The incidence of both any acute ROP, and of the more severe stages, varies inversely with gestational age at birth. ROP is unusual (except in the mildest forms) in infants of greater than 31 weeks gestation, and severe complications such as retinal detachment occur in less than one half of one percent of infants greater than 31 weeks gestation (Palmer 1991). However, 84% of infants less than 28 weeks gestation develop some ROP, and close to 11% develop "threshold ROP" and undergo ablative surgery (cryotherapy or laser photocoagulation) to the peripheral avascular retina to reduce the risk of disease progression to retinal detachment (CRYO-ROP 1990).
The pathophysiology is understood to start with injury to the incomplete developing retinal capillaries. This could potentially occur before or during birth, but is thought to primarily occur in the days following delivery. Once the developing vessels have been damaged, it is hypothesized that the retina responds with the production of vascular growth factors stimulating neovascularization (which is the observable retinopathy) which may successfully revascularize the retina (regression of the ROP), or progress to neovascular membranes in the vitreous and subsequent scarring (cicatrix) and retinal detachment. Recent research suggests that vascular endothelial cell growth factor (VEGF) is one of the most important growth factors involved in this process (Aiello 1996, Provis 1997).
Interventions:
Efforts to reduce morbidity from ROP can be grouped into preventive
and interdictive categories. While prevention would be best aimed at preventing
premature birth, once that birth is inevitable such efforts are directed
at reducing stresses that may lead to injury of the developing retinal
capillaries. To date, these have focused on antioxidants, reduction of
light exposure, and control of exogenous oxygen delivery. Animal models
or clinical data have suggested that each of these are candidates for causing
retinal injury. For purposes of determining what preventive treatments
to consider using, it is important to remember that preventive interventions
must be applied to all premature infants, not just those infants who develop
ROP, and therefore potential side effects should be minimal.
Interdictive approaches target just those eyes that already have ROP of a defined severity. The goal is to control or arrest the progression of the neovascularization (even at the sacrifice of some of the retina) in order to preserve central vision. Cryosurgical or laser ablation of the peripheral avascular retina destroys the cells that are the putative source of the neovascular growth factors, thus allowing regression of the neovascularization and ablating retina that would need the new vessels.
Exogenous Light Exposure:
It is hypothesized that oxygen free radicals are one cause of injury
to developing retinal capillaries in the premature infant (Hepner
1949, Locke 1952A, Riley
1969). Energy from light striking the retina may induce, or increase
the number of oxygen free radicals in the retina, particularly in the face
of high levels of tissue oxygen. Numerous animal studies have demonstrated
retinal injury from light, but these injuries have been to other parts
of the retina than the blood vessels, namely the photoreceptors, cornea
or lens, depending on the amount and wavelengths of the light used (Ricci
1990, Penn 1992, Wesolowski
1994, Lawwill 1982).
Previous Overviews of Light Exposure:
A search of Medline, EMBASE, bibliographic references of published
research on light exposure, and personal discussion with investigators
involved in ROP research uncovered only one systematic review, published
in the book "Effective Care of the Newborn Infant" (Watts
1992). No meta-analysis was attempted in that review due to methodologic
difficulties with the reported studies. New data had been published since
that review (Seiberth 1994, Lopes
1997) and therefore the first Cochrane review was carried out and published
in Feb. 1997. Subsequent new research has led to updates in July 1997 (adding
Kennedy 1997), and August 1998 (adding Reynolds
1998). The present review updates the existing review of Light reduction
to prevent ROP which was published in the Cochrane Library Disk Issue 3,
1997 (Phelps 1998), and updated in 1998.
Valid: In addition to relevant:
Randomized or quasi-randomized assignment
Concealment of group assignment prior to randomization
Measurement/control of light reduction
Masking of Ophthalmologists making the outcome determination
Follow up rate >80%
Studies were excluded if there was no random or quasi-random assignment to study group.
