Eileen M. Walsh

Neonatal Cytokines and Cerebral Palsy in Very Preterm Infants

To examine the relationship of cytokines in blood of very preterm neonates with later diagnosis of spastic cerebral palsy (CP) compared with infants of similar gestational age without CP, we measured concentrations of inflammatory cytokines and other substances in archived neonatal blood by recycling immunoaffinity chromatography. Subjects were surviving children born before 32 wk gestational age (GA) to women without preeclampsia, 64 with later diagnoses of CP and 107 control children. The initial analyses were augmented by measurement of 11 cytokines by a bead-based flow analytic system (Luminex) in an additional 37 children with CP and 34 control children from the same cohort. Concentrations of examined substances did not differ by presence of indicators of infection in mother, infant, or placenta. On ANOVA, concentrations of a number of cytokines were significantly related to neonatal ultrasound abnormalities (periventricular leukomalacia, ventricular enlargement, or moderate or severe germinal matrix hemorrhage). None of the substances measured either by immunoaffinity chromatography or flow analytic methods, including IL-1, -6, and -8 and tumor necrosis factor-α, was related to later diagnosis of CP or its subtypes. Inflammatory cytokines in neonatal blood of very premature infants did not distinguish those with later diagnoses of CP from control children.

First-day weight loss predicts eventual weight nadir for breastfeeding newborns

Objective To examine the relationship between high (≥5%) weight loss during the first 24 h after birth and eventual excess weight loss (EWL) of ≥10% of birth weight. Design Retrospective cohort study. Setting Kaiser Permanente Northern California hospitals. Patients 63 096 infants born at ≥36 weeks in 2009–2010, of whom 59 761 (94.5%) had a weight subsequent to birth weight measured at <24 h. Main predictor measure Per cent of birth weight lost by 24 h of age. Main outcome measure Weight nadir, defined as the lowest recorded inpatient or outpatient weight in the first 30 days after birth, expressed as a percentage of birth weight. Results Among infants who breastfed at least once, mean (±SD) weight nadir was 6.3±3.5% below birth weight, and 9.6% of the newborns lost ≥10% of birth weight. Among 2670 infants who lost ≥5% of their birth weight in the first 24 h, 782 (29%) eventually developed EWL, compared with 4840 (8%) of 57 109 infants who lost <5% (p<0.0005). In multivariate analysis, ≥5% first-day weight loss predicted eventual EWL (≥10%) with an OR of 4.06 (95% CI 3.69 to 4.46) after adjusting for gestational age, method of delivery, maternal race/ethnicity and hospital of birth. Conclusions High first-day weight loss predicts eventual weight nadir and can be used to identify infants who might benefit from targeted interventions to support breastfeeding and prevent EWL.

Prevalence and neonatal factors associated with autism spectrum disorders in preterm infants.

OBJECTIVES To determine the prevalence of autism spectrum disorders (ASD) across gestational age, examine the risk of ASD by gestational age controlling for other risk factors, and identify potential risk factors in the neonatal intensive care unit. STUDY DESIGN A retrospective cohort of infants born at ≥ 24 weeks between January 1, 2000, and December 31, 2007 at 11 Kaiser Permanente Northern California hospitals (n = 195,021). ASD cases were defined by a diagnosis made at a Kaiser Permanente ASD evaluation center, by a clinical specialist, or by a pediatrician. Cox proportional hazards regression models were used to evaluate the association between gestational age and ASD as well as potential risk factors in the neonatal intensive care unit and ASD. RESULTS The prevalence of ASD in infants <37 weeks was 1.78% compared with 1.22% in infants born ≥ 37 weeks (P < .001). Compared with term infants, infants born at 24-26 weeks had an adjusted hazard ratio (HR) for a diagnosis of ASD of 2.7 (95% CI 1.5-5.0). Infants born at 27-33 weeks (adjusted HR 1.4, 95% CI 1.1-1.8) and 34-36 weeks (adjusted HR 1.3, 95% CI 1.1-1.4) were also at increased risk. High frequency ventilation and intracranial hemorrhage were associated with ASD in infants < 34 weeks. CONCLUSIONS ASD was ~ 3 times more prevalent in infants <27 weeks compared with term infants. Each week of shorter gestation was associated with an increased risk of ASD. High frequency ventilation and intracranial hemorrhage were associated with ASD among infants <34 weeks.

