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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.

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.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.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.Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.ClinicalTrials.gov: NCT02811263.

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.

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.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.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).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.).

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 increased risk for AIS. Post-infectious inflammatory mechanisms following infections with herpesviruses may lead to focal cerebral arteriopathy (FCA), one of the most common causes of AIS in a previously healthy child. Other agents such as parvovirus B19, dengue virus, and SARS-CoV-2 have recently been implicated as other potential triggers. Infections are compelling treatable stroke risk factors, with available therapies for both pathogens and downstream inflammatory effects. However, infections are common in childhood, while stroke is uncommon. The ongoing VIPS II (Vascular effects of Infection in Pediatric Stroke) study aims to identify the array of pathogens that may lead to childhood AIS and whether either unusual strains or unusual combinations of pathogens explain this paradox. Immune modulation with corticosteroids for FCA is another active area of research, with European and U.S. trials launching soon. The results of these new pediatric stroke studies combined with findings emerging from the larger field of immune-mediated post-infectious diseases will likely lead to new approaches to the prevention and treatment of pediatric stroke. This review highlights recent developments from both clinical and animal model research enhancing our understanding of this relationship between infection, inflammation, and stroke in neonates and children.

To investigate the associations between maternal or paternal age at the time of delivery and offspring's risk for cerebral palsy (CP) in California.We conducted a population-based, case-control study that included 8,736 singleton CP cases and 90,250 singleton controls, matched by sex and birth year selected from California birth certificate records from 1994 to 2010. We estimated odds ratios (OR) and 95% confidence intervals (CIs) for CP diagnosis according to maternal and paternal age recorded on the birth certificates. Causal mediation analysis was performed to estimate direct and indirect effects of parental ages on CP with preterm delivery as a potential mediator.Children born to younger mothers (≤19 years) or older mothers (35-39 years; ≥40 years) had a higher risk of CP compared with children of mothers aged 25-29 years (ORs ranging from 1.13 to 1.59). Compared with paternal age 25-29 years, older paternal age (40-44 years; ≥45 years) was also associated with an increased risk for CP independent of maternal age. When analyzing jointly using both parents of ages 20-34 years as the reference, the highest risk was estimated for older parents (≥35 years). Preterm birth was estimated to mediate 19-34% of the total effects between maternal or paternal age and offspring CP risk.Young maternal age and an older age in either or both parents were associated with a higher risk of CP in their children. Although preterm birth was a mediator, additional factors related to parental age need further exploration to explain risk of CP.

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 and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

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.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.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%).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.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.

Challenges to obtaining consent for clinical research in acute settings are ubiquitous and yet highly specific to clinical context. Dickert and colleagues bring to light the challenges inherent in ...

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. 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. 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. 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.

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. In the context of a phase II multi-center trial evaluating erythropoietin for neuroprotection in neonatal encephalopathy (NE), DBS were collected at enrollment (

A 36-week, 5-day-old boy was born through uncomplicated vaginal delivery to a healthy, 36-year-old G7P4 mother. His resuscitation included tactile warmth, drying, and stimulation, and his Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. He was small for gestational age with a birth weight of 2100 g (0.16 percentile). His course was unremarkable with normal behavior and breastfeeding for approximately 40 hours of life.

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.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.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.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.

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 criteria: clinical signs of neonatal encephalopathy, NICU admission, and either a 10-minute Apgar of ≤5 or a base excess of ≤-15 mmol/L. Neonatal acidemia was defined as a base excess of ≤-12 mmol/L. We ascertained antenatal and intrapartum complications from electronic records. Multivariable analysis was performed using logistic regression. Results There were 45 infants (1.0 per 1000) with HIE and 197 (4.4 per 1000) with neonatal acidemia. Of the infants with HIE, 64% had an intrapartum complication consisting of a sentinel event (36%), clinical chorioamnionitis (40%), or both (11%). Risk factors for HIE on multivariable analysis were sentinel event (relative risk [RR], 16.1; 95% CI, 8.4-33) and clinical chorioamnionitis (RR, 5.2; 95% CI, 2.7-9.9). After removing the 16 infants with HIE who were exposed to a sentinel event from multivariate analysis, maternal age of ≥35 years (RR, 2.5; 95% CI, 1.1-5.6) and a urinary tract infection during pregnancy (RR, 2.6; 95% CI, 1.0-6.5) emerged as potential antenatal risk factors for HIE. Conclusions A significant proportion of HIE is preceded by a sentinel event, emphasizing the importance of developing improved methodologies to predict and prevent this perinatal complication. Strategies focused on reducing other complications such as clinical chorioamnionitis and/or maternal pyrexia may also improve our ability to prevent HIE.

