Red blood cell parameters as biomarkers of retinopathy of prematurity in preterm infants born before 30 weeks of gestation

Red blood cell parameters as biomarkers of retinopathy of prematurity in preterm infants born before 30 weeks of gestation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Red blood cell parameters as biomarkers of retinopathy of prematurity in preterm infants born before 30 weeks of gestation Hajime Maeda, Hayato Go, Hajime Iwasa, Shun Hiruta, Hirotaka Ichikawa, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3872014/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Retinopathy of prematurity (ROP) is a major cause of preventable blindness in preterm infants. The association between red blood cell (RBC) parameters and the development of ROP remains unclear. The objectives of the present study were to evaluate the association between RBC parameters and ROP treatment. This single-center, retrospective cohort study included preterm infants born at < 30 weeks of gestation. Data pertaining to RBC parameters and ROP treatment were obtained from the medical records. A receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of the RBC parameters according to the need for ROP treatment. Multiple logistic regression analyses assessed the association between ROP treatment and RBC parameters at birth and on day of life (DOL) 28. We included 202 infants, and 44.1% were treated for ROP. After adjusting for confounders, associations between ROP treatment and hemoglobin (Hb) values of < 9.9 g/dL (adjusted odds ratio [aOR]:3.0; 95% confidence intervals [CI]:1.4–6.7) and hematocrit (Hct) values of < 31.0% (aOR:2.7; 95% CI:1.3–5.6) on DOL 28 were detected. In conclusion, our study showed that infants born at < 30 weeks of gestation with Hb < 9.9 g/dL and Hct < 31.0% on DOL 28 had an increased risk of receiving ROP-warranting treatment. Health sciences/Biomarkers Health sciences/Diseases Health sciences/Medical research Health sciences/Risk factors Figures Figure 1 Introduction Retinopathy of prematurity (ROP) is a major cause of preventable blindness in preterm infants. 1 It is characterized by abnormal retinal vascularization that can lead to retinal detachment, severe visual impairment, or blindness. In 2010, approximately 184,700 preterm infants worldwide developed ROP of any stage; 20,000 developed ROP-induced blindness or severe visual impairment, and 12,300 developed mild or moderate visual impairment. 2 In the USA, the incidence of severe ROP in preterm infants born at a gestational age of ≤ 30 weeks increased from 3.4% in 2009 to 5.3% in 2018. 3 In Japan, the mortality rate of extremely preterm infants is low, whereas the incidence of severe ROP in such infants is approximately 15%, much higher than that reported in other countries. 4 , 5 ROP is a multifactorial disease with risk factors including maternal, prenatal, and perinatal factors; demographics; medical interventions; comorbidities of prematurity; nutrition; and genetics. 6 Moreover, low birth weight, low gestational age, and high or fluctuating oxygen levels at birth and during the neonatal period are well-known risk factors for ROP. 7 – 12 Most stage 1, 2, and early stage-3 ROP spontaneously regress without any serious residual eye disease; blindness or serious visual impairment results from progression to retinal detachment or severe posterior retinal distortion. 13 Therefore, the eyes should be screened for ROP to ensure timely treatment and prevention of ROP-induced blindness. However, ROP screening can be stressful for preterm infants and can cause apnea, bradycardia, and serious gastrointestinal complications. Therefore, efforts should be made to enable safe and efficient retinal examination on infants scheduled for multiple examinations. Predictive biomarkers of ROP may be useful in determining ROP screening schedules. Additionally, there have been several reports on the association between anemia and the development of ROP. 14 – 19 However, the results of these studies are controversial. Furthermore, reports on the association between red blood cell (RBC) parameters and ROP treatments are limited. 20 – 22 Thus, we aimed to evaluate the association between RBC parameters and ROP treatment. Results Information on 1,621 infants was obtained from medical records, of which 202 were eligible for participation in the study (Fig. 1 ). Of the 202 infants, 89 (44.1%) underwent ROP treatment (Table 1 ). A higher incidence of ROP treatment was associated with lower gestational age, lower birth weight, antenatal steroid use, history of PROM, lower Apgar scores at 1 and 5 min, iNO use, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and RBC transfusion before DOL 28 (Table 2 ). The mean values of Hb, Hct, and MCH at birth and on DOL 28, MCV at birth, and RDW on DOL 28 were significantly different (Table 2 ). No differences were detected in mean MCV on DOL 28 or RDW at birth (Table 2 ). Table 1 Characteristics of the study participants. Characteristics Value GA, weeks, mean ± SD 26.0 ± 2.0 Birth weight, g, mean ± SD, 793 ± 251 SGA, n (%) 32 (15.8%) Male, n (%) 104 (51.5%) Antenatal steroid use, n (%) 161 (79.7%) CAM, n (%) 96 (47.8%) PROM, n (%) 53 (26.2%) HDP, n (%) 22 (10.9%) Apgar score at 1 min, mean ± SD 4.0 ± 2.0 Apgar score at 5 min, mean ± SD 6.2 ± 2.1 RDS, n (%) 163 (80.7%) PDA, n (%) 108 (53.5%) iNO, n (%) 22 (10.9%) Oxygen supplementation on DOL 28, n (%) 95 (47.0%) Mechanical ventilation on DOL 28, n (%) 160 (79.2%) RBC transfusion before DOL 28, n (%) 112 (55.5%) Hb at birth, g/dL, mean ± SD, 15.0 ± 2.6 Hb on DOL 28, g/dL, mean ± SD, 10.4 ± 1.7 Hct at birth, %, mean ± SD 44.4 ± 6.9 Hct on DOL 28, %, mean ± SD 31.1 ± 5.0 MCV at birth, fL, mean ± SD 117.7 ± 8.1 MCV on DOL 28, fL, mean ± SD 98.3 ± 7.3 MCH at birth, pg, mean ± SD 39.6 ± 2.4 MCH on DOL 28, pg, mean ± SD 32.7 ± 2.2 RDW at birth, mean ± SD 16.1 ± 1.5 RDW on DOL 28, mean ± SD 20.0 ± 3.3 ROP, n (%) 89 (44.1%) CAM, chorioamnionitis; DOL, day of life; GA, gestational age; Hb, hemoglobin; Hct, hematocrit; HDP, hypertensive disorders of pregnancy; iNO, inhaled nitric oxide; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; PDA, patent ductus arteriosus; PROM, premature rupture of membrane; RBC, red blood cells; RDS, respiratory distress syndrome; RDW, red cell distribution width; ROP, retinopathy of prematurity; SGA, Small for gestational age Table 2 Characteristics of the infants in the ROP treatment and non-ROP treatment groups. Characteristics ROP treatment (n = 89) non-ROP treatment (n = 113) p -value GA, weeks, mean ± SD 24.8 ± 1.3 27.0 ± 1.9 < 0.001 Birth weight, g, mean ± SD 648.2 ± 151.7 907.1 ± 256.0 < 0.001 SGA, n (%) 15 (16.9%) 17 (15.0%) 0.727 Male, n (%) 51 (57.3%) 53 (46.9%) 0.142 Antenatal steroids use, n (%) 81 (91.0%) 80 (70.8%) < 0.001 CAM, n (%) 46 (51.7%) 50 (44.2%) 0.321 PROM, n (%) 31 (34.8%) 22 (19.5%) < 0.05 HDP, n (%) 8 (9.0%) 14 (12.4%) 0.441 Apgar score at 1 min, mean ± SD 3.3 ± 1.9 4.5 ± 2.0 < 0.001 Apgar score at 5 min, mean ± SD 5.7 ± 2.4 6.6 ± 1.9 < 0.01 RDS, n (%) 75 (84.3%) 88 (77.9%) 0.253 PDA, n (%) 54 (60.7%) 54 (47.8%) 0.068 iNO, n (%) 15 (16.9%) 7 (6.2%) < 0.05 Oxygen supplementation on DOL 28, n (%) 63 (70.8%) 32 (28.3%) < 0.001 Mechanical ventilation on DOL 28, n (%) 88 (98.9%) 72 (63.7%) < 0.001 RBC transfusion before DOL 28, n (%) 66 (74.2%) 46 (40.7%) < 0.001 Hb at birth, g/dL, mean ± SD 14.1 ± 2.4 15.7 ± 2.6 < 0.001 Hb on DOL 28, g/dL, mean ± SD 9.8 ± 1.8 10.9 ± 1.5 < 0.001 Hct at birth, %, mean ± SD 42.3 ± 6.6 46.1 ± 6.7 < 0.001 Hct on DOL 28, %, mean ± SD 29.6 ± 5.2 32.3 ± 4.5 < 0.001 MCV at birth, fL, mean ± SD 121.2 ± 8.0 114.8 ± 6.9 < 0.001 MCV on DOL 28, fL, mean ± SD 98.1 ± 7.7 98.5 ± 6.9 0.7017 MCH at birth, pg, mean ± SD 40.4 ± 2.5 39.1 ± 2.2 < 0.001 MCH on DOL 28, pg, mean ± SD 32.3 ± 2.4 33.0 ± 2.0 < 0.05 RDW at birth, mean ± SD 16.1 ± 1.6 16.0 ± 1.4 0.6514 RDW on DOL 28, mean ± SD 21.5 ± 3.3 18.8 ± 2.7 < 0.001 CAM, chorioamnionitis; DOL, days of life, GA, gestational age; Hb, hemoglobin; Hct, hematocrit; HDP, hypertensive disorders of pregnancy; iNO, inhaled nitric oxide; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; PDA, patent ductus arteriosus; PROM, premature rupture of membrane; RBC, red blood cells; RDS, respiratory distress syndrome; RDW, red cell distribution width; ROP, retinopathy of prematurity; SGA, small for gestational age The cut-off values for Hb, Hct, MCV, MCH, and RDW at birth and on DOL 28 were 16.7 g/dL (AUC:0.659) and 9.9 g/dL (0.674), 49.5% (0.639) and 31.0% (0.668), 117.3 fL (0.725) and 92.3 fL (0.528), 39.4 pg (0.642) and 31.8 pg (0.600), and 19.2 (0.513) and 18.5 (0.744), respectively (Table 3 ). Table 3 Cut-off values of the RBC parameters for the treatment of ROP and its AUC, sensitivity, and specificity. Parameter Cut-off AUC Sensitivity Specificity Hb at birth 16.7 g/dL 0.6592 37.2 89.9 Hb on DOL 28 9.9 g/dL 0.6741 76.1 51.7 Hct at birth 49.5% 0.639 30.1 92.1 Hct on DOL 28 31.0% 0.6678 65.5 62.9 MCV at birth 117.3 fL 0.7248 68.5 69.9 MCV on DOL 28 92.3 fL 0.5281 84.1 23.6 MCH at birth 39.4 pg 0.642 62.9 58.4 MCH on DOL 28 31.8 pg 0.6002 74.3 42.7 RDW at birth 19.2 0.513 3.5 89.9 RDW on DOL 28 18.5 0.7439 83.2 50.4 AUC, area under the curve; DOL, days of life; Hb, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RDW, red cell distribution width; ROP, retinopathy of prematurity In the univariate analysis, the need for ROP treatment was significantly associated with Hb < 16.7 g/dL, Hct 117.3 fL, and MCH > 39.4 pg at birth, and Hb < 9.9 g/dL, Hct < 31.0%, MCH 18.5 at DOL 28 (Table 5 ). After adjusting for confounders, the need for ROP treatment was significantly associated with Hb values of < 9.9 g/dL [adjusted ORs (aOR) = 3.0; 95% CI, 1.4–6.7] and Hct values of < 31.0% [aOR = 2.7; 95% CI, 1.3–5.6] at DOL 28 (Tables 4 , 5 ). Table 4 Logistic regression analysis of the characteristics of the infants in the ROP treatment and non-ROP treatment groups. Characteristic ROP treatment (n = 89) n (%) non-ROP treatment (n = 113) n (%) p -value GA < 28 weeks 87 (97.8%) 70 (61.9%) < 0.001 Birth weight < 1,000 g 88 (98.9%) 71 (62.8%) < 0.001 SGA 15 (16.9%) 17 (15.0%) 0.727 Oxygen supplementation on DOL 28 63 (70.8%) 32 (28.3%) < 0.001 Mechanical ventilation on DOL 28 88 (98.9%) 72 (63.7%) < 0.001 RBC transfusion before DOL 28 66 (74.2%) 46 (40.7%) < 0.001 Hb at birth < 16.7 g/dL 80 (89.9%) 71 (62.8%) < 0.001 Hb on DOL 28 < 9.9 g/dL 52 (58.4%) 27 (23.9%) < 0.001 Hct at birth < 49.5% 82 (92.1%) 79 (69.9%) < 0.001 Hct on DOL 28 < 31.0% 58 (65.2%) 45 (39.8%) 117.3 fL 61 (68.5%) 33 (29.2%) < 0.001 MCV on DOL 28 39.4 pg 55 (61.8%) 44 (38.9%) < 0.01 MCH on DOL 28 19.2 7 (7.9%) 4 (3.5%) 0.179 RDW on DOL 28 > 18.5 69 (77.5%) 47 (41.6%) < 0.001 DOL: day of life; GA, gestational age; Hb, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RBC, red blood cells; RDW, red cell distribution width; ROP, retinopathy of prematurity; SGA, small for gestational age Table 5 Association between the risk of developing ROP warranting treatment and RBC parameters at birth and on DOL 28. Parameter cOR (95% CI) aOR (95% CI) Hb at birth < 16.7 g/dL 5.3 (2.4–11.6) 1.9 (0.7–5.3) Hb on DOL 28 < 9.9 g/dL 3.4 (1.9–6.2) 3.0 (1.4–6.7) Hct at birth < 49.5% 5.0 (2.1–12.0) 2.2 (0.7–6.7) Hct on DOL 28 117.3 fL 5.3 (2.9–9.7) 2.0 (0.9–4.5) MCV on DOL 28 39.4 pg 2.5 (1.4–4.5) 1.3 (0.6–3.0) MCH on DOL 28 19.2 2.3 (0.7–8.2) 1.5 (0.3–7.1) RDW on DOL 28 > 18.5 5.8 (3.0–11.3) 1.9 (0.8–4.4) aOR, adjusted odds ratio; CI, confidence interval; cOR, crude odds ratio; DOL, day of life; Hb, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RDW, red cell distribution width; ROP, retinopathy of prematurity aOR: The model was adjusted for potential confounders, including gestational age, birth weight, small for gestational age, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and red blood cell transfusions. Discussion Our analyses demonstrated that Hb values of < 9.9 g/dL and Hct values of < 31.0% on DOL 28 were independent risk factors for ROP treatment, even after adjusting for gestational age, birth weight, SGA, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and RBC transfusion before DOL 28. To the best of our knowledge, this is the first study to evaluate the association between a wide range of RBC parameters, including RDW, and the need for ROP treatment, and to determine the cut-off values of the RBC parameters. Several reports have examined the association between anemia, Hb levels, and ROP development. However, reports on RBC parameters, such as RDW and ROP, are limited. Tandon et al. determined that anemia is a significant risk factor for ROP development and identified the statistically significant mean Hb levels for each ROP stage: stage 1, 10.41 g/dL; stage 2, 10.56 g/dL; stage 3, 9.47 g/dL; stage 4, 9.3 g/dL; and matured retina, 12.15 g/dL. 22 Logistic regression performed by Akyüz Ünsal et al. revealed that the risk of ROP development was negatively correlated with Hb levels four weeks postnatally and positively correlated with RDW at four weeks postnatally. Furthermore, MCH (cutoff: 34.43 pg) was the most prominent risk factor according to the Classification and Regression Tree. 20 In a multicenter, prospective, observational cohort study, Fevereiro-Martins et al. determined that MCV was significantly and independently associated with the development of ROP in Portuguese infants born at a gestational age of 29.6 weeks or a birth weight of 1175.7 g. 21 In our study, RDW, MCH, and MCV were not independent risk factors for ROP after adjusting for multiple confounders. These differences may be due to variable sample sizes, gestational ages, birth weights, follow-up times, case definitions, and adjustments for confounding factors. Furthermore, our study included infants with a lower gestational age (26 weeks) and birth weight (793 g) after adjusting for multiple confounders. In our study, ROP treatment was significantly associated with Hb levels of < 16.7 g/dL at birth; however, after adjusting for confounders, there was no statistically significant difference. Lundgren et al. found that Hb levels during