates with HIE treated with therapeutic hypothermia (TH) across regional NICUs in the US. METHODS: Children's Hospital Neonatal Database and Pediatric Health Information Systems data were linked for 1658 neonates ≥36 weeks' gestation, > 1800 g birthweight, with HIE treated with TH, from 20 NICUs, between 2010 and 2016. ICV in AED use was evaluated using a mixed-effect regression model. Rates of AED exposure, duration, prescription at discharge and standardized AED costs per patient were calculated as different measures of utilization. RESULTS: Ninety-five percent (range: 83-100%) of patients with electrographic seizures, and 26% (0-81%) without electrographic seizures, received AEDs. Phenobarbital was most frequently used (97.6%), followed by levetiracetam (16.9%), phenytoin/fosphenytoin (15.6%) and others (2.4%; oxcarbazepine, topiramate and valproate). There was significant ICV in all measures of AED utilization. Median cost of AEDs per patient was $89.90 (IQR $24.52,$258.58). CONCLUSIONS: Amongst Children's Hospitals, there is marked ICV in AED utilization for neonatal HIE. Variation was particularly notable for HIE patients without electrographic seizures, indicating that this population may be an appropriate target for QI processes to harmonize neuromonitoring and AED practices across centers.

Neurodevelopmental Outcomes in Neonates with Mild Hypoxic Ischemic Encephalopathy Treated with Therapeutic Hypothermia.

OBJECTIVE: To review developmental outcomes of neonates with mild hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). STUDY DESIGN: Neonates ≥35 weeks' gestation with mild HIE/TH (TH group, n = 30) were matched with healthy term-born infants (control group, n = 30) and reviewed for the presence and severity of magnetic resonance imaging (MRI)-detected neurological injury. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant Development (BSID). RESULTS: MRI injury was present in 13/30 (43.3%) neonates (11 mild, 1 moderate, and 1 severe injuries) in the TH group. The mean (standard deviation [SD]) corrected age at BSID III was 29.3 (3.9) months in the controls compared with 14.7 (3.9) months in the TH group (p < 0.01). The mean (SD) cognitive, language, and motor composite scores in neonates in the TH group (n = 16, 53.3%) and control groups (n = 30, 100%) were 99.4 (17.1) versus 93.0 (12.3), (p = 0.15), 89.5 (15.5) versus 100.2 (18.4), (p = 0.054), and 93.1 (15.4) versus 100.8 (16.3) (p = 0.13), respectively. CONCLUSION: Developmental outcomes of neonates with mild HIE/TH were similar to healthy, term-born neonates.

Predictors of mortality for preterm infants with intraventricular hemorrhage: a population-based study.

PURPOSE: The goal of this longitudinal, population-level study was to examine factors affecting mortality in preterm infants with intraventricular hemorrhage (IVH). METHODS: The study examined patients who were born at 36 weeks estimated gestational age (EGA) or less with a diagnosis of IVH between the years 2005 and 2014 using data from the New York and Nebraska State Inpatient Databases. Potential predictors for mortality were investigated with multivariable survival analysis. RESULTS: The cohort included 7437 preterm infants with IVH. All-cause inpatient mortality occurred in 746 (10.0%). The majority of deaths were in infants born at less than 25 weeks EGA (378 or 50.7%) and with birthweight less than 750 g (459 or 61.5%). Mortality was highest for children with grade IV IVH (306/848 or 36.1%), followed by grades III (203/955 or 21.3%), II (103/1328 or 7.8%), and I (134/4306 or 3.1%). Hydrocephalus was diagnosed within 6 months in 627 (8.4%) patients, with cerebrospinal fluid shunts required in 237 (3.2%). Shunts were eventually revised in 122 (51.5% of shunts), and 43 (18.1%) had infections. Multivariable Cox survival analyses found male sex (HR 1.3 [95% CI 1.1-1.5]), Asian race (HR 1.5 [1.1-2.2]), lower EGA (HR 9.9 [6.3-15.5] for < 25 weeks), higher IVH grade (HR 6.1 [4.9-7.6] for grade IV), gastrostomy (HR 4.0 [2.0-7.7]), tracheostomy (HR 3.5 [1.7-7.1]), and shunt infection (HR 3.2 [1.0-9.9]) to be independently associated with increased mortality risk. CONCLUSIONS: This database is the first of its kind assembled for population-based investigations of long-term neurosurgical outcomes in preterm infants with IVH.

Effect of Immediate vs Delayed Pushing on Rates of Spontaneous Vaginal Delivery Among Nulliparous Women Receiving Neuraxial Analgesia: A Randomized Clinical Trial.