Stratification of Risk of Early-Onset Sepsis in Newborns ≥34 Weeks’ Gestation

OBJECTIVE: To define a quantitative stratification algorithm for the risk of early-onset sepsis (EOS) in newborns ≥34 weeks’ gestation. METHODS: We conducted a retrospective nested case-control study that used split validation. Data collected on each infant included sepsis risk at birth based on objective maternal factors, demographics, specific clinical milestones, and vital signs during the first 24 hours after birth. Using a combination of recursive partitioning and logistic regression, we developed a risk classification scheme for EOS on the derivation dataset. This scheme was then applied to the validation dataset. RESULTS: Using a base population of 608 014 live births ≥34 weeks’ gestation at 14 hospitals between 1993 and 2007, we identified all 350 EOS cases <72 hours of age and frequency matched them by hospital and year of birth to 1063 controls. Using maternal and neonatal data, we defined a risk stratification scheme that divided the neonatal population into 3 groups: treat empirically (4.1% of all live births, 60.8% of all EOS cases, sepsis incidence of 8.4/1000 live births), observe and evaluate (11.1% of births, 23.4% of cases, 1.2/1000), and continued observation (84.8% of births, 15.7% of cases, incidence 0.11/1000). CONCLUSIONS: It is possible to combine objective maternal data with evolving objective neonatal clinical findings to define more efficient strategies for the evaluation and treatment of EOS in term and late preterm infants. Judicious application of our scheme could result in decreased antibiotic treatment in 80 000 to 240 000 US newborns each year.

Risk of childhood asthma following infant bronchiolitis during the respiratory syncytial virus season

