Chorioamnionitis and Early Childhood Outcomes Among Extremely Low-Gestational-Age Neonates

Importance  Chorioamnionitis is strongly linked to preterm birth and neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral, and neurodevelopmental outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18- to 22-month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates.

Objective  To compare the neonatal and neurodevelopmental outcomes of 3 groups of extremely low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis.

Design, Setting, and Participants  Longitudinal observational study at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Two thousand three hundred ninety extremely preterm infants born at less than 27 weeks’ gestational age (GA) between January 1, 2006, and December 31, 2008, with placental histopathology and 18 to 22 months’ corrected age follow-up data were eligible.

Main Exposure  Chorioamnionitis.

Main Outcomes and Measures  Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant and Toddler Development, Third Edition), and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth.

Results  Neonates exposed to chorioamnionitis had a lower GA and higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of GA in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological plus clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (adjusted odds ratio [OR], 2.38 [95% CI, 1.32 to 4.28] without GA; adjusted OR, 2.00 [95% CI, 1.10 to 3.64] with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological plus clinical chorioamnionitis (adjusted OR, 0.68 [95% CI, 0.52 to 0.89] without GA; adjusted OR, 0.66 [95% CI, 0.49 to 0.89] with GA as a covariate). Risk of behavioral problems did not differ statistically between groups.

Conclusions and Relevance  Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.

The increased survival of extremely low-gestational-age neonates has focused attention on the importance of assessing and improving long-term neurodevelopmental outcomes. It is estimated that as many as 11% to 15% of extremely preterm infants develop cerebral palsy (CP) and approximately half have other adverse outcomes including abnormalities in cognition, language development, and behavior.^1-3 Chorioamnionitis and perinatal inflammation are thought to play a causal role in inciting preterm birth and white matter injury.^4-6 The association of chorioamnionitis and cognitive and neurobehavioral deficits remains unclear. Published studies in extremely preterm neonates offer inconclusive findings, with reports suggesting associations with CP and periventricular leukomalacia,^7-9 lower Mental Developmental Index scores,¹⁰ and, alternatively, reports of no association between chorioamnionitis and neurodevelopmental outcomes.^11-14 Disparate results may be related to differences in the definitions of chorioamnionitis (histological vs clinical), the gestational age (GA) range studied, the age at follow-up, the outcomes selected (eg, brain lesions, neurological outcomes, or composite death/impairment), and issues of sample size and single- vs multiple-center recruitment. Gestational age is particularly important because it not only conveys maturity, but also conveys information on the immune response^15-18 and other developmentally regulated phenomena¹⁹; some studies have grouped extremely low-gestational-age neonates with moderate or late preterm infants.

In the present study, we evaluate whether histological and clinical chorioamnionitis are associated with increased risk of in-hospital morbidities, mortality, and neurodevelopmental impairment (NDI) at 18 to 22 months’ corrected age among extremely preterm neonates less than 27 weeks’ GA. At early gestations (prior to central nervous system myelination), inflammatory injury may be diffuse and result in unique pathological and clinical manifestations. Beyond periventricular leukomalacia and CP, we aimed to report on neurocognitive and behavioral outcomes. We hypothesized that (1) extremely preterm infants exposed to chorioamnionitis would have a higher risk for neonatal morbidities, mortality, and poor neurodevelopmental outcomes compared with infants with no exposure and (2) more severe, clinically manifest chorioamnionitis would be associated with worse outcomes.

This is a retrospective analysis of prospectively collected data on a cohort of extremely preterm neonates with and without exposure to histological or clinical chorioamnionitis. Preterm infants less than 27 weeks’ GA born between January 1, 2006, and December 31, 2008, at centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) were included in the study if they had placental histopathology data and follow-up to 18 to 22 months’ corrected age. Infants with congenital or chromosomal anomalies were excluded. Routine placental pathology is recommended for premature and high-risk deliveries by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists,²⁰ and this recommendation is generally followed by the NRN centers (performed in 82% of inborn infants during the study period). Neonates were divided into 3 exposure groups: no chorioamnionitis, histological chorioamnionitis alone, and histological plus clinical chorioamnionitis. Clinically apparent chorioamnionitis was deemed the highest exposure group; a strong association with fetal inflammatory response syndrome has been reported by some investigators.^8,21 Data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development NRN Generic Database²² and Follow-up studies²³ were used. The studies were approved by the institutional review board of each participating NRN center (Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island; Case Western Reserve University, Rainbow Babies & Children's Hospital; Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital; Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital; Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services; Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children's Hospital; University of Alabama at Birmingham Health System and Children’s Hospital of Alabama; University of Iowa, Children's Hospital; University of Rochester Medical Center, Golisano Children’s Hospital; University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System, and Children's Medical Center Dallas; University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children's Medical Center; Wayne State University, Hutzel Women’s Hospital and Children’s Hospital of Michigan; Yale University, Yale–New Haven Children’s Hospital, and Bridgeport Hospital) and written informed consent was obtained from the parents or guardians for longitudinal follow-up per requirement of the individual institutional review boards.