Poor ROP Outcome: In either the acute period, or in follow up, the ROP observed advanced to Stage 4b (partial retinal detachment involving the macula), extensive cicatrix obscuring the visual axis, or stage 5 ROP (total retinal detachment), or the ROP advanced to the point where cryotherapy or laser treatment was used for Threshold ROP.
A special note regarding data from eyes (two) vs infant (one) is warranted. In ROP, outcomes between eyes are strongly correlated, but not perfectly so. Therefore it is important in each study to carefully consider whether outcomes in eyes, or outcomes in infants are being reported; and if by infant whether the worst stage in the worst eye is used (usually the case), or some sort of average.
Because so few citations were expected, the search was not limited by type of methodology used. In addition to the following databases, reports were retrieved from cross references to bibliographies from retrieved articles and interviews of expert informants. Databases searched included: The Cochrane Neonatal Group's Specialized Register of Controlled Trials, MEDLINE January 1966 - November 2000, CINAHL through July 1996, EMBASE through - August 2000, HealthSTAR to August 1996, Science Citation Index (Current Contents) Database from January 1984 through November 2000, CANCERLIT, the Oxford Database of Perinatal Trials, and the Cochrane Library, Issue 2, 2000.
One reviewer scanned all citations (title and abstract if listed) retrieved with this search strategy (over 90) and determined 24 to be possibly relevant as meeting the selection criteria for relevancy (human premature infants, light reduced in the first week, and ROP outcome data reported). An independent reviewer(CC) made the same determination on a subset of 20 of these citations and selected all of the same top ranked 18 citations that appeared in that subset, plus four others. However, upon review of photocopies of those additional 4 full citations, none proved to be relevant and the decisions of the first reviewer were accepted on the remainder for identifying all the possibly relevant articles (DLP). During the search process, two sets of unpublished data (part of the 24), two abstracts, and one ongoing trial were identified. No new trials were identified since the last update in 1998.
Photocopies of the 24 possibly relevant articles were provided to two independent reviewers to determine the true relevance of the article and the methodology used in the study (DLP, JLW). Thirteen relevant studies contained in 12 citations were identified (one citation contained two studies). Twelve other citations proved to be editorials, letters, duplicate abstracts or subsequent publications based on the data from one of the 10 studies. The two citations of unpublished data sets were also evaluated by the reviewers: one was technical pilot data without a control group, and the other involved a problematic comparison group. One trial that may be ongoing (Lopes) was identified.
Photocopies of the 12 relevant citations were provided to two reviewers to independently determine the methodology used. Methods were evaluated for masking of randomization, masking of intervention, completeness of follow up and masking of outcome measurement. Five randomized or quasi-randomized trials were identified. Five cohort studies comparing a period of reduced light to a non-randomized control cohort were identified, and two studies had no controls.
For the five studies determined to be randomized or quasi-randomized trials, both reviewers independently extracted the data into a set of uniform tables. When possible, data were extracted separately for infants of <1000g birth weight, and those 1000-2000g birth weight, as well as combined. Because ROP occurs more frequently in smaller infants, there is the potential that any benefit of light reduction could occur at different rates in smaller vs larger premature infants.
It is important in each study to carefully consider whether outcomes in eyes, or outcomes in infants are being reported. In the Locke study, the intervention (patching) was applied to one eye with the opposite eye serving as control, and thus each infant contributed two outcomes, one for the treated group and one for the control. In Seiberth 1994, Lopes 1997, Kennedy 1997, and Reynolds 1998, both eyes of each infant were treated in the same way. Therefore, each infant could contribute only once to the outcomes, and was reported/recorded as the worst stage of ROP observed (presumably in either eye).
Additionally, because light hypothetically might be expected to affect Acute ROP differently than severe ROP (Poor ROP Outcome), data were also extracted in categories of ROP severity, if possible. "Poor ROP Outcome" was defined as retinal detachments, partial or complete (stages 4b or 5 in the International Classification of ROP detachments, ICROP II 1987 ), or ROP of threshold severity requiring cryo/laser surgery. Original authors kindly confirmed data extraction and responded to questions that were unclear from their publications (Seiberth, Locke and Lopes).