the first week of life were significantly lower in infants requiring ROP treatment than in those who did not require treatment (12.5 g/dL vs. 13.8 g/dL, p < 0.001). Furthermore, they determined that the number of days with anemia during the first week of life is an independent risk factor for ROP, warranting treatment even after adjusting for gestational age. 14 In another prospective study of 78 infants born below a gestational age of 28 weeks in Sweden, Lundgren et al. found that infants who required ROP treatment developed anemia more frequently than those who did not require treatment during the first (42.9% vs. 8.0%, p = 0.003) and second (40.9% vs. 6.3%, p = 0.002) postnatal week. 15 In our study, the Hb cut-off values at birth were routinely measured prior to ROP treatment; however, anemia at birth or the number of early postnatal days with anemia might be important factors affecting ROP treatment. At our institution, blood samples are routinely collected at birth and on DOL 28; however, they are not routinely collected during the early postnatal period. Therefore, we could not evaluate the relationship between anemia during early postnatal weeks and ROP development. A two-phase hypothesis regarding the development of ROP has been proposed. In phase 1, immediately following birth, there is delayed physiological retinal vascularization, vaso-attenuation, and obliteration, which are thought to be related to premature neonatal physiological stressors, extrauterine hyperoxia, low levels of insulin-like growth factor 1, and delayed expression of VEGF receptor 2. In phase 2 (approximately 4–8 weeks after birth), there is abnormal proliferation of retinal vascular cells and neovascularization of the retina and vitreous. This is stimulated by the increased VEGF levels in the peripheral avascular retina in response to local hypoxia induced by metabolic cellular demands. 23 , 24 Therefore, preventing hyperoxia during resuscitation and up to 30–32 weeks of postmenstrual age decreases the risk of ROP. In contrast, preventing hypoxia beyond 32 weeks of postmenstrual age decreases the risk of ROP. This is consistent with our findings that Hb values < 9.9 g/dL and Hct values < 31.0% on DOL 28 are independent risk factors for ROP treatment, which can lead to hypoxia beyond DOL 28. The main strength of our study is the use of logistic regression to control for multiple confounders. Additionally, cut-off values were calculated using a wide range of RBC parameters. The limitations of our study include its single-center retrospective nature, the small number of treated infants, and lack of comparison between RBC parameters other than those at birth and on DOL 28. In conclusion, our study showed that infants born at < 30 weeks of gestation with Hb values < 9.9 g/dL and Hct values < 31.0% on DOL 28 had an increased risk of developing ROP, warranting treatment. Large prospective studies are required to validate the association between RBC parameters and ROP treatment. Methods Study design This single-center, retrospective cohort study was conducted at the neonatal intensive care unit (NICU) of Fukushima Medical University Hospital in Fukushima, Japan, between January 1, 2011, and July 31, 2022. Preterm infants born at < 30 weeks’ gestation were included in this study. Infants with congenital anomalies, missing data, and those who died or were transferred to another hospital within one month of life were excluded. The Ethics Committee of Fukushima Medical University, guided by local policy, national law, and the World Medical Association Declaration of Helsinki, approved this study without requiring informed consent from guardians, but consent could be rescinded in the form of opt-out. Data collection We extracted the following data from medical records: gestational age; birth weight; small for gestational age (SGA); sex; antenatal steroid use; a history of chorioamnionitis, premature rupture of membrane (PROM) or hypertensive disorders of pregnancy; Apgar score at 1 min and 5 min; the presence of respiratory distress syndrome or patent ductus arteriosus; a history of inhaled nitric oxide (iNO) use, oxygen supplementation on day of life (DOL) 28, mechanical ventilation on DOL 28, or RBC transfusion before DOL 28; laboratory values; and a history of ROP. Blood samples (approximately 250 µL) were collected in EDTA tubes from the peripheral veins of premature infants at birth and on DOL 28. Complete blood counts, including hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCH), and red blood cell distribution width (RDW), were measured using a coagulation analyzer (Sysmex XE-5000; Sysmex, Kobe, Japan). SGA was defined as both birth weight and length below the 10th percentile for gestational age or birth weight or length of ≤ -2.0 standard deviation scores (SDS), which was calculated according to sex-specific standards for birth weight and length or height during infancy in a Japanese population, for gestational age. 25 In this study, we included premature infants treated with iNO in the first 28 days of life for hypoxic respiratory failure (defined as the need for mechanical ventilation with an oxygenation index score of ≥ 10) or pulmonary hypertension identified on echocardiography. Indications for RBC transfusion in the NICU were Hb values < 7 g/dL, Hb values < 11 g/dL for infants requiring oxygen supplementation, and Hb values < 12 g/dL within 24 h of birth. ROP screening All infants were screened and diagnosed with ROP by three ophthalmologists with sufficient knowledge and experience to accurately locate and identify sequential changes in ROP. Infants were examined during the study period using the International Classification of Retinopathy of Prematurity Revised (ICROP). 26 The initial screening was performed at 31–33 weeks of gestation for infants born before 28 weeks and 4–6 weeks after birth for those born after 28 weeks. The ophthalmologists decided on follow-up examinations and treatments with laser photocoagulation or anti-vascular endothelial growth factor (VEGF) injections based on the ICROP findings. Outcomes and confounding factors The study outcome was the association between ROP treatment and RBC parameters at birth and on DOL 28. Infants were assigned to ROP treatment or non-ROP treatment groups based on the need for ROP treatment. The following factors were considered as possible confounders in the regression analyses: gestational age, birth weight, SGA, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and RBC transfusion before DOL 28. 