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Abstract
Objective This study investigates whether and to what extent cerebral injury is associated with bilateral blindness in extremely preterm infants, which has been attributed mainly to retinopathy of prematurity (ROP).
Design Multicentre analysis of children born from 1994 to 2021 at gestational age 22 0/7 to 28 6/7 weeks with follow-up at 18–26 months. Logistic regression examined the adjusted association of bilateral blindness with severe ROP and/or cerebral injury among extremely preterm infants.
Exposures Severe ROP and cerebral injury, the latter defined as any of the following on cranial imaging: ventriculomegaly; blood/increased echogenicity in the parenchyma; cystic periventricular leukomalacia.
Main outcome measures Bilateral blindness, defined as a follow-up examination meeting criteria of ‘blind—some functional vision’ or ‘blind—no useful vision’ in both eyes.
Results The 19 863 children included had a mean gestational age of 25.6±1.7 weeks, mean birth weight of 782±158 g and 213 (1%) had bilateral blindness. Multiplicative interaction between ROP and cerebral injury was statistically significant. For infants with only severe ROP (n=3130), odds of blindness were 8.14 times higher (95% CI 4.52 to 14.65), and for those with only cerebral injury (n=2836), odds were 8.38 times higher (95% CI 5.28 to 13.28), compared with the reference group without either condition. Risks were not synergistic for infants with both severe ROP and cerebral injury (n=1438, adjusted OR=28.7, 95% CI 16.0 to 51.7, p<0.0001).
Conclusions In a group of extremely preterm infants, severe ROP and cerebral injury were equally important risk factors for blindness. Besides ROP, clinicians should consider cerebral injury as a cause of blindness in children born extremely preterm.
Trial registration number NCT00063063.
- Neonatology
- Infant Development
- Neurology
- Intensive Care Units, Paediatric
- Ophthalmology
Data availability statement
Data are available upon reasonable request. Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Extremely preterm infants are at risk for blindness, which has been primarily attributed to retinopathy of prematurity (ROP) but could also be due to cerebral injury, the leading cause of paediatric visual impairment in developed countries.
WHAT THIS STUDY ADDS
In this retrospective analysis of prospectively collected data on 19 863 extremely preterm infants, severe ROP and cerebral injury were associated with similar and significant increases in the risk for blindness (adjusted ORs 8.14 and 8.38, respectively).
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Besides ROP, clinicians should have a high index of suspicion for cerebral injury when considering risk factors for blindness in children born extremely preterm.
Introduction
Infants born preterm are at increased risk of blindness relative to those born at term.1 Approximately 1% of extremely preterm infants develop severe visual impairment.2 Retinopathy of prematurity (ROP), a disruption of retinal vascularisation, is the most widely recognised cause of visual impairment affecting preterm infants.1 3 Approximately 13% of extremely preterm infants develop severe ROP needing treatment.2 4 Among infants with severe ROP, 6.4% develop bilateral blindness with no functional vision.5 6
While many clinicians and researchers may largely attribute blindness in infants born preterm to severe ROP, the leading cause of visual impairment among all children in developed countries is cerebral in nature.7 Risk factors for cerebral visual impairment (CVI) among all infants include intracranial haemorrhage, immature cerebrovascular development, inadequate autoregulation of cerebral blood flow and insults in utero.8 Preterm infants are especially vulnerable to cerebral damage due to a fragile network of cerebral blood vessels called the germinal matrix, which is at risk for haemorrhage with ventricular extension or periventricular parenchymal involvement.9 White matter ischaemia and/or inflammation may manifest as periventricular leukomalacia (PVL) in preterm infants. Hypoxic ischaemic encephalopathy (HIE), PVL and hydrocephalus are well-known causes of paediatric CVI, with perinatal or postnatal HIE being the most common cause of CVI in preterm and term infants.7
The relative contribution of severe ROP and CVI to blindness in children born extremely preterm remains unclear. While cerebral injury is appropriately recognised in the general paediatric population, its association with blindness in premature infants may be underappreciated. This study was designed to test the hypothesis that cerebral injury is associated with bilateral blindness in extremely preterm infants and can account for some of the variance not explained by severe ROP alone.