Data from the five cohort observational studies were also extracted by both reviewers, but were used only for discussion purposes.
Relative risk and absolute risk reduction were examined for each study and for the pooled data using a fixed effects model.
2. Locke 1952A: Included.
In this study, conducted before knowledge of the oxygen link to ROP,
one eye of each of 22 infants (<2001g birth weight) was patched from
within 24 after birth through discharge. Non-survivors are not mentioned.
Although selection of which eye was to be patched is not described, there
is no biologic rationale to expect one eye to be more likely to develop
ROP than another. Control eyes were examined weekly with a direct ophthalmoscope,
and patched eyes only at the time of discharge. If mild, transient ROP
were an outcome, this would be problematic; however, the type and severity
of ROP that could be detected with the direct ophthalmoscope would have
been the same in both groups given the timing of examinations. Outcomes
are based on eyes, rather than infants since each eye received different
treatment. The first author performed all eye examinations and was not
masked as to study group. No differences were observed.
3. Lopes 1997 (abstract, also 1996 abstract) Included. A randomized controlled trial enrolling 184 infants of <1600g birth weight or <32 weeks gestation. In the experimental group, patching of both eyes began on the day of birth and continued until 35 weeks post-menstrual age. Because a paired randomization within birth weight groups (2 per block) was used, the investigator obtaining consent sometimes was aware of what the next randomization assignment would be. Indirect ophthalmoscopy was performed every two weeks and recorded according to the International Classification of ROP. To date, results in 74 control and 75 experimental group survivors are reported. In both groups, 37% of surviving infants developed some degree of ROP. Two control and no experimental infants were treated with cryotherapy (presumed to have threshold ROP). It is unclear whether this study is ongoing. (Authors kindly provided additional information in addition to that in published abstracts.)
4. Kennedy 1997: Included. A randomized controlled trial randomizing infants weighing 1250g or less, or of gestational age 32 weeks or less, at 0-6 hours after birth with consent subsequently obtained to continue the study. Goggles were worn until 31 weeks, and the primary outcome was electroretinograms at 35 weeks postmenstrual age. 71/135 infants born <1251g during the study period were randomized and 10 families subsequently refused consent to continue in the study (6 control and 4 goggles). Of the 61 infants in the study, 11 had no outcomes due to death (6 control, 3 goggles), or protocol violation (1 goggle) or per study criteria of second surviving twin (1 control). ROP was a secondary outcome, determined by residents or attendings who were masked to study assignment, and reported only as present or as reaching prethreshold stage according to the CRYO-ROP study definitions. Therefore, only acute ROP can be reported. Acute ROP rates were similar in both groups: 29% goggles, 31% controls. While the loss to follow up by this unusual randomization method raises some concern, similar numbers from each group withdrew at the point of consent.
5. Reynolds 1998: Included. Infants of less than 31 weeks gestation and less than 1251 grams birth weight were randomized after informed consent through a central registry to wearing goggles or control. The goggles were placed on the infant within 24 hours of birth, reduced light by 97% (100% of ultraviolet) and were continued until the infant was 31 weeks postmenstrual age or 4 weeks chronologic age, whichever occurred later. Oxygen exposure and use was not reported. Certified study ophthalmologists masked to group assignment examined all infants starting at 32 weeks postmenstrual age and classified ROP according to the International Classification of ROP. Confirmed ROP was required for the study outcome and consisted of at least 3 clockhours of ROP in any zone observed on at least two examinations. However, "any ROP" was also reported in the tables permitting direct comparison of results with previous studies. Of the 409 infants randomized, 46 died before ROP outcome could be determined and 2 were lost to follow up (distribution of these 48 infants between the 17 missing goggled infants (8.3%) and 31 missing controls (15%) is not described but has to approximate mortality in the two groups since only 2 infants were not lost because of death).