21 Statistical analyses The characteristics of the mothers and their children were summarized according to the ROP treatment. Receiver operating characteristic (ROC) curve analysis was performed to determine the RBC parameter cut-off values according to ROP treatment. Cut-off values were determined using Youden’s index analysis. The sensitivity and specificity of the cut-off values and the area under the curve (AUC) were also calculated. Chi-square test and one-way analysis of variance were used to compare categorical and continuous variables. Multiple logistic regression analysis was performed to determine the association between the need for ROP treatment and RBC parameters by calculating the odds ratio (OR), which was adjusted for the confounders and 95% confidence intervals (CIs). All the statistical analyses were performed using Stata (version 15.0; Stata StataCorp LLC, College Station, TX, USA). p -values of < 0.05 were considered statistically significant. Declarations Author Contribution H.M. had primary responsibility for protocol development, patient screening, enrollment, outcome assessment, preliminary data analysis and writing the manuscript. H.G. and H.I. participated in the development of the protocol and analytical framework for the study and contributed to the writing of the manuscript. S.H., H.I., Y.S., and K.O. contributed in the same ways as HG and HI and was responsible for patient screening. N.M., T.S., and M.H. supervised the design and execution of the study, performed the final data analyses and contributed to the writing of the manuscript. Data availability The datasets analyzed during the current study are not publicly available, because the consent obtained from the participants specified that the data can be used only for research purposes at our institution. The datasets can only be available from the corresponding author upon reasonable request and after the approval of the ethics committee of Fukushima Medical University. Competing interests The authors declare no competing interests. References Sabri, K., Ells, A. L., Lee, E. Y., Dutta, S. & Vinekar, A. Retinopathy of Prematurity: A Global Perspective and Recent Developments. Pediatrics 150 , doi:10.1542/peds.2021-053924 (2022). Blencowe, H., Lawn, J. E., Vazquez, T., Fielder, A. & Gilbert, C. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. Pediatr Res 74 Suppl 1 , 35-49, doi:10.1038/pr.2013.205 (2013). Cudjoe, G. A. et al. National trends in the incidence and management of retinopathy of prematurity in the United States, 2009 -2018. J Neonatal Perinatal Med 15 , 553-557, doi:10.3233/npm-210826 (2022). Isayama, T. The clinical management and outcomes of extremely preterm infants in Japan: past, present, and future. Transl Pediatr 8 , 199-211, doi:10.21037/tp.2019.07.10 (2019). Isayama, T. et al. Comparison of mortality and morbidity of very low birth weight infants between Canada and Japan. Pediatrics 130 , e957-965, doi:10.1542/peds.2012-0336 (2012). Kim, S. J. et al. Retinopathy of prematurity: a review of risk factors and their clinical significance. Surv Ophthalmol 63 , 618-637, doi:10.1016/j.survophthal.2018.04.002 (2018). Ali, A. A., Gomaa, N. A. S., Awadein, A. R., Al-Hayouti, H. H. & Hegazy, A. I. Retrospective cohort study shows that the risks for retinopathy of prematurity included birth age and weight, medical conditions and treatment. Acta Paediatr 106 , 1919-1927, doi:10.1111/apa.14019 (2017). Chen, M. L., Guo, L., Smith, L. E., Dammann, C. E. & Dammann, O. High or low oxygen saturation and severe retinopathy of prematurity: a meta-analysis. Pediatrics 125 , e1483-1492, doi:10.1542/peds.2009-2218 (2010). Di Fiore, J. M. et al. A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity. J Pediatr 157 , 69-73, doi:10.1016/j.jpeds.2010.01.046 (2010). Higgins, R. D. Oxygen Saturation and Retinopathy of Prematurity. Clin Perinatol 46 , 593-599, doi:10.1016/j.clp.2019.05.008 (2019). Lundgren, P. et al. Low birth weight is a risk factor for severe retinopathy of prematurity depending on gestational age. PLoS One 9 , e109460, doi:10.1371/journal.pone.0109460 (2014). Yucel, O. E., Eraydin, B., Niyaz, L. & Terzi, O. Incidence and risk factors for retinopathy of prematurity in premature, extremely low birth weight and extremely low gestational age infants. BMC Ophthalmol 22 , 367, doi:10.1186/s12886-022-02591-9 (2022). Ju, R. H. et al. Spontaneous regression of retinopathy of prematurity: incidence and predictive factors. Int J Ophthalmol 6 , 475-480, doi:10.3980/j.issn.2222-3959.2013.04.13 (2013). Lundgren, P. et al. Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. Acta Paediatr 107 , 759-766, doi:10.1111/apa.14187 (2018). Lundgren, P. et al. Erythropoietin serum levels, versus anaemia as risk factors for severe retinopathy of prematurity. Pediatr Res 86 , 276-282, doi:10.1038/s41390-018-0186-6 (2019). Nguyen, T. T. B., Bui, V. T., Pham, V. P. T. & Pham, T. N. Retinopathy of Prematurity: A Study of Incidence and Risk Factors in a Tertiary Hospital in Vietnam. Clin Ophthalmol 16 , 3361-3367, doi:10.2147/opth.S386808 (2022). Rekha, S. & Battu, R. R. Retinopathy of prematurity: incidence and risk factors. Indian Pediatr 33 , 999-1003 (1996). Ugurbas, S. C. et al. Comparison of UK and US screening criteria for detection of retinopathy of prematurity in a developing nation. J aapos 14 , 506-510, doi:10.1016/j.jaapos.2010.07.012 (2010). Yau, G. S. et al. Incidence and Risk Factors of Retinopathy of Prematurity From 2 Neonatal Intensive Care Units in a Hong Kong Chinese Population. Asia Pac J Ophthalmol (Phila) 5 , 185-191, doi:10.1097/apo.0000000000000167 (2016). Akyüz Ünsal, A. et al. Can Complete Blood Count Parameters Predict Retinopathy of Prematurity? Turk J Ophthalmol 50 , 87-93, doi:10.4274/tjo.galenos.2019.45313 (2020). Fevereiro-Martins, M., Santos, A. C., Marques-Neves, C., Guimarães, H. & Bicho, M. Complete blood count parameters as biomarkers of retinopathy of prematurity: a Portuguese multicenter study. Graefes Arch Clin Exp Ophthalmol , doi:10.1007/s00417-023-06072-7 (2023). Tandon, M., Ranjan, R., Muralidharan, U. & Kannan, A. Influence of Anaemia on Multifactorial Disease Retinopathy of Prematurity: A Prospective Observational Study. Cureus 14 , e27877, doi:10.7759/cureus.27877 (2022). Dammann, O., Hartnett, M. E. & Stahl, A. Retinopathy of prematurity. Dev Med Child Neurol 65 , 625-631, doi:10.1111/dmcn.15468 (2023). Hartnett, M. E. & Penn, J. S. Mechanisms and management of retinopathy of prematurity. N Engl J Med 367 , 2515-2526, doi:10.1056/NEJMra1208129 (2012). Fujita, K. et al. Prevalence of small for gestational age (SGA) and short stature in children born SGA who qualify for growth hormone treatment at 3 years of age: Population-based study. Pediatr Int 58 , 372-376, doi:10.1111/ped.12859 (2016). Fierson, W. M. Screening Examination of Premature Infants for Retinopathy of Prematurity. Pediatrics 142 , doi:10.1542/peds.2018-3061 (2018). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 03 May, 2024 Reviews received at journal 28 Apr, 2024 Reviewers agreed at journal 06 Apr, 2024 Reviews received at journal 23 Mar, 2024 Reviewers agreed at journal 11 Mar, 2024 Reviewers invited by journal 09 Feb, 2024 Editor assigned by journal 30 Jan, 2024 Editor invited by journal 21 Jan, 2024 Submission checks completed at journal 21 Jan, 2024 First submitted to journal 17 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3872014","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":268550761,"identity":"3a9dfe95-e08f-4fe2-a1c5-5cf0ef4d8296","order_by":0,"name":"Hajime Maeda","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYBACAxDBw2DDD+WzEa0lTbKBVC2HYVqIAOZihx8+eFNzXkJ3RgLjhx8MfHkEtVjOTjM2nHPstoTZjQRmyR4GtmLCDrudYCbNw3a7DqiFQRrol0SCLjS4nf79N8+/c2BbfhOpJceMmbftAEgLG7G25BRLzu1LljA787DNsseAKL+kb/zw5pudhNnx5MM3flQcIxxiSIAR6CSDYwmkaAGDGtK1jIJRMApGwbAHAEiFO39zY6d7AAAAAElFTkSuQmCC","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":true,"prefix":"","firstName":"Hajime","middleName":"","lastName":"Maeda","suffix":""},{"id":268550762,"identity":"3d755cdf-9cad-4f12-8cfe-ab7f18d41904","order_by":1,"name":"Hayato Go","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hayato","middleName":"","lastName":"Go","suffix":""},{"id":268550763,"identity":"792cc895-49fa-44de-ae0b-9a2abca6cdb3","order_by":2,"name":"Hajime Iwasa","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hajime","middleName":"","lastName":"Iwasa","suffix":""},{"id":268550764,"identity":"47fc220f-880e-4e04-b358-132e500fefa5","order_by":3,"name":"Shun Hiruta","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shun","middleName":"","lastName":"Hiruta","suffix":""},{"id":268550765,"identity":"5b7365c0-2030-4567-b7ea-ca081c83566d","order_by":4,"name":"Hirotaka Ichikawa","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hirotaka","middleName":"","lastName":"Ichikawa","suffix":""},{"id":268550766,"identity":"89f4f79c-dad2-485c-951e-9042a3183062","order_by":5,"name":"Yukinori Sugano","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yukinori","middleName":"","lastName":"Sugano","suffix":""},{"id":268550767,"identity":"d5507db6-6431-4b4b-81fd-142ba8de4ed4","order_by":6,"name":"Kei Ogasawara","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Ogasawara","suffix":""},{"id":268550768,"identity":"718ddf57-be29-4921-b097-c7440469c8b9","order_by":7,"name":"Nobuo Momoi","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Nobuo","middleName":"","lastName":"Momoi","suffix":""},{"id":268550769,"identity":"0595ac06-6cea-414d-9e46-0faac1ac1685","order_by":8,"name":"Tetsuju Sekiryu","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tetsuju","middleName":"","lastName":"Sekiryu","suffix":""},{"id":268550770,"identity":"14d490a0-0ec4-4f55-96b9-912d0c72253f","order_by":9,"name":"Mitsuaki Hosoya","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mitsuaki","middleName":"","lastName":"Hosoya","suffix":""}],"badges":[],"createdAt":"2024-01-17 06:14:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3872014/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3872014/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-84030-x","type":"published","date":"2025-01-02T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50116830,"identity":"fa355e4a-ba52-4f07-b3c8-057d69bb4d48","added_by":"auto","created_at":"2024-01-24 18:52:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":48493,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of sample selection for analysis\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3872014/v1/884c94e2eaa7729e5c03ef93.jpg"},{"id":73093184,"identity":"0c820890-c6bc-4c29-9d08-b3644c8627bf","added_by":"auto","created_at":"2025-01-06 16:09:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":685564,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3872014/v1/40ecdd75-f6f5-4d05-810e-52ab9c2e70d6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Red blood cell parameters as biomarkers of retinopathy of prematurity in preterm infants born before 30 weeks of gestation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinopathy of prematurity (ROP) is a major cause of preventable blindness in preterm infants. \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e It is characterized by abnormal retinal vascularization that can lead to retinal detachment, severe visual impairment, or blindness. In 2010, approximately 184,700 preterm infants worldwide developed ROP of any stage; 20,000 developed ROP-induced blindness or severe visual impairment, and 12,300 developed mild or moderate visual impairment. \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e In the USA, the incidence of severe ROP in preterm infants born at a gestational age of \u0026le;\u0026thinsp;30 weeks increased from 3.4% in 2009 to 5.3% in 2018. \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e In Japan, the mortality rate of extremely preterm infants is low, whereas the incidence of severe ROP in such infants is approximately 15%, much higher than that reported in other countries. \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e ROP is a multifactorial disease with risk factors including maternal, prenatal, and perinatal factors; demographics; medical interventions; comorbidities of prematurity; nutrition; and genetics. \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Moreover, low birth weight, low gestational age, and high or fluctuating oxygen levels at birth and during the neonatal period are well-known risk factors for ROP. \u003csup\u003e\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMost stage 1, 2, and early stage-3 ROP spontaneously regress without any serious residual eye disease; blindness or serious visual impairment results from progression to retinal detachment or severe posterior retinal distortion. \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Therefore, the eyes should be screened for ROP to ensure timely treatment and prevention of ROP-induced blindness. However, ROP screening can be stressful for preterm infants and can cause apnea, bradycardia, and serious gastrointestinal complications. Therefore, efforts should be made to enable safe and efficient retinal examination on infants scheduled for multiple examinations. Predictive biomarkers of ROP may be useful in determining ROP screening schedules. Additionally, there have been several reports on the association between anemia and the development of ROP. \u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e However, the results of these studies are controversial. Furthermore, reports on the association between red blood cell (RBC) parameters and ROP treatments are limited. \u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Thus, we aimed to evaluate the association between RBC parameters and ROP treatment.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eInformation on 1,621 infants was obtained from medical records, of which 202 were eligible for participation in the study (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Of the 202 infants, 89 (44.1%) underwent ROP treatment (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). A higher incidence of ROP treatment was associated with lower gestational age, lower birth weight, antenatal steroid use, history of PROM, lower Apgar scores at 1 and 5 min, iNO use, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and RBC transfusion before DOL 28 (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The mean values of Hb, Hct, and MCH at birth and on DOL 28, MCV at birth, and RDW on DOL 28 were significantly different (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). No differences were detected in mean MCV on DOL 28 or RDW at birth (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of the study participants.