Methods
The current study is a retrospective analysis of prospectively collected data on extremely preterm infants with birth weight of 401–1000 g or gestational age of 22 weeks 0 day to 28 weeks 6 days who received care at one of 28 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centres from 1994 to 2021 and participated in the NRN follow-up study at 18–26 months with complete assessment of visual outcomes by a certified examiner. NRN registry databases include in-hospital and follow-up outcomes for infants born before 29 weeks’ gestational age. Trained research coordinators prospectively collect maternal and neonatal data from birth until discharge home, transfer, death or 120 days. For infants transferred or still hospitalised at 120 days, vital status is collected until 1 year of age. Surviving infants are eligible for comprehensive follow-up assessment at 18–26 months’ corrected age. The institutional review board at each participating hospital approved data collection protocols and participation in the registry. Waiver of consent for registry enrolment was granted at most affiliated hospitals, but parental consent was required at five hospitals. Most hospitals required written parental consent for participation in the follow-up study, but five hospitals allowed participation under waiver of consent. Follow-up data were collected from 1995 to 2023. Infants with genetic syndromes, congenital neurological malformations or ocular malformations and those who did not participate in follow-up were excluded, as were infants missing data on blindness, cerebral injury or severe ROP. Gestational age was determined by best obstetric estimate or, if unavailable, by neonatal estimate. Infants were classified as small for gestational age based on a birth weight below the 10th percentile for gestational age according to the Alexander growth curve. Sex was reported as female, male or ambiguous, requiring confirmation of ambiguous genitalia by genetics consult. Race and ethnic group were reported by the parent or guardian. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.10
Outcomes
Bilateral blindness was defined based on follow-up examinations meeting criteria of ‘blind—some functional vision’ or ‘blind—no useful vision’ in both eyes. Before 2006, the NRN criterion was ‘blind—no useful vision’, defined as refraction of <20/200 (legally blind) in both eyes. For infants born in 2006 or later, bilateral blindness was defined as both eyes with either ‘blind–no useful vision’ or ‘blind—some functional vision’, a condition that requires the child to have an object held directly in front of their face to see it, consistent with a refraction of <20/200.
Exposures
Criteria for severe ROP included the following: either eye with stage 3 ROP or worse; retinal detachment; Plus disease; receipt of peripheral retinal laser ablation, scleral buckling, vitrectomy and/or treatment with anti-Vascular Endothelial Growth Factor (VEGF) drugs. Cerebral injury was determined by cranial imaging (ultrasound, magnetic resonance, CT) through 36 weeks’ postmenstrual age that demonstrated any of the following: ventriculomegaly with or without hydrocephalus; blood/increased echogenicity in the parenchyma; and/or cystic PVL. In additional analysis, severe cerebral palsy (CP) was defined as a Gross Motor Function Classification System level of 4 or 5, and grade 3 bronchopulmonary dysplasia (BPD) was defined as invasive mechanical ventilation administered at 36 weeks’ postmenstrual age.11
Statistical analysis
Covariates including birth year, sex, gestational age, birth weight, multiple birth, NRN centre (as a cluster effect), antenatal corticosteroids, maternal race and ethnicity, maternal insurance, maternal hypertension and maternal insulin-dependent diabetes were considered in a backward selection model using stepwise regression to develop the final model. Sex, birth weight, multiple birth, centre and race were retained in the final logistic regression model that compared the outcome of bilateral blindness among infants with two potential risk factors (cerebral injury, severe ROP), using generalised estimating equations to account for centre effects. The model included an interaction term for cerebral injury with severe ROP. A separate model used linear regression to assess risk differences (RD) and fit an additive interaction model. Linear regression was used only for the RD model with additive interactions to avoid convergence issues in the binomial model, acknowledging the limitation that the parameter space for the estimated probabilities is not restricted to (0, 1).
Logistic regression modelling was again used to explore the odds of blindness associated with each type of defined cerebral injury. This included a category for infants with two or more types of injury, and a category for severe hydrocephalus, defined as placement of a ventricular shunt in the setting of other cerebral injury. As CP12 13 and BPD are known to coexist with late cerebral injury, ROP and blindness, sensitivity analysis explored the relationship between cerebral injury and blindness independent of these diagnoses. Such analysis incorporated CP and BPD statuses into the model as covariates and was limited to infants born in 2006 or after due to limitation in determining grade 3 BPD status.
Given the augmented NRN blindness data in 2006, we also examined the odds of blindness during the epochs before and after the definition change. Because some infants may have had cerebral injuries falling outside this study’s definition, additional analysis compared those with cerebral injury to infants with normal brain imaging. Post hoc analysis was performed using criteria for cerebral injury which did not include parenchymal blood/echodensity in the definition.