Neonatal and maternal data were collected prospectively for all live-born infants from birth until death, hospital discharge, transfer, or 120 days, whichever occurred first.²² Infant follow-up data were collected during a comprehensive follow-up evaluation at 18 to 22 months’ corrected age. Maternal and neonatal demographic characteristics included age, race, prenatal care, maternal complications, preterm premature rupture of membranes more than 18 hours, antenatal antibiotics, antenatal corticosteroids, chorioamnionitis, cesarean delivery, birth weight, GA, sex, small for GA status,²⁴ delivery room resuscitation, Apgar scores, cord pH, and base deficit.

Histopathological chorioamnionitis was recorded if chorioamnionitis was noted on the placental pathology report or if acute or subacute chorioamnionitis or chronic chorionitis (as defined by the Stillbirth Collaborative Research Network Pathology Protocol²⁵) were documented. Assessment of histopathological chorioamnionitis was based on local reports made by individual site pathologists. Clinical chorioamnionitis (typically characterized by 2 or more of maternal fever, uterine tenderness, malodorous amniotic fluid, maternal or fetal tachycardia, or evidence of inflammation) also was noted if recorded in the mother’s medical record by the treating clinicians and confirmed histopathologically. Cases of clinical chorioamnionitis without histopathological confirmation were excluded to avoid misclassification.

In-hospital morbidities included mortality, early-onset and late-onset sepsis, bronchopulmonary dysplasia,²⁶ periventricular-intraventricular hemorrhage,²⁷ ventriculomegaly, cystic periventricular leukomalacia, necrotizing enterocolitis,²⁸ and retinopathy of prematurity stage 3 or greater as defined in prior publications.²²

As part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development NRN Follow-up Study, surviving infants underwent a comprehensive follow-up assessment at 18 to 22 months’ corrected age performed by certified examiners trained to reliability.²³ Psychometric testing was performed using the cognitive and language subscales of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III).²⁹ A score of 100 ± 15 on the Bayley-III represents the mean ± 1 SD; a score less than 70 represents 2 SDs below the mean. Children who were so severely developmentally delayed that they could not be assessed were assigned scores (54 for severe cognitive delay and 46 for severe language delay). Behavioral screening was performed using the Brief Infant-Toddler Social and Emotional Assessment administered to the primary caregiver in the form of a structured interview.³⁰ The Brief Infant-Toddler Social and Emotional Assessment is a nationally standardized behavioral screener used to determine the need for diagnostic assessment for socioemotional and behavioral problems. Total problem scores can be compared with specific percentile rankings of normative populations; low percentile rankings (≤25%) are associated with higher problem scores (externalizing, internalizing, dysregulation problems, and behaviors seen in autism spectrum disorders).

Cerebral palsy was defined as a nonprogressive central nervous system disorder with abnormal muscle tone in at least 1 extremity and abnormal control of movement and posture that interfered with age-appropriate activities.³ Disabling CP was classified based on the modified Gross Motor Function Classification System (≥level II).³¹ Neurodevelopmental impairment was defined by 1 or more of disabling CP, Bayley-III cognitive score less than 70, Gross Motor Function level II or greater, blindness, or permanent hearing loss that did not permit the child to understand or communicate despite amplification.

