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Introduction
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Publications
Publications (164)
Importance
Outcomes after hypoxic-ischemic encephalopathy (HIE) are variable. Predicting death or severe neurodevelopmental impairment (NDI) in affected neonates is crucial for guiding management and parent communication.
Objective
To predict death or severe NDI in neonates who receive hypothermia for HIE.
Design, Setting, and Participants
This p...
Hypoxic‐ischemic encephalopathy (HIE) is a neurologic condition that is caused by insufficient oxygen and blood flow to a newborn infant’s brain. Although therapeutic hypothermia can reduce the degree of brain injury in some infants with HIE, many infants with HIE will have significant lifelong disabilities despite receiving this treatment. Several...
Background:
The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia demonstrated no neurodevelopmental benefit but was associated with a higher rate of serious adverse events (SAEs). Understanding if targeted Epo plasma exposures were ach...
Importance:
Epidural analgesia is used by approximately 70% of birthing persons in the US to alleviate labor pain and is a common cause of elevated temperature in the birthing parent during labor, which, in turn, is associated with adverse neonatal outcomes such as hypoxic-ischemic encephalopathy (HIE).
Objective:
To determine whether epidural a...
Background
Both perinatal arterial ischemic stroke (PAIS) and hypoxic-ischemic encephalopathy (HIE) can present with neonatal encephalopathy. We hypothesized that among infants undergoing therapeutic hypothermia, presence of PAIS is associated with a higher risk of seizures and a lower risk of persistent encephalopathy after rewarming.
Methods
We...
Purpose To develop a deep learning algorithm to predict 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy using MRI and basic clinical data. Materials and Methods In this study, MRI data of term neonates with encephalopathy in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial (ClinicalTrials...
This article describes the methods used to build a large-scale database of more than 250,000 electronic fetal monitoring (EFM) records linked to a comprehensive set of clinical information about the infant, the mother, the pregnancy, labor, and outcome. The database can be used to investigate how birth outcome is related to clinical and EFM feature...
Brain extraction, or skull-stripping, is an essential data preprocessing step for machine learning approaches to brain MRI analysis. Currently, there are limited extraction algorithms for the neonatal brain. We aim to adapt an established deep learning algorithm for the automatic segmentation of neonatal brains from MRI, trained on a large multi-in...
Objective
Selective serotonin reuptake inhibitor (SSRI) use is common in pregnancy. It is associated with delayed neonatal adaptation. Most previous studies have not adjusted for the severity of maternal mental health disorders or examined the impact of SSRI type and dosage. We examined whether treatment with SSRIs in late pregnancy (after 20 weeks...
Objective
To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE).
Design
Secondary analysis of the H igh-dose E rythropoietin for A sphyxia and Encepha L opathy Trial. Adjusted ORs (aORs) for deat...
The objective of this work was to evaluate the utility of using intrapartum fetal heart rate (FHR) and uterine pressure (UP) events to detect infants at risk of hypoxic-ischemic encephalopathy (HIE). We analyzed data from 40,976 term births from three groups: 374 infants that developed HIE, 3,056 that developed fetal acidosis without HIE, and 37,54...
Introduction:
Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset...
Background
Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal...
Nulliparous pregnancies, those where the mother has not previously given birth, are associated with longer labors and hence expose the fetus to more contractions and other adverse intrapartum conditions such as chorioamnionitis. The objective of the present study was to test if accounting for nulliparity could improve the detection of fetuses at in...
Background and Objectives
Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin (Epo) or p...
Background
Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood.
Methods
We conducted a case-control study...
Objective:
We aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelo...
Objectives:
In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE und...
Background Multiple qualitative scoring systems have been created to capture the imaging severity of hypoxic ischemic brain injury. Purpose To evaluate quantitative volumes of acute brain injury at MRI in neonates with hypoxic ischemic brain injury and correlate these findings with 24-month neurodevelopmental outcomes and qualitative brain injury s...
Importance:
The ability to predict neurodevelopmental impairment (NDI) for infants diagnosed with hypoxic ischemic encephalopathy (HIE) is important for parental guidance and clinical treatment as well as for stratification of patients for future neurotherapeutic studies.
Objectives:
To examine the effect of erythropoietin on plasma inflammatory...
Background:
There is a critical need for development of physiological biomarkers in infants with birth asphyxia to identify the physiologic response to therapies in real time. This is an ancillary single site study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (Wu et al., 2022 [1]) to measure neurovascular coupling (NVC) non-inva...
Objective:
To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs).
Study design:
500 infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypot...
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 se...
Inconsistent enrollment among hospitals for neonatal clinical trials may lead to study populations that are not representative of the patient population in the neonatal intensive care unit. The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial was a multisite randomized clinical trial investigating erythropoietin as a neuroprote...
The research objective of our group is to improve the intrapartum detection of cardiotocography tracings associated with an increased risk of developing fetal acidosis and subsequent hypoxic-ischemic encephalopathy (HIE). The detection methods that we aim to develop must be sensitive to abnormal tracings without causing excessive unnecessary interv...