A sample size analysis was not performed in this secondary analysis of available registry data for all infants meeting certain criteria. A two-sided p<0.05 was used to indicate statistical significance. Analyses were performed using SAS V.9.4 between July and December 2023. All continuous variables are presented as mean±SD except 5 min Apgar score (median and 5th–95th percentiles). Because blindness is a rare outcome, an adjusted OR (aOR) was deemed adequate to closely approximate the relative risk of blindness.14
Results
NRN follow-up data were available for 21 745 infants during the study period. Of these, 696 (3.2%) were excluded due to birth defects, 55 (0.3%) were excluded due to missing data on blindness and 1131 (5.2%) were excluded due to missing data on cerebral injury and/or severe ROP (online supplemental eFigure 1 and eTable 1). The 19 863 children in the final study population had a mean gestational age of 25.6±1.7 weeks and mean birth weight of 782±158 g (table 1, online supplemental eTables 2 and 3).
Supplemental material
Baseline characteristics by group
Of infants included, 23% (4568/19 863) had severe ROP, and 22% (4274/19 863) had cerebral injury. Overall, 1% (213/19 863) of children had bilateral blindness. Of blind children, 25% (53/213) had severe ROP only, 22% (47/213) had cerebral injury only, 40% (86/213) had both and 13% (27/213) had neither (table 2). Multiplicative interaction between cerebral injury and ROP was found to be statistically significant (p=0.01), indicating that the association of ROP (or cerebral injury) with blindness depended on whether the infant also had cerebral injury (or ROP). In infants without severe ROP, cerebral injury was associated with an 8.38-fold increase in adjusted odds of blindness (95% CI 5.28 to 13.28). In those without cerebral injury, severe ROP was associated with an 8.14-fold increase in adjusted odds of blindness (95% CI 4.52 to 14.65). Those with both severe ROP and cerebral injury were 28.7 times more likely to be blind (95% CI 15.96 to 51.71) using a four-level variable model (cerebral injury only, severe ROP only, both, neither) with no interaction term.
Risk factors for blindness
In the linear regression model incorporating additive interaction, the RD for cerebral injury was 1.4% (RD=0.9–1.8%), indicating that those with cerebral injury had 14 (95% CI 9 to 18) additional cases of blindness per 1000 infants compared with those who did not have cerebral injury (online supplemental eTable 4). The RD for severe ROP was also 1.4% (RD=0.8–2.0%), indicating that those with severe ROP had 14 (95% CI 8 to 20) additional cases of blindness per 1000 infants compared with those who did not have severe ROP. There was a significant additive interaction (p<0.001) with an additional RD of 2.9% (RD=1.2–4.5%), such that children with both risk factors had 29 (95% CI 12 to 45) additional cases of blindness per 1000 infants compared with those with neither risk factor.
Among cerebral injuries, hydrocephalus requiring shunt in the setting of other defined cerebral injury was associated with the greatest increase in the risk of blindness (aOR=12.7, 95% CI 8.86 to 18.2), followed by PVL (aOR=8.94, 95% CI 4.60 to 17.4) (table 3). None of the 200 infants with blood/echodensity in the parenchyma as the sole abnormality were blind. Severe CP was found to be a significant risk factor for blindness (aOR=40.6, 95% CI 27.9 to 58.9, p=0.002), but there was no association between grade 3 BPD and blindness (p=0.62) (table 4). During the epoch before the augmented NRN blindness data in 2006, severe ROP had a stronger association with blindness than cerebral injury (aOR 10.2 vs 5.0) (online supplemental eTable 5). During the later epoch, cerebral injury had a stronger association with blindness than severe ROP (aOR 10.7 vs 6.2). Additional sensitivity analyses yielded overall similar results (online supplemental eTables 6–9).
Secondary investigation using adjusted OR (aOR) and 95% CI for visual outcomes based on type of cerebral injury, relative to no cerebral injury
Adjusted OR (aOR) and 95% CI for blindness, adjusting for severe CP and grade 3 BPD (2006–2021 births)
Discussion
This retrospective analysis of extremely preterm infants with 18–26 months’ follow-up evaluated severe ROP and cerebral injury as possible risk factors for the outcome of bilateral blindness. The results suggest that cerebral injury is associated with blindness and accounts for variance not explained by severe ROP alone. Furthermore, cerebral injury and severe ROP are equally important risk factors for blindness. These results highlight the potential for diverse mechanisms for blindness in extremely preterm infants and emphasise the likelihood that some blindness is cerebral in nature. While both conditions are risk factors for blindness, studies have also demonstrated that ROP15 16 and severe ROP17 18 are associated with cerebral injury and structural brain abnormalities. Thus, the link between severe ROP and blindness may be partially mediated through cerebral injury, possibly through common mechanisms that result in both ROP and cerebral injury. While both exposures increase the odds of blindness, the actual risk remains rather low, with 1.7% of infants with only cerebral injury and 1.7% of those with only severe ROP demonstrating blindness. Even among infants with both risk factors, 94% were not blind. Among those with bilateral blindness, 13% had neither severe ROP nor cerebral injury, supporting that other factors affect this outcome.