Children with and without exposure to chorioamnionitis defined histologically or clinically were compared with respect to maternal and neonatal baseline characteristics and outcome measures. Demographic characteristics were analyzed for the entire sample, as well as separately for infants excluded or lost to follow-up. For outcome measures, 3 exposure groups were compared: no chorioamnionitis, histological chorioamnionitis alone, and histological plus clinical chorioamnionitis. Multivariable logistic and linear regression models were developed to assess the primary (death/NDI) and secondary outcomes adjusting for important covariates available at the time of birth that were selected a priori (maternal age, multiple birth, parity, antenatal steroids, maternal hypertension, antepartum hemorrhage, sex, GA, small for GA status, insurance, race, and center). Models including GA at delivery were compared with those without any GA at delivery variable, considering that while GA at delivery lies in the causal pathway between chorioamnionitis and outcomes, it also provides important information about the risks of adverse outcomes in extremely preterm newborns.

Three thousand eighty-two infants were assessed for eligibility and the following groups were excluded: infants with chromosomal or congenital anomalies (n = 55), infants with “clinical chorioamnionitis” with normal histopathology (n = 82), and infants lacking placental histopathology (n = 555). The final study cohort consisted of 2390 inborn infants (Figure). Infants with and without placental histopathology had similar baseline characteristics except for 5-minute Apgar score (Apgar score <3 occurred in 20.8% among those with placental histopathology vs 26.4% without) and base deficit (4.99 mmol/L among those with histopathology vs 4.28 mmol/L without). Mothers whose placentas were examined were more likely to have prepartum hemorrhage (22.9% vs 17.6%), receive antibiotics (66.9% vs 58%) or antenatal steroids (75.4% vs 66.9%), and have cesarean delivery (54% vs 46.8%) (Table 1). Of the eligible participants, 38% were born to mothers with histological chorioamnionitis alone and 19% were born to mothers with histological plus clinical chorioamnionitis. Primary outcome (death/NDI) was available for 2235 of all eligible infants (93.5%).

Mothers with histological or histological plus clinical chorioamnionitis were more likely to identify with black race, have preterm premature rupture of membranes greater than 18 hours, deliver vaginally, receive intrapartum antibiotics, and be normotensive as compared with mothers without chorioamnionitis (Table 2). Neonates exposed to antenatal chorioamnionitis had a lower GA and lower Apgar scores as compared with unexposed neonates (despite a higher cord pH). A smaller proportion of neonates exposed to chorioamnionitis were small for GA as compared with infants with no exposure.

Of the 1376 infants exposed to any chorioamnionitis, 44.8% with histological chorioamnionitis died by 18 to 22 months’ corrected age compared with 51.2% with histological plus clinical chorioamnionitis. In comparison, 46.1% with no exposure to chorioamnionitis died. A greater proportion of infants born to mothers with histological or clinical chorioamnionitis had early-onset sepsis (3.6% and 5.9%, respectively, vs 1.3% without chorioamnionitis) and a greater proportion received intravenous antibiotics (55% and 76.5% vs 45.3%). Adjusted risks of sepsis and antibiotic administration were elevated for the histological plus clinical chorioamnionitis group as compared with the other 2 groups. Among infants with histological plus clinical chorioamnionitis, adjusted risk of severe periventricular-intraventricular hemorrhage also was increased (P = .03) (Table 3). No statistically significant differences in the risks of late-onset sepsis, bronchopulmonary dysplasia, central nervous system ventriculomegaly, cystic periventricular leukomalacia, necrotizing enterocolitis, or retinopathy of prematurity were observed between groups.

Survivors to 18 to 22 months’ corrected age included 512 infants whose mothers had no chorioamnionitis and 682 whose mothers had chorioamnionitis. Children with neurodevelopmental assessments at 18 to 22 months’ corrected age and children lost to follow-up were comparable for all baseline characteristics except for mode of delivery and maternal age and race (proportionally more children born vaginally and proportionally more children born to younger mothers and mothers of Hispanic race were lost to follow-up) (eTable 1 in Supplement). Of infants followed up to 18 to 22 months’ corrected age, infants exposed to histological plus clinical chorioamnionitis had a significantly higher risk of cognitive impairment (defined as a cognitive score <70) as compared with the no chorioamnionitis (P = .02) and histological chorioamnionitis alone (P = .03) groups (Table 3). Adjusted risks of CP were not significantly different despite increasing rates with increasing exposure to inflammation: 4.5% among unexposed infants, 4.9% among infants exposed to histological chorioamnionitis alone, and 8.1% among those exposed to histological plus clinical chorioamnionitis. Similarly, there were no significant differences in the risks of spastic diplegia, gross motor functional limitation, language delay, or behavioral problems between groups.