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eValue\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGA, weeks, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight, g, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD,\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e793\u0026thinsp;\u0026plusmn;\u0026thinsp;251\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSGA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (15.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e104 (51.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntenatal steroid use, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e161 (79.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96 (47.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePROM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (26.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDP, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (10.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 1 min, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 5 min, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDS, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e163 (80.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePDA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e108 (53.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eiNO, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (10.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOxygen supplementation on DOL 28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95 (47.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation on DOL 28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e160 (79.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRBC transfusion before DOL 28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112 (55.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb at birth, g/dL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD,\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb on DOL 28, g/dL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD,\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct at birth, %, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct on DOL 28, %, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV at birth, fL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e117.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV on DOL 28, fL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH at birth, pg, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH on DOL 28, pg, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW at birth, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW on DOL 28, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eROP, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89 (44.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCAM, chorioamnionitis; DOL, day of life; GA, gestational age; Hb, hemoglobin; Hct, hematocrit; HDP, hypertensive disorders of pregnancy; iNO, inhaled nitric oxide; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; PDA, patent ductus arteriosus; PROM, premature rupture of membrane; RBC, red blood cells; RDS, respiratory distress syndrome; RDW, red cell distribution width; ROP, retinopathy of prematurity; SGA, Small for gestational age\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of the infants in the ROP treatment and non-ROP treatment groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eROP treatment\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;89)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enon-ROP treatment\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;113)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGA, weeks, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight, g, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e648.2\u0026thinsp;\u0026plusmn;\u0026thinsp;151.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e907.1\u0026thinsp;\u0026plusmn;\u0026thinsp;256.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSGA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (16.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (15.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.727\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51 (57.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (46.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.142\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntenatal steroids use, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e81 (91.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (70.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46 (51.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (44.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.321\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePROM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31 (34.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (19.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDP, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (9.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (12.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.441\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 1 min, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 5 min, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDS, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75 (84.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88 (77.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.253\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePDA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54 (60.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54 (47.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.068\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eiNO, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (16.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (6.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOxygen supplementation on DOL 28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63 (70.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (28.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation on DOL 28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88 (98.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72 (63.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRBC transfusion before DOL 28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66 (74.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46 (40.