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 pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to 6 doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 hours of treatment [AUC48h] 140,000 mU*h/ml). Results Birth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (p

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.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.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.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.

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 disparities in research participation. Objective To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial. Design, Setting, and Participants This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020. Exposure Parental choice of enrollment in neonatal clinical trial. Main Outcomes and Measures Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child’s medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant’s illness, (3) study comprehension, and (4) trust in clinicians and researchers. Results Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%];P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%];P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant’s medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment. Conclusions and Relevance In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities.

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’ gestation in 1995–2011 followed for ≥60 days, we excluded 1773 that exceeded exchange transfusion thresholds and 1237 with seizure diagnoses at RESULTS: A total of 37 683 (7.6%) infants received any phototherapy. The mean (SD) follow-up time was 8.1 (5.2) years. The crude incidence rate per 1000 person-years of the primary outcome was 1.24 among phototherapy-exposed children and 0.76 among those unexposed (rate ratio: 1.63; 95% confidence interval [CI]: 1.44 to 1.85). The adjusted hazard ratio (aHR) was 1.22 (95% CI: 1.05 to 1.42; P = .009). Boys were at higher risk of seizures overall (aHR = 1.18; 95% CI: 1.10 to 1.27) and had a higher aHR for phototherapy (1.33; 95% CI: 1.10 to 1.61) than girls (1.07; 95% CI: 0.84 to 1.37), although effect modification by sex was not statistically significant (P = .17). The adjusted 10-year excess risks per 1000 were 2.4 (95% CI: 0.6 to 4.1) overall, 3.7 (95% CI: 1.2 to 6.1) in boys, and 0.8 (95% CI: −1.7 to 3.2) in girls. CONCLUSIONS: Phototherapy in newborns is associated with a small increased risk of childhood seizures, even after adjusting for bilirubin values, and the risk is more significant in boys.

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 provide additional neuroprotection. Objectives: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. Methods: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. Results and Conclusions: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

BACKGROUND AND OBJECTIVES: 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). METHODS: Infants born at ≥35 weeks gestation in 15 Kaiser Permanente Northern California hospitals from 1995-2011 were eligible (N = 525 409). We used a nested double cohort design. The exposed cohort included subjects with ≥1 bilirubin level at or above ETT. The unexposed cohort was a 3.6% random sample of subjects with all bilirubin levels below ETT (10 unexposed per exposed). An audiologist, blinded to bilirubin levels, reviewed the charts of children in whom SNHL had been diagnosed before age 8 years to confirm the diagnosis. We calculated Cox proportional hazard ratios for time to diagnosis of SNHL. RESULTS: SNHL was confirmed in 11 (0.60%) of the 1834 exposed subjects and in 43 (0.23%) of the 19 004 unexposed. Only bilirubin levels ≥10 mg/dL above ETT were associated with a statistically significant increased risk of SNHL (hazard ratio: 36 [95% confidence interval (CI): 13 to 101]). Likewise, only bilirubin levels ≥35 mg/dL were associated with a statistically significant increased risk of SNHL (hazard ratio: 91 [95% CI: 32 to 255]). For subjects with total serum bilirubin levels 0 to 4.9 mg/dL above ETT, the upper limit of the 95% CI for excess risk was 0.5%. CONCLUSIONS: Only bilirubin levels well above ETT were associated with SNHL. At lower bilirubin levels, the excess risk of SNHL was low.

Neonatal seizures are common and frequently indicate significant underlying brain abnormality. The epidemiology of neonatal seizures has been evaluated in several population and hospital-based studies and these investigations have lead to identification of important maternal, intrapartum and infant risk factors. Identifying and avoiding risks factors for neonatal seizures may lead to lower infant neurological morbidity and mortality.

