retinopathy of prematurity ( rop ) is a vasoproliferative disease of the retina , that is , one of the most common causes of infant and childhood blindness . fortunately , the visual impairment related to rop is largely preventable with timely treatment   after its diagnosis by ophthalmoscopic examination [ 3 , 4 ] . however , it has recently been reported that disagreement may arise between ophthalmologists regarding the existence of plus disease , indicating subjectivity in diagnosis based on indirect ophthalmoscopic examination . to address the medical and legal issues that may arise regarding diagnosis of rop , ophthalmologists have begun using new imaging systems such as retcam ( clarity , usa ) , a digital fundus camera or computerized image analysis [ 68 ] . optical coherence tomography ( oct ) is an imaging system used for diagnosis and monitoring of many retinal diseases that captures cross - sectional images from the retinal pigment epithelium and photoreceptor layer . while oct may provide more objective findings than other modalities , it is difficult to use in the imaging of infants . fortunately , difficulty regarding the fixation and positioning of infants for imaging has been largely resolved with the development of portable oct devices . there are many studies about using portable oct for imaging infants ' retinas [ 1016 ] . studies performed with spectral domain ( sd ) oct in premature infants have demonstrated the presence of several macular changes , such as cystoid macular edema [ 1014 ] , retinoschisis , and preretinal structures [ 15 , 16 ] , which were not detected by clinical examinations . nevertheless , use of sd oct in premature infants has not become widespread . to examine the macular findings in infants with rop , we evaluated the capture of macular data and measurement of central foveal thickness by sd oct . the study was approved by the local ethics committee and performed in accordance with the ethical standards outlined in the declaration of helsinki . informed consent was obtained by the parents or guardians of all participating subjects prior to their inclusion in the study . the macular sd oct images of all of the 190 premature infants ( 103 males and 87 females ) who had participated in the rop screening program at our hospital were analyzed retrospectively between june 2013 and may 2014 . infants with anterior segment anomalies like congenital glaucoma or congenital cataract and with corneal edema and posterior segment anomalies like choroidal coloboma , morning glory anomaly , and oculocutaneous albinism were excluded from the study . in all rop examinations , after placement of a lid speculum , central and peripheral fundus were examined carefully with scleral indentation using an indirect video ophthalmoscope ( heine optotechnik , herrsching , germany ) . next , oct images were obtained from the center of the fovea with a sd oct ( ivue , optovue , fremont , usa ) . istand which is a rolling floor stand option for ivue was used for scanning in supine position . when mounted to istand , cross line scan gives us one horizontal and one vertical 2  6  mm image with 2.048  a scans and 5 micron resolutions . the device uses image averaging ( 20  b scans ) to decrease the signal - to - noise ratio . this feature allows us to evaluate the choroidal thickness in some patients . in this study , infants were scanned with cross line pattern in supine position . during scanning , his / her hands and head were held by a nurse . at least three scans were performed within 10  min for every patient to ensure obtaining at least three images of sufficient quality , in accordance with the manufacturer 's suggestion . a pacifier dipped in dextrose 30% was used to calm the infants without using any anesthesia and a lubricant eye drop ( systane , alcon pharmaceuticals ltd , barcelona , spain ) was instilled for hydrating the cornea as necessary . infants with type i rop ( zone i , any stage with plus disease ; zone i , stage 3 without plus disease ; zone ii , stages 2 - 3 with plus disease ) were treated with laser photocoagulation and/or intravitreal ranibizumab injection . infants were then examined at intervals of four weeks , regardless of whether retinal vascularization had been completed , until the cystoid macular edema had been resolved . the sd oct sections closest to the fovea were graded according to the following scale . grade 1 : one or more cysts with no changes in the foveal contour ( figure 1(b ) ) . grade 2 : one or more cysts with changes in the foveal contour ( figure 1(c ) ) . grade 1 : one or more cysts with no changes in the foveal contour ( figure 1(b ) ) . grade 2 : one or more cysts with changes in the foveal contour ( figure 1(c ) ) . to evaluate central foveal thickness , defined as the distance from the internal limiting membrane to the retina pigment epithelium ( rpe ) , the oct image at the steepest foveal excavation from the cross line scan was examined . when cystoid macular edema disruption of the foveal contour was present , measurement was performed at the point that protruded most greatly . using the digital caliper tool built into sd oct system , central foveal thickness was measured by two experienced observers who were blind to all group data . using the mean value of two measurements , statistical analysis was performed using analytical software ( spss inc . , demographic characteristics and other data regarding the infants were analyzed statistically and reported in terms of the mean  standard deviation ( sd ) , frequency , and percentage . data regarding central foveal thickness , cyst grading , and macular edema were compared using nonparametric tests ( the pearson chi - square test , mann - whitney u test , and kruskal - wallis h test ) . the correlations between the central foveal thickness with gestational age and birth weight were calculated with spearman 's correlation test . the results were obtained from 358 eyes of 179 infants ( 81 girls , 98 boys ) . the images