Importance: It is unclear whether the timing of second stage pushing efforts affects spontaneous vaginal delivery rates and reduces morbidities. Objective: To evaluate whether immediate or delayed pushing results in higher rates of spontaneous vaginal delivery and lower rates of maternal and neonatal morbidities. Design, Setting, and Participants: Pragmatic randomized clinical trial of nulliparous women at or beyond 37 weeks' gestation admitted for spontaneous or induced labor with neuraxial analgesia between May 2014 and December 2017 at 6 US medical centers. The interim analysis suggested futility for the primary outcome and recruitment was terminated with 2414 of 3184 planned participants. Follow-up ended January 4, 2018. Interventions: Randomization occurred when participants reached complete cervical dilation. Immediate group participants (n = 1200) began pushing immediately. Delayed group participants (n = 1204) were instructed to wait 60 minutes. Main Outcomes and Measures: The primary outcome was spontaneous vaginal delivery. Secondary outcomes included total duration of the second stage, duration of active pushing, operative vaginal delivery, cesarean delivery, postpartum hemorrhage, chorioamnionitis, endometritis, perineal lacerations (≥second degree), and a composite outcome of neonatal morbidity that included neonatal death and 9 other adverse outcomes. Results: Among 2414 women randomized (mean age, 26.5 years), 2404 (99.6%) completed the trial. The rate of spontaneous vaginal delivery was 85.9% in the immediate group vs 86.5% in the delayed group, and was not significantly different (absolute difference, -0.6% [95% CI, -3.4% to 2.1%]; relative risk, 0.99 [95% CI, 0.96 to 1.03]). There was no significant difference in 5 of the 9 prespecified secondary outcomes reported, including the composite outcome of neonatal morbidity (7.3% for the immediate group vs 8.9% for the delayed group; between-group difference, -1.6% [95% CI, -3.8% to 0.5%]) and perineal lacerations (45.9% vs 46.4%, respectively; between-group difference, -0.4% [95% CI, -4.4% to 3.6%]). The immediate group had significantly shorter mean duration of the second stage compared with the delayed group (102.4 vs 134.2 minutes, respectively; mean difference, -31.8 minutes [95% CI, -36.7 to -26.9], P < .001), despite a significantly longer mean duration of active pushing (83.7 vs 74.5 minutes; mean difference, 9.2 minutes [95% CI, 5.8 to 12.6], P < .001), lower rates of chorioamnionitis (6.7% vs 9.1%; between-group difference, -2.5% [95% CI, -4.6% to -0.3%], P = .005), and fewer postpartum hemorrhages (2.3% vs 4.0%; between-group difference, -1.7% [95% CI, -3.1% to -0.4%], P = .03). Conclusions and Relevance: Among nulliparous women receiving neuraxial anesthesia, the timing of second stage pushing efforts did not affect the rate of spontaneous vaginal delivery. These findings may help inform decisions about the preferred timing of second stage pushing efforts, when considered with other maternal and neonatal outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02137200.

Safety and Short-Term Outcomes of Therapeutic Hypothermia in Preterm Neonates 34-35 Weeks Gestational Age with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To evaluate the safety and short-term outcomes of preterm neonates born at 34-35 weeks gestation with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia. STUDY DESIGN: Medical records of preterm neonates born at 34-35 weeks gestational age with HIE treated with therapeutic hypothermia were retrospectively reviewed. Short-term safety outcomes and the presence, severity (mild, moderate, severe), and patterns of brain injury on magnetic resonance imaging were reviewed using a standard scoring system, and compared with a cohort of term neonates with HIE treated with therapeutic hypothermia. RESULTS: Thirty-one preterm and 32 term neonates were identified. Therapeutic hypothermia-associated complications were seen in 90% of preterm infants and 81.3% of term infants (P = .30). In the preterm infants, hyperglycemia (58.1% vs31.3%, P = .03) and rewarming before completion of therapeutic hypothermia (19.4% vs 0.0%, P = .009) were more likely compared with term infants. All deaths occurred in the preterm group (12.9% vs 0%, P = .04). Neuroimaging showed the presence of injury in 80.6% of preterm infants and 59.4% of term infants (P = .07), with no differences in injury severity. Injury to the white matter was more prevalent in preterm infants compared with term infants (66.7% vs 25.0%, P = .001). CONCLUSIONS: Therapeutic hypothermia in infants born at 34-35 weeks gestational age appears feasible. Risks of mortality and side effects warrant caution with use of therapeutic hypothermia in preterm infants.

Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome.

In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01913340.