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb at birth, g/dL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb on DOL 28, g/dL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct at birth, %, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct on DOL 28, %, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV at birth, fL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV on DOL 28, fL, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.7017\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH at birth, pg, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH on DOL 28, pg, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW at birth, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6514\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW on DOL 28, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eCAM, chorioamnionitis; DOL, days of life, GA, gestational age; Hb, hemoglobin; Hct, hematocrit; HDP, hypertensive disorders of pregnancy; iNO, inhaled nitric oxide; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; PDA, patent ductus arteriosus; PROM, premature rupture of membrane; RBC, red blood cells; RDS, respiratory distress syndrome; RDW, red cell distribution width; ROP, retinopathy of prematurity; SGA, small for gestational age\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe cut-off values for Hb, Hct, MCV, MCH, and RDW at birth and on DOL 28 were 16.7 g/dL (AUC:0.659) and 9.9 g/dL (0.674), 49.5% (0.639) and 31.0% (0.668), 117.3 fL (0.725) and 92.3 fL (0.528), 39.4 pg (0.642) and 31.8 pg (0.600), and 19.2 (0.513) and 18.5 (0.744), respectively (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCut-off values of the RBC parameters for the treatment of ROP and its AUC, sensitivity, and specificity.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCut-off\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSensitivity\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSpecificity\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb at birth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.7 g/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6592\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb on DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.9 g/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6741\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct at birth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.639\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct on DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.0%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6678\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV at birth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e117.3 fL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.7248\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV on DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92.3 fL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.5281\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e84.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH at birth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39.4 pg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.642\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH on DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.8 pg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.6002\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e74.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW at birth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.513\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89.9\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW on DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.7439\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50.4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eAUC, area under the curve; DOL, days of life; Hb, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RDW, red cell distribution width; ROP, retinopathy of prematurity\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn the univariate analysis, the need for ROP treatment was significantly associated with Hb\u0026thinsp;\u0026lt;\u0026thinsp;16.7 g/dL, Hct\u0026thinsp;\u0026lt;\u0026thinsp;49.5%, MCV\u0026thinsp;\u0026gt;\u0026thinsp;117.3 fL, and MCH\u0026thinsp;\u0026gt;\u0026thinsp;39.4 pg at birth, and Hb\u0026thinsp;\u0026lt;\u0026thinsp;9.9 g/dL, Hct\u0026thinsp;\u0026lt;\u0026thinsp;31.0%, MCH\u0026thinsp;\u0026lt;\u0026thinsp;31.8 pg, and RDW\u0026thinsp;\u0026gt;\u0026thinsp;18.5 at DOL 28 (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). After adjusting for confounders, the need for ROP treatment was significantly associated with Hb values of \u0026lt;\u0026thinsp;9.9 g/dL [adjusted ORs (aOR)\u0026thinsp;=\u0026thinsp;3.0; 95% CI, 1.4\u0026ndash;6.7] and Hct values of \u0026lt;\u0026thinsp;31.0% [aOR\u0026thinsp;=\u0026thinsp;2.7; 95% CI, 1.3\u0026ndash;5.6] at DOL 28 (Tables\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eLogistic regression analysis of the characteristics of the infants in the ROP treatment and non-ROP treatment groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eROP treatment\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;89)\u003c/p\u003e\n\u003cp\u003en (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enon-ROP treatment\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;113)\u003c/p\u003e\n\u003cp\u003en (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGA\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e87 (97.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (61.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight\u0026thinsp;\u0026lt;\u0026thinsp;1,000 g\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88 (98.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71 (62.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSGA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (16.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (15.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.727\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOxygen supplementation on DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63 (70.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (28.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation on DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88 (98.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72 (63.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRBC transfusion before DOL 28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66 (74.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46 (40.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb at birth\u0026thinsp;\u0026lt;\u0026thinsp;16.7 g/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (89.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71 (62.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;9.9 g/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (58.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (23.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct at birth\u0026thinsp;\u0026lt;\u0026thinsp;49.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e82 (92.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79 (69.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;31.0%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58 (65.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (39.