Background:
An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonat...
Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30–50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a cr...
Infections play an important role in the pathogenesis of acute ischemic stroke (AIS) in neonates and children. In neonates, chorioamnionitis or intrauterine inflammation has been implicated as a common risk factor for AIS. In infants and children, recent investigations demonstrated that even minor childhood infections are associated with subsequent...
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...
Visual assessment of the evolution of fetal heart rate (FHR) and uterine pressure (UP) patterns is the standard of care in the intrapartum period. Unfortunately, this assessment has high levels of intra- and inter-observer variability. This study processed and analyzed FHR and UP patterns using computerized pattern recognition tools. The goal was t...
Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy (CP) and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HI...
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...
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:
Survey conducted at 12 US NICUs of parents of infants who enrolled in the High dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who w...
Abstarct
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...
Introduction:
MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS bioma...
Importance
It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease dispar...
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 hy...
Background:
Data correlating dried blood spots (DBS) and plasma concentrations for neonatal biomarkers of brain injury are lacking. We hypothesized that candidate biomarker levels determined from DBS can serve as a reliable surrogate for plasma levels.
Methods:
In the context of a phase II multi-center trial evaluating erythropoietin for neuropr...
: media-1vid110.1542/5804915133001PEDS-VA_2018-0648Video Abstract BACKGROUND AND OBJECTIVES: In a recent Danish study, researchers found an increased risk of childhood epilepsy after phototherapy but only in boys. We investigated this association in a Kaiser Permanente Northern California cohort.
Methods:
From 499 642 infants born at ≥35 weeks' g...
Objective:
To identify risk factors for hypoxic-ischemic encephalopathy (HIE) within a recent US birth cohort.
Study design:
In a retrospective cohort study of 44 572 singleton infants ≥36 weeks of gestation born at Kaiser Permanente Northern California in 2008-2015, we identified all infants with HIE based on the presence of 3 inclusion criteri...
Background:
Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to...
Objectives:
To evaluate plasma brain specific proteins and cytokines as biomarkers of brain injury in newborns with hypoxic-ischemic encephalopathy (HIE) and, secondarily, to assess the effect of erythropoietin (Epo) treatment on the relationship between biomarkers and outcomes.
Study design:
A study of candidate brain injury biomarkers was cond...
Trial registration:
ClinicalTrials.gov: NCT01913340.
Background:
High-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies.
Methods:
We performed a population pharmacokine...
Objective:
Whether neonatal hyperbilirubinemia and/or phototherapy increase the risk of autism spectrum disorder (ASD) is unclear. We sought to quantify the risk of ASD associated with elevated total serum bilirubin (TSB) levels and with phototherapy.
Methods:
In a retrospective cohort study of 525?409 infants born at ?35 weeks' gestation in 15...
Objective:
To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy.
Methods:
In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n...
Background:
Vigabatrin (VGB) is one of two FDA-approved medications for treatment of infantile spasms. Despite demonstrated efficacy, its use has been curtailed by reports indicating a substantial risk of VGB-associated visual field loss (VAVFL). As these reports have conflicted with our clinical observations in routine practice, we systematically...
Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated c...
Objective:
De novo mutations of the gene sodium channel 1α (SCN1A) are the major cause of Dravet syndrome, an infantile epileptic encephalopathy. US incidence of DS has been estimated at 1 in 40 000, but no US epidemiologic studies have been performed since the advent of genetic testing.
Methods:
In a retrospective, population-based cohort of al...
High bilirubin levels are associated with sensorineural hearing loss (SNHL). However, few large studies of relative and excess risk exist. We sought to quantify the risk of SNHL in newborns who had bilirubin levels at or above American Academy of Pediatrics exchange transfusion thresholds (ETT).
Infants born at ≥35 weeks gestation in 15 Kaiser Perm...
The prevalence of motor examination abnormalities among a general pediatric population is unknown. We determined the frequency of motor abnormalities noted at five years of age during a neurologic examination by a child neurologist. As part of a follow-up study of neonatal jaundice in a population of 106,627 births, we randomly selected 419 five-ye...
Cerebral palsy (CP) is a poorly understood disorder with no cure. We determined the landscape of National Institutes of Health (NIH) funding for CP-related research.
We searched NIH databases Research Portfolio Online Reporting Tools Expenditures and Results, and Research, Condition, and Disease Categorization for keywords 'cerebral palsy' among al...
Perinatal hypoxic-ischaemic encephalopathy (HIE) occurs in 1 to 3 per 1000 term births. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes and is the current standard of care. Yet, clinical trials suggest that 44-53% of infants who receive hypothermia will die or suffer moderate to severe neurological dis...
Exchange transfusion is recommended for newborns with total serum bilirubin (TSB) levels thought to place them at risk for cerebral palsy (CP). However, the excess risk for CP among these infants is unknown.
To quantify the risks for CP and CP consistent with kernicterus that are associated with high TSB levels based on the 2004 American Academy of...