of five infants that were of low quality , of 4 infants due to being obtained too far from the fovea , and of two infants in whom one - sided peters ' anomaly was detected were excluded from further examination . the mean gestational age was 30.9  2.7 weeks ( range 2436 weeks ) , the mean birth weight was 1609  477  g ( range 6402530  g ) , and the mean postmenstrual age at sd oct imaging was 38.2  3.9 weeks ( table 1 ) . a total 126 eyes had rop , while 232 eyes had no rop in visit . there was no significant differences in the mean postmenstrual age at the sd oct imaging between the infants as a stage of rop ( p = 0.15 , kruskal - wallis h test ) . based on evaluation of the measurements , 139 eyes were diagnosed with macular edema and 219 eyes without macular edema . a greater percentage of eyes with rop were found to have macular edema ( 53.9% ) than eyes without rop ( 30.5% ) , a difference that reached a level of statistical significance ( p = 0.001 ; mann - whitney u test ) . the incidence of macular edema was found to be 46.3% for stage 1 , 57.1% for stage 2 , and 87.5% for stage 3 . the presence of macular edema in eyes with rop was increasing with rising of rop stages ( table 2 ) . figure 2 shows the results of comparison of mean cft between the eyes with and without rop . the mean cft of all eyes was 175.2  106.5  m , while that of eyes without rop was 163.3  105.3 and that of eyes with rop was 199.8  97.3  m ( stage 1 : 192.2  102.5  m , stage 2 : 192.4  70.7  m , and stage 3 : 239.3  69.7  m ) . the mean cft was found to be significantly larger in eyes with rop than eyes without rop ( p = 0.001 , mann - whitney u test ) . analysis of cyst grading based on oct scanning revealed a significant difference between classifications of rop stage , with cyst grade found to increase with increasing rop stage ( figure 3 ) . at a mean postmenstrual age of 44.2 3.5 weeks , regression of cystoid macular edema was observed in 71 eyes ( figure 4 ) . intravitreal ranibizumab injection was administered to five infants for treatment of type 1 rop at a mean postmenstrual age of 36.2  1.9 weeks . cft increased in three infants and did not increase in two infants within one week after intravitreal ranibizumab treatment ( figure 5 ) . of the two infants in whom cft did not increase , cystoid macular edema resolved in one infant two months after intravitreal ranibizumab injection ( figure 6 ) . at the mean 38.2  3.9 weeks of postmenstrual age , there was a weakly inverse correlation between cft and gestational age ( p = 0.025 , r = 0.227 ) ( figure 7 ) and between cft and birth weight ( p = 0.002 , r = 0.182 ) ( figure 8) . sd oct is widely used in the diagnosis and monitoring of many retinal diseases in adult patients . however , its use in the pediatric population has been limited due to the need to conduct scanning in the upright position . nevertheless , maldonado and toth have identified two oct devices , the bioptigen and ivue systems , commercially available in the united states that are capable of obtaining sd oct images while the patient is in the supine position . although only the bioptigen has obtained food and drug administration ( fda ) approval for usage in children in the united states , the ivue can be obtained commercially in turkey . as our hospital has obtained an ivue one advantage of using of the ivue is that it can be mounted to the istand , which minimizes the production of imaging artifacts due to operator movement . in a study with 31 prematurely born neonates imaged from 31 to 42 postmenstrual weeks ( median birth weight was 825  g , median gestational age 26 weeks , and final rop stage < 2 ) , maldonado et al . identified cystoid macular edema in 58% of patients . in a study of 42 neonates , dubis et al the first to be conducted in a turkish population , we detected cystoid macular edema in 38% of patients with a mean gestational age of 31 weeks and mean birth weight of 1609  g. several factors may account for the discrepancy between our findings and those of other researchers . infants that we examined were with higher gestational age and heavier birth weight than previous study . the discrepancy between our findings and those of dubis et al . and maldonado et al . could be attributed to the older age and greater body weight of the patients in the current study , whose initial imaging session was conducted at an older age compared to that of patients in previous studies . while the median age of the patient population in our study was similar to that in vinekar et al . 's study , the use of different imaging devices may account for the differences found regarding cystoid macular edema . specifically , vinekar et al . reported a mean cft of 156.9  28.3  m , 206.5  98.7  m , and 135.9  17.6  m for stage 1 , stage 2 , and no rop , respectively ( age at oct imaging for stage 2 patients : 37.18  1.95 weeks of postmenstrual age ) . in contrast , we found a mean cft of 192.2  102.5  m , 192.4  70.7  m , 239.3  69.7  m , and 163.3  105.3  m for stage 1 , stage 2 , stage 3 , and no rop , respectively ( age at oct imaging for stage 2 patients : 38.4  4.3 weeks of postmenstrual age ) . maldonado et al . and vinekar et al . have suggested that cystoid macular edema in prematurity may be related with vascular endothelial growth factor ( vegf ) , as is the cystoid macular edema observed in diabetic retinopathy and retinal vein occlusion [ 10 , 11 ] . indeed , it has been shown that growth factors , including vegf , neuropilin , and semaphorin , have a role in the development of rop fovea [ 18 , 19 ] . however , upon observing development of cystoid macular edema after intravitreal bevacizumab injection in a premature infant and finding no correlation between stage of rop and cystoid macular edema , dubis et al . proposed that mechanical traction and neurohumoral factors other than vegf could have a role in the development of cystoid macular edema in premature infants . having found that the density of rpe cells in premature