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV at birth\u0026thinsp;\u0026gt;\u0026thinsp;117.3 fL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (68.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (29.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;92.3 fL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (37.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (30.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.295\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH on birth\u0026thinsp;\u0026gt;\u0026thinsp;39.4 pg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55 (61.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44 (38.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;31.8 pg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (13.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW at birth\u0026thinsp;\u0026gt;\u0026thinsp;19.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (7.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (3.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.179\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW on DOL 28\u0026thinsp;\u0026gt;\u0026thinsp;18.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69 (77.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47 (41.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eDOL: day of life; GA, gestational age; Hb, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RBC, red blood cells; RDW, red cell distribution width; ROP, retinopathy of prematurity; SGA, small for gestational age\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAssociation between the risk of developing ROP warranting treatment and RBC parameters at birth and on DOL 28.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ecOR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eaOR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb at birth\u0026thinsp;\u0026lt;\u0026thinsp;16.7 g/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.3 (2.4\u0026ndash;11.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.9 (0.7\u0026ndash;5.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHb on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;9.9 g/dL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.4 (1.9\u0026ndash;6.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.0 (1.4\u0026ndash;6.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct at birth\u0026thinsp;\u0026lt;\u0026thinsp;49.5%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.0 (2.1\u0026ndash;12.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.2 (0.7\u0026ndash;6.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHct on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;31.0%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.2 (1.8\u0026ndash;5.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.7 (1.3\u0026ndash;5.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV at birth\u0026thinsp;\u0026gt;\u0026thinsp;117.3 fL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.3 (2.9\u0026ndash;9.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.0 (0.9\u0026ndash;4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCV on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;92.3 fL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.6 (0.8\u0026ndash;3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.3 (0.5\u0026ndash;3.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH at birth\u0026thinsp;\u0026gt;\u0026thinsp;39.4 pg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.5 (1.4\u0026ndash;4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.3 (0.6\u0026ndash;3.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMCH on DOL 28\u0026thinsp;\u0026lt;\u0026thinsp;31.8 pg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.2 (1.2\u0026ndash;3.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.4 (0.6\u0026ndash;3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW at birth\u0026thinsp;\u0026gt;\u0026thinsp;19.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.3 (0.7\u0026ndash;8.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.5 (0.3\u0026ndash;7.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDW on DOL 28\u0026thinsp;\u0026gt;\u0026thinsp;18.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.8 (3.0\u0026ndash;11.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.9 (0.8\u0026ndash;4.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eaOR, adjusted odds ratio; CI, confidence interval; cOR, crude odds ratio; DOL, day of life; Hb, hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; RDW, red cell distribution width; ROP, retinopathy of prematurity\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eaOR: The model was adjusted for potential confounders, including gestational age, birth weight, small for gestational age, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and red blood cell transfusions.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur analyses demonstrated that Hb values of \u0026lt;\u0026thinsp;9.9 g/dL and Hct values of \u0026lt;\u0026thinsp;31.0% on DOL 28 were independent risk factors for ROP treatment, even after adjusting for gestational age, birth weight, SGA, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and RBC transfusion before DOL 28. To the best of our knowledge, this is the first study to evaluate the association between a wide range of RBC parameters, including RDW, and the need for ROP treatment, and to determine the cut-off values of the RBC parameters.\u003c/p\u003e \u003cp\u003eSeveral reports have examined the association between anemia, Hb levels, and ROP development. However, reports on RBC parameters, such as RDW and ROP, are limited. Tandon et al. determined that anemia is a significant risk factor for ROP development and identified the statistically significant mean Hb levels for each ROP stage: stage 1, 10.41 g/dL; stage 2, 10.56 g/dL; stage 3, 9.47 g/dL; stage 4, 9.3 g/dL; and matured retina, 12.15 g/dL. \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Logistic regression performed by Aky\u0026uuml;z \u0026Uuml;nsal et al. revealed that the risk of ROP development was negatively correlated with Hb levels four weeks postnatally and positively correlated with RDW at four weeks postnatally. Furthermore, MCH (cutoff: 34.43 pg) was the most prominent risk factor according to the Classification and Regression Tree. \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e In a multicenter, prospective, observational cohort study, Fevereiro-Martins et al. determined that MCV was significantly and independently associated with the development of ROP in Portuguese infants born at a gestational age of 29.6 weeks or a birth weight of 1175.7 g. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e In our study, RDW, MCH, and MCV were not independent risk factors for ROP after adjusting for multiple confounders. These differences may be due to variable sample sizes, gestational ages, birth weights, follow-up times, case definitions, and adjustments for confounding factors. Furthermore, our study included infