Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment

We retrospectively analyzed prospectively collected data on all extremely preterm (gestational age [GA] <27 weeks) infants born at or admitted within 72 hours of age to any of the 18 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) centers from April 1, 2011, to June 30, 2015. All infants enrolled in the NRN generic database (GDB) registry who were diagnosed with retinal detachment or who received bevacizumab or laser surgery and/or cryotherapy in either eye within 120 days after birth were included. We used this pragmatic definition of severe ROP because we did not have data regarding specific criteria for type 1 ROP.¹⁶ Laser surgery and cryotherapy for retinal ablation were not differentiated. Infants treated with both bevacizumab and surgery (n = 16) were excluded. Choice of therapy was based on the clinician’s preference. Appropriate consents or waivers were approved by the institutional review board of each site.

Data collection in the GDB registry was until discharge from the hospital, transfer, or death on or before 120 days of age. Limited additional data, including treatment of ROP and date of death or discharge, were collected for infants who remained hospitalized after 120 days until 1 year of age. Prenatal care was defined as at least 1 visit. Infants with a birth weight below the 10th percentile for GA were considered small for gestational age (SGA).¹⁷ Data on respiratory distress syndrome (surfactant receipt at <72 hours of age), patent ductus arteriosus (PDA) with receipt of treatment, intracranial hemorrhage, cystic periventricular leukomalacia or porencephalic cysts on cranial imaging, early-onset (≤72 hours of age) and late-onset (>72 hours) sepsis or meningitis (positive results on the blood or spinal-fluid culture), seizures (anticonvulsant treatment of >72 hours), necrotizing enterocolitis (NEC) (modified Bell’s staging criteria above stage II A), and bronchopulmonary dysplasia (BPD) (by the physiologic definition) were obtained.^18,19 

ROP status was documented after ROP treatment at discharge or 120 days of life as favorable if each eye had (1) fully vascularized mature vessels, (2) immature vessels or stage 1 or 2 ROP in zone III for 2 consecutive examinations, or (3) ROP in zone II or III but clearly regressing. ROP status was defined as severe in the presence of retinal detachment or receipt of bevacizumab or laser surgery or cryotherapy in either eye. ROP status was undetermined if neither eye was severe and if at least 1 eye had immature vessels in zone I or II, reaching zone III for only 1 examination, stage 1 or 2 ROP in zone III for 1 examination, stage 3 ROP in zone III, ROP in zone I or II, or plus disease.

The age at follow-up assessments changed from 18–22 to 22–26 months’ corrected age after June 30, 2012. Follow-up assessments included neurologic examination; Bayley-III cognitive, language, and motor composite scores (expected population mean 100; SD 15) and scaled scores for fine and gross motor skills; and receptive and expressive language, (mean 10; SD 3). Children who were not successfully tested because of severe developmental delay, blindness, or profound hearing loss were assigned a cognitive score of 54 and language and motor scores of 46.²⁰ Vision was categorized as (1) normal in both eyes, (2) corrective lenses or abnormality, (3) blind (corrected vision <20/200) with some function in at least 1 eye, or (4) blind with no useful vision. The primary outcome was a composite of severe NDI or death. Severe NDI was defined as a Bayley-III cognitive or motor score <70, a Gross Motor Functional Classification Scale (GMFCS) level ≥2,²¹ bilateral blindness (blind and/or blind with some functional vision in both eyes), or severe to profound hearing impairment (permanent hearing loss, which prevented understanding of instructions, with or without amplification). Secondary outcomes included components of the primary outcome. Cutoff values of 70 and 85 were reported in view of 97% agreement between the Bayley-III cognitive score of 85 and the Bayley Scales of Infant Development, Second Edition Mental Developmental Index of <70 and because motor impairment may be overestimated at a cutoff of 85.^22,23 

