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Table 1.  
Characteristics of the Children and Their Familiesa
Characteristics of the Children and Their Familiesa
Table 2.  
Rates of Disabilities at Age 5 Years in Children With and Without Severe Retinopathy of Prematurity (ROP)
Rates of Disabilities at Age 5 Years in Children With and Without Severe Retinopathy of Prematurity (ROP)
1.
Msall  ME, Phelps  DL, DiGaudio  KM,  et al; Behalf of the Cryotherapy for Retinopathy of Prematurity Cooperative Group.  Severity of neonatal retinopathy of prematurity is predictive of neurodevelopmental functional outcome at age 5.5 years. Pediatrics. 2000;106(5):998-1005.
PubMedArticle
2.
Schmidt  B, Asztalos  EV, Roberts  RS, Robertson  CM, Sauve  RS, Whitfield  MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators.  Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003;289(9):1124-1129.
PubMedArticle
3.
Cryotherapy for Retinopathy of Prematurity Cooperative Group.  Multicenter trial of cryotherapy for retinopathy of prematurity: natural history ROP: ocular outcome at 5(1/2) years in premature infants with birth weights less than 1251 g. Arch Ophthalmol. 2002;120(5):595-599.
PubMedArticle
4.
Hintz  SR, Kendrick  DE, Vohr  BR, Poole  WK, Higgins  RD; National Institute of Child Health and Human Development Neonatal Research Network.  Changes in neurodevelopmental outcomes at 18 to 22 months’ corrected age among infants of less than 25 weeks’ gestational age born in 1993-1999. Pediatrics. 2005;115(6):1645-1651.
PubMedArticle
5.
Doyle  LW, Roberts  G, Anderson  PJ; Victorian Infant Collaborative Study Group.  Changing long-term outcomes for infants 500-999 g birth weight in Victoria, 1979-2005. Arch Dis Child Fetal Neonatal Ed. 2011;96(6):F443-F447.
PubMedArticle
6.
Schmidt  B, Anderson  PJ, Doyle  LW,  et al; Caffeine for Apnea of Prematurity (CAP) Trial Investigators.  Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012;307(3):275-282.
PubMedArticle
Research Letter
February 5, 2014

Association Between Severe Retinopathy of Prematurity and Nonvisual Disabilities at Age 5 Years

Author Affiliations
  • 1Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 2Department of Paediatrics, University of Melbourne, Melbourne, Australia
  • 3Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
  • 4Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
  • 5Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
JAMA. 2014;311(5):523-525. doi:10.1001/jama.2013.282153

Severe retinopathy of prematurity is a serious complication of neonatal intensive care for preterm infants.1,2 Before effective screening and treatment became available, approximately 5% of infants with birth weights of 1250 g or less had visual acuity of 20/200 or worse at 5.5 years.3 In such children, the severity of retinopathy was a predictor of functional disability in multiple domains.1 Although the incidence of severe retinopathy has increased since the late 1980s,4 blindness caused by retinopathy has become rare in developed countries.5 Consequently, clinicians and parents may conclude that severe retinopathy is no longer associated with childhood impairments. We investigated whether infants with severe retinopathy who were diagnosed and treated under modern protocols retain an increased risk of nonvisual disabilities compared with those without severe retinopathy.

Methods

This exploratory analysis used data from the inception cohort assembled for the Caffeine for Apnea of Prematurity trial. Study participants were infants with birth weights between 500 g and 1250 g who were born at 31 centers between 1999 and 2004 and followed-up at age 5 years (2005-2011).6

Severe retinopathy of prematurity was defined as unilateral or bilateral stage 4 or 5 disease or as receipt of retinal therapy in at least 1 eye. The incidence in this cohort was 6.5% but only 0.9% of participants were bilaterally blind at 5 years. Five-year outcomes included motor impairment, cognitive impairment, behavioral problems, poor general health, severe hearing loss, and bilateral blindness.6 Infants from intervention and placebo groups were analyzed together in this observational study. We expressed the association between severe retinopathy of prematurity and 5-year outcomes as an odds ratio (OR) estimated via a logistic model with adjustment for prespecified baseline covariates (gestational age, sex, antenatal steroid exposure, multiple birth, and maternal educational level). SAS version 9.2 was used (SAS Institute Inc). All P values were 2-sided and considered significant if <.05. Research ethics boards at all centers approved the protocol and written informed consent was obtained from parents or guardians.

Results

Of 2006 infants enrolled, 191 died or were born in centers that did not participate in the 5-year follow-up. Of 1815 eligible survivors, 1582 children (87%) had complete (n = 1523) or partial (n = 59) 5-year assessments; 95 had severe retinopathy. Children with severe retinopathy had lower gestational age and less exposure to antenatal corticosteroids than those without or with less severe retinopathy (Table 1). Of the children with severe retinopathy, 39.5% had at least 1 nonvisual disability at 5 years compared with 15.8% of children without it (adjusted OR, 2.89; 95% CI, 1.77-4.72; P < .001; Table 2). Fourteen of 94 children (14.9%) with and 36 of 1487 children (2.4%) without severe retinopathy had more than 1 nonvisual disability at 5 years (adjusted OR, 6.98; 95% CI, 3.27-14.89; P < .001).