Background and objectives:
Total serum bilirubin (TSB) levels ≥ 30 mg/dL are rare but potentially hazardous. A better understanding of their incidence, causes, and outcomes could help inform preventive efforts.
Methods:
We identified infants born ≥ 35 weeks' gestational age from 1995-2011 in Kaiser Permanente Northern California (n = 525409) and...
AimThe aim of the study was to determine survival probabilities and life expectancies for individuals with cerebral palsy based on data collected over a 28-year period in California.Method
We identified all individuals with cerebral palsy, aged 4 years or older, who were clients of the California Department of Developmental Services between 1983 an...
Aim:
To determine whether the trend of improved survival among individuals with cerebral palsy (CP) in California during the 1980s and 1990s has continued during the most recent decade.
Method:
In an observational cohort study we evaluated individuals with CP, aged 4 years and older, who were clients of the California Department of Developmental...
Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide polymorphism (SNP), rs1800795, in the promoter region of the interleukin-6 (IL6) gene has been implicated in the pathogenesis of CP by mediating IL-6 protein leve...
We report a patient with pantothenate kinase-associated neurodegeneration presenting as idiopathic basal ganglia calcifications, previously known as Fahr's disease.
A teenage girl presented with slowly progressive dystonia. Her brain magnetic resonance imaging scan revealed T1 and T2 hypointensities in both globus pallidi, and no eye-of-the-tiger s...
To examine the association between maternal hospital diagnoses of obesity and risk of cerebral palsy (CP) in the child.
For all California hospital births from 1991-2001, we linked infant and maternal hospitalization discharge abstracts to California Department of Developmental Services records of children receiving services for CP. We identified m...
The cause of perinatal arterial ischemic stroke is unknown in most cases. We explored whether genetic polymorphisms modify the risk of perinatal arterial ischemic stroke. In a population-based case-control study of 1997-2002 births at Kaiser Permanente Northern California, we identified 13 white infants with perinatal arterial ischemic stroke. Cont...
We present a case of intraparenchymal hemorrhage in a neonate with cleidocranial dysostosis, a skeletal dysplasia that leads to delayed skull ossification. The patient's details are reported, including neuroimaging, photographs of classic dysmorphic features, and genetic testing. After spontaneous vaginal birth, the patient was hypotonic and enceph...
To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10 000 U/L; area under the curve = 117 000-140 000 U...
Concerns persist about a possible link between infertility and risk of autism spectrum disorders (ASD). Interpretation of existing studies is limited by racial/ethnic homogeneity of study populations and other factors. Using a case-control design, we evaluated infertility history and treatment documented in medical records of members of Kaiser Perm...
Asians have a reduced risk for cerebral palsy (CP) compared with whites. We examined whether individual Asian subgroups have a reduced risk of CP and whether differences in sociodemographic factors explain disparities in CP prevalence.
In a retrospective cohort of 629 542 Asian and 2 109 550 white births in California from 1991 to 2001, we identifi...
Studies suggest that genetic polymorphisms may increase an individual's susceptibility to CP. Most findings have yet to be corroborated in an independent cohort. This case-control study is nested within all 334,333 infants ≥36 wk gestation born at Kaiser Permanente Medical Care Program, 1991-2002. We included only non-Hispanic whites who had a neon...
In a population-based retrospective cohort of 5,353,022 California births from 1991 to 2000, 3,152 newborns were diagnosed with congenital hydrocephalus during the birth hospitalization. We compared demographic and clinical characteristics of infants with and without congenital hydrocephalus, and examined in-hospital fatality rates. The prevalence...
To examine pregnancy outcomes in preterm delivered children with cerebral palsy (CP).
A retrospective population-based cohort study of children born in California (January 1, 1991 and December 31, 2001) with CP were identified (State databases) and compared to children without CP. We examined demographic data and pregnancy outcomes by gestational a...
The goal of this study was to characterize long-term social and functional outcomes in adults treated for idiopathic normal pressure hydrocephalus (NPH). Data for 252 patients treated medically or surgically for idiopathic NPH were obtained through the Hydrocephalus Association Database Project. Data on post-surgical outcomes including improvement...
Although some have suggested that kernicterus disappeared in the United States in the 1970s to 1980s and dramatically reappeared in the 1990s, population-based data to support such a resurgence are lacking.
We used diagnosis codes on data collection forms from the California Department of Developmental Services (DDS) to identify kernicterus cases a...
Racial and ethnic disparities in cerebral palsy have been documented, but the underlying mechanism is poorly understood. We determined whether low birth weight accounts for ethnic disparities in the prevalence of cerebral palsy and whether socioeconomic factors impact cerebral palsy within racial and ethnic groups.
In a retrospective cohort of 6.2...
The objective of the study was to determine the relationship between nighttime delivery and neonatal encephalopathy (NE).
The design of the study was a retrospective population-based cohort of 1,864,766 newborns at a gestation of 36 weeks or longer in California, 1999-2002. We determined the risk of NE associated with nighttime delivery (7:00 (PM)...
