Neurodevelopmental Outcomes of Extremely Low Gestational Age Neonates with Low Grade Periventricular-Intraventricular Hemorrhage

Abstract

Objective

To compare neurodevelopmental outcomes at 18–22 months corrected age for extremely low gestational age infants with low grade (Grade 1 or 2) periventricular-intraventricular hemorrhage to infants with either no hemorrhage or severe (Grade 3 or 4) hemorrhage on cranial ultrasound.

Design

Longitudinal observational study

Setting

Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

Participants

1472 infants born at <27 weeks gestational age between 2006–2008 with ultrasound results within the first 28 days of life and surviving to 18–22 months with complete follow-up assessments were eligible.

Main Exposure

Low grade periventricular-intraventricular hemorrhage

Outcome Measures

Outcomes included cerebral palsy, gross motor functional limitation, Bayley III cognitive and language scores, and composite measures of neurodevelopmental impairment. Regression modeling evaluated the association of hemorrhage severity with adverse outcomes while controlling for potentially confounding variables and center differences.

Results

Low grade hemorrhage was not associated with significant differences in unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared to infants without hemorrhage. Compared with low grade hemorrhage, severe hemorrhage was associated with decrease in adjusted continuous cognitive (−3.91, [95% Confidence Interval [CI]: −6.41, −1.42]) and language (−3.19 [−6.19, −0.19]) scores as well as increased odds of each adjusted categorical outcome except severe cognitive impairment (OR: 1.46 [0.74, 2.88]) and mild language impairment (OR: 1.35 [0.88, 2.06]).

Conclusion

At 18–22 months, the neurodevelopmental outcomes of extremely low gestational age infants with low grade periventricular-intraventricular hemorrhage are not significantly different from those without hemorrhage.

INTRODUCTION

Periventricular-intraventricular hemorrhage (PIVH) is the most common form of intracranial hemorrhage among premature infants¹ and affects approximately 1/3^rd of infants born < 29 weeks estimated gestational age (EGA).² Grading of PIVH is traditionally based on Papile’s classification system³ and its use remains pervasive in the literature and clinical setting despite debate regarding appropriate nomenclature.^4,5 Presence of severe PIVH (grade 3 or 4) is understood to correlate strongly with adverse motor and cognitive outcomes. Outcomes of survivors with low grade PIVH (grade 1 or 2) are less fully understood despite accounting for 50–80% of all PIVH cases. Neonatologists continue to face uncertainty when relating the consequences of low grade PIVH to parents of affected infants.^2,6,7

Developmental biology may suggest that any PIVH for extremely low gestational age (ELGA, <27 weeks EGA) infants has potential to destroy glial precursor cells.¹ Interruption of oligodendrocyte and astrocyte development may affect myelination and organization of the cerebral cortex. Destruction of these precursors could theoretically result in adverse neurodevelopmental outcomes.

Previous studies addressing low grade PIVH outcomes have reached differing conclusions. Some studies report no differences between low grade and no PIVH groups^8–11, while others report outcomes ranging from increased risk of mild to severe delays in specific domains^3,12–16 or “global” delays^17–21. Differences in the results of these studies may be attributable to study design, cohort definition, evaluation methods, and evolution of practice.

The objective of this study was to characterize 18–22 month corrected age (CA) outcomes associated with low grade PIVH among ELGA infants in the Eunice Kennedy Shriver NICHD Neonatal Research Network (NRN). We compared outcomes of these infants to ELGA infants: 1) without PIVH and 2) with severe PIVH. We hypothesized infants with low grade PIVH would be at increased risk of cognitive impairment compared to those without PIVH but at lower risk compared to infants with severe PIVH.

METHODS

Infants born at ≤ 26 6/7 weeks EGA within 16 NRN centers between January 1, 2006 and December 31, 2008 with documented cranial ultrasound (CUS) results within 28 days of life (DOL) and surviving to 18–22 months CA with complete follow-up assessment were identified. Subjects with major congenital anomaly, porencephalic cyst on CUS prior to 28 DOL, meningitis, or hydrocephalus requiring shunt were excluded as these factors have been independently associated with poor neurodevelopmental outcomes and may exist outside of the causal pathway between PIVH and outcome.^22–25

Infants were grouped according to the most severe grade of PIVH reported on CUS reports within 28 DOL. Infants with Grade 1 or 2 PIVH were categorized as “low grade” PIVH. Infants with Grade 3 or 4 PIVH were categorized as “severe” PIVH.