102/188 (54%) goggled infants developed confirmed ROP, as did 100/173 (58%) of controls. The comparable numbers for "any ROP" were 130 (69%) in the goggled group, and 121 (70%) in the controls and these numbers are the ones used in this review. For prethreshold ROP it was 19/188 (10%) goggled vs 15/173 (9%) controls, and for threshold ROP it was 9/188 (4.8%) goggled vs 9/173 (5.2%) controls. For the subgroup analysis (<1kg and >1kg only "confirmed ROP" was reported and therefore was used in the data tables in this review.) There were no significant differences between the two groups. Examination of the baseline characteristics revealed only minimal differences between the groups and these were associated with a slightly higher predicted risk of ROP in the control group and therefore do not affect the conclusions. Poor ROP Outcomes as vision loss was not reported, however, threshold ROP was used for the "Poor Outcome" variable. Oxygen exposure, oxygen use and vitamin E use were not reported, and the statistical section did not address sample size or power.
6. Locke 1952B: Used for discussion. In Locke's second study, 33 premature infants in one nursery had both eyes patched from within 24 hours of birth until discharge, and were compared to 33 premature infants of matched birth weights from the immediately preceding time period in the same nursery. Determinations of eye outcomes were with direct ophthalmoscopes as noted in study A from the same citation. These historical controls were close in time and from the same nursery, but leave reason to be concerned about the results because of potential changes in practice even over this time period. No significant differences were observed.
7. Hommura 1988: Used for discussion. Control infants included all 21 survivors of <1501g birth weight born in one hospital in 1983-84. Treated infants were all 16 survivors of <1501g birth weight born in 1985-86. Treated infants had both eyes patched from the day of birth until discharge home. Examinations were conducted weekly by one ophthalmologist not masked to study group. There were fewer cases of Acute ROP in the patched infants. The results, when reported as eyes rather than as infants, are statistically significant, but not so if reported as infants. This is concerning because left and right eyes are closely correlated in this disease and therefore not independent events. For this discussion, eye outcomes were converted to infant outcomes based on the worst eye from each infant. The authors provided supplemental information to Professor Ogawa who assisted in translation.
8. Glass 1985: Used for discussion. This study was designed to have an immediately preceding control cohort because the authors believed that concurrent controls were not possible. They felt that personnel accustomed to shielded incubators would insist on shielding all infants once the intervention had been taught. Premature infants from two nurseries had light reduction via shields placed over the incubators. The time from birth to placement in incubators that were then shielded was not controlled. This creates a potential bias against finding an effect of shielding because the sickest infants, and therefore the ones most likely to get ROP, could be more likely to stay in the radiant warmers longer, and therefore could have had later shielding from light than more healthy infants.
Eye examinations were conducted by experienced ophthalmologists according to usual practice, and they were unaware of group assignment, which could have meant that they were unaware of the research project, particularly during the control period. No mention of specific research data forms is made in the report. This is problematic because the manner in which ophthalmologists viewed ROP and its staging and medical record notes were undergoing significant changes during just this period of time. The first meeting to talk about a new international classification for ROP occurred in 1981 at the Ross Conference on ROP held in Washington DC. The second meeting which resulted in a draft classification which was to be taken home and tried out for a year occurred in Calgary, Canada in 1982. The third meeting was held at the NIH in 1983, and led to the final International Classification of ROP published in 1984. This evolution of the classification was happening during this study which recruited controls mostly in 1982, and shielded infants mostly in 1983.
Therefore, these data raise concerns around the definitions of diagnoses changing with time as the study moved from enrolling controls to enrolling treated infants, as well as the non-random allocation. Statistically significantly lower rates of ROP were observed in the shielded infants. The results are used for discussion.