Characteristics were compared between the bevacizumab and surgery groups, with statistical significance determined by the Wilcoxon rank test for continuous measures, Mantel-Haenszel mean score tests by using modified ridit scores for ordinal categorical measures, and χ² tests for categorical measures. Primary and secondary outcomes were analyzed by using generalized linear models with generalized estimating equations after adjusting for GA, sex, severe intracranial hemorrhage or white-matter injury, BPD, surgical NEC, and maternal public insurance while controlling for center as a random effect. Birth year and its interaction with treatment was explored but not found to be statistically significant (P = .300). Adjusted generalized linear models could not be fit for hearing impairment and bilateral blindness, and therefore differences in these outcomes were evaluated by using χ² tests. To assess the robustness of the findings, 2 sensitivity analyses for the primary outcome were conducted; 1 was used for assuming that all missing outcomes were unfavorable, and the second included only infants cared for in centers that provided exclusively either laser surgery or bevacizumab during the study period. Significance was taken at a level <.05.

An anticipated sample size of 230 infants in the ROP surgery group and 140 in the bevacizumab treatment group yielded 97% power to detect a 20% difference in the primary outcome and 80% power to detect a 15% difference, respectively. A 5-point or greater difference in Bayley-III composite cognitive scores could also be detected between the groups with over 80% power, assuming a normal distribution. All analyses were performed by using SAS version 9.4 (SAS Institute, Inc, Cary, NC).

Of the 5016 infants enrolled in the registry, 2413 had ROP, of whom 469 underwent ROP surgery (n = 258; 55.0%), received bevacizumab (n = 195; 41.6%), or were treated with both (n = 16; 3.4%) (Fig 1). Infants who received both therapies were excluded from further analyses. Of the remaining 453 infants, 413 survived until follow-up; primary outcome data were available in 405 (89.4%) infants. Infants who were excluded (n = 48) because of missing follow-up data were comparable with those who were included (n = 405) in most maternal and neonatal characteristics except for a longer median (IQR) length of stay (137 [112–169] vs 124 [109–143] days; P = .02) and a higher incidence of ventriculomegaly (27% vs 10%; P = .01) among included infants (Table 1).

A comparison between groups of infants who received bevacizumab therapy (n = 181) or ROP surgery (n = 224) revealed lower rates of Medicaid insurance (50% vs 62%; P = .02) and single mothers (43% vs 57%; P = .006) and a lower median (IQR) birth weight (640 [541–709] vs 660 [573–750] g; P = .02) in the group treated with bevacizumab (Table 2). Infants in the bevacizumab treatment group had a lower rate of treated PDA (45% vs 63%; P < .001) and longer median (IQR) durations of conventional ventilator support (35 [21–58] vs 33 [18–49] days; P = .04) and supplemental oxygen (112 [94–120] vs 105 [84.5–120] days; P = .01) compared with those in the ROP surgery group. ROP status at discharge, transfer, or 120 days of life differed significantly (P = .003) between the 2 groups, with more frequent favorable statuses (17% vs 7%) in the laser surgery group (Table 2).

A greater proportion of infants in the group treated with bevacizumab died (17 [9.4%] vs 8 [3.6%]) or remained hospitalized (6 [3.3%] vs 3 [1.3%]), and fewer were discharged from the hospital (155 [85.6%] vs 203 [90.6%]) or transferred (3 [1.7%] vs 10 [4.5%]) up to 1 year of age. The median (IQR) age of death in the 17 infants who died after bevacizumab treatment was 160 (146–233) days, compared with 165.5 (156–208.5) days in the 8 infants in the ROP surgery group (P = .60). Causes of death in the bevacizumab group were BPD (n = 6), BPD with infection (n = 3), BPD with severe intracranial injury (n = 5), short bowel syndrome (n = 2), and other cause (n = 1). Infants in the ROP surgery group died of BPD (n = 2), proven sepsis or infection (n = 1), or other causes (n = 5). In addition, 9 infants in the bevacizumab group and 6 in the ROP surgery group died after discharge from the hospital and before follow-up assessment. Table 3 is a description of infants who died in the 2 groups.

Among infants who survived to follow-up, 365 of 413 (88.4%) had available data on NDI classification. Twenty-four infants could not be tested for the cognitive score and were assigned a score of 54; 7 were classified as blind (1 of whom was deaf), 6 were blind with some function (1 of whom was deaf), 8 had corrective lenses or abnormality (2 of whom were deaf), 2 had normal vision, and 2 had no vision classification. These 24 infants and an additional 1 with corrective lenses could not be tested for language skills; the 25 infants and another classified as blind and deaf could not be tested for motor scores, and all were assigned a score of 46. Among 13 infants who were bilaterally blind with no or some functional vision, 8 were able to be tested.