To the Editor: The etiology of asthma remains unclear but is thought to include nonmodifiable risk factors such as family history and genetic predisposition, as well as potentially modifiable risk factors including viral bronchiolitis in infancy. During the winter months, the predominant virus detected in infants with viral bronchiolitis is respiratory syncytial virus (RSV). By age 1 year, approximately 70% of the children have been infected with RSV, and this increases to almost 100% by age 2 years. Infant RSV bronchiolitis is associated with recurrent wheeze or asthma throughout childhood and even into early adulthood, with a dose-response relationship identified between the severity of the bronchiolitis and the risk of developing asthma, and evidence for a causal relationship. The aim of our study was to determine what proportion of childhood asthma is associated with infant bronchiolitis during the RSV season. We analyzed cohort data of children born from 1996 to 2003 and cared for at Northern California Kaiser Permanente (KPNC), an integrated health care delivery system, and children born from 1995 to 2003 and enrolled in Tennessee Medicaid (TennCare). KPNC and TennCare provide health insurance for approximately one-third of Northern California residents and approximately one-half of infants born in Tennessee, respectively. Eligible infants had a minimum gestation age of 32 weeks, had no chronic lung disease, and were continuously enrolled in either TennCare or KPNC during the first year of life. The main predictor variable was infant bronchiolitis during the RSV season defined by International Classification of Diseases, Ninth Revision codes for bronchiolitis and limited to the RSV season, October through March, during the first year of life. The main outcome variable was early childhood asthma determined using an algorithm of International Classification of Diseases, Ninth Revision codes for asthma and asthma-specific medication utilization between ages 4.5 and 6 years. The Vanderbilt University Institutional Review Board and the KPNC Institutional Board for the Protection of Human Subjects approved the study. The Bureau of TennCare approved the use of Tennessee Medicaid data. To ascertain the proportion of childhood asthma in the TennCare or KPNC population that is associated with bronchiolitis exposure during the RSV season, we calculated both the attributable risk of infants with a bronchiolitis event during infancy and the population-attributable risk. We estimated the attributable fraction of bronchiolitis from adjusted risk ratios that were calculated from multivariable Poisson regression models with a robust error variance for the early childhood asthma outcome. Adjustment covariates included gender, race, gestational age, birth weight, siblings, maternal age, and maternal smoking. Statistical analyses were performed with R version 2.12.1 software. A total of 264,010 infant births (KPNC 81,550, TennCare 182,460) were included in this study and followed until age 6 years. Table I highlights key characteristics of the 2 cohorts. Compared with the TennCare population, the KPNC population had more Hispanic and Asian participants, less African American participants, higher rates of maternal education beyond high school, and lower rates of maternal smoking. Overall, 15% of the infants had bronchiolitis during the RSV season. The proportion of children diagnosed with asthma among the KPNC and TennCare cohorts was 8% and 12%, respectively, for those without a history of infant bronchiolitis during the RSV season and 16% and 23%, respectively, for those with a history of infant bronchiolitis during the RSV season. The populationattributable risk for asthma contributed by infant bronchiolitis during the RSV season was 10% for the KPNC cohort, and among the subset of children with infant bronchiolitis during the RSV season, the attributable risk was 49% (95% CI, 47% to 52%); in TennCare, it was 13% and 47% (95% CI, 45% to 48%), respectively (see Fig 1). The unadjusted risk ratio of childhood asthma following infant bronchiolitis during the RSV season for KPNC was 1.97 (95% CI, 1.87-2.09), and the multivariate adjusted risk ratio of childhood asthma following infant bronchiolitis during the RSV season was 1.94 (95% CI, 1.84-2.05); for TennCare, it was 1.87 (95% CI, 1.82-1.92) and 1.81 (95% CI, 1.77-1.86), respectively. In our analysis restricting to term infants (gestational age >_37 weeks), results remain unchanged (data not shown). In both the KPNC and TennCare cohorts, the proportion of children who developed asthma was almost 2 times higher in childrenwith a history of infant bronchiolitis during theRSVseason than in the childrenwhodidnot have a history of infant bronchiolitis during the RSV season. The almost identical attributable risk and population-attributable risk findings are notable given the significant differences between the 2 populations. Adjustment of risk ratios for potential confounders did not change the results. Despite the strengths of our large population-based study, several limitations deserve mention. This study relied on existing electronic data; however, the use of electronic data has been previously validated as both sensitive and specific. Second, the study was unable to detect infants with asymptomatic or mild bronchiolitis during the RSV season as well as those who did not seek treatment. In addition, we were unable to confirm the diagnosis of RSV as the etiology of bronchiolitis events although prior studies support that the majority of infant bronchiolitis events during the RSV season are attributable to RSV. In a retrospective study by Stemple et al in which bronchiolitis was defined by International Classification of Diseases, Ninth Revision codes for bronchiolitis, RSV was detected in the nasal wash samples of 77% of the children younger than age 2 years collected between October and April. By limiting our study to bronchiolitis episodes during the winter months, RSV is likely to be the associated viral pathogen. Last, while human rhinovirus infection has also been implicated in asthma inception, infant rhinovirus bronchiolitis is far less common than infant RSV bronchiolitis, and occurs in older infants, those born to parents with asthma, or those who have already been allergically sensitized, suggesting that rather than being causal, rhinovirus bronchiolitis is a clinical biomarker of future asthma risk. In summary, in 2 representative US populations with significantly varying baseline characteristics, there were consistent findings that nearly 50% of the asthma cases in children with a history of infant bronchiolitis during the RSV season were associated with bronchiolitis. On a population level, 13% of the

A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis.