infants is low , we propose that lower rpe cell density may contribute to formation of cystoid macular edema in premature infants . having observed a correlation between stage of rop and cystoid macular edema in the current study , we also propose that the main factor in development of cystoid macular edema is vegf . nevertheless , we observed full retinal vascularization and regression of rop in three infants who had cystoid macular edema ( one of them with grade 1 , others with grade 2 ) . we also observed increase in cystoid macular edema one week after intravitreal ranibizumab injection in three of five infants to whom we administered this treatment . spontaneous regression of cystoid macular edema has been observed in previous studies [ 1014 ] . among them , vinekar et al . observed regression of cystoid macular edema in 19 eyes of 10 babies at 52-week postmenstrual age , while maldonado et al . observed the earliest regression of cystoid macular edema at 36 weeks and the latest at 43 weeks of postmenstrual age in nine babies . in three patients in dubis el al 's study , cystoid macular edema was resolved at 52-week postmenstrual age in one and at postmenstrual age of 40 weeks in two . we observed regression of cystoid macular edema in 71 eyes of 37 premature infants at a mean age of 44.2  3.5 weeks of postmenstrual age and regression of cystoid macular edema after intravitreal ranibizumab injection in one infant at 44 weeks of postmenstrual age . primary treatment of rop with intravitreal ranibizumab injection has been shown effective in decreasing cystoid macular edema secondary to diabetic retinopathy , retinal vein occlusion , and many other retinal diseases [ 2124 ] . nevertheless , dubis et al . observed no regression of cystoid macular edema in four patients after intravitreal bevacizumab injection during the follow - up period . however , in the small sample examined in our study , cystoid macular edema resolved in one patient two month after treatment , while cystoid macular edema grade increased in three patients one week after treatment and did not change in the month following treatment . although bevacizumab and ranibizumab are used in treatment of rop but not cystoid macular edema , their effect on the cystoid macular edema observed in rop indicates that cystoid macular edema may be related with vegf . confirmation of the effects of ranibizumab treatment on the timing of cystoid macular edema regression now requires investigation of a larger sample over a longer follow - up period . among the many studies that have evaluated eyes with history of rop [ 2527 ] , park and oh found that total retinal thickness and outer nuclear layer thickness in preterm infants were larger than those in term infants . while , however , they and other researchers found that retinal thickness in preterm infants is not correlated with visual acuity [ 2527 ] , parks et al . similarly , we found an inverse correlation between birth week and central foveal thickness , although this correlation was weak . although no association has been found between visual acuity and foveal structure , a multifocal electroretinography study observed that the most striking functional deficit was in the central region . this finding leads us to speculate that this functional deficit may be associated with the cystoid macular edema observed during prematurity . gaining greater understanding of the effect of cystoid macular edema on future visual function now requires follow - up of our patients over a longer period of time . first , as the study design was retrospective , we could not evaluate macula with sd oct imaging on a weekly basis . second , we used the ivue sd oct system , which , to our knowledge , had not been previously used in premature infants . third , although we believe we obtained high - quality images , we did not use the method for imaging premature infants defined by maldonado et al . and other authors . we instead used the method defined for adults , specifically the cross line mode rather than the retinal map mode , which allowed us to take one horizontal and one vertical high - quality image . therefore , we may have failed to detect small cysts in other parts of the retina , and as the ivue system does not have a tracking system , repeated images could not pass in exactly the same place . as a result , fovea of premature infants transient cystoid macular edema is frequently seen in prematurity and the incidence of cystoid macular edema increases with the severity of rop . conducting a study with a larger sample over a longer follow - up period is necessary to evaluate the clinical significance of the cystoid macular edema observed in premature infants .
purpose . to examine the macular findings obtained with spectral domain optical coherence tomography ( sd oct ) in infants with retinopathy of prematurity ( rop ) . 
 materials and methods . 
 the macular sd oct images of 190 premature infants were analyzed . 
 data regarding central foveal thickness ( cft ) , cystoid macular edema ( cme ) , and cyst grading were compared . 
 the relationships of cft with gestational age and birth weight were investigated . 
 results . 
 the results were obtained from 358 eyes of 179 infants ( 81 females and 98 males ) of a mean gestational age of 30.9  2.7 weeks and a mean birth weight of 1609  477  g. rop was diagnosed in 126 eyes and cme in 139 eyes . 
 a significantly greater percentage of eyes with rop were found to have cme ( 54% ) compared to eyes without rop ( 31% ; p = 0.001 ) . 
 the incidence of cme was 46.3% for stage 1 rop , 57.1% for stage 2 , and 87.5% for stage 3 . 
 there was a weakly inverse correlation between cft , gestational age , and birth weight ( p = 0.025 , r = 0.227 ; p = 0.002 , r = 0.182 , resp . 
 , spearman correlation test ) . 
 conclusions . 
 high - quality sd oct images can be obtained from premature infants using the ivue system . 
 severity and frequency of cme in premature infants increase as stage of rop increases .