Rates of death or severe NDI were 51.4% in the group treated with bevacizumab and 43.8% in the ROP surgery group, which was not a statistically significant difference. Death reported through the follow-up time frame was significantly higher in the group treated with bevacizumab compared with the ROP surgery group (14.4% vs 6.3%; adjusted odds ratio [aOR] 2.54 [95% CI 1.42 to 4.55]; P = .002) (Table 4). Rates of severe NDI among survivors were not different (43% vs 40%; aOR 1.14 [95% CI 0.76 to 1.70]; P = .54). The adjusted mean cognitive score was not significantly different between groups; however, the proportion of infants with cognitive scores <85 was higher (58% vs 47%) in the bevacizumab group (aOR 1.78 [95% CI 1.09 to 2.91]; P = .02). A GMFCS level ≥2 was also more frequent (30% vs 22%; aOR 1.73 [95% CI 1.04 to 2.88]; P = .04).

A sensitivity analysis for death or NDI used to compare bevacizumab (n = 195) with ROP surgery (n = 258), assuming that all missing outcomes were unfavorable, was not statistically significant (54.9% vs 51.2%; aOR 1.15 [95% CI 0.81 to 1.63]; P = .43). A sensitivity analysis that included only infants (n = 162) who were cared for in centers (n = 12) that performed only laser surgery or bevacizumab exclusively revealed an increased risk of death among infants treated with bevacizumab (15.9% vs 7.5%; aOR 2.60 [95% CI 1.11 to 6.07]; P = .03) (Table 5).

The current observational study involved extremely preterm infants cared for at centers of the NICHD NRN over a 4-year period after publication of the results of the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) RCT revealing efficacy of bevacizumab therapy.² The primary outcome of death or severe NDI was not significantly different between the bevacizumab and ROP surgery groups. Bevacizumab therapy for severe ROP was significantly associated with death before follow-up, compared with ROP surgery alone. A cognitive score <85 was more frequent in the group treated with bevacizumab.

ROP, a neovascular retinal disorder, remains a leading global cause of childhood blindness.²⁴ Reported rates of severe ROP among preterm participants of recent multicenter trials range from 6.0% to 13.4%.^25,26 Extreme prematurity, prolonged invasive ventilator support, and oxygen exposure are risk factors for ROP.²⁷ Compared with the nonsevere ROP group, children with severe ROP have a significantly lower longitudinal IQ from 2 to 18 years, after adjustment for perinatal risk factors.²⁸ Severe ROP is independently correlated with adverse 18-month and 5-year outcomes and with a nearly threefold increased risk of nonvisual impairment, cognitive and motor impairment, and severe hearing loss.^26,29,30 