Importance Current algorithms for management of neonatal early-onset sepsis (EOS) result in medical intervention for large numbers of uninfected infants. We developed multivariable prediction models for estimating the risk of EOS among late preterm and term infants based on objective data available at birth and the newborn’s clinical status. Objectives To examine the effect of neonatal EOS risk prediction models on sepsis evaluations and antibiotic use and assess their safety in a large integrated health care system. Design, Setting, and Participants The study cohort includes 204 485 infants born at 35 weeks’ gestation or later at a Kaiser Permanente Northern California hospital from January 1, 2010, through December 31, 2015. The study compared 3 periods when EOS management was based on (1) national recommended guidelines (baseline period [January 1, 2010, through November 31, 2012]), (2) multivariable estimates of sepsis risk at birth (learning period [December 1, 2012, through June 30, 2014]), and (3) the multivariable risk estimate combined with the infant’s clinical condition in the first 24 hours after birth (EOS calculator period [July 1, 2014, through December 31, 2015]). Main Outcomes and Measures The primary outcome was antibiotic administration in the first 24 hours. Secondary outcomes included blood culture use, antibiotic administration between 24 and 72 hours, clinical outcomes, and readmissions for EOS. Results The study cohort included 204 485 infants born at 35 weeks’ gestation or later: 95 343 in the baseline period (mean [SD] age, 39.4 [1.3] weeks; 46 651 male [51.0%]; 37 007 white, non-Hispanic [38.8%]), 52 881 in the learning period (mean [SD] age, 39.3 [1.3] weeks; 27 067 male [51.2%]; 20 175 white, non-Hispanic [38.2%]), and 56 261 in the EOS calculator period (mean [SD] age, 39.4 [1.3] weeks; 28 575 male [50.8%]; 20 484 white, non-Hispanic [36.4%]). In a comparison of the baseline period with the EOS calculator period, blood culture use decreased from 14.5% to 4.9% (adjusted difference, −7.7%; 95% CI, −13.1% to −2.4%). Empirical antibiotic administration in the first 24 hours decreased from 5.0% to 2.6% (adjusted difference, −1.8; 95% CI, −2.4% to −1.3%). No increase in antibiotic use occurred between 24 and 72 hours after birth; use decreased from 0.5% to 0.4% (adjusted difference, 0.0%; 95% CI, −0.1% to 0.2%). The incidence of culture-confirmed EOS was similar during the 3 periods (0.03% in the baseline period, 0.03% in the learning period, and 0.02% in the EOS calculator period). Readmissions for EOS (within 7 days of birth) were rare in all periods (5.2 per 100 000 births in the baseline period, 1.9 per 100 000 births in the learning period, and 5.3 per 100 000 births in the EOS calculator period) and did not differ statistically (P = .70). Incidence of adverse clinical outcomes, including need for inotropes, mechanical ventilation, meningitis, and death, was unchanged after introduction of the EOS calculator. Conclusions and Relevance Clinical care algorithms based on individual infant estimates of EOS risk derived from a multivariable risk prediction model reduced the proportion of newborns undergoing laboratory testing and receiving empirical antibiotic treatment without apparent adverse effects.

Incidence, Etiology, and Outcomes of Hazardous Hyperbilirubinemia in Newborns

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 = 525 409) and examined the medical records of infants with a TSB ≥30 mg/dL to determine etiology and the occurrence of acute bilirubin encephalopathy. We reviewed inpatient and outpatient encounters through 2013 for evidence of sensorineural hearing loss (SNHL) or cerebral palsy (CP). RESULTS: We identified 47 infants with TSB ≥30 mg/dL (8.6 per 100 000 births). In 44 infants (94%), the hyperbilirubinemia occurred after the initial birth hospitalization. The etiology was not identified in 33 (70%). Glucose-6-phosphate dehydrogenase (G6PD) activity was measured in only 25 (53%) of whom 10 (40%) were deficient. Four children had acute bilirubin encephalopathy of whom 2 developed both CP and SNHL, and 1 developed isolated SNHL. These 3 infants all had G6PD deficiency and TSB >40 mg/dL. One additional 35-week infant with TSB 38.2 mg/dL had SNHL. CONCLUSIONS: Hazardous (≥30 mg/dL) hyperbilirubinemia is a rare event. No etiology could be identified from the clinical record in most cases. G6PD deficiency was the leading cause of hazardous hyperbilirubinemia when an etiology was identified, but many were not tested. Chronic, bilirubin-induced neurotoxicity was uncommon and occurred only in the setting of additional risk factors and TSB values well over (>15 mg/dL) the American Academy of Pediatrics exchange transfusion thresholds.

Incidence of Dravet Syndrome in a US Population.