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-year-old children as healthy controls, of whom 168 consented. Child neurologists blinded to the children’s history performed standard neurologic examinations to determine the presence of definite or subtle motor abnormalities. Standardized data on motor and cognitive function were also obtained. Among eight (5%) children diagnosed with a definite motor abnormality, the most common finding was corticospinal tract dysfunction (four unilateral, two bilateral). Two children demonstrated hypotonia and hyporeflexia, one of whom also exhibited proximal weakness. An additional 12 (7%) children were noted to have subtle motor findings that were not clearly abnormal, such as subtle incoordination, mild dystonic posturing, tremor, posting, or hyperreflexia. Children with definite or subtle motor findings were more likely to receive an abnormal score on the Motor Performance Checklist (57% vs. 32%, P = 0.02). There was also a trend towards these children having a lower mean verbal IQ compared to children with normal motor examinations (95.3 vs. 102.1, P = 0.07). Motor examination abnormalities in otherwise healthy 5-year-old children may be more common than previously thought. However, the proportion of children with motor examination abnormalities who have an unrecognized neurologic disorder remains unknown.

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 Services. Medical diagnoses, functional disabilities, and special health care requirements were assessed with Client Development Evaluation Reports made between 1983 and 2010. Trends in birth cohort survival were analyzed with Kaplan‒Meier curves and Cox regression. Calendar year period effects were analyzed with Poisson regression. Results A total of 51 923 persons with CP (28 789 males [55%], 23 134 females [45%]; mean age 14y 11mo, SD 14y 1mo, range 4y 0mo to 96y 10mo) collectively contributed 662 268 years of follow-up. There were 7690 deaths for an overall mortality rate of 11.6 per 1000 persons per year. No significant birth cohort effects on survival were observed in 4-year-olds who had no severe disabilities. By contrast, children who did not lift their heads in prone position who were born in more recent years had significantly lower mortality rates (Cox hazard ratio 0.971, p

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 .

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 Kaiser Permanente Northern California (KPNC) hospitals, 1995–2011, we obtained all TSB levels and determined which infants received phototherapy. From the KPNC Autism Registry, we identified patients with ASD diagnosed at a KPNC Autism Center, by a clinical specialist, or by a pediatrician. We calculated Cox proportional hazard ratios (HRs) for time to diagnosis of ASD, adjusting for confounding factors.RESULTS:Among infants in the birth cohort, 2% had at least 1 TSB level ≥20 mg/dL, and 8% received phototherapy. The rate of ASD was 13 per 1000 births. Crude analyses revealed an association between TSB ≥20 and ASD (relative risk: 1.4; 95% confidence interval [CI]: 1.1–1.6), and between phototherapy and ASD (relative risk: 1.7; 95% CI: 1.5–1.8). After adjusting for confounders, TSB ≥20 (HR: 1.09; 95% CI: 0.89–1.35) and phototherapy (HR: 1.10; 95% CI: 0.98–1.24) were no longer significantly associated with ASD. Independent risk factors for ASD included maternal and paternal age; maternal and paternal higher education; male sex; birth weight CONCLUSIONS:After adjustment for the effects of sociodemographic factors and birth weight, neither hyperbilirubinemia nor phototherapy was an independent risk factor for ASD.

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 = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar RESULTS: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05). CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

BackgroundChorioamnionitis is a risk factor for cerebral palsy. The relationship between extra-amniotic infections and cerebral palsy is less well studied. We examined maternal intra-amniotic and extra-amniotic infections and risk of cerebral palsy in the child.MethodsAmong a retrospective cohort of 6 million Californian births, 1991-2001, we analyzed administrative maternal and newborn hospital discharge abstracts linked to records of all children receiving services for cerebral palsy at the California Department of Developmental Services. We identified maternal hospital diagnoses of intra-amniotic (chorioamnionitis) and extra-amniotic (other genitourinary and respiratory) infections occurring up to 12 months before delivery. Using multivariable logistic regression, we determined the independent association between maternal infections and cerebral palsy, adjusting for infant sex, maternal age, race, education, socioeconomic status, and obesity.ResultsAbout 5.5% of mothers had a hospital discharge diagnosis of at least one of the following: chorioamnionitis (2.0%), other genitourinary (3.1%), and respiratory infection (0.6%). An infection diagnosis was more common in mothers of the 8473 infants with cerebral palsy than in mothers of unaffected children (13.7% vs 5.5%, P&nbsp

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 cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.