Extremely preterm infants account for about 1% of all births,19 and approximately 1% of these infants develop severe visual impairment.2 ROP is the most widely recognised cause of visual impairment affecting preterm infants,1 with increasing incidence at lower gestational ages.3 20 ROP outcomes range from resolution with normal vision to bilateral blindness.3 Infants with mild to moderate ROP typically have normal vision. More advanced and progressive ROP can cause retinal detachment and is associated with a higher risk of blindness.3 21 Approximately 13% of extremely preterm infants develop severe ROP needing treatment.2 4 Among those with severe ROP, 6.4% develop bilateral blindness with no functional vision.5 6
A known cause of visual impairment in both term and preterm infants is CVI, for which risk factors include intracranial haemorrhage, immature cerebrovascular development, inadequate autoregulation of cerebral blood flow and various insults in utero.8 A prior meta-analysis identified retinal pathologies and CVI as the top two causes of severe visual impairment and blindness among children in nations of high socioeconomic index,22 and CVI is now the leading cause of paediatric visual impairment in developed countries.7 However, these data describe the general paediatric population. It has been unclear to what extent cerebral causes are similarly responsible for visual impairment in children born extremely preterm.
Because ROP is a familiar and unique aetiology of visual impairment among preterm infants, blindness in this population is often attributed to ROP. Thus, while cerebral injury is appropriately recognised in the general paediatric population, its significance as a cause of blindness in preterm infants may be underappreciated. An individual participant meta-analysis demonstrated that, among infants born before 28 weeks’ gestation, an oxygen-targeting intervention that lowered the incidence of severe ROP did not reduce blindness,2 suggesting that other contributing factors may be overlooked.
Prior studies of preterm infants have demonstrated that PVL portends a poor visual prognosis23 due to injury to visual association fibres and optic radiations,24 but it is not known whether other more common cerebral abnormalities in extremely preterm infants are associated with visual impairment. This study found the strongest risk factors for blindness to be a combination of cerebral injury and hydrocephalus requiring shunt, followed by PVL and ventriculomegaly.
Limitations
NRN data do not include information on pupillary reflex, a physiological response left intact in the setting of cerebral blindness but often impaired or absent in ROP.25 26 Because we lacked information regarding the location of abnormalities in cranial imaging studies, it was not possible to localise cerebral injuries—for example, to the occipital lobe, which houses the visual cortex. The data also do not capture the spectrum of severity in cerebral injury, so varying degrees of injury were not considered. Assessing vision in young children with severe cerebral injury is challenging, potentially leading to overestimation or underestimation of visual impairment. A certified neurological examiner assessed vision outcomes at follow-up using history and observation, but there was no formal evaluation by an ophthalmologist; any resulting bias should have a small effect. Our data are not generalisable to all extremely preterm infants because we excluded infants with genetic syndromes, congenital neurological and/or ocular malformations, and those who did not receive care at NRN centres. Due to the large sample size and the relatively few excluded infants, this bias likely exerts a modest effect. Strengths include a large database and population, multiple variables collected and robust follow-up.
Conclusions
In this retrospective analysis of extremely preterm infants, cerebral injury and severe ROP were equally important risk factors for blindness. Besides ROP, clinicians should consider cerebral injury among causes of blindness in this population.