9. Ackerman 1989: Used for discussion.
This study compared historical
controls from an immediately preceding period to similar infants after
instituting shielding of incubators. In this manner, most of the problems
from the Glass study are replicated, except that the possible changing
of the ROP classification is less of a problem. The time from birth until
shielding is not well described, with the same bias against finding an
effect as in the Glass study. Some infants may have been in open warmers
for more than a week after birth before being shielded. Ophthalmologists
determining outcomes were unaware of shielding status, and no differences
between the two cohorts was observed. There are significant chances for
bias and therefore these data are used only for discussion.
10. Hepner 1949: Excluded . Five premature infants had both eyes covered by 30 hours after birth, and the patching was continued until near discharge when the first eye examination was performed. There were no controls or mention of baseline or historical rates of ROP in the paper. Four of the five infants developed severe ROP in both eyes. Ironically, the generous use of oxygen is well documented in each of these careful case histories. The authors accepted these findings as having ruled out the possibility that ambient light caused ROP. Without controls, the data cannot contribute to a meta-analysis.
11. Repka MX (unpublished): Excluded. These data are unpublished, and found only as a personal communication in a Manual of Procedures for a current ongoing study (Reynolds, Spencer, et al). The data were discussed with the author (MXR) and describe the incidence of ROP in two different nurseries with different ambient levels of light by actual measurement. All infants were <1000g birth weight, and the brighter nursery had a higher incidence of ROP. However, the nurseries have very different populations (race, illness rates, insurance, etc), and different physicians and policies involved in their care. Therefore, it is not appropriate to compare these outcomes directly, and the investigators have decided not to submit the outcomes for publication.
12. Reynolds pilot (unpublished): Excluded. Pilot data testing the technical feasibility of using eye goggles on premature infants to reduce light exposure. ROP outcome was stated to be lower than in previous periods of time, but no comparison group was described. The information is referred to in the Manual of Procedures for a current ongoing trial (Reynolds, Spencer, et. al.), and discussion with the investigators reveals no plans to publish the pilot information.
Locke 1952A
Concealed randomization - can't tell, probably not
Masked intervention - not possible
Complete follow up - yes (although non-survivors not described)
Masked Outcome Assessment - can't tell, probably not
Lopes 1997
Concealed randomization - not masked about one third to one half the
time
Masked intervention - not possible
Complete follow up - all randomized accounted for, and of the 35 excluded
33 were deaths before ROP outcomes.
Masked Outcome Assessment - yes
Kennedy 1997
Concealed randomization - yes
Masked intervention - not possible
Complete follow up - 9/61 died, 2 excluded, all others completed
Masked Outcome Assessment - yes
Reynolds 1998
Concealed randomization - yes
Masked intervention - not possible
Complete follow up - 2/363 lost to follow up
Masked Outcome Assessment - yes
To consider the question at a less rigorous level, the data from the five observational cohort studies were incorporated by repeating the analysis with all ten studies (data not shown in graphs). The pooled results also indicate that reducing light exposure produced no effect on the incidence of Acute ROP, or Poor ROP Outcomes in all premature infants, those under 1000 grams birth weight, or those of 1001-2000g (where data were available). The 95% CI intervals for the relative risks all encompassed 1.0, even with these larger aggregate sample sizes.
If such a relatively simple, inexpensive intervention as reducing light could reduce poor visual outcomes it would be extremely valuable, and it has been important to settle the question. The addition of the LIGHT-ROP study (Reynolds 1998) strengthens the conclusion that light reduction is not the solution to preventing ROP vision loss. Critics of this study state that the goggles should have been placed on the infants sooner than within the first 24 hours, but subgroup analysis of the 15% who were goggled within 6 hours of birth also showed no difference (similarly for the Kennedy 1997 study where infants were also goggled within 6 hours of birth.)
The confidence intervals around these conclusions are fairly narrow for reducing ROP overall so that a true absolute difference in the incidence rates would be no more than 7%, and the relative risk is contained within the interval of 0.88 to 1.14. However, the 95% confidence interval for the relative risk difference in Poor Retinal Outcomes is larger because the rates are so low. With the current aggregate sample sizes, the relative risk could fall between 0.52 and 2.38, although the absolute risk reduction would fall between a 3.1% reduction to a 4.1% increase in absolute rates of poor retinal outcomes.