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 Permanente Northern California. Among singletons (349 cases, 1,847 controls), we found no evidence to support an increase in risk of ASD associated with infertility. Among multiple births (21 cases, 54 controls), we found an increased risk associated with infertility history and with infertility evaluations and treatment around the time of index pregnancy conception; however, small sample size and lack of detailed data on treatments preclude firm interpretation of results for multiple births.

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 in symptoms, the need for in-home care, ability to drive, and employment status were analyzed. Most patients (73.7%) surveyed were treated with a shunt, an endoscopic third ventriculostomy (ETV), or both. More patients who underwent surgery reported driving and being employed compared to those who did not have surgery. Most shunt patients had improvements in gait (81.1%), urinary incontinence (55.9%), and dementia (64.4%). Overall, shunt patients reported more dramatic improvements in quality of life as compared to ETV patients (72.2% versus 55.6%). Treating idiopathic NPH with cerebrospinal fluid diversion facilitates a return to independence through improved functional and social outcomes.

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 age groups controlling for multiple co-founders.Of 2733 preterm infants (total of 8397, 33%37 weeks of gestation) with CP, delivery28 weeks had the largest impact upon the development of CP (Odds ratio (OR) 18.2 95%CI (16.7, 19.9)) with delivery 28-31 6/7 weeks having less impact (OR 8.8 (8.0, 9.7) when compared to term deliveries. Birth asphyxia (OR 5.9 (5.3, 6.6) was associated with the future development of CP as were birth defects (OR 4.3 (4.1. 4.5), cord prolapse (OR 2.0 (1.6, 2.4)) and fetal distress (OR 2.1 (1.9, 2.2)) the latter 2 being less so.Prematurity had the greatest impact upon the future development of CP; however, birth asphyxia, birth defects and adverse labor events contributed significantly to the future development of CP as well, suggesting that the cause of CP in the preterm infant is most likely multifactorial.

BACKGROUND: 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. METHODS: We used diagnosis codes on data collection forms from the California Department of Developmental Services (DDS) to identify kernicterus cases among children born from 1988 to 1997. We examined kernicterus mortality trends in the United States from 1979 to 2006 using death certificate data from the National Center for Health Statistics. RESULTS: We identified 25 cases of physician-diagnosed kernicterus. This figure was augmented to reflect estimates of cases lost to infant mortality, yielding incidence estimates of 1 in 200 000 California live births, 1 in 2500 among children who received services from DDS, and 1 in 400 children with cerebral palsy. There was no significant trend in kernicterus incidence from 1988 to 1997 (P = .77). Incidence before and after the 1994 publication of the AAP practice parameter for hyperbilirubinemia in healthy term infants was not significantly different (P = .92). Nationally, there were 3 reported infant deaths from kernicterus in 1994 and 2 or fewer in the other 28 years from 1979 to 2006 (0.28 deaths per million live births): there was no significant increase in kernicterus mortality over this period. CONCLUSION: Data from California do not support a resurgence of kernicterus in the 1990s. Deaths from kernicterus in the United States have remained rare, with no apparent increase during the last 25 years.

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.A study of candidate brain injury biomarkers was conducted in the context of a phase II multicenter randomized trial evaluating Epo for neuroprotection in HIE. Plasma was collected at baseline (24 hours) and on day 5. Brain injury was assessed by magnetic resonance imaging (MRI) and neurodevelopmental assessments at 1 year. The relationships between Epo, brain-specific proteins (S100B, ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], total Tau, neuron specific enolase), cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, IL-12P70, IL-13, interferon-gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], brain-derived neurotrophic factor [BDNF], monocyte chemoattractant protein-1), and brain injury were assessed.In 50 newborns with encephalopathy, elevated baseline S100B, Tau, UCH-L1, IL-1β, IL-6, IL-8, IL-10, IL-13, TNF-α, and IFN-γ levels were associated with increasing brain injury severity by MRI. Higher baseline Tau and lower day 5 BDNF were associated with worse 1 year outcomes. No statistically significant evidence of Epo treatment modification on biomarkers was detected in this small cohort.Elevated plasma brain-specific proteins and cytokine levels in the first 24 hours of life are associated with worse brain injury by MRI in newborns with HIE. Only Tau and BDNF levels were found to be related to neurodevelopmental outcomes. The effect of Epo treatment on the relationships between biomarkers and brain injury in HIE requires further study.ClinicalTrials.gov: 01913340.