This study is a secondary analysis of the NRN’s Generic Database and Follow-Up Study protocols. Per each center’s institutional review board policies, informed consent or waiver of consent was obtained for the Generic Database; informed consent was obtained for the Follow-Up Study. Trained research coordinators prospectively gathered maternal, delivery, and neonatal data according to each study’s manual of operations and common definitions.^2,26,27

Baseline Demographics and Characteristics

I. Maternal Characteristics

Maternal hypertension (mHTN) refers to obstetric documentation of any hypertension diagnosis during pregnancy, acute or chronic. Prolonged rupture of membranes (PROM) was defined as rupture > 18 hours prior to delivery. Chorioamnionitis was determined by clinical obstetric documentation. Antenatal steroid (ANS) exposure was defined as maternal receipt of ≥ 1 dose of any corticosteroid for the purpose of accelerating fetal lung maturity.

II. Neonatal Characteristics

EGA was determined by best obstetric estimate. Cardiopulmonary resuscitation (CPR) in the delivery period was defined as receipt of chest compressions or epinephrine. Bronchopulmonary dysplasia (BPD) was defined by physiologic definition at 36 weeks postmenstrual age.²⁸ Postnatal steroid exposure (PNS) was defined as any corticosteroids given for prevention or treatment of BPD. Patent ductus arteriosus (PDA) was diagnosed on clinical or echocardiographic exam. PDA-Surgical refers to PDA closure by surgical ligation. Indomethacin or ibuprofen use was classified as: “PDA-Medical” for closure of a diagnosed PDA and “PDA/PIVH prophylaxis” for empiric prevention of either condition. Periventricular leukomalacia (PVL) was defined as evidence of cystic lesions in the periventricular area on any CUS during the neonatal admission. Sepsis was defined as positive blood culture any time during the neonatal admission. Necrotizing enterocolitis (NEC) was defined as Bell’s Staging Criteria ≥ IIA.²⁹

Neurodevelopmental Assessment

Comprehensive neurodevelopmental assessment at 18–22 months CA consisted of structured medical history and a battery of neurologic, developmental, and behavioral tests, as previously described.^30,31 Neurologic and developmental testing was performed by annually certified examiners trained to reliability. Gross motor function was assessed by Palisano’s Gross Motor Function Classification System (GMFCS).³² Cognitive and language development was assessed using the Bayley Scales of Infant Development, 3^rd Edition (Bayley III)³³ with mean scores of 100 and standard deviations of 15.

Outcome Definitions

Cerebral palsy (CP) is a nonprogressive central nervous system disorder. “Any CP” was defined as abnormal tone or reflexes in at least one extremity and abnormal control of movement or posture to a degree that interferes with age-appropriate activity. GMFCS > 2 indicated gross motor functional limitation. Infants with a diagnosis of “moderate-severe CP” were non-ambulatory or required an assistive device for ambulation. Severe visual impairment was defined as bilateral acuity < 20–200. Deafness was defined as bilateral permanent hearing loss requiring amplification.

“NDI (<70)” is a composite measure of neurodevelopmental impairment (NDI) defined as having any one of the following: moderate-severe CP, severe visual impairment, deafness, or cognitive score < 70 (−2 SD). “NDI (<85)” was defined using the same composite components as NDI (<70) but with a cognitive score cut-off of < 85 (−1 SD). The primary outcome for this study was the continuous Bayley III cognitive score. Secondary outcomes included: cognitive score < 70, cognitive score < 85, continuous language score, language score < 70, language score < 85, any CP, GMFCS > 2, severe visual impairment, deafness, NDI (<70), and NDI (<85).