On multivariable analyses, the association between chorioamnionitis and outcome was significantly impacted by inclusion of GA in the model. With GA as a covariate (along with other important covariates impacting outcome), the association between chorioamnionitis and adverse outcomes was diminished (Table 4). Sequential analysis of each variable in the logistic regression models revealed that only GA impacted the association between chorioamnionitis and outcome in this manner. Compared with no chorioamnionitis, histological plus clinical chorioamnionitis was associated with a heightened risk of low cognitive score (<70) (adjusted odds ratio [OR], 2.38 [95% CI, 1.32 to 4.28] without GA; adjusted OR, 2.00 [95% CI, 1.10 to 3.64] with GA) and a decreased continuous cognitive score (β, −3.87 [95% CI, −6.19 to −1.54] without GA and β, −3.25 [95% CI, −5.56 to −0.93] with GA). Compared with histological plus clinical chorioamnionitis, histological chorioamnionitis alone was associated with reduced odds of death/NDI (adjusted OR, 0.68 [95% CI, 0.52 to 0.89] without GA; adjusted OR, 0.66 [95% CI, 0.49 to 0.89] with GA) and NDI (adjusted OR, 0.57 [95% CI, 0.35 to 0.94] without GA; adjusted OR, 0.59 [95% CI, 0.36 to 0.98] with GA). Histological chorioamnionitis also was associated with reduced risk of death/NDI as compared with the no chorioamnionitis group, but only in models that included GA as a covariate (adjusted OR, 1.00 [95% CI, 0.80 to 1.26] without GA; adjusted OR, 0.72 [95% CI, 0.56 to 0.93] with GA). Direct comparison of the unadjusted rates of death and neurodevelopmental outcomes by week of gestation revealed the same patterns of association (eTable 2 in Supplement). The rate of death was lower in the histological chorioamnionitis group than in the no chorioamnionitis or histological plus clinical chorioamnionitis groups for each week less than 27. The rate of cognitive impairment was highest in the clinical plus histological chorioamnionitis group for each gestational week at delivery and nearly 2-fold higher than the other exposure groups overall. We further tested for an interaction between histological or clinical chorioamnionitis and GA in models for NDI or death, death (alone), and NDI (alone), and there was no significant interaction effect in any of the models. (The smallest interaction P value was .19 and it occurred in the NDI model).

Conflicting reports on neonatal outcomes following exposure to chorioamnionitis among extremely premature neonates make prediction of outcomes difficult. This study evaluated the neonatal and neurodevelopmental outcomes of neonates less than 27 weeks’ GA exposed to no chorioamnionitis, histological chorioamnionitis alone, and histological plus clinical chorioamnionitis. Compared with unexposed neonates, neonates exposed to any chorioamnionitis had a lower GA and higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage. In multivariable models evaluating death and neurodevelopmental outcomes, histological plus clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis. Histological chorioamnionitis alone was associated with lower odds of death/NDI as compared with histological plus clinical chorioamnionitis. Histological chorioamnionitis alone also was associated with lower odds of death/NDI as compared with the no chorioamnionitis group, but only when GA at delivery was included in the multivariable model. Both composite and noncomposite outcomes are presented because noncomposite outcomes ignore censoring from infant deaths.

Our findings are consistent with the results of Hendson et al,¹⁰ who reported an association between chorioamnionitis and lower Bayley-II Mental Developmental Index scores. We reported on cognitive impairment specifically using Bayley-III cognitive scores. Histological chorioamnionitis was found to be protective for death/NDI with GA included as a covariate. Because GA may lie in the causal pathway between chorioamnionitis and death and neurodevelopmental outcomes, one may argue whether adjustment for GA is appropriate. Regardless, other causes of prematurity may impact survival more profoundly (eg, aberrant placentation or hypoxia-ischemia). Additionally, a regulated maternal or fetal immune response that triggers parturition and removes the fetus from an inflammatory intrauterine environment may be protective.^32,33 Histological chorioamnionitis is consistently less detrimental than histological plus clinical chorioamnionitis. In a study evaluating all fetal outcomes, Lahra and Jeffery³⁴ reported a survival advantage for neonates with histological chorioamnionitis; surviving premature neonates less than 30 weeks’ GA were more likely to have histological chorioamnionitis or histological evidence of a fetal response as compared with fetuses who were stillborn or preterm neonates who died within 28 days. We collected no data on fetal deaths.