Objective Chorioamnionitis is associated with increased risk for cerebral palsy (CP) in term infants. A functional polymorphism in the interleukin-6 (IL-6) gene has been implicated in newborn brain injury. We studied whether the IL-6 -174 G/C polymorphism confers increased risk for CP in term infants. Methods This population-based case–control study included 334,333 live-born infants born at ≥36 weeks gestation within Kaiser Permanente Medical Care Program from 1991 to 2002. Case patients (n = 250) were identified from electronic records and confirmed by chart review, and comprised all infants with spastic or dyskinetic CP not caused by developmental abnormalities who had a neonatal blood specimen available for study. Control patients (n = 305) were randomly selected from the study population. Results Compared with genotype GG, the less common CC genotype was associated with increased risk for overall CP (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5–4.6), quadriparetic CP (OR, 4.1; 95% CI, 1.8–9.3), and hemiparetic CP (OR, 2.7; 95% CI, 1.3–5.7), after controlling for race. The C allele conferred increased risk for CP in both recessive and additive genetic models. In multivariate analysis controlling for race, independent risk factors for CP included CC genotype compared with GG (OR, 2.4; 95% CI, 1.3–4.4), clinical chorioamnionitis (OR, 4.6; 95% CI, 2.1–10.4), maternal age ≥ 35 (OR, 2.6; 95% CI, 1.6–4.1), and male sex (OR, 1.6; 95% CI, 1.1–2.4). Interpretation Our data suggest that a functional polymorphism in the IL-6 gene is a risk factor for CP among term and near-term infants. Ann Neurol 2009;66:663–670

Background and Purpose— Prior annualized estimates of pediatric ischemic stroke incidence have ranged from 0.54 to 1.2 per 100 000 US children but relied purely on diagnostic code searches to identify cases. We sought to obtain a new estimate using both diagnostic code searches and searches of radiology reports and to assess the relative value of these 2 strategies. Methods— Using the population of 2.3 million children (International Classification of Diseases, 9th Revision codes suggestive of stroke and cerebral palsy; and (2) radiology reports for key words suggestive of infarction. Cases were confirmed through chart review. We calculated sensitivities and positive predictive values for the 2 search strategies. Results— We identified 1307 potential cases from the International Classification of Diseases, 9th Revision code search and 510 from the radiology search. A total of 205 ischemic stroke cases were confirmed, yielding an ischemic stroke incidence of 2.4 per 100 000 person-years. The radiology search had a higher sensitivity (83%) than the International Classification of Diseases, 9th Revision code search (39%), although both had low positive predictive values. For perinatal stroke, the sensitivity of the stroke International Classification of Diseases, 9th Revision codes alone was 12% versus 57% for stroke and cerebral palsy codes combined; the radiology search was again the most sensitive (87%). Conclusions— Our incidence estimate doubles that of prior US reports, a difference at least partially explained by our use of radiology searches for case identification. Studies relying purely on International Classification of Diseases, 9th Revision code searches may underestimate childhood ischemic stroke rates, particularly for neonates.

OBJECTIVES. Predictors for perinatal arterial ischemic stroke include both maternal and intrapartum factors, but predictors of perinatal hemorrhagic stroke have not been studied. We sought to determine both the prevalence and predictors of perinatal hemorrhagic stroke within a large, multiethnic population.PATIENTS AND METHODS. We performed a case-control study nested within the cohort of all infants born from 1993 to 2003 in the Northern California Kaiser Permanente Medical Care Program, a health maintenance organization providing care for >3 million members. Cases of symptomatic perinatal hemorrhagic stroke and perinatal arterial ischemic stroke in neonates (28 weeks' gestational age through 28 days of life) were identified through electronic searches of diagnosis and radiology databases and confirmed by medical chart review. Three controls per case were randomly selected and matched on birth year and facility. This analysis included cases of perinatal hemorrhagic stroke (intracerebral hemorrhage or subarachnoid hemorrhage, excluding pure intraventricular hemorrhage) and all controls. Predictors of perinatal hemorrhagic stroke were assessed by using logistic regression, adjusting for the matching criteria.RESULTS. Among 323 532 live births, we identified 20 cases of perinatal hemorrhagic stroke (19 intracerebral hemorrhage and 1 subarachnoid hemorrhage), which yielded a population prevalence for perinatal hemorrhagic stroke of 6.2 in 100 000 live births. Cases presented with encephalopathy (100%) and seizures (65%). Perinatal hemorrhagic stroke was typically unifocal (74%) and unilateral (83%). Etiologies included thrombocytopenia (n = 4) and cavernous malformation (n = 1); 15 (75%) were idiopathic. Univariate predictors of perinatal hemorrhagic stroke included male gender, fetal distress, emergent cesarean delivery, prematurity, and postmaturity but not birth weight. When entered into a multivariate model, fetal distress and postmaturity continued to be independent predictors.CONCLUSIONS. Fetal distress is an independent predictor of perinatal hemorrhagic stroke, perhaps suggesting a prenatal event. Postmaturity also predicts perinatal hemorrhagic stroke, an association not explained by large birth weight in our study.