Sample Size Estimate

Sample size estimates were calculated for two-sided t-tests of pair-wise comparisons of the continuous cognitive score. To detect a 5 point difference in group means with 80% power and α=0.05, each group would need at least 143 subjects. Further assuming a 30% incidence in PIVH, 70% of PIVH cases being low grade, 10% meeting exclusion criteria, 75% survival, 15% loss to follow-up, and 6% incomplete follow-up testing, an estimated 2900 infants would be required (a Follow-Up birth cohort of approximately three years).

Statistical Analyses

Unadjusted comparisons of maternal demographics, neonatal characteristics and neurodevelopmental outcomes between the no PIVH, low grade PIVH, and severe PIVH groups were made using chi-square or Fisher’s exact tests for categorical data and two-sided t-tests for continuous data.

Multivariate mixed effects regression modeling was performed to adjust for potential confounders of the relationship between PIVH severity and outcomes of interest. Model covariates included: PIVH severity (3-levels), EGA, sex, race/ethnicity, maternal education less than high school (HS), chorioamnionitis, sepsis, ANS, PNS, high frequency ventilation (HFV), and PDA. To preserve the largest possible sample, missing values for predictor variables were imputed as not having the exposure. Less than 2% of predictor data was imputed. NRN Center was included in all models as a random effect to control for center differences in clinical management and variability in local CUS readings. The a priori model was applied en bloc without further paring down procedures as the model was not intended to be predictive. A correlation matrix to assess potential multicollinearity indicated no significant correlations between any covariates, including with PIVH.

RESULTS

2514 infants < 27 weeks EGA with CUS data were identified during the birth cohort (Figure 1). 87% of eligible survivors completed follow-up. The final cohort consists of 1472 ELGA infants with follow-up at 18–22 months CA. 30.6% of these infants had PIVH: 140 with Grade 1, 130 with Grade 2, and 181 with Grades 3 or 4.

Figure 1.

Study enrollment flow

Baseline Characteristics

Demographics, maternal and neonatal course characteristics are shown in Table 1. There were no differences in birth weight, race/ethnicity, maternal age, educational level, or marital status between groups. There was no difference in mean EGA between low grade and no PIVH infants. However, severe PIVH infants had lower mean EGA than low grade or no PIVH infants. Any PIVH infants were more likely to be male but less likely to be exposed to mHTN or Cesarean section delivery than no PIVH infants. Any PIVH infants were also more likely to have PVL or HFV exposure; these likelihoods increased with PIVH severity. There were no differences in rates of BPD, PDA interventions, PDA/PIVH prophylaxis, sepsis, NEC, and ANS or PNS exposure among infants with low grade or no PIVH.

Table 1.

Population Demographics

	No PIVH n = 1021	Low Grade n = 270	Severe PIVH n = 181	p- value
	(%)	(%)	(%)
Infant Characteristics
Gestational Age (wks, mean(sd))	25.1 (0.9)	25.0 (1)	24.7 (1)	b, c
Birth Weight (g, mean(sd))	769 (154)	769 (151)	749 (154)
Gender (Male)	47	61	57	a, b
Race (Black)	39	39	35
Maternal Characteristics
Age (yrs, mean(sd))	28 (6)	27 (7)	27 (6)
≥ High School Education	83	81	81
Married	47	47	44
Hypertension	23	16	14	a,b
Prolonged ROM	28	28	19	b,c
Chorioamnionitis	17	21	29	b,c
Cesarean Section	68	58	57	a,b
Antenatal Steroids, Any	91	89	78	b,c
Antenatal Steroids, Full	61	57	44	b,c
Neonatal Course
5-minute Apgar < 6	21	26	31	b
CPR	9	8	14	b,c
Surfactant	88	90	92
High Frequency Ventilator	37	46	61	ab,c
Pneumothorax	4	5	7
Postnatal Steroids	14	14	22	b, c
BPD, physiologic	47	53	60	b
PDA - Medical	38	41	49
PDA - Surgical	17	20	29	b
PDA/PIVH Prophylaxis	44	38	35	b
PVL	2	5	14	a, b, c
Sepsis	39	44	49	b
NEC	10	10	8

Antenatal Steroids: “Any”: ≥ 1 dose of corticosteroids prior to delivery; “Full”: two doses betamethasone 12–24h apart or four doses dexamethasone 6h apart and delivery ≥24h from initial dose.

