Incidence of encephalopathy and comorbidity in infants with perinatal asphyxia: a comparative prospective cohort study.

Background: Programs that aim to improve the detection hypoxic-ischemic encephalopathy (HIE) should establish which neonates suffering from perinatal asphyxia need to be monitored within the first 6 h of life. Method: An observational prospective cohort study of infants with gestational age ≥35 weeks, and above 1,800g, were included according to their arterial cord pH value (ApH): ≤7.00 vs. 7.01-7.10. Data was collected including obstetrical history, as well as neonatal comorbidities, including the presence of HIE, that happened within 6 h of life. A standardized neurological exam was performed at discharge. Results: There were 9,537 births; 176 infants with ApH 7.01-7.10 and 117 infants with ApH ≤7.00. All 9 cases with moderate-to-severe HIE occurred among infants with ApH ≤7.00. The incidence of global and moderate-severe HIE was 3/1,000 and 1/1,000 births, respectively. Outcome at discharge (abnormal exam or death) showed an OR 12.03 (95% CI 1.53, 94.96) in infants with ApH ≤7.00 compared to ApH 7.01-7.10 cohort. Ventilation support was 5.1 times (95% CI 2.87, 9.03) more likely to be needed by those with cord ApH ≤7.00 compared to those with ApH 7.01-7.10, as well as hypoglycemia (37% vs. 25%; p = 0.026). In 55%, hypoglycemia occurred despite oral and/or intravenous glucose administration had been already initiated. Conclusions: Cord pH 7.00 might be a safe pH cut-off point when developing protocols to monitor infants born with acidemia in order to identify infants with moderate or severe HIE early on. There is non-negligible comorbidity in the ApH ≤7.00 cohort, but also in the 7.01-7.10 cohort.

Association between early echocardiography screening of low systemic blood flow and intraventricular hemorrhage in preterm infants: a multicenter cohort study.

OBJECTIVE: To determine whether early echocardiography screening of low systemic blood flow reduces intraventricular hemorrhage in preterm infants. STUDY DESIGN: Prospective multicenter study in preterm infants below 33 weeks of gestational age at nine neonatal units. Five units performed early echocardiography screening for low systemic blood flow and guided clinical management (exposure group) and 4 units did not (control group). Our main outcome was ≥grade II intraventricular hemorrhage or death within the first 7 days of life. The main analysis used the inverse probability of treatment weighting. RESULTS: Three hundred and thirty-two preterm infants (131 in the exposure group and 201 in the control group) were included. Exposure to early echocardiography screening was associated with a significant reduction in ≥grade II intraventricular hemorrhage or early death [odds ratio 0.285 (95% CI: 0.133-0.611); p = 0.001]. CONCLUSIONS: Early echocardiography screening for low systemic blood flow may reduce the incidence of intraventricular hemorrhage in preterm infants.

Motor, cognitive and behavioural outcomes after neonatal hypoxic-ischaemic encephalopathy.

INTRODUCTION: The current neurodevelopmental status of patients with neonatal hypoxic-ischaemic encephalopathy (HIE) in Spain is unknown. Recent European studies highlight a shift of severe pathology towards mild motor disorders and emotional problems. The aim of this study was to analyse neurodevelopmental outcomes in a cohort of neonates with HIE at age 3 years. PATIENTS AND METHOD: Multicentre observational study of neonates born at 35 or more weeks of gestation with moderate to severe HIE in 2011-2013 in 12 hospitals in a large Spanish region (91 217 m2), with the recruitment extended through 2017 in the coordinating hospital. We analysed the findings of neonatal neuroimaging and neurodevelopmental test scores at 3 years (Bayley-III, Peabody Picture Vocabulary Test and Child Behavior Checklist). The sample included 79 controls with no history of perinatal asphyxia. RESULTS: Sixty-three patients were recruited, of whom 5 (7.9%) were excluded due to other pathology and 14 (24%) died. Of the 44 survivors, 42 (95.5%) were evaluated. Of these 42, 10 (24%) had adverse outcomes (visual or hearing impairment, epilepsy, cerebral palsy or developmental delay). Other detected problems were minor neurological signs in 6 of the 42 (14%) and a higher incidence of emotional problems compared to controls: introversion (10.5% vs. 1.3%), anxiety (34.2% vs. 11.7%) and depression (28.9% vs. 7.8%) (P < .05). The severity of the lesions on neuroimaging was significantly higher in patients with motor impairment (P = .004) or who died or had an adverse outcome (P = .027). CONCLUSION: In addition to classical sequelae, the followup of patients with neonatal HIE should include the diagnosis and treatment of minor motor disorders and social and emotional problems.

Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy.

INTRODUCTION: We do not have population data in Spain on the application of therapeutic hypothermia (TH). The objective was to examine adherence to management standards during TH of infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Multicenter observational cohort study from the beginning of TH (year 2010) in 5 hospitals in a Spanish region, until year 2019. RESULTS: 133 patients were recruited, 72% diagnosed with moderate HIE and the rest of them with severe HIE. In 84% of infants, passive hypothermia was started at birth. Active TH was started at a median age of 5 h of life (IQR 3.3; 6.3), although the central targeted temperature (33-34 °C) was reached at a median age of 3.5 h (IQR 1; 6). Those born extramural, initiated active TH 3.3 h on average later than those born intramural, but without differences in the age at which the targeted temperature was reached. Sedoanalgesia was used in 97%. 100% were monitored with amplitude-integrated EEG and 59% with cerebral oxymetry. MRI was performed in 94% with moderate HIE vs. 65% with severe; P < .001. Neuron-specific enolase in cerebrospinal fluid was determined in 42%. The average duration of rewarming was median 10 h (IQR 8; 12), with no differences depending on the degree of HIE (P = .57). CONCLUSIONS: The implementation of TH successfully met the standards. However, aspects of care that could be improved were detected. Auditing newborn care with HIE is crucial to achieving programs with a high quality of care in each region.

Inter-observer reliability for amplitude-integrated electroencephalography in the newborn with perinatal asphyxia.

INTRODUCTION: Amplitude integrated electroencephalography (aEEG) is a tool widely used for neuromonitoring in the critical neonate. In the patient with perinatal asphyxia, its interpretation is key to identifying candidates for therapeutic hypothermia, detecting subclinical seizures and providing pronostic information. Our aim was to analyze the concordance in the interpretation of aEEG among neonatologists with different levels of experience. MATERIAL AND METHODS: Unicenter retrospective study of newborns ≥ 35 weeks with perinatal asphyxia included consecutively over a two-year period and monitored with aEEG for at least 6 h. The bedside neonatologist interpreted aEEG regarding background pattern, sleep-wake cycling, and seizures. The aEEG tracings were blindly reviewed by two neonatologists with different experience. The aEEG tracings were divided into periods of 0-3 h and 3-6 h of life, and the concordance (Cohen Kappa coefficient, k), between the two examiners and that of their consensus with the bedside neonatologist, was analyzed. RESULTS: Seventy-five newborns were included, 5 of them were not aEEG-monitored. 132 tracings were analyzed with a very good concordance between the two examiners in the three characteristics of the aEEG. The k for the bedside neonatologist was very good for background pattern (k = 0.93), moderate (k = 0.52) for sleep-wake cycling, and weak (k = 0.32) for seizures. CONCLUSIONS: This study supports that background pattern is easily interpreted compared to sleep-wake cycling or crisis, improving when targeted training on aEEG is received.

[Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy]. / Adherencia a los estándares en el tratamiento con hipotermia del recién nacido con encefalopatía hipóxico-isquémica.