Objective: To determine if diffusion tensor imaging (DTI) metrics of the pyramidal tracts correlate with motor outcome in infants presenting with motor dysfunction. Methods: DTI tractography of the pyramidal tracts was performed in 21 patients with clinical motor dysfunction who were less than 30 months of age and in 22 age-matched controls. We plotted tract-specific DTI metrics (fractional anisotropy, parallel diffusivity, transverse diffusivity, and mean diffusivity) against age for the controls and generated normative curves. For each patient, we calculated the deviation from the normative curves. Patients returned for a neurodevelopmental evaluation when they were over 36 months of age, and motor outcome measures were performed. We analyzed the association between normative deviation in DTI metrics and motor outcome measures using linear and logistic regression models. Results: Normative deviation in fractional anisotropy and transverse diffusivity were significantly correlated with all measures of motor outcome. Lower fractional anisotropy and higher transverse diffusivity compared to controls were associated with worse motor outcome. Furthermore, children who were eventually diagnosed with permanent motor dysfunction had lower fractional anisotropy and higher transverse diffusivity compared with those whose motor dysfunction normalized. Conclusions: Diffusion tensor imaging metrics correlate with motor outcome in infants presenting with motor dysfunction. The identification of a quantitative imaging marker that can be applied to infants at the time of clinical presentation has implications for the evaluation of early motor dysfunction.

Background and Purpose— Although hemorrhagic strokes (HS) account for half of all strokes in children, rates and predictors of recurrent HS have not been studied. Methods— We collected data on all documented cases of HS (intracerebral hemorrhage, subarachnoid hemorrhage, and intraventricular hemorrhage, except neonatal intraventricular hemorrhage), among 2.3 million children ( Results— Among 116 children with atraumatic incident HS followed for a mean of 4.2 years, 11 had a recurrent HS at a median of 3.1 months (range 7 days to 5.7 years), yielding an overall 5-year cumulative recurrence rate (CRR) of 10% (95% CI, 58% to 18%). Sixty-four percent of recurrences were within the first 6 months. Whereas children with idiopathic HS (n=29) had no recurrences, children with structural lesions (vascular malformations or tumors) had a 5-year cumulative recurrence rate of 13% (95% CI, 7% to 25%; 9 recurrences among 71 children; P Conclusions— Overall, 1 in 10 children with HS experienced a recurrence within 5 years, despite available therapies. Whereas idiopathic HS rarely recurred, and HS due to medical etiologies tended to recur acutely, children with structural lesions had a high and prolonged risk for recurrence.

BACKGROUND AND PURPOSE: Children with congenital hemiparesis have greater asymmetry in diffusion parameters of the pyramidal tracts compared with control subjects. We hypothesized that the asymmetry correlates with the severity of hemiparesis and that diffusion metrics would be abnormal in the affected tracts and normal in the unaffected tracts. MATERIALS AND METHODS: Fifteen patients with congenital hemiparesis and 17 age-matched control subjects were studied with diffusion tensor MR imaging tractography. Hemipareses were scored as mild, moderate, or severe. We measured tract-specific diffusion parameters (fractional anisotropy, mean, and directional diffusion coefficients) of the pyramidal tracts. We compared tract-specific parameters and asymmetry between the right and left tracts of the differing severity groups and control subjects. RESULTS: We observed many different causes of congenital hemiparesis including venous infarction, arterial infarction, and polymicrogyria. Clinical severity of hemiparesis correlated with asymmetry in fractional anisotropy (P < .0001), transverse diffusivity (P < .0001), and mean diffusivity (P < .03). With increasing severity of hemiparesis, fractional anisotropy decreased (P < .0001) and transverse diffusivity (P < .0001) and mean diffusivity (P < .02) increased in the affected pyramidal tract compared with controls. Diffusion metrics in the unaffected tract were similar to those in the control subjects. CONCLUSION: Asymmetry in fractional anisotropy, transverse diffusivity, and mean diffusivity, as well as the degree of abnormality in the actual values of the affected pyramidal tracts themselves, correlates with the severity of motor dysfunction in infants and children with congenital hemiparesis from different causes. This suggests that abnormalities detected by diffusion tensor MR imaging tractography in the affected pyramidal tract are related to the functional ability of the affected pyramidal tract, regardless of the etiology of motor dysfunction.