^ap<0.05 (Low Grade vs No PIVH),

^bp<0.05 (Severe vs No PIVH),

^cp<0.05 (Severe vs Low Grade PIVH)

Severe PIVH infants were more likely to have chorioamnionitis but less likely to have exposure to ANS or PROM compared to the low grade or no PIVH groups. Severe PIVH infants were less likely to have received PDA/PIVH prophylaxis compared to infants without PIVH. These infants were also more likely to have other neonatal morbidities.

Unadjusted Neurodevelopmental Outcomes

Low grade PIVH was not associated with increases in poor neurodevelopmental outcomes compared to infants without PIVH (Table 2). Severe PIVH was associated with increased rates of poor outcomes when compared to low grade PIVH for every outcome except mild language impairment.

Table 2.

Unadjusted Neurodevelopmental Outcomes by PIVH Grade

	No PIVH n = 1021	Low Grade n = 270	Severe PIVH n = 181	p-value
	(%)	(%)	(%)
Any CP	8	9	28	b,c
Moderate-Severe CP	4	2	10	b,c
GMFCS > 2	5	3	14	b,c
Severe Visual Impairment	1	1	1
Deafness	3	3	2
Cognitive Score (mean(SD))	90 (14)	89 (14)	84 (15)	b,c
Cognitive < 70	7	7	15	b,c
Cognitive < 85	25	29	44	b,c
Language Score (mean(SD))	86 (17)	83 (15)	80 (18)	a*, b,c
Language < 70	16	16	29	b,c
Language < 85	45	53	59	a*, b
NDI (< 70)	10	10	22	b,c
NDI (< 85)	27	30	46	b,c

^a*(0.05 < p ≤ 0.1) for Low Grade PIVH vs No PIVH,

^bp < 0.05 for Severe vs No PIVH,

^cp < 0.05 for Severe PIVH vs Low Grade PIVH

Adjusted Neurodevelopmental Outcomes

Compared with no PIVH, low grade PIVH was not independently associated with any adverse outcomes at 18–22 months CA after adjusting for model covariates (Table 3, Figure 2). Compared with low grade PIVH, severe PIVH was associated with significant decrease in continuous cognitive and language scores as well as increased odds of each categorical outcome with exception of severe cognitive impairment and mild language impairment. Modeling was impossible for severe vision impairment or deafness due to small numbers.

Table 3.

Adjusted Neurodevelopmental Outcomes by PIVH Grade

	Low Grade vs. None	Severe vs. None	Severe vs. Low Grade
Any CP	1.00 (0.61, 1.64)	3.43 (2.24, 5.27)	3.44 (1.96, 5.98)
GMFCS > 2	0.66 (0.32, 1.39)	2.51 (1.43, 4.44)	3.79 (1.67, 8.61)
Cognitive Score	−0.54 (−2.34, 1.25)	−4.46 (−6.62, −2.30)	−3.91 (−6.41, −1.42)
Cognitive < 70	0.94 (0.54, 1.61)	1.37 (0.79, 2.37)	1.46 (0.74, 2.88)
Cognitive < 85	1.03 (0.75, 1.43)	1.82 (1.26, 2.64)	1.76 (1.14, 2.72)
Language Score	−0.31 (−2.45, 1.83)	−3.50 (−6.10,−0.90)	−3.19 (−6.19, −0.19)
Language < 70	0.76 (0.52, 1.13)	1.57 (1.04, 2.37)	2.05 (1.24, 3.39)
Language < 85	1.08 (0.80, 1.45)	1.45 (1.00, 2.10)	1.35 (0.88, 2.06)
NDI (< 70)	0.82 (0.51, 1.31)	1.68 (1.06, 2.65)	2.04 (1.15, 3.64)
NDI (< 85)	1.00 (0.73, 1.37)	1.78 (1.24, 2.57)	1.79 (1.16, 2.75)

For categorical outcomes, the adjusted OR (95% CI) from logistic regression models are presented. For continuous outcomes, the regression coefficient for PIVH grade (β (95% CI)) from linear regression models reflects the adjusted difference in score with exposure.