Studies on chorioamnionitis in older GA neonates report a strong association between chorioamnionitis and white matter injury and CP,^6,35 alluding to possible differences in critical GA windows or immune maturity.^15,18 Studies in very preterm infants report mixed results^{7,8,11-13,36,37} and are limited by retrospective assessment of outcomes, incongruent definitions of chorioamnionitis, single-center design (necessitating study over many years, when perinatal care may have changed), and small or inadequate sample sizes over broader GA ranges. Few prospective studies have addressed the potential association of histological chorioamnionitis with the outcomes of extremely preterm neonates. One noteworthy exception is the study by Leviton et al⁹ that evaluated neonates less than 28 weeks’ GA (n = 899 with placental data and neurological assessment at 24 months’ corrected age). Histological chorioamnionitis, defined using stricter criteria than in our study, was associated with an increased risk of ventriculomegaly and diparetic CP. The risk of ventriculomegaly was further increased by recovery of a single or multiple placental organisms, whereas the risk of CP was not. We found no association of ventriculomegaly with chorioamnionitis, but measurements of ventricular size were not ascertained. Our study also found no statistically significant association with CP, though the percentage of infants with CP increased with increasing severity of perinatal inflammation (4.5% with no chorioamnionitis vs 8.1% with histological plus clinical chorioamnionitis). Strunk et al³⁸ reported a reduced risk of late-onset sepsis following chorioamnionitis. We found no difference in the rate of late-onset sepsis among neonates with and without exposure to chorioamnionitis. Our study also evaluated behavioral outcomes based on screening using the Brief Infant-Toddler Social and Emotional Assessment. Though we found no significant association with chorioamnionitis, this does not rule out possible effects that would be detected later in childhood or with other behavioral instruments.

Studies that assess chorioamnionitis without assessing fetal inflammatory response (including our own) lack important data in that fetal involvement is likely a more important predictor of neonatal outcomes than isolated maternal or intrauterine inflammation. Further, inflammatory biomarkers (eg, measurements of cytokines, chemokines, or damage markers) or amniotic or placental microbiological studies are an important omission. Early biomarkers of clinically significant disease may provide more rapid and accurate risk characterization. Though the NRN centers used the Stillbirth Collaborative Research Network Pathology Protocol to classify chorioamnionitis, the NRN registry provided no information on the details of these assessments. Additionally, histopathological assessments were performed by multiple pathologists, raising the possibility of interobserver and intercenter variability; we had no ratings of interrater reliability. Center variation also may have impacted the decision to obtain placental histopathology and the care provided. Ideally, placental histopathology would have been performed for all neonates born during the study period. Additionally, as in other studies targeting preterm infants, a healthy comparison group is lacking. Prematurity in the absence of histological chorioamnionitis is likely a result of other pathological processes that may alter the risk of death/impairment. Evaluation of inflammation over time (not only throughout gestation but in the postnatal period) is important as well.³⁹ Preclinical models have shown that the timing of an inflammatory exposure may alter the course of injury (eg, preconditioning or sensitization).^40-43 Subacute exposure to lipopolysaccharide 24 hours prior to a second noxious exposure lessened brain injury in a rodent model compared with exposure to the second insult alone. In contrast, very acute (6 hours prior) or remote exposures (72 hours prior) intensified injury following the second exposure.⁴⁰ It is possible that histological chorioamnionitis may correspond to this subacute exposure or that combining all forms of histological chorioamnionitis blurs the distinction between acute, subacute, and chronic intrauterine inflammation. We have not considered the impact of postnatal inflammation.

The strengths of our study include the large sample size of 2390 neonates born prior to 27 weeks (including 1376 exposed to chorioamnionitis), the multicenter study design over a 3-year period, and the detailed follow-up and careful neurodevelopmental assessments that included cognitive and behavioral outcomes. Studying a narrow GA cohort of extremely preterm neonates allowed us to focus on the impact of chorioamnionitis on very immature neonates, while much of the literature has combined neonates of broader gestational ranges.

Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.

Corresponding Author: Athina Pappas, MD, Wayne State University School of Medicine, Children’s Hospital of Michigan, 3901 Beaubien Blvd, Detroit, MI 48201 (apappas@med.wayne.edu).

Accepted for Publication: September 5, 2013.

Published Online: December 30, 2013. doi:10.1001/jamapediatrics.2013.4248.