Motor impairment, cognitive impairment, and severe hearing loss were 3 to 4 times more common in children with severe retinopathy than those without severe retinopathy.

Discussion

In this cohort of very low-birth-weight infants, we observed a strong association between the development of severe retinopathy of prematurity and the presence of 1 or more nonvisual disabilities at age 5 years. This observation may help improve the ability to counsel parents and to select high-risk infants for long-term follow-up.

Although the risk of vision loss was increased after severe retinopathy, most children with severe retinal disease did not become bilaterally blind. Unfavorable exposures that promote the development of retinopathy may simultaneously damage the immature brain. We did not adjust our analysis for acquired neonatal comorbidities such as bronchopulmonary dysplasia because we wanted to investigate the prognostic importance of severe retinopathy, not the possible independent causal relationship between it and childhood disability. Limitations of our study include an attrition rate of 13% at 5 years. Compared with those analyzed, children not seen at 5 years were less likely to have been part of a multiple birth and had mothers who had less education. We likely underestimated the prevalence of multiple nonvisual disabilities because some impaired children had incomplete outcome assessments.

Severe retinopathy of prematurity remains an adverse outcome of neonatal intensive care with poor prognosis for child development, although blindness can mostly be prevented by timely retinal therapy.

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Article Information
Section Editor: Jody W. Zylke, MD, Senior Editor.

Corresponding Author: Barbara Schmidt, MD, MSc, Division of Neonatology, Hospital of the University of Pennsylvania, 3400 Spruce St, Ravdin 8, Philadelphia, PA 19104 (barbara.schmidt@uphs.upenn.edu).

Author Contributions: Mr Roberts had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Schmidt, Davis, Solimano, Roberts.

Acquisition of data: All authors.

Analysis and interpretation of data: Schmidt, Roberts.

Drafting of the manuscript: Schmidt.

Critical revision of the manuscript for important intellectual content: Davis, Asztalos, Solimano, Roberts.

Statistical analysis: Roberts.

Obtained funding: Schmidt, Asztalos, Roberts.

Administrative, technical, or material support: Schmidt, Davis, Solimano.

Study supervision: Schmidt, Davis, Solimano.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: The Caffeine for Apnea of Prematurity trial was supported by grant MCT 13288 from the Canadian Institutes of Health Research and by the National Health and Medical Research Council of Australia.

Role of the Sponsors: Canadian Institutes of Health Research and the National Health and Medical Research Council of Australia 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.

Additional Contributions: In addition to the named authors, the following members of the Steering Committee for the 5-Year Follow-Up of the Caffeine for Apnea of Prematurity trial participants contributed to the manuscript: Lex W. Doyle, MD, MSc, Peter J. Anderson, PhD, Ruth E. Grunau, PhD, Arne Ohlsson, MD, MSc, Deborah Dewey, PhD, Diane Moddemann, MD, MEd, and Win Tin, MD. None of the additional contributors received any compensation for their contributions to this study.

References
1.
Msall  ME, Phelps  DL, DiGaudio  KM,  et al; Behalf of the Cryotherapy for Retinopathy of Prematurity Cooperative Group.  Severity of neonatal retinopathy of prematurity is predictive of neurodevelopmental functional outcome at age 5.5 years. Pediatrics. 2000;106(5):998-1005.
PubMedArticle
2.
Schmidt  B, Asztalos  EV, Roberts  RS, Robertson  CM, Sauve  RS, Whitfield  MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators.  Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003;289(9):1124-1129.
PubMedArticle
3.
Cryotherapy for Retinopathy of Prematurity Cooperative Group.  Multicenter trial of cryotherapy for retinopathy of prematurity: natural history ROP: ocular outcome at 5(1/2) years in premature infants with birth weights less than 1251 g. Arch Ophthalmol. 2002;120(5):595-599.
PubMedArticle
4.
Hintz  SR, Kendrick  DE, Vohr  BR, Poole  WK, Higgins  RD; National Institute of Child Health and Human Development Neonatal Research Network.  Changes in neurodevelopmental outcomes at 18 to 22 months’ corrected age among infants of less than 25 weeks’ gestational age born in 1993-1999. Pediatrics. 2005;115(6):1645-1651.
PubMedArticle
5.
Doyle  LW, Roberts  G, Anderson  PJ; Victorian Infant Collaborative Study Group.  Changing long-term outcomes for infants 500-999 g birth weight in Victoria, 1979-2005. Arch Dis Child Fetal Neonatal Ed. 2011;96(6):F443-F447.
PubMedArticle
6.
Schmidt  B, Anderson  PJ, Doyle  LW,  et al; Caffeine for Apnea of Prematurity (CAP) Trial Investigators.  Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012;307(3):275-282.
PubMedArticle
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