Figure 2.

Comparison of Adjusted Odds Ratios for Neurodevelopmental Outcomes. Odds ratios with 95% confidence intervals are represented by the horizontal bars. Vertical line is a reference line equal to OR=1. Confidence intervals crossing the reference line are not significant (p>0.05).

Independent predictors of the outcomes of interest, after adjusting for all other specified model covariates, are summarized in eTable 1. No covariate was an independent predictor of every poor outcome after adjusting for all other covariates. Low grade PIVH and chorioamnionitis did not independently predict any outcome. PDA approached significance as a predictor only of mild language delay (p=0.06). Male sex was a predictor of all outcomes except isolated poor motor outcomes. Where ANS was a predictor, receipt was a protective effect against the outcome. Severe PIVH, lower EGA, PNS, HFV, and sepsis were predictors of poor outcome. Maternal education less than HS was a predictor of poor cognitive outcomes, mild language impairment, and decreased continuous language score. Where race was a predictor, black infants were at increased risk of poor outcome. Hispanic infants were at increased risk for language impairment.

In post-hoc analysis, PNS and HFV were eliminated from the model together and separately due to the possibility these covariates could be considered elements in the causal pathway between PIVH and outcome. There were no differences in the above results with any of these model iterations.

COMMENT

This analysis of a large, multi-center contemporary cohort of ELGA infants surviving to 18–22 months CA demonstrates that neurodevelopmental outcomes of infants with Grade 1 or 2 PIVH are not significantly different from those without PIVH, even after adjusting for potential confounders. The inclusion of comparisons between severe PIVH and no PIVH provide internal validity to our results.

The results of our study are in contrast to a cluster of studies reporting on outcomes of low grade hemorrhage for extremely preterm infants born in the 1990s. Two regional cohorts found no significant differences in cognitive or educational outcomes for infants with low grade hemorrhage.^14,16,34 However, both studies^14,16 suggest an increased risk of CP associated with even Grade 2 PIVH. In a single center retrospective birth cohort, Patra et al (2006)¹⁹ found dramatic increases in the rates of NDI, major neurologic abnormality, and cognitive/language impairment at 20 months CA, each with adjusted odds ratios approximately two-fold when comparing infants with low grade PIVH to infants without PIVH. The results of Patra et al are intriguing as they reflect higher risk of major disability than generally reported in relation to low grade hemorrhages. Differences in results of the current and prior studies may be related to issues of study design.

Previous studies reporting on low grade PIVH have used various cohort definitions including narrow and broad ranges of either birth weight (from <1000g to <2000g) or gestational age (<27 weeks to <32 weeks).^3,8–21,34 Results for broadly defined cohorts may be biased towards the null hypothesis as the incidence of PIVH in older and larger preterm infants is lower and the impact of PIVH may be less than for extremely premature infants. Our study defines ELGA using a cut-off of <27 weeks EGA as this is the population at greatest risk for PIVH.^2,35

Multi-center studies benefit from rapid accumulation of large sample sizes and increased power. The time period required to establish a cohort is a matter of not only efficiency but also minimizing variability in cohort demographics, clinical exposures, treatments, and evaluation methods. As a result, multi-center studies typically have greater ability to generalize results to the population beyond the study cohort. However, center-to-center differences in multi-center studies may influence outcomes as demonstrated by Vohr et al (2004).³⁰ To control for clustering of infants by center and potential center differences in our study, “center” was included as a random effect in mixed effects regression modeling. Although the homogeneity of the populations across centers is not explicitly stated in the EPIPAGE^14,34 nor Sherlock et al¹⁶ studies, neither controlled for center differences within their multi-center studies.