Data availability statement
Data are available upon reasonable request. Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Acknowledgments
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @_BenHonan, @ambaln, @HopeEArnold, @SusanHintzMD
Collaborators The following investigators, in addition to those listed as authors, participated in this study: NRN Steering Committee Chair: Richard A Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University (2011–2023). Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (UG1 HD27904): Abbot R Laptook, MD; Martin Keszler, MD; Betty R Vohr, MD; Angelita M Hensman, PhD, RNC-NIC; Elisa Vieira, BSN, RN; Lucille St Pierre, BS; Barbara Alksninis, RNC, PNP; Andrea Knoll; Mary L Keszler, MD; Teresa M Leach, MEd, CAES; Elisabeth C McGowan, MD; Victoria E Watson, MS, CAS. Case Western Reserve University, Rainbow Babies & Children's Hospital (UG1 HD21364): Anna Maria Hibbs, MD, MSCE; Deanne E Wilson-Costello, MD; Michele C Walsh, MD, MS; Nancy S Newman, RN; Bonnie S Siner, RN; Harriet G Friedman, MA. Children’s Mercy Hospital (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; Allison Scott, RNC-NIC, BSN, CCRC; Prabhu S Parimi, MD; Lisa Gaetano, RN, MSN. Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (UG1 HD27853, UL1 TR77): Stephanie L Merhar, MD, MS; Brenda B Poindexter, MD, MS; Kurt Schibler, MD; Tanya E Cahill, MD; Cathy Grisby, BSN, CCRC; Kristin Kirker, CRC; Sandra Wuertz, RN, BSN, CLC; Juanita Dudley, RN, BSN; Julia Thompson, RN, BSN; Lisa Henkes, RN, BSN; Sara Stacey, BA; Devan Hayes, BS. Duke University School of Medicine, University Hospital, University of North Carolina, Duke Regional Hospital, and WakeMed Health & Hospitals (UG1 HD40492, UL1 TR1117): Ronald N Goldberg, MD; William F Malcolm, MD; Patricia L Ashley, MD; Deesha Mago-Shah, MD; Mollie Warren, MD; Joanne Probst, RN, JD; Kimberley A Fisher, PhD, FNP-BC, IBCLC; Kathryn E Gustafson, PhD; Matthew M Laughon, MD, MPH; Carl L Bose, MD; Janice Bernhardt, MS, RN; Gennie Bose, RN; Janice Wereszczak, CPNP-AC/PC; Andrea Trembath, MD, MPH; Jennifer Talbert, MS, RN; Stephen D Kicklighter, MD; Ryan Moore, MD; Alexandra Bentley, MD; Laura Edwards, MD; Ginger Rhodes-Ryan, ARNP, MSN, NNP-BC; Donna White, RN-BC, BSN. Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (UG1 HD27851, UL1 TR454): Ravi M Patel, MD, MSc; David P Carlton, MD; Brenda B Poindexter, MD, MS; Nathalie L Maitre, MD, PhD; Ira Adams-Chapman, MD (deceased); Yvonne Loggins, RN; Diane Bottcher, RN; Sheena L Carter, PhD; Ellen C Hale, RN, BS, CCRC; Salathiel Kendrick-Allwood, MD; Maureen Mulligan LaRossa, RN; Judith Laursen, RN; Colleen Mackie, RRT; Amy Sanders, PsyD; Gloria Smikle, PNP; Lynn Wineski, NNP. Eunice Kennedy Shriver National Institute of Child Health and Human Development: Michele C Walsh, MD, MS; Andrew A Bremer, MD, PhD; Stephanie Wilson Archer, MA. Harvard Medical School and Brigham and Women’s Hospital (U10 HD34167): Ann R Stark, MD; Kerri Fournier, RN. Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (UG1 HD27856, UL1 TR6): Gregory M Sokol, MD; Brenda B Poindexter, MD, MS; Lu Ann Papile, MD; Dianne E Herron, RN, CCRC; Abbey C Hines, PsyD; Carolyn Lytle, MD, MPH; Lucy Smiley, CCRC; Leslie Dawn Wilson, BSN, CCRC; Donna Watkins, MSN, NNP-BC; Susan Gunn, NNP-BC, CCRC; Jeff Joyce, CCRC (deceased). McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, and Memorial Hermann Southwest Hospital (U10 HD21373, UG1 HD87229): Matthew A Rysavy, MD, PhD; Amir M Khan, MD; Kathleen A Kennedy, MD, MPH; Barbara J Stoll, MD; Ricardo A Mosquera, MD, MS; Andrea F Duncan, MD, MS; Elizabeth Allain, PhD; Julie Arldt-McAlister, MSN, APRN; Fatima Boricha, MD; Allison G Dempsey, PhD; Carmen Garcia, RN, BSN; Donna J Hall, RN; Janice John, CPNP; M