INTRODUCTION: We do not have population data in Spain on the application of therapeutic hypothermia (TH). The objective was to examine adherence to management standards during TH of infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Multicenter observational cohort study from the beginning of TH (year 2010) in 5 hospitals in a Spanish region, until year 2019. RESULTS: 133 patients were recruited, 72% diagnosed with moderate HIE and the rest of them with severe HIE. In 84% of infants, passive hypothermia was started at birth. Active TH was started at a median age of 5hours of life (IQR: 3.3-6.3), although the central targeted temperature (33-34°C) was reached at a median age of 3.5hours (IQR: 1-6). Those born extramural, initiated active TH 3.3hours on average later than those born intramural, but without differences in the age at which the targeted temperature was reached. Sedoanalgesia was used in 97%. The 100% were monitored with amplitude-integrated EEG and 59% with cerebral oxymetry. MRI was performed in 94% with moderate HIE vs. 65% with severe; P<.001. Neuron-specific enolase in cerebrospinal fluid was determined in 42%. The average duration of rewarming was median 10hours (IQR: 8-12), with no differences depending on the degree of HIE (P=.57). CONCLUSIONS: The implementation of TH successfully met the standards. However, aspects of care that could be improved were detected. Auditing newborn care with HIE is crucial to achieving programs with a high quality of care in each region.

Temporal Trends in the Severity and Mortality of Neonatal Hypoxic-Ischemic Encephalopathy in the Era of Hypothermia.

INTRODUCTION: There is a paucity of studies examining temporal trends in the incidence and mortality of moderate-to-severe hypoxic-ischemic encephalopathy (HIE) during the last decade of therapeutic hypothermia (TH). METHODS: Multicenter cross-sectional study of all infants ≥35 weeks gestational age diagnosed with moderate-to-severe HIE within 6 h of birth in an extensive region of Spain between 2011 and 2019, in order to detect trend changes over time in the (1) annual incidence, (2) severity of neurological and systemic organ involvement, and (3) neonatal death from HIE. RESULTS: Annual incidence rate of moderate-to-severe HIE was 0.84 (95% confidence interval [CI] 0.7-0.97) per 1,000 births, without trend changes over time (p = 0.8), although the proportion of severe HIE infants showed an average annual decline of 0.86 points (95% CI 0.75-0.98). There were 102 (70%) infants diagnosed with moderate HIE and 44 (30%) with severe HIE. TH was offered to 139/146 (95%) infants. Infants with clinical and/or electrical seizures showed a decreasing trend from 56 to 28% (p = 0.006). Mortality showed a nonstatistically significant decline (p = 0.4), and the severity of systemic damage showed no changes (p = 0.3). Obstetric characteristics remained unchanged, while higher perinatal pH values (p = 0.03) and Apgar scores (p = 0.05), and less need for resuscitation (p = 0.07), were found over time. CONCLUSION: The annual incidence of moderate-to-severe HIE has stabilized at around 1 per 1,000 births, with a temporal trend toward a decrease in severe HIE infants and a slight decline of mortality. No association was found between temporal trends and changes in perinatal/obstetric characteristics over time.

[Inter-observer reliability for amplitude-integrated EEG in the newborn with perinatal asphyxia]. / Concordancia interobservador del electroencefalograma integrado por amplitud en el neonato con asfixia perinatal.

INTRODUCTION: Amplitude integrated electroencephalography (aEEG) is a widely tool used for neuromonitoring in the critical neonate. In the patient with perinatal asphyxia, its interpretation is key to identifying candidates for therapeutic hypothermia, detecting subclinical seizures and providing pronostic information. Our aim was to analyze the concordance in the interpretation of aEEG among neonatologists with different level of experience. MATERIAL AND METHODS: Unicenter retrospective study of newborns ≥35 weeks with perinatal asphyxia included consecutively over a two-year period and monitored with aEEG for at least 6h. The bedside neonatologist interpreted aEEG regarding background pattern, sleep-wake cycling, and seizures. The aEEG tracings were blindly reviewed by two neonatologists with different experience. The aEEG tracings were divided into periods of 0-3h and 3-6h of life, and the concordance (Cohen Kappa coefficient, k), between the two examiners and that of their consensus with the bedside neonatologist, was analyzed. RESULTS: Seventy-five newborns were included, 5 of them were not aEEG-monitored. 132 tracings were analyzed with a very good concordance between the two examiners in the three characteristics of the aEEG. The k for the bedside neonatologist was very good for background pattern (k=0.93), moderate (k=0.52) for sleep-wake cycling, and weak (k=0.32) for seizures. CONCLUSIONS: This study supports that background pattern is easily interpreted compared to sleep-wake cycling or crisis, improving when targeted training on aEEG is received.