Historical and clinical practice contexts must also be considered when comparing studies across time. For example, the role of steroids in neonatology has changed over the past 20–30 years. ANS are now considered standard of care for mothers in the setting of imminent preterm delivery but wide-spread use started only after the release of a 1994 National Institutes of Health Consensus statement.³⁶ PNS were frequently used in the 1980s–90s to facilitate extubation from mechanical ventilation. However, since the late 1990s PNS have been used more sparingly due to concerning links to increased rates of CP. Patra et al’s¹⁹ eight year cohort (1992–2000) encompassed the era of these important changes and the lack of consideration for steroid use raises the possibility that differences in outcomes may have been related to steroids.

Changes in evaluation methods may further complicate comparisons of outcomes over time. The Bayley II³⁷, used for infants born 1993–2005, reports a Mental Developmental Index (MDI) - an inseparable composite measure of cognitive and language domains. However, the Bayley III³³ separates these scores into two reportable domains. Direct comparison of Bayley III scores and Bayley II MDI is problematic although conversion methods are being sought.³⁸ The NRN began uniformly using the Bayley III for infants born on or after January 1, 2006, thus the entire cohort in this study was assessed using the Bayley III. Comparison of our study to a study using an entirely Bayley II evaluated cohort should not focus on the numeric score attained by each group but the overall trend of how the low grade group performs relative to the control group.

The limitations of our study involve the interrater reliability of CUS detection of PIVH, particularly at the lowest grades, and the power of both tests of categorical outcomes and tests between levels of low grade PIVH. Additionally, excluding early porencephalic cyst and hyderocephalus requiring shunt may underestimate severe PIVH impairment for the sake of providing the clearest possible picture of low grade PIVH.

CUS technique and interpretation is highly operator dependent such that systematic differences between radiologists may exist. Hintz et al (2007)³⁹ report 40% agreement for “low grade” PIVH between two NRN centralized readers while the agreement for grade 1 or grade 2 hemorrhage specifically was only 26% and 20% respectively. The sensitivity of local reads compared to centralized readers for low grade PIVH was 48–68%.

Our study was powered on a primary outcome of continuous cognitive score. While the comparison of low grade PIVH to either no PIVH or severe PIVH is highly powered, we were unable to reach the goal sample size of 143 subjects per group for comparisons between Grade 1 vs. Grade 2 PIVH despite a three year cohort of infants. In underpowered analyses of Grade 1 vs. Grade 2 PIVH, there were no significant differences in neurodevelopmental outcomes. To achieve adequate power for categorical outcomes, larger cohorts, typically 5–7 year birth cohorts would be necessary. Also, while it would be clinically useful to distinguish results of Grade 1 vs. Grade 2 PIVH, the poor interrater reliability, as previously mentioned, renders such discrete differences difficult to gauge.

While we have shown that neurodevelopmental outcomes at 18–22 months are not negatively impacted by low grade PIVH, it cannot be assumed that the same could be said at later ages. The overall stability in diagnoses between toddler-hood and early school age is typically poor.^40–42 Significant motor delay is more likely to remain stable while cognitive diagnoses are not stable and the direction of change varies between reports.

In addition, cognitive test scores represent only one piece of the puzzle in assessing late outcomes. Nearly 2/3rds of extremely low birth weight children require special education and are more likely than term peers to have subject-specific learning problems.⁴³ High prevalence/low severity disabilities such as attention deficit/hyperactivity disorders, specific neuropsychological deficits, and behavioral problems may gradually emerge and contribute to the trend of worsening outcomes over time for these children. It is not clear what contribution low grade PIVH may have to these more subtle disabilities.

Cranial ultrasound has been used routinely as a screening and diagnostic method since the late 1970s. While magnetic resonance imaging continues to emerge as an important research tool in understanding brain development and pathophysiology, CUS continues to have a strong clinical presence due to its portability, speed, and lower cost. As such, further investigating the predictive abilities of this modality, particularly over time as more subtle disabilities may emerge will be useful for counseling parents on the potential outcomes of their ELGA infants.

The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network’s Generic Database and Follow-up Studies.

Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, Drs. Abhik Das (DCC Principal Investigator) and Carla Bann (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:

NRN Steering Committee Chair: Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine.

Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Abbot R. Laptook, MD; Angelita M. Hensman, RN BSN; Robert Burke, MD; Melinda Caskey, MD; Katharine Johnson, MD; Barbara Alksninis, PNP; Dawn Andrews, RN MS; Kristen Angela, RN; Theresa M. Leach, MEd CAES; Victoria E. Watson, MS CAS; Suzy Ventura.

Case Western Reserve University, Rainbow Babies & Children’s Hospital (U10 HD21364, M01 RR80) – Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Nancy S. Newman, BA RN; Bonnie S. Siner, RN; Monika Bhola, MD; Gulgun Yalcinkaya, MD; Harriet G. Friedman, MA.

Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, M01 RR8084) – Kurt Schibler, MD; Edward F. Donovan, MD; Kate Bridges, MD; Barbara Alexander, RN; Cathy Grisby, BSN CCRC; Holly L. Mincey, RN BSN; Jody Hessling, RN; Teresa L. Gratton, PA; Jean J. Steichen, MD; Kimberly Yolton, PhD.

Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492, M01 RR30) – Ronald N. Goldberg, MD; C. Michael Cotten, MD MHS; Kathy J. Auten, MSHS; Kimberley A. Fisher, PhD FNP-BC IBCLC; Sandra Grimes, RN BSN; Kathryn E. Gustafson, PhD; Melody B. Lohmeyer, RN MSN.

Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39) – Barbara J. Stoll, MD; David P. Carlton, MD; Ellen C. Hale, RN BS CCRC; Ira Adams-Chapman, MD.

Eunice Kennedy Shriver National Institute of Child Health and Human Development – Rosemary D. Higgins, MD; Stephanie Wilson Archer, MA.

Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, M01 RR750) – Brenda B. Poindexter, MD MS; Anna M. Dusick, MD; Leslie Dawn Wilson, BSN CCRC; Faithe Hamer, BS; Carolyn Lytle, MD MPH; Heike M. Minnich, PsyD HSPP.

RTI International (U10 HD36790) – Abhik Das, PhD; W. Kenneth Poole, PhD; Dennis Wallace, PhD; Jamie E. Newman, PhD MPH; Jeanette O’Donnell Auman, BS; Margaret Cunningham, BS; Carolyn M. Petrie Huitema, MS; Kristin M. Zaterka-Baxter, RN BSN.

Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital (U10 HD27880, M01 RR70) – Krisa P. Van Meurs, MD; David K. Stevenson, MD; Susan R. Hintz, MD MS Epi, Alexis S. Davis, MD MS Epi; M. Bethany Ball, BS CCRC; Andrew W. Palmquist, RN; Melinda S. Proud, RCP; Elizabeth Bruno, PhD; Maria Elena DeAnda, PhD; Anne M. DeBattista, RN PNP; Jean G. Kohn, MD MPH; Hali E. Weiss, MD.

Tufts Medical Center, Floating Hospital for Children (U10 HD53119, M01 RR54) – Ivan D. Frantz III, MD; John M. Fiascone, MD; Brenda L. MacKinnon, RNC; Anne Furey, MPH; Ellen Nylen, RN BSN; Elisabeth C. McGowan, MD.

University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, M01 RR32) – Waldemar A. Carlo, MD; Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD MPH; Monica V. Collins, RN BSN MaEd; Shirley S. Cosby, RN BSN; Fred J. Biasini, PhD; Kristen C. Johnston, MSN CRNP; Kathleen G. Nelson, MD; Cryshelle S. Patterson, PhD; Vivien A. Phillips, RN BSN; Sally Whitley, MA OTR-L FAOTA.

University of California – San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461) – Neil N. Finer, MD; Yvonne E. Vaucher, MD MPH; David Kaegi, MD; Maynard R. Rasmussen, MD; David Kaegi, MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Martha G. Fuller, RN MSN; Wade Rich, BSHS RRT; Radmila West PhD.