Layne Lillie, RN, BSN; Karen Martin, RN; Georgia E McDavid, RN; Shannon L McKee, EdS; Michelle Poe, PhD, RN; Kimberly Rennie, PhD; Tina Reddy, MD; Shawna Rodgers, RNC-NIC, BSN; Daniel K Sperry, RN; Emily Stephens, BSN, RNC-NIC; Sharon L Wright, MT (ASCP). Nationwide Children’s Hospital, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Center for Perinatal Research, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, and Riverside Methodist Hospital (UG1 HD68278): Pablo J Sánchez, MD; Leif D Nelin, MD; Jonathan L Slaughter, MD, MPH; Sudarshan R Jadcherla, MD; Nathalie L Maitre, MD, PhD; Christopher Timan, MD; Omid Fathi, MD; Keith O Yeates, 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, PCS; Michelle Chao, BS; Stephanie Burkhardt, BS, MPH; Margaret Sullivan, BS; Lina Yossef-Salameh, MD; Mary Ann Nelin, MD; Erna Clark, BA; Julie C Shadd, BSN, RD; Courtney Park, RN, BSN; Courtney Cira, BS; Erin Fearns; Kristi Small, BS; Sarah A Keim, PhD, MA, MS; Christine A Fortney, RN, PhD; Aubrey Fowler, BS; Jacqueline McCool; Lindsay Pietruszewski, PT, DPT; Jessica Purnell, BS, CCRC; Kyrstin Warnimont, BS; Laura Marzec, MD; Bethany Miller, RN, BSN; Demi R Beckford, MHS; Hallie Baugher, BS, MSN; Julia Newton, MPH; Katelyn Levengood, PT, DPT; Nancy Batterson, OT/L; Brittany DeSantis, BS. RTI International (UG1 HD36790): Carla M Bann, PhD; Dennis Wallace, PhD; Jeanette O’Donnell Auman, BS; Margaret Crawford, BS; Jenna Gabrio, BS, MPH; Jamie E Newman, PhD, MPH; Lindsay Parlberg, BS; Carolyn M Petrie Huitema, MS; Kristin M Zaterka-Baxter, RN, BSN. Stanford University, El Camino Hospital, and Lucile Packard Children’s Hospital (UG1 HD27880, UL1 TR93): Krisa P Van Meurs, MD; Valerie Chock, MD, MS, Epi; David K Stevenson, MD; Neha Kumbhat, MD, MS, Epi; M Bethany Ball, BS, CCRC; Barbara P Recine, MA; Marian M Adams, MD; Alexis S Davis, MD, MS, Epi; Dona Bahmani, CRC; 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 E Lucash, PhD; Melinda S Proud, RCP; Elizabeth N Reichert, MA, CCRC; Heather Taylor, PhD; Hali E Weiss, MD; R Jordan Williams, MD. Tufts Medical Center (U10 HD53119): Ivan D Frantz III, MD; John M Fiascone, MD; Brenda L MacKinnon, RNC; Anne Furey, MPH; Ellen Nylen, RN, BSN; Paige T Church, MD. University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (UG1 HD34216): Myriam Peralta-Carcelen, MD, MPH; Kirstin J Bailey, PhD; Fred J Biasini, PhD (deceased); Stephanie A Chopko, PhD; Monica V Collins, RN, BSN, MaEd; Shirley S Cosby, RN, BSN; Cindie L Buie, RN, BSN; Kristy A Domnanovich, PhD; Chantel J Jno-Finn, PT, DPT; Morissa Ladinsky, MD; Mary Beth Moses, PT, MS, PCS; Tara E McNair, RN, BSN; Vivien A Phillips, RN, BSN; Julie Preskitt, MSOT, MPH; Richard V Rector, PhD; Kimberlly Stringer, MD, MPH; Sally Whitley, MA, OTR-L, FAOTA; Sheree York Chapman, PT, DPT, PCS. 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; Rachel Geller, RN, BSN. University of California–San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461): Neil N Finer, MD; Paul R Wozniak, MD; Maynard R Rasmussen, MD; Kathy Arnell, RNC; Clarence Demetrio, RN; Chris Henderson, RCP, CRTT; Wade Rich, BSHS, RRT. University of Iowa, Mercy Medical Center, and Sanford Health (UG1 HD53109, UL1 TR442): Tarah T Colaizy, MD, MPH; Edward F Bell, MD; Jane E Brumbaugh, MD; Heidi M Harmon, MD; Michelle L Baack, MD; Karen J Johnson, RN, BSN; Mendi L Schmelzel, RN, MSN; Jacky R Walker, RN; Claire A Goeke, RN; Diane L. Eastman, RN CPNP MA; Michelle L. Baack, MD; Laurie A Hogden, MD; Megan M Henning, RN; Chelsey Elenkiwich, BSN, RN; Megan Broadbent, RN, BSN; Sarah Van Muyden, RN, BSN; Dan L Ellsbury, MD; Tracy L Tud, RN. University of Miami, Holtz Children’s Hospital (U10 HD21397, M01 RR16587): Shahnaz Duara, MD; Ruth Everett-Thomas, RN, MSN. University