The question for investigators and funding agencies now is the issue of whether to commit further resources to conducting even larger studies of light reduction. The chance that a true effect of light reduction has been missed is now small. Complicating this decision is that there are other reasons for reducing light exposure in the NICU, along with noise reduction and other noxious stimuli related to better rest and recovery and growth. These are the subjects of other studies and will complicate future efforts to examine, in isolation, the effects of light reduction.
Future research is unlikely to change the conclusion reached in this analysis; that light reduction to the retina of premature infants does not significantly reduce the incidence or severity of ROP.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Kennedy 1997 | Randomized Controlled Trial | Infants <1251g birth weight or <33 weeks. 71 infants randomized and 61 infants' family's consented to study (28 goggles, 33 controls). 9 died (3 goggles and 6 controls) and 2 were excluded for protocol reasons (total lost, 4 goggled and 7 controls). | Goggles on both eyes within 6 hours of birth and continued until 31 weeks postmenstrual age or 4 weeks chronologic age, whichever was later. | Electroretinograms showed no differences. Acute ROP any stage was reported in 7/24 (29%) goggled infants and in 8/26 (31%) controls, and prethreshold ROP occurred in one of each group. | Primary outcome was electroretinogram, sample size was not determined to detect changes in ROP frequency. | A |
| Locke 1952A | Quasi-random. Controlled within each subject: treated one eye, the other control. Allocation not described, but biology does not suggest any difference to be expected between eyes. Caretakers could not be masked to intervention. Ophthalmologist determining outcome was not masked to study assignment. Follow up complete. | 22 infants of birth weight <2001g Each infant was both control and intervention. Number of infants enrolled who died before ROP evaluation was not reported. | One eye patched from <24 hours after birth to discharge home, with no examinations until discharge. The control eye was not patched, and was examined with a direct ophthalmoscope weekly. | ROP occurred in both of the eyes of 10 of the 22 infants. This advanced to Poor ROP Outcomes (blind) in both eyes in 2 infants. In addition, one patched eye developed massive vitreal hemorrhage. | This manuscript contains two studies; the other is in the excluded listing. | B |
| Lopes 1997 | Quasi-randomized controlled trial. Assigned in pairs within birth weight groups, with first of pair randomized blindly (per authors). | Infants <1600g birth weight or <32 weeks gestation. 184 randomized. | Patching of both eyes from birth to 35 weeks post-menstrual age | 35 of 184 died or were transferred out before ROP evaluation/outcome. Survivors evaluated included 74 controls, and 75 in the patched group. Acute ROP occurred in 28/74 (37.8%) of controls and 28/75 (37.3%) of patched infants. In controls 2 received cryotherapy, and among the patched infants none were treated with cryotherapy. | Abstract also published at an earlier stage in 1996 . | C |
| Reynolds 1998 | randomized controlled trial, concealed assignment, examiners masked to study group. | Infants <1251g birth weight and <31 weeks gestation. | 97% light reducing goggles worn in the intervention group only from within 24 hours of birth to 31 weeks postmenstrual age or 4 weeks chronologic age, whichever was longer. | 409 randomized (205 goggles, 204 controls), and 46 died and 2 were lost to follow up (17 in goggles and 31 in controls). Among survivors evaluated, 130/188 (69%) goggled infants developed any ROP, and 121/173 (70%) of controls. Threshold ROP occurred in 4.7% of goggled, vs 5.2% of controls (9 in each group). Poor visual outcome or need for cryo/laser treatment was not reported. | No differences in ROP between groups. Also no difference in the subgroup that was goggled within 6 hours of birth. The difference in mortality between the two groups is not addressed by the authors, and no apparent biologic explanation is forthcoming. Note: authors used "confirmed ROP" as the primary outcome in their report, but "any ROP" is used here in order to be consistent with other reports in the analysis. | A |
| Seiberth 1994 | Randomized Controlled Trial.