University of Iowa, Children’s Hospital (U10 HD53109, M01 RR59) – Edward F. Bell, MD; Michael J. Acarregui, MD; Karen J. Johnson, RN BSN; Diane L. Eastman, RN CPNP MA. University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587) – Shahnaz Duara, MD; Charles R. Bauer, MD; Ruth Everett-Thomas, RN MSN; Sylvia Hiriart-Fajardo, MD; Arielle Rigaud, MD; Maria Calejo, MS; Silvia M. Frade Eguaras, MA; Michelle Harwood Berkowits, PhD; Andrea Garcia, MA; Helina Pierre, BA; Alexandra Stoerger, BA.

University of New Mexico Health Sciences Center (U10 HD53089, M01 RR997) – Kristi L. Watterberg, MD; Jean R. Lowe, PhD; Janell F. Fuller, MD; Robin K. Ohls, MD; Conra Backstrom Lacy, RN; Rebecca Montman, BSN.

University of Rochester Medical Center, Golisano Children’s Hospital (U10 HD40521, UL1 RR24160, M01 RR44) – Dale L. Phelps, MD; Gary J. Myers, MD; Linda J. Reubens, RN CCRC; Erica Burnell, RN; Diane Hust, MS RN CS; Julie Babish Johnson, MSW; Rosemary L. Jensen; Emily Kushner, MA; Joan Merzbach, LMSW; Kelley Yost, PhD; Lauren Zwetsch, RN MS PNP.

University of Texas Health Science Center at Houston Medical School, Children’s Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373) – Kathleen A. Kennedy, MD MPH; Jon E. Tyson, MD MPH; Nora I. Alaniz, BS; Patricia W. Evans, MD; Charles Green, PhD; Beverly Foley Harris, RN BSN; Margarita Jiminez, MD MPH; Anna E. Lis, RN BSN; Sarah Martin, RN BSN; Georgia E. McDavid, RN; Brenda H. Morris, MD; M. Layne Poundstone, RN BSN; Saba Siddiki, MD; Maegan C. Simmons, RN; Patti L. Pierce Tate, RCP; Sharon L. Wright, MT(ASCP).

University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children’s Medical Center Dallas (U10 HD40689, M01 RR633) – Pablo J. Sánchez, MD; Roy J. Heyne, MD; Walid A. Salhab, MD; Charles R. Rosenfeld, MD; Alicia Guzman; Melissa H. Leps, RN; Nancy A. Miller, RN; Gaynelle Hensley, RN; Sally S. Adams, MS RN CPNP; Linda A. Madden, RN CPNP; Elizabeth Heyne, PsyD PA-C; Janet S. Morgan, RN; Catherine Twell Boatman, MS CIMI; Lizette E. Torres, RN.

University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124, M01 RR64, UL1 RR25764) – Roger G. Faix, MD; Bradley A. Yoder, MD; Karen A. Osborne, RN BSN CCRC; Cynthia Spencer, RNC; Kimberlee Weaver-Lewis, RN BSN; Shawna Baker, RN; Karie Bird, RN; Jill Burnett, RNC; Mike Steffen, PhD; Karen Zanetti, RN.

Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (U10 HD40498, M01 RR7122) – T. Michael O’Shea, MD MPH; Robert G. Dillard, MD; Lisa K. Washburn, MD; Barbara G. Jackson, RN, BSN; Nancy Peters, RN; Korinne Chiu, MA; Deborah Evans Allred, MA LPA; Donald J. Goldstein, PhD; Raquel Halfond, MA; Carroll Peterson, MA; Ellen L. Waldrep, MS; Cherrie D. Welch, MD MPH; Melissa Whalen Morris, MA; Gail Wiley Hounshell, PhD.

Wayne State University, Hutzel Women’s Hospital and Children’s Hospital of Michigan (U10 HD21385) – Seetha Shankaran, MD; Athina Pappas, MD; Rebecca Bara, RN BSN; Laura A. Goldston, MA.

Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 RR24139, M01 RR125) – Richard A. Ehrenkranz, MD; Harris Jacobs, MD; Christine G. Butler, MD; Patricia Cervone, RN; Sheila Greisman, RN; Monica Konstantino, RN BSN; JoAnn Poulsen, RN; Janet Taft, RN BSN; Joanne Williams, RN BSN; Elaine Romano, MSN.