of New Mexico Health Sciences Center (UG1 HD53089, UL1 TR41): Janell Fuller, MD; Kristi L Watterberg, MD; Conra Backstrom Lacy, RN; Carol Hartenberger, BSN, MPH; Sandra Sundquist Beauman, MSN, RNC-NIC; Mary Ruffner Hanson, RN, BSN; Jean R Lowe, PhD; Elizabeth Kuan, RN, BSN. University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, Children’s Hospital of Philadelphia, and Virtua Voorhees Hospital (UG1 HD68244): Sara B DeMauro, MD, MSCE; Eric C Eichenwald, MD; Barbara Schmidt, MD, MSc; Haresh Kirpalani, MB, MSc; Sara C Handley, MD, MSCE; John Flibotte, MD; Karen M Puopolo, MD, PhD; Andrea F Duncan, MD, MClinRes; Soraya Abbasi, MD; Elizabeth E Foglia, MD, MSCE; Aasma S Chaudhary, BS, RRT; Toni Mancini, RN, BSN, CCRC; Dara M Cucinotta, RN; Judy C Bernbaum, MD; Marsha Gerdes, PhD; Sarvin Ghavam, MD; Hallam Hurt, MD; Jonathan Snyder, RN, BSN; Kristina Ziolkowski, CMA (AAMA), CCRP. University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (UG1 HD68263, UL1 TR42): Carl T D’Angio, MD; Ronnie Guillet, MD, PhD; Satyan Lakshminrusimha, MD; Gary J Myers, MD; Anne Marie Reynolds, MD; Holly I M Wadkins; Michael G Sacilowski, BS; Rosemary L Jensen; Joan Merzbach, LMSW; William Zorn, PhD; Osman Farooq, MD; Stephanie Guilford, BS; Kelley Yost, PhD; Mary Rowan, RN; Diane Prinzing; Ann Marie Scorsone, MS, CCRC; Michelle Hartley-McAndrew, MD; Kyle Binion, BS; Constance Orme; Premini Sabaratnam, MPH; Alison Kent, BMBS, FRACP, MD; Brenna Cavanaugh, PsyD, BCBA-D; Rachel Jones; Elizabeth Boylin, BA; Daisy Rochez, BS, MHA; Emily Li, BA; Jennifer Kachelmeyer, BS; Kimberly G McKee, BS; Kelly R Coleman, PsyD; Deanna Maffett, RN; Dale Phelps, MD; Linda Reubens, RN, CCRC; Erica Burnell, RN; Julianne Hunn, BS; Diane Hust, MS, RN, CS; Julie Babish Johnson, MSW; Emily Kushner, MA; Lauren Zwetsch, RN, MS, PNP; Cait Fallone, MA; Ashley Williams, MSEd. University of Tennessee Health Science Center (U10 HD21415): Sheldon B Korones, MD; Henrietta S Bada, MD; Tina Hudson, RN, BSN. University of Texas Southwestern Medical Center, Parkland Health & Hospital System, and Children's Medical Center Dallas (UG1 HD40689): Myra H Wyckoff, MD; Luc P Brion, MD; Roy J Heyne, MD; Charles R Rosenfeld, MD; Walid A Salhab; Pablo J Sánchez, MD; Joanne Duran, RN, BSN; Michelle Harrod, RN, BSN, MSN; Lijun Chen, RN, PhD; Maria M De Leon, RN, BSN; Frances Eubanks, RN, BSN; Gaynelle Hensley, RN; Jackie F Hickman, RN; Melissa H Leps, RN; Susie Madison, RN; Nancy A Miller, RN; Janet S Morgan, RN; Lara Pavageau, MD; Pollieanna Sepulveda, RN; Diana M Vasil, MSN, BSN, RNC-NIC; Sally S Adams, MS, RN, CPNP; Alicia Guzman; Elizabeth Heyne, MS, MA, PA-C, PsyD; Lizette E Lee, RN; Linda A Madden, BSN, RN, CPNP; E Rebecca McDougald, MSN, APRN, CPNP-PC/AC; Anna Puentez, MSN, RN, CPNP-PC; Azucena Vera, AS; Jillian Waterbury, DNP, RN, CPNP-PC; Cathy Twell Boatman, MS, CIMI; Kristine Tolentino-Plata, MS, PhD. University of Utah Medical Center, Intermountain Medical Center, McKay-Dee Hospital, Utah Valley Hospital, and Primary Children’s Medical Center (UG1 HD87226, UL1 TR105): Robin K Ohls, MD; Bradley A Yoder, MD; Mariana Baserga, MD, MSCI; Roger G Faix, MD; Sarah Winter, MD; Stephen D Minton, MD; Mark J Sheffield, MD; Carrie A Rau, RN, BSN, CCRC; Shawna Baker, RN; Jill Burnett, RNC, BSN; Susan Christensen, RN; Sean D Cunningham, PhD; Brandy Davis, RN, BSN; Jennifer O Elmont, RN, BSN; Becky Hall, APRN; Erika R Jensen, APRN; Jamie Jordan, RN, BSN; Manndi C Loertscher, BS, CCRP; Trisha Marchant, RNC, BSN; Earl Maxson, RN, CCRN; Kandace M McGrath, BS; Hena G Mickelsen, BA; Galina Morshedzadeh, BSN, APRN; D Melody Parry, RN, BSN; Susan T Schaefer, RN, BSN, RRT; Kelly Stout, PhD; Ashley L Stuart, PhD; Katherine Tice, RN, BSN; Kimberlee Weaver-Lewis, RN, MS; Kathryn D Woodbury, RN, BSN. Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children’s Hospital (U10 HD40498, M01 RR7122): T Michael O’Shea, MD, MPH; Nancy J Peters, RN, CCRP. Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (UG1 HD21385) and University of Michigan Ann Arbor: Seetha Shankaran, MD; Beena G Sood, MD, MS; Athina Pappas, MD; Girija Natarajan, MD; Sanjay Chawla, MD; Monika Bajaj, MD; Prashant Agarwal, MD; Jeanette Prentice, MD; Melissa February, MD; Lilia De Jesus, MD; Gerry Muran, RN; Rebecca Bara, RN, BSN; Kirsten Childs, RN, BSN; Bogdan Panaitescu, MD; Eunice Woldt, RN, MSN; Mary E Johnson, RN, BSN; Laura A Goldston, MA; Stephanie A Wiggins, MS; Mary K Christensen, BA, RRT; Diane F White, RN, MSN; Martha Carlson, MD; John Barks, MD. Yale University, Yale New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 TR142): Richard A Ehrenkranz, MD (deceased); 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.
Contributors Concept and design: BMH, CPT, VVS, NA, CMC, VJ, NP, JET, SRH, SAW, MGG, AD, WAC. Acquisition of data: SAM, AD. Analysis and interpretation of data: BMH, SAM, CPT, VVS, NA, CMC, VJ, HEA, NP, JET, SRH, SAW, MGG, AD, WAC. Drafting of the manuscript: BMH, WAC. Critical revision of the manuscript for important intellectual content: BMH, SAM, CPT, VVS, NA, CMC, VJ, HEA, NP, JET, SRH, SAW, MGG, AD, WAC. Statistical analysis: BMH, SAM, CPT, VVS, NA, CMC, VJ, HEA, NP, JET, SRH, SAW, MGG, AD, WAC. Administrative and technical support: SAM, AD. Supervision: AD, WAC. Guarantor: WAC. On behalf of the NRN, SAM and AD with RTI International had full access to all of the data in the study and, with the NRN centre principal investigators, take responsibility for the integrity of the data and accuracy of the data analysis.
Funding The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (U10 HD27871, U10 HD53119, UG1 HD21364, UG1 HD21373, UG1 HD21385, UG1 HD27851, UG1 HD27853, UG1 HD27856, UG1 HD27880,UG1 HD27904, UG1 HD34216, UG1 HD36790, UG1 HD40492, UG1 HD40689, UG1 HD53089, UG1 HD53109, UG1 HD68244, UG1 HD68270, UG1 HD68278, UG1 HD68263, UG1 HD68284, UG1 HD87226, UG1 HD87229), the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Sciences (NCATS) (UL1 TR6, UL1 TR41, UL1 TR42, UL1 TR77, UL1 TR93, UL1 TR442, UL1 TR454, UL1 TR1117) provided grant support for the Neonatal Research Network's Generic Database and Follow-up Studies through cooperative agreements.
Disclaimer While the NICHD staff had input into the study design, conduct, analysis and manuscript drafting, the comments and views of the authors do not necessarily represent the views of the NICHD, the National Institutes of Health, the Department of Health and Human Services or the US government. NCRR and NCATS cooperative agreements provided infrastructure support to the NRN. No other funders had a 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.
Competing interests NA is an advisor to ResBiotic and Alveolus Bio and serves on the Data and Safety Monitoring Board for Shire/Oak Hill Bio. CMC has a consulting agreement with ReAlta Life Sciences (for a new drug in clinical trials for hypoxic ischaemic encephalopathy), and IP in a company, CryoCell (for a cell therapy for HIE). AD has a grant from the Neonatal Research Network (NRN). CPT is supported by grants from the National Institutes of Health (K23HL157618). CPT is supported by a grant from Owlet Baby Care for an investigator-initiated study (ClinicalTrials.gov identifier: NCT05774470) and also has a patent application pending for a bradycardia predictor and interrupter. VVS is supported by a grant from the American Heart Association (23CDA1048106).
Provenance and peer review Not commissioned; externally peer reviewed.
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