Author Contributions: On behalf of the NRN, Dr Das (data coordinating center [DCC] principal investigator) and Mr Kendrick (DCC statistician) had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.

Study concept and design: Pappas, Shankaran, Bell, Hale, Higgins.

Acquisition of data: Pappas, Shankaran, Stoll, Walsh, Hale, Newman.

Analysis and interpretation of data: Pappas, Kendrick, Shankaran, Bell, Laptook, Das, Hale, Higgins.

Drafting of the manuscript: Pappas, Kendrick, Hale, Newman.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kendrick, Shankaran, Das.

Obtained funding: Shankaran, Stoll, Bell, Walsh.

Administrative, technical, or material support: Stoll, Higgins.

Study supervision: Das, Higgins.

Conflict of Interest Disclosures: None reported.

Funding/Support: The National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Research Resources, and National Center for Advancing Translational Sciences provided grant support for the NRN Generic Database and Follow-up studies.

Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: 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 (grant U10 HD27904): Betty R. Vohr, MD, Angelita M. Hensman, RN, BSN, Robert Burke, MD, Melinda Caskey, MD, Katharine Johnson, MD, Barbara Alksninis, PNP, Theresa M. Leach, MEd, CAES, Victoria E. Watson, MS, CAS; Case Western Reserve University, Rainbow Babies & Children's Hospital (grants U10 HD21364 and M01 RR80): Avroy A. Fanaroff, MD, Deanne E. Wilson-Costello, MD, 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 (grants U10 HD27853 and 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 (grants U10 HD40492 and M01 RR30): Ronald N. Goldberg, MD, C. Michael Cotten, MD, MHS, Ricki F. Goldstein, MD, 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 (grants U10 HD27851 and M01 RR39): David P. Carlton, MD, Ira Adams-Chapman, MD; Eunice Kennedy Shriver National Institute of Child Health and Human Development: Stephanie Wilson Archer, MA; Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (grants U10 HD27856 and 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 (grant U10 HD36790): W. Kenneth Poole, PhD, Dennis Wallace, PhD, Jamie E. Newman, PhD, MPH, Jeanette O’Donnell Auman, BS, Margaret M. Crawford, BS, CCRP, Carolyn M. Petrie Huitema, MS, CCRP, Kristin M. Zaterka-Baxter, RN, BSN, CCRP; Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children's Hospital (grants U10 HD27880 and 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 (grants U10 HD53119 and 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 (grants U10 HD34216 and 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 (grant U10 HD40461): Neil N. Finer, MD, Yvonne E. Vaucher, MD, MPH, David Kaegi, MD, Maynard R. Rasmussen, MD, Kathy Arnell, RNC, Clarence Demetrio, RN, Martha G. Fuller, RN, MSN, Wade Rich, BSHS, RRT; University of Iowa, Children's Hospital (grants U10 HD53109 and M01 RR59): Michael J. Acarregui, MD, Karen J. Johnson, RN, BSN, Diane L. Eastman, RN, CPNP, MA; University of Miami, Holtz Children's Hospital (grants U10 HD21397 and M01 RR16587): Shahnaz Duara, MD, Charles R. Bauer, MD, Ruth Everett-Thomas, RN, MSN, Sylvia Fajardo-Hiriart, MD, Arielle Rigaud, MD, Maria Calejo, MS, Silvia M. Frade Eguaras, MA, Michelle Harwood Berkowits, PhD, Andrea Garcia, MS, Helina Pierre, BA, Alexandra Stoerger, BA; University of New Mexico Health Sciences Center (grants U10 HD53089 and 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 (grants U10 HD40521, UL1 RR24160, and 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 (grant 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 (grants U10 HD40689 and 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 T. Heyne, MS, MA, PA-C, PsyD, 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 (grants U10 HD53124, M01 RR64, and 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, Michael Steffen, MS, CPM; Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (grants U10 HD40498 and 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 (grant U10 HD21385): Rebecca Bara, RN, BSN, Laura A. Goldston, MA; Yale University, Yale–New Haven Children’s Hospital, and Bridgeport Hospital (grants U10 HD27871, UL1 RR24139, and 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.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Information: Data collected at participating sites of the Eunice Kennedy Shriver National Institute of Child Health and Human Development NRN were transmitted to RTI International, the DCC for the network, which stored, managed, and analyzed the data for this study.

Additional Contributions: We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.