The Cochrane meta-analysis included 4 RCTs in which bevacizumab therapy and laser surgery were compared for type 1 ROP.^2,5,31,–33 The unknown long-term systemic adverse effects of the drug and insufficient data were thought to preclude strong conclusions favoring routine use of intravitreal anti-VEGF agents in preterm infants with ROP.³¹ Bevacizumab was not associated with a reduction in the risk of retinal detachment, mortality before discharge, nor risk of ROP recurrence requiring retreatment.³¹ The BEAT-ROP study revealed a significant reduction in high myopia at 30 months of age.¹⁴ In our cohort, there were no differences in visual outcomes between groups at 2 years of age, although details of refractive errors were not available. In the BEAT-ROP RCT, there was no difference in mortality at 30 months of age (relative risk 0.86; 95% CI 0.30 to 2.45).¹⁴ Death was not directly related to ROP therapy in any case, and in only 1 case, death was within a week of treatment. There were no deaths until 90 weeks’ postmenstrual age (PMA) in either treatment group in another RCT.³² In the current study, we were the first to observe that mortality through infancy was significantly higher in the bevacizumab group compared with the ROP surgery group. These findings are confounded by baseline differences between the groups and the longer receipt of ventilatory support and supplemental oxygen in infants treated with bevacizumab, although BPD rates were similar. It is certainly possible that the group of infants treated with bevacizumab was sicker and that clinical severity of illness at the time of intervention, which could not be ascertained, influenced the decision for bevacizumab therapy versus ROP surgery. In infants who are critical, an injection of bevacizumab may be perceived as safer than ROP surgery, with the accompanying anesthesia and intubation risks. We also recognize that unknown confounders that modify risk of death or adverse neurologic outcome may have been associated with the choice of bevacizumab therapy or laser surgery. However, the differences in mortality persisted after adjustment for multiple known confounders and even when we included only centers that treated severe ROP with either bevacizumab or laser surgery exclusively (presumably without considering severity of illness), lending credence to our findings. VEGF activity is important for maintenance of tissue function and integrity; VEGF suppression with intravenous bevacizumab in adults is associated with hypertension, thromboembolic events, bowel perforation, and delayed wound healing.³⁴ In adults with cancer, an association between systemic bevacizumab and fatal adverse effects has been noted.³⁵ Systemic treatment of newborn rats with a VEGF receptor inhibitor impaired pulmonary vascular growth and postnatal alveolarization, resulting in pulmonary hypertension, which persisted into adulthood.³⁶ 

The authors of 2 observational studies compared neurodevelopmental outcomes of infants treated with bevacizumab or laser surgery for ROP.^15,37 The Canadian Neonatal Network included 125 preterm infants born at <29 weeks’ GA who were treated with bevacizumab (n = 27; mean birth weight 739 g) or laser therapy (n = 98; mean birth weight 714 g); the follow-up rate was 72%, and mortality was 1.7%.¹⁵ Infants in the bevacizumab therapy group had a higher median (IQR) Score for Neonatal Acute Physiology-II score (24 [19–31] vs 19 [13–28]; P = .03) and more severe ROP compared with infants in the laser surgery group. Infants treated with bevacizumab had lower adjusted motor scores at 18 to 22 months’ corrected age. The proportions with cognitive scores <85 were higher in the bevacizumab group (42% vs 25%), with an aOR of 2.6 (95% CI 0.9–7.7). Adjusted odds of severe NDI (defined as a Bayley-III composite score <70, a GMFCS level of 3–5, hearing aids, or bilateral blindness) were 3.1 times higher in infants treated with bevacizumab versus laser surgery. Compared with the Canadian cohort, our study cohort had lower birth weights and GAs, less maternal education at or beyond high school, and higher rates of severe intraventricular hemorrhage (IVH). Severe NDI definitions in the 2 studies had slight differences (a GMFCS level of 2–5 in the NICHD NRN study versus 3–5 in the Canadian study), whereas rates (38% in the Canadian study versus 37% in the NICHD NRN study) were similar. We too found that the likelihood of having cognitive scores <85 was 1.78-fold higher in the bevacizumab group, and the adjusted mean score was 3 points lower. In contrast to the Canadian study, however, adjusted odds of severe NDI and motor scores did not differ between groups. In another single-center study in which infants received intravitreal bevacizumab (n = 12), laser surgery (n = 33), or both (n = 16) on the basis of parental choice, no differences in neurodevelopment were found at 24 months of age between the bevacizumab and laser surgery groups.³⁷ Infants who received both therapies had a higher incidence of significant mental and psychomotor impairment than those in the laser surgery group. In our study, we excluded infants receiving both therapies.

We acknowledge several limitations of our study. Visual outcomes were limited, and confirmatory ophthalmologic examinations were not available. We were unable to identify additional bevacizumab treatment after discharge. Infants in the bevacizumab treatment group had a lower median birth weight and longer length of conventional ventilator support and supplemental oxygen, which were not adjusted for because of the collinearity of birth weight with GA and because length of respiratory support could be attributable to differences in ROP therapy. The absence of dosing information on bevacizumab and missing data on maternal education are limitations. Importantly, the reason for the decision for ROP surgery versus bevacizumab therapy was not captured and may have affected the comparability of the groups. The cohort study design was not ideal for comparing mortality differences between groups or for uncovering associations between single comorbidities or therapies with childhood outcomes.