Usefulness of video recordings for validating neonatal encephalopathy exams: a population-based cohort study.

OBJECTIVE: To determine the usefulness of video recordings for validating neonatal encephalopathy (NE) exams. DESIGN: Population-based prospective cohort study. NE was assessed and recorded at 1, 3 and 5 hours after birth by the attending physician. Recordings were reviewed blindly after the recruitment period by two specialists. Outcome was assessed at 36 months of age. SETTING: Twelve intensive care units in Spain. PATIENTS: Infants of ≥35 weeks' gestational age with perinatal asphyxia. MAIN OUTCOMES MEASURES: Weighted kappa to measure disagreement between the two specialists and between the attending physician and the specialists' classification agreed on by consensus. Regression models to test the association of disagreement on NE assessment and outcome. RESULTS: Of the 32 325 liveborn infants, 217 met the inclusion criteria. Video-recordings were not available for 43 infants (20%). Weighted kappa statistic was 0.74 (95% CI 0.67 to 0.81) between the specialists and the attending physicians. Disagreement occurred in 93 of the 417 (22%) videos, specifically in 39 (14%), 43 (47%), 11 (34%) and 0 exams categorised as no, mild, moderate and severe NE, respectively. According to the specialist consensus assessment, there was disagreement on the therapeutic hypothermia decision in 10 infants.When there was consensus among the specialists assessing a more severe NE degree compared with the attending physicians in 170 infants, those infants had lower cognitive scores with a median of -5.33 points (95% CI -9.85 to -8.16; p=0.02). CONCLUSIONS: This study supports the feasibility and benefit of using video recordings to identify NE in infants with perinatal asphyxia.

Lack of Variability in Cerebral Oximetry Tendency in Infants with Severe Hypoxic-Ischemic Encephalopathy Under Hypothermia.

Cerebral oximetry using near-infrared spectroscopy (NIRS) provides continuous, noninvasive assessment of the degree of hemoglobin saturation of the brain tissue. Previous studies suggest that high values of regional cerebral tissue oxygen saturation (rScO2) during the first days in neonates with significant hypoxic-ischemic encephalopathy (HIE) are correlated with an adverse neurological outcome. However, the results are not consistent among the studies. To examine the correlation of rScO2 values and their variability over time with HIE severity, amplitude integrated electroencephalography (aEEG) background and seizure activity, neuron-specific enolase levels in cerebrospinal fluid, magnetic resonance imaging (MRI) findings, and neurological outcome. Retrospective study that included all consecutive infants with moderate-to-severe HIE born at ≥35 weeks gestational age admitted between January 2011 and December 2014. NIRS monitoring was initiated at admission and maintained during therapeutic hypothermia up to 12 hours after rewarming. To analyze rScO2, different periods (0-6, 6-24, 24-48, 48-72, and 72-100 hours of life) and three ranges (<55%, 55-90%, >90%) were considered. Variability in each patient was considered ≤5% when changes in rScO2 values in all periods were ≤5%. Twenty-three newborns were included. Infants who suffered from severe HIE, seizures, abnormal aEEG background, altered MRI or death, and abnormal outcome had rScO2 values >90% and with less variability (≤5%). rScO2 values >90% and a lack of variability over time in infants with HIE during cooling provide useful information about the severity of neurological status.