BACKGROUND: Risk factors for ventriculoperitoneal (VP) shunt complications have not been assessed with population cohort data since the advent of modern surgical techniques. We examined demographic factors and VP shunt complications in a population-based retrospective cohort study of all nonfederal California hospital admissions between 1990 and 2000. METHODS: We identified all admissions in a statewide administrative hospital discharge database that indicated aVP shunt insertion. Repeat hospital admissions within California generating a discharge diagnosis of surgical shunt complication, defined as a shunt replacement, revision, removal, or exploration, represented the primary outcome of interest. We performed Kaplan-Meier survival analyses and Cox proportional hazards modeling to analyze sex, age, ethnicity, socioeconomic status based on payer status, and type of hydrocephalus in relation to the risk of shunt complications. RESULTS: The annual population incidence ofVP shunt placement was 5.5 per 100,000. Among 14,455 individuals with 65,040 person-years of follow-up, the cumulative complication rate at 5 years was 32%. Children demonstrated a higher rate of shunt complications than did adults at 5 years (48 versus 27%, P < 0.0001). The following demographic factors were independently associated with increased risk of shunt complications: male sex (hazard ratio [HR], 1.1; 95% confidence interval [Cl], 1.03-1.2), low socioeconomic status (HR, 1.2; 95% CI, 1.1-1.3), and age younger than 19 years (HR, 1.6; 95% CI, 1.4-1.7). Compared with communicating hydrocephalus, obstructive hydrocephalus was also associated with increased risk of shunt complications (HR, 1.7; 95% CI, 1.5-1.9). CONCLUSION: VP shunt complications are common, especially in children. Further study is needed to explain the associations between demographic factors and elevated shunt complication rates.

The goal in this study was to determine the long-term effects of childhood hydrocephalus.A patient-reported survey completed by 1953 participants was used to collect data in a subgroup of 1459 individuals who had been treated for hydrocephalus in childhood. Data on shunt complications, including total shunt revisions and infections, were examined in those whose hydrocephalus had been diagnosed at least 10 years earlier (718 patients). Social and functional outcomes were examined in patients who were 20 years of age or older at the time of survey completion (403 individuals). Specific questions addressed the presence of depression, the patient's marital status, independent living arrangements, and the educational level attained. Shunt complications were common; 54% of patients had four or more shunt revisions, and 9% had three or more shunt infections. Depression requiring treatment occurred in 45% of participants. Other measures of social functioning all reflected a major impact of childhood hydrocephalus. In general, a worse outcome was found in patients whose hydrocephalus was diagnosed before 18 months of age.The lifelong morbidity associated with shunt placement to treat childhood hydrocephalus is substantial, and it includes shunt-related complications and comorbidities that adversely affect social functioning.

This study examined growth of children and adolescents with cerebral palsy (CP) who received services from the California Department of Developmental Services from 1987 to 2002. In all, 141 961 measurements of height and weight were taken from 24920 patients with CP (14103 males, 10817 females). Centiles of weight and height were determined by age, sex, and five levels of functional ability ranging from fully ambulatory to unable to walk, crawl, or feed self, and fed via gastrostomy tube. Resulting charts of height and weight centiles were compared with Centers for Disease Control and Prevention weight and height charts for the general population of the US. Centiles of height and weight of patients with CP were close to those of the general population for the highest functioning groups with CP, but lagged substantially for other groups. Presence of a feeding tube was associated with greater height and weight in the lowest functioning groups, with centiles for weight being 2 to 5 kg higher for those with gastrostomy tubes. The charts may assist in early identification of nutritional or metabolic difficulties beyond what might be expected for patients with similar functional disabilities.