Nonetheless, given the increasing use of bevacizumab and in view of previous safety concerns, this comparative evaluation is important. Our study was derived from a diverse multicenter cohort with prospective data capture, included all eligible infants, had detailed neurodevelopmental follow-up, and had a high follow-up rate.

Although confounded by baseline differences between groups and the likelihood that treatment options varied by center and varied over time, we found a statistical association of bevacizumab treatment of severe ROP with death and adverse cognitive outcomes after adjustment for multiple covariates and on sensitivity analyses that attempted to address variation in choice of therapy. Although not conclusive, these results do underscore the need for rigorous appraisal of the risks and benefits of bevacizumab in a large randomized trial with neurodevelopmental follow-up. Until then, cautious use of this therapy may be prudent.

The following investigators, in addition to those listed as authors, participated in this study: NRN Steering Committee Chair: Michael S. Caplan, MD (The University of Chicago Pritzker School of Medicine); Alpert Medical School of Brown University and Women and Infants Hospital of Rhode Island (UG1 HD27904): Abbot R. Laptook, MD, Martin Keszler, MD, Angelita M. Hensman, MS, RNC-NIC, Elisa Vieira, RN, BSN, Emilee Little, RN, BSN, Robert Burke, MD, Melinda Caskey, MD, Katharine Johnson, MD, Barbara Alksninis, PNP, Mary Lenore Keszler, MD, Andrea M. Knoll, Theresa M. Leach, MEd, CAES, Elisabeth C. McGowan, MD, Victoria E. Watson, MS, CAS, and Suzy Ventura; Case Western Reserve University and Rainbow Babies and Children’s Hospital (UG1 HD21364): Michele C. Walsh, MD, MS, Avroy A. Fanaroff, MD, Anna Maria Hibbs, MD, MSCE, Nancy S. Newman, BA, RN, Allison H. Payne, MD, MS, Deanne E. Wilson-Costello, MD, Bonnie S. Siner, RN, Monika Bhola, MD, Gulgun Yalcinkaya, MD, and Harriet G. Friedman, MA; Children’s Mercy Hospital and University of Missouri-Kansas City School of Medicine (UG1 HD68284): William E. Truog, MD, Eugenia K. Pallotto, MD, MSCE, Howard W. Kilbride, MD, Cheri Gauldin, RN, BS, CCRC, Anne Holmes, RN, MSN, MBA-HCM, CCRC, Kathy Johnson, RN, CCRC, and Allison Knutson, BSN, RNC-NIC; Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (UG1 HD27853, M01 RR8084): Brenda B. Poindexter, MD, MS, Kurt Schibler, MD, Barbara Alexander, RN, Cathy Grisby, BSN, CCRC, Teresa L. Gratton, PA, Jean J. Steichen, MD, Estelle E. Fischer, MHSA, MBA, Lenora Jackson, CRC, Kristin Kirker, CRC, Greg Muthig, BS, Stacey Tepe, BS, and Kimberly Yolton, PhD; Duke University School of Medicine, Duke University Hospital, University of North Carolina at Chapel Hill, and Duke Regional Hospital (UG1 HD40492; UL1 TR1117; UL1 TR1111): Ronald N. Goldberg, MD, C. Michael Cotten, MD, MHS, Ricki F. Goldstein, MD, William F. Malcolm, MD, Patricia L. Ashley, MD, PhD, Kimberley A. Fisher, PhD, FNP-BC, IBCLC, Joanne Finkle, RN, JD, Kathryn E. Gustafson, PhD, Matthew M. Laughon, MD, MPH, Carl L. Bose, MD, Janice Bernhardt, MS, RN, Gennie Bose, RN, and Janice Wereszczak, CPNP-AC/PC; Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (UG1 HD27851): David P. Carlton, MD, Barbara J. Stoll, MD, Ellen C. Hale, RN, BS, CCRC, Ira Adams-Chapman, MD, Yvonne Loggins, RN, Sheena L. Carter, PhD, Maureen Mulligan LaRossa, RN, Diane I. Bottcher, RN, MSN, and Colleen Mackie, BS, RRT; NICHD: Stephanie Wilson Archer, MA; Indiana University, Indiana University Health University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (UG1 HD27856): Gregory M. Sokol, MD, Brenda B. Poindexter, MD, MS, Lu-Ann Papile, MD, Heidi M. Harmon, MD, MS, Abbey C. Hines, PsyD, Leslie Dawn Wilson, BSN, CCRC, Dianne E. Herron, RN, CCRC, Susan Gunn, NNP, CCRC, and Lucy Smiley, CCRC; McGovern Medical School at The University of Texas Health Science Center at Houston and Children’s Memorial Hermann Hospital (UG1 HD87229; U10 HD21373): Jon E. Tyson, MD, MPH, Julie Arldt-McAlister, RN, BSN, Katrina Burson, RN, BSN, Allison G. Dempsey, PhD, Andrea Freeman Duncan, MD, Carmen Garcia, RN, CCRP, Janice John, CPNP, Patrick M. Jones, MD, Layne M. Lillie, RN, BSN, Karen Martin, RN, Sara C. Martin, RN, Georgia E. McDavid, RN, Shawna