Elisabeth C. McGowan

Differential Effects of the Single-Family Room Neonatal Intensive Care Unit on 18- to 24-Month Bayley Scores of Preterm Infants

Objectives To determine the effects of human milk and social/environmental disparities on developmental outcomes of infants born preterm cared for in a single‐family room (SFR) neonatal intensive care unit (NICU). Study design Outcomes were compared between infants weighing ≤1250 g cared for in an open‐bay NICU (1/2007‐8/2009) (n = 394) and an SFR NICU (1/2010‐12/2011) (n = 297). Human milk provision at 1 week, 4 weeks and discharge, and 4 week volume (mL/kg/day) were analyzed. At 18‐24 months of age, the Bayley III was administered. Group differences were evaluated and multiple linear regression analyses were run. Results Infants cared for in the SFR NICU had higher Bayley III cognitive and language scores, higher rates of human milk provision at 1 and 4 weeks, and higher human milk volume at 4 weeks. In adjusted regression models, the SFR NICU was associated with a 2.55‐point increase in Bayley cognitive scores and 3.70‐point increase in language scores. Every 10 mL/kg/day increase of human milk at 4 weeks was independently associated with increases in Bayley cognitive, language, and motor scores (0.29, 0.34, and 0.24, respectively). Medicaid was associated with decreased cognitive (−4.11) and language (−3.26) scores, and low maternal education and non‐white race with decreased language scores (−4.7 and −5.8, respectively). Separate models by insurance status suggest there are differential benefits from SFR NICU and human milk between infants with Medicaid and private insurance. Conclusions Infants born preterm cared for in the SFR NICU have higher Bayley language and cognitive scores and receive more human milk. Independent effects on outcomes were derived from SFR NICU, provision of human milk, and social and environmental factors.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial

Importance Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks’ or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks’ or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks’ gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, −1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration clinicaltrials.gov Identifier: NCT00614744

Social Emotional Factors Increase Risk of Postpartum Depression in Mothers of Preterm Infants

OBJECTIVE To examine the association of maternal mental health, perceptions of readiness at neonatal intensive care unit (NICU) discharge, and social risk factors with depressive symptoms 1 month postdischarge in mothers of early (<32 weeks), moderate (32-33 weeks), and late (34-36 weeks) preterm infants. A secondary objective was to compare depressive symptoms among mothers in all preterm groups. STUDY DESIGN Mothers (n = 734) of preterm infants cared for >5 days in the NICU and participating in a Transition Home Program completed the Fragile Infant Parent Readiness Evaluation prior to discharge for perceptions of NICU staff support, infant well-being, maternal well-being (emotional readiness/competency), and maternal comfort (worry about infant). Mental health history and social risk factors were obtained. At 1 month postdischarge the Edinburgh Postnatal Depression Scale was administered. Group comparisons and logistic regression analyses were run to predict possible depression (Edinburgh Postnatal Depression Scale  ≥10). RESULTS Mothers of early, moderate, and late preterm infants reported similar rates of possible depression (20%, 22%, and 18%, respectively) 1 month after NICU discharge. History of mental health disorder, decreased perception of maternal well-being, decreased maternal comfort regarding infant, and decreased perception of family cohesion were associated with possible depression at 1 month postdischarge. CONCLUSIONS Mothers with a previous mental health disorder and experiencing negative perceptions of self and infant at NICU discharge were at increased risk for depressive symptomatology 1 month postdischarge regardless of infant gestational age. Comprehensive mental health assessment prior to discharge is essential to identify women at risk and provide appropriate referral.

Impact of a Transition Home Program on Rehospitalization Rates of Preterm Infants

Objectives To evaluate the effects of a transition home program on 90‐day rehospitalization rates of preterm (PT) infants born at <37 weeks gestational age implemented over 3 years for infants with Medicaid and private insurance, and to identify the impact of social/environmental and medical risk factors on rehospitalization. Study design In this prospective cohort study of 954 early, moderate, and late PT infants, all families received comprehensive transition home services provided by social workers and family resource specialists (trained peers) working with the medical team. Rehospitalization data were obtained from a statewide database and parent reports. Group comparisons were made by insurance type. Regression models were run to identify factors associated with rehospitalization and duration of rehospitalization. Results In bivariable analyses, Medicaid was associated with more infants hospitalized, more than 1 hospitalization, and more days of hospitalization. Early PT infants had more rehospitalizations by 90 days than moderate (P = .05) or late PT infants (P = .01). In regression modeling, year 3 of the transition home program vs year 1 was associated with a lower risk for rehospitalization by 90 days (OR, 0.57; 95% CI, 0.36‐0.93; P = .03). Medicaid (P = .04), non–English‐speaking (P = .02), multiple pregnancies (P = .05), and bronchopulmonary dysplasia (P = .001) were associated with increased risk. Both bronchopulmonary dysplasia and Medicaid were associated with increased days of rehospitalization in adjusted analyses. The major cause of rehospitalization was respiratory illness (61%). Conclusions Transition home prevention strategies must be directed at both social/environmental and medical risk factors to decrease the risk of rehospitalization.

Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

ABSTRACT Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)

Preterm Neuroimaging and School-Age Cognitive Outcomes

With this prospective, multicenter study of infants born EPT, we assess the relative value of neonatal neuroimaging to predict cognitive impairment and disability at school age. BACKGROUND AND OBJECTIVES: Children born extremely preterm are at risk for cognitive difficulties and disability. The relative prognostic value of neonatal brain MRI and cranial ultrasound (CUS) for school-age outcomes remains unclear. Our objectives were to relate near-term conventional brain MRI and early and late CUS to cognitive impairment and disability at 6 to 7 years among children born extremely preterm and assess prognostic value. METHODS: A prospective study of adverse early and late CUS and near-term conventional MRI findings to predict outcomes at 6 to 7 years including a full-scale IQ (FSIQ) <70 and disability (FSIQ <70, moderate-to-severe cerebral palsy, or severe vision or hearing impairment) in a subgroup of Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial enrollees. Stepwise logistic regression evaluated associations of neuroimaging with outcomes, adjusting for perinatal-neonatal factors. RESULTS: A total of 386 children had follow-up. In unadjusted analyses, severity of white matter abnormality and cerebellar lesions on MRI and adverse CUS findings were associated with outcomes. In full regression models, both adverse late CUS findings (odds ratio [OR] 27.9; 95% confidence interval [CI] 6.0–129) and significant cerebellar lesions on MRI (OR 2.71; 95% CI 1.1–6.7) remained associated with disability, but only adverse late CUS findings (OR 20.1; 95% CI 3.6–111) were associated with FSIQ <70. Predictive accuracy of stepwise models was not substantially improved with the addition of neuroimaging. CONCLUSIONS: Severe but rare adverse late CUS findings were most strongly associated with cognitive impairment and disability at school age, and significant cerebellar lesions on MRI were associated with disability. Near-term conventional MRI did not substantively enhance prediction of severe early school-age outcomes.

Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants

Background & Objectives Neonatal neurobehavioral performance measures, such as the NICU Network Neurobehavioral Scale (NNNS), have been developed to assess the neurobehavioral characteristics of infants and provide insights into future developmental trajectories. The identification of molecular biomarkers of very early life neurobehavioral experiences could lead to better predictions of the long-term developmental outcomes of high-risk infants including preterm infants. To this end, we aimed to examine whether variability in DNA methylation (DNAm) or epigenetic age from surrogate tissues are associated with NNNS profiles in a cohort of infants born less than 30 weeks postmenstrual age (PMA). Methods This study was performed within the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study and included those infants with complete NNNS assessment data and DNAm measured from buccal cells, collected at near term-equivalent age using the Illumina EPIC array (N=536). We tested whether epigenetic age and age acceleration differed between infants based on their NNNS profile classifications. Then we performed an epigenome-wide association study, to test whether DNAm at individual epigenetic loci varied between these NNNS profile groupings. Models were adjusted for recruitment site, infant sex, postmenstrual age, and estimated tissue heterogeneity. Results We found that infants with an optimal NNNS profile had slightly older epigenetic age than other NOVI infants (β1 = 0.201, p-value = 0.026), and that infants with an atypical NNNS profile had differential methylation at 29 CpG sites (FDR < 10%). The genes annotated to these differentially methylated CpGs included PLA2G4E, TRIM9, GRIK3, and MACROD2, which have previously been associated with neurological structure and function, or with neurobehavioral disorders. Conclusions Greater epigenetic age is associated with optimal NNNS responses while altered DNAm of multiple genes are associated with an atypical neurobehavioral profile at near-term equivalent age. These findings build upon the existing evidence that epigenetic variations in buccal cells may serve as markers of neonatal neurobehavior and might facilitate early identification of children at risk for abnormal developmental outcome.

Transition Home Plus Program Reduces Medicaid Spending and Health Care Use for High-Risk Infants Admitted to the Neonatal Intensive Care Unit for 5 or More Days

Objective To evaluate the effects of a transition home intervention on total Medicaid spending, emergency department visits, and unplanned readmissions for preterm infants born at ≤366/7 weeks gestation and high‐risk full‐term infants. Study design The Transition Home Plus (THP) program incorporated enhanced support services before and after discharge from the neonatal intensive care unit (NICU) provided by social workers and family resource specialists (trained peers) working with the medical team from October 2012 to October 2014. Rhode Island Medicaid claims data were used to study the 321 infants cared for in the NICU for ≥5 days, who were enrolled in the THP program. THP infants were compared with a historical comparison group of 365 high‐risk infants born and admitted to the same NICU in 2011 before the full launch of the THP program. Intervention and comparison group outcomes were compared in the eight 3‐month quarters after the infants birth. Propensity score weights were applied in regression models to balance demographic characteristics between groups. Results Infants in the intervention group had significantly lower total Medicaid spending, fewer emergency department visits, and fewer readmissions than the comparison group. Medicaid spending savings for the intervention group were

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks’ Gestational Age: A Randomized Clinical Trial

4591 per infant per quarter in our study period. Conclusions Transition home support services for high‐risk infants provided both in the NICU and for 90 days after discharge by social workers and family resource specialists working with the medical team can reduce Medicaid spending and health care use.

Effects of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-ischemic Encephalopathy

Importance Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. Objective To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks’ gestational age. Design, Setting, and Participants Randomized clinical trial included 638 infants younger than 28 weeks’ gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. Interventions A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. Main Outcomes and Measures Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. Results Among 638 infants (mean, 26 weeks’ gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks’ postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%). Conclusions and Relevance Among premature infants younger than 28 weeks’ gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.