Concealed randomization. Not possible to mask caretakers as to group assignment. All randomized described, but some lost to follow up. Ophthalmologists masked to group when determining outcome. |
169 infants of <1501g birth weight and <33 weeks gestation, stratified within birth weight groups. 169 infants were randomized (85 patched and 84 controls). | Both eyes were patched from the day of birth until 35 weeks postmenstrual age (= gestational age at birth plus chronologic age in weeks). | Death occurred in 6 patched and 8 controls, 3 infants from the patched group were withdrawn by parents, and 25 were lost because of transfer before complete evaluation (14 patched and 11 controls). Similar numbers developed Acute ROP: 26/62 patched and 25/65 controls. Two cases of Poor ROP Outcome causing blindness occurred, both in the patched group. | Despite a predetermined sample size, this study was stopped early because of a trend favoring the controls at an interim analysis. | A |
| Study | Reason for exclusion |
| Ackerman 1989 | The comparison cohort was not randomly allocated (from a preceding time period). |
| Glass 1985 | The comparison cohort was not randomly allocated. |
| Hepner 1949 | No control group was reported. |
| Hommura 1988 | The comparison group was a historical control cohort. |
| Locke 1952B | The comparison cohort was not randomly allocated. |
| Repka | Control cohort not randomly allocated. Rates of ROP from two different nurseries with different ambient light levels. |
| Reynolds pilot | No control group |
| Study | Trial name or title | Participants | Interventions | Outcomes | Starting date | Contact information | Notes |
| Braz et al |
Kennedy KA, Ipson MA, Birch DG, Tyson JE, Anderson JL, Nusinowitz S, et al. Light reduction and the electroretinogram of preterm infants. Arch Dis Child 1997;76:F168-F173.
Locke 1952A {published data only}
Locke JC, Reese AB. Retrolental Fibroplasia. The negative role of light, mydriatrics, and the ophthalmoscopic examination in Its etiology. Arch Ophthalmol 1952;48:44-47.
Lopes 1997 {published data only}
* Lopes JM, Braz RRT, Moreira MEEL, Motta M, de Carvalho M, Rebello A, Chemtob S, Aranda JV. A randomized trial of the effects of ambient light on the incidence of retinopathy (ROP). Pediatric Research 1997;41:954A.
Braz RRT, Moreira MEL, Motta M, Rebello A, de Carvalho M, Lopes JM. Efeitos da luz ambiente no desenvolvimento da retinopatia da prematuridade(RPP). In: Abstract #119, XV Congresso Brasileiro de Perinatologia, XII Reuniao de enfernagem Perinatal. 23-29 de Novembro de 1996. Minascentro Belo Horizonte.
Reynolds 1998 {published data only}
Reynolds JD, Hardy RJ, Kennedy KA, Spencer R, van Heuven WA, Fielder AR. Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light Reduction in Retinopathy of Prematurity (LIGHT-ROP) Cooperative Group. New Engl J Med 1998;338:1572-1576.
Seiberth 1994 {published data only}
* Seiberth V, Linderkamp O, Knorz MC, Liesenhoff H. A controlled clinical trial of light and retinopathy of prematurity. Am J Ophthalmol 1994;118:492-495.
Seiberth V, Linderkamp O, Poepel B, Knorz MC, Liesenhoff H. Light and acute retinopathy of prematurity. A controlled clinical trial [abstract]. Investig Ophthalmol Vis Sci 1992;33:1085.
Ackerman B, Sherwonit E, Williams J. Reduced incidental light exposure: effect on the development of retinopathy of prematurity in low birth weight infants. Pediatrics 1989;83:958-962.
Glass 1985 {published data only}
* Glass P, Avery GB, Subramanian KN, Keys MP, Sostek AM, Friendly DS. Effect of bright light in the hospital nursery on the incidence of retinopathy of prematurity. N Engl J Med 1985;313:401-404.