Rodgers, RN, Saba Siddiki, MD, Daniel Sperry, RN, Patti L. Pierce Tate, RCP, and Sharon L. Wright, MT (American Society for Clinical Pathology); Nationwide Children’s Hospital, The Research Institute at Nationwide Children’s Hospital, The Ohio State University Wexner Medical Center, The Ohio State University College of Medicine, Center for Perinatal Research at Nationwide Children’s Hospital (UG1 HD68278; U10 HD68278): Leif D. Nelin, MD, Sudarshan R. Jadcherla, MD, Christopher Timan, MD, Nathalie L. Maitre, MD, PhD, Patricia Luzader, RN, Julie Gutentag, RN, BSN, Jennifer L. Grothause, BA, RN, BSN, Melanie Stein, RRT, BBS, Rox Ann Sullivan, RN, BSN, Cole D. Hague, BA, MS, Helen Carey, PT, DHSc, Michelle Chao, Stephanie Burkhardt, BS, MPH, Margaret Sullivan, BA, Lina Yossef-Salameh, MD, Jennifer Notestine, RN, Mary Ann Nelin, MD, Erna Clark, BA, Julie C. Shadd, BSN, RD, and Courtney Park, RN, BSN; RTI International (U10 HD36790): Dennis Wallace, PhD, Jamie E. Newman, PhD, MPH, Jeanette O’Donnell Auman, BS, Margaret Crawford, BS, Jenna Gabrio, BS, CCRP, Marie G. Gantz, PhD, Carolyn M. Petrie Huitema, MS, and Kristin M. Zaterka-Baxter, RN, BSN; Stanford University and Lucile Packard Children’s Hospital (UG1 HD27880; UL1 TR93): Krisa P. Van Meurs, MD, David K. Stevenson, MD, M. Bethany Ball, BSc, CCRC, Melinda S. Proud, RCP, Barbara Bentley, PsychD MSEd, Maria Elena DeAnda, PhD, Anne M. DeBattista, RN, PNP, PhD, Beth Earhart, PhD, Lynne C. Huffman, MD, Casey E. Krueger, PhD, Ryan Lucash, PhD, and Hali E. Weiss, MD; University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (UG1 HD34216): 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, Cryshelle S. Patterson, PhD, Vivien A. Phillips, RN, BSN, and Sally Whitley, MA, OTR-L, FAOTA; University of California, Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (UG1 HD68270): Uday Devaskar, MD, Meena Garg, MD, Isabell B. Purdy, PhD, CPNP, Teresa Chanlaw, MPH, and Rachel Geller, RN, BSN; University of Iowa and Mercy Medical Center (UG1 HD53109): Tarah T. Colaizy, MD, MPH, Jane E. Brumbaugh, MD, Dan L. Ellsbury, MD, Jonathan M. Klein, MD, Karen J. Johnson, RN, BSN, Jacky R. Walker, RN, Donia B. Campbell, RNC-NIC, and Diane L. Eastman, RN, CPNP, MA; University of New Mexico Health Sciences Center (UG1 HD53089; UL1 TR41): Kristi L. Watterberg, MD, Jean R. Lowe, PhD, Janell F. Fuller, MD, Robin K. Ohls, MD, Conra Backstrom Lacy, RN, Andrea F. Duncan, MD, Tara Dupont, MD, and Elizabeth Kuan, RN, BSN; University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (UG1 HD68244): Barbara Schmidt, MD, MSc, Haresh Kirpalani, MB, MSc, Aasma S. Chaudhary, BS, RRT, Soraya Abbasi, MD, Toni Mancini, RN, BSN, CCRC, Judy C. Bernbaum, MD, Marsha Gerdes, PhD, Hallam Hurt, MD, Noah Cook, MD, and Dara M. Cucinotta, RN; University of Rochester Medical Center, Golisano Children’s Hospital, and Women and Children’s Hospital of Buffalo (UG1 HD68263; UL1 TR42): Carl T. D’Angio, MD, Ronnie Guillet, MD, PhD, Satyan Lakshminrusimha, MD, Anne Marie Reynolds, MD, MPH, Rosemary L. Jensen, Joan Merzbach, LMSW, Gary J. Myers, MD, Ashley Williams, MSEd, Kelley Yost, PhD, William Zorn, PhD, Karen Wynn, RN, Deanna Maffett, RN, Diane Prinzing, Julianne Hunn, BS, Stephanie Guilford, BS, Farooq Osman, MD, Mary Rowan, RN, Michael G. Sacilowski, BS, Holly I.M. Wadkins, MA, Melissa Bowman, MSN, Linda J. Reubens, RN, CCRC, Cait Fallone, MA, Kyle Binion, BS, Constance Orme, Ann Marie Scorsone, MS, CCRC, and Michelle Andrews-Hartley, MD; University of Texas Southwestern Medical Center, Parkland Health and Hospital System, and Children’s Medical Center Dallas (UG1 HD40689): Pablo J. Sánchez, MD, Luc P. Brion, MD, Diana M. Vasil, RNC-NIC, Lijun Chen, PhD, RN, Roy J. Heyne, MD, Sally S. Adams, MS, RN, CPNP, Linda A. Madden, RN, BSN, CPNP, Elizabeth Heyne, PsyD, PA-C, Alicia Guzman; Lizette E. Torres, RN, and Catherine Twell Boatman, MS, CIMI; and Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (UG1 HD21385): Athina Pappas, MD, Sanjay Chawla, MD, Monika Bajaj, MD, Melissa February, MD, Prashant Agarwal, MD, Kirsten Childs, RN BSN, Eunice Woldt, RN, MSN, Rebecca Bara, RN, BSN, Laura A. Goldston, MA, John Barks, MD, Mary Christensen, RT, Stephanie Wiggins, MS, and Diane White, RT.