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 all infants born at Kaiser Permanente Northern California during 2007–2010, we electronically identified patients who received ≥2 seizure diagnoses before age 12 months and who were also prescribed anticonvulsants at 24 months. A child neurologist reviewed records to identify infants who met 4 of 5 criteria for clinical Dravet syndrome: normal development before seizure onset; ≥2 seizures before age 12 months; myoclonic, hemiclonic, or generalized tonic-clonic seizures; ≥2 seizures lasting >10 minutes; and refractory seizures after age 2 years. SCN1A gene sequencing was performed as part of routine clinical care. RESULTS: Eight infants met the study criteria for clinical Dravet syndrome, yielding an incidence of 1 per 15 700. Six of these infants (incidence of 1 per 20 900) had a de novo SCN1A missense mutation that is likely to be pathogenic. One infant had an inherited SCN1A variant that is unlikely to be pathogenic. All 8 experienced febrile seizures, and 6 had prolonged seizures lasting >10 minutes by age 1 year. CONCLUSIONS: Dravet syndrome due to an SCN1A mutation is twice as common in the United States as previously thought. Genetic testing should be considered in children with ≥2 prolonged febrile seizures by 1 year of age.

Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy

BackgroundRespiratory syncytial virus (RSV) infection in infancy is associated with subsequent recurrent wheezing.MethodsA retrospective cohort study examined children born at ≥32 weeks gestation between 1996–2004. All children were enrolled in an integrated health care delivery system in Northern California and were followed through the fifth year of life. The primary endpoint was recurrent wheezing in the fifth year of life and its association with laboratory-confirmed, medically-attended RSV infection during the first year, prematurity, and supplemental oxygen during birth hospitalization. Other outcomes measured were recurrent wheezing quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions.ResultsThe study sample included 72,602 children. The rate of recurrent wheezing in the second year was 5.6% and fell to 4.7% by the fifth year. Recurrent wheezing rates varied by risk status: the rate was 12.5% among infants with RSV hospitalization, 8% among infants 32–33 weeks gestation, and 18% in infants with bronchopulmonary dysplasia. In multivariate analyses, increasing severity of respiratory syncytial virus infection was significantly associated with recurrent wheezing in year 5; compared with children without RSV infection in infancy, children who only had an outpatient RSV encounter had an adjusted odds ratio of 1.38 (95% CI,1.03–1.85), while children with a prolonged RSV hospitalization had an adjusted odds ratio of 2.59 (95% CI, 1.49–4.50).ConclusionsLaboratory-confirmed, medically attended RSV infection, prematurity, and neonatal exposure to supplemental oxygen have independent associations with development of recurrent wheezing in the fifth year of life.

Early Weight Loss Nomograms for Exclusively Breastfed Newborns

BACKGROUND: The majority of newborns are exclusively breastfed during the birth hospitalization, and weight loss is nearly universal for these neonates. The amount of weight lost varies substantially among newborns with higher amounts of weight loss increasing risk for morbidity. No hour-by-hour newborn weight loss nomogram exists to assist in early identification of those on a trajectory for adverse outcomes. METHODS: For 161 471 term, singleton neonates born at ≥36 weeks’ gestation at Northern California Kaiser Permanente hospitals in 2009–2013, data were extracted from the birth hospitalization regarding delivery mode, race/ethnicity, feeding type, and weights from electronic records. Quantile regression was used to create nomograms stratified by delivery mode that estimated percentiles of weight loss as a function of time among exclusively breastfed neonates. Weights measured subsequent to any nonbreastmilk feeding were excluded. RESULTS: Among this sample, 108 907 newborns had weights recorded while exclusively breastfeeding with 83 433 delivered vaginally and 25 474 delivered by cesarean. Differential weight loss by delivery mode was evident 6 hours after delivery and persisted over time. Almost 5% of vaginally delivered newborns and >10% of those delivered by cesarean had lost ≥10% of their birth weight 48 hours after delivery. By 72 hours, >25% of newborns delivered by cesarean had lost ≥10% of their birth weight. CONCLUSIONS: These newborn weight loss nomograms demonstrate percentiles for weight loss by delivery mode for those who are exclusively breastfed. The nomograms can be used for early identification of neonates on a trajectory for greater weight loss and related morbidities.