Glass P. Light and the developing retina [Review]. Documenta Ophthalmologica 1990;74:195-203.
Glass P. Role of light toxicity in the developing retinal vasculature [Review]. Birth Defects: Original Article Series 1988;24:103-117.
Hepner 1949 {published data only}
Hepner WR, Krause AC, Davis ME. Retrolental fibroplasia and light. Pediatrics 1949;3:824-828.
Hommura 1988 {published data only}
Hommura S, Usuki Y, Takei K, Tsuboi K, Sekine Y, Fukuda Y, Terauchi M. Ophthalmic care of very low birthweight infants. Report 4. Clinical studies on the influence of light on the incidence of retinopathy of prematurity [Japanese]. Nippon Ganka Gakkai Zasshi - Acta Societatis Ophthalmologicae Japonicae 1988;92:456-461.
Locke 1952B {published data only}
Locke JC, Reese AB. Retrolental Fibroplasia. The negative role of light, mydriatrics, and the ophthalmoscopic examination in Its etiology. Arch Ophthalmol 1952;48:44-47.
Repka MX, Fulton AB, Petersen RA, Robinson J, Simons M. Retinopathy of prematurity and light, unpublished. Referred to in the manual of procedures from the LIGHT-ROP Study, an on going clinical trial (1995).
Reynolds pilot {unpublished data only}
Reynolds J, Spencer R. Feasibility trial of goggles for light reduction for retinopathy of prematuriy. No controls, testing of goggles only. Authors do not plan to publish. 1996.
Braz RRT, Moreira MEL, Motta M, Rebello A, de Carvalho M, Lopes JM. Data from abstracts at interim analysis reported in "Included Studies" (see Lopes 1997). Planning to continue to full sample size of 200 completing study.
* indicates the primary reference for the study
Aiello LP. Vascular endothelial growth factor and the eye - past, present, and future. Arch Ophthalmol 1996;114:1252-1254.
Multicenter trial of cryotherapy for retinopathy of prematurity. One-year outcome--structure and function. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 1990;108:1408-1416.
An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. Arch Ophthalmol 1984;102:1130-1134.
International Committee for Classification of ROP. An international classification of retinopathy of prematurity. II. The classification of retinal detachment. Archives of Ophthalmology 1987;105(7):906-912.
Lawwill T. Three major pathologic processes caused by light in the primate retina: a search for mechanisms. Trans Am Ophthal Soc 1982;80:517-579.
Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips CL, Schaffer DB, et al. Incidence and early course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 1991;98:1628-1640.
Penn JS, Tolman BL, Lowery LA, Koutz CA. Oxygen-induced retinopathy in the rat: hemorrhages and dysplasias may lead to retinal detachment. Current Eye Research 1992;11:939-953.
Provis JM, Leech J, Diaz CM, Penfold PL, Stone J, Keshet E. Development of the human retinal vasculature - cellular relations and VEGF expression. Experimental Eye Research 1997;65:555-568.
Ricci B, Lepore D, Iossa M, Santo A, D'Urso M, Maggiano N. Effect of light on oxygen-induced retinopathy in the rat model. Light and OIR in the rat. Documenta Ophthalmologica 1990;74:287-301.
Riley PA, Slater TF. Pathogenesis of retrolental fibroplasia. Lancet 1969;2(614):265.
Wesolowski E, Smith LE. Effect of light on oxygen-induced retinopathy in the mouse. Investig Ophthalmol Vis Sci 1994;35:112-119.
Phelps DL, Watts JL. Early light reduction to prevent retinopathy of prematurity in very low birth weight infants. In: The Cochrane Library, Issue 4, 1998. Oxford: Update Software.
Watts JL. Retinopathy of prematurity. In: Sinclair JC, Bracken MB, editor(s). Effective care of the newborn infant. Oxford: Oxford University Press, 1992:617-639.