The National Institutes of Health, the NICHD, and the National Center for Advancing Translational Sciences provided grant support for the NRN GDB and follow-up studies. The NICHD staff provided input into the study design, conduct, analysis, and drafting of the article; National Center for Advancing Translational Sciences cooperative agreements provided infrastructure support to the NRN. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Data collected at participating sites of the NICHD NRN were transmitted to RTI International (the data coordinating center [DCC] for the network), which stored, managed, and analyzed the data included in this study. On behalf of the NRN, Drs 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. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.

aOR

adjusted odds ratio

Bayley-III

Bayley Scales of Infant and Toddler Development, Third Edition

BPD

bronchopulmonary dysplasia

CI

confidence interval

DCC

data coordinating center

GA

gestational age

GDB

generic database

GMFCS

Gross Motor Functional Classification Scale

IQR

interquartile range

IVH

intraventricular hemorrhage

NDI

neurodevelopmental impairment

NEC

necrotizing enterocolitis

NICHD

Eunice Kennedy Shriver National Institute of Child Health and Human Development

NRN

Neonatal Research Network

PDA

patent ductus arteriosus

PMA

postmenstrual age

RCT

randomized controlled trial

ROP

retinopathy of prematurity

SGA

small for gestational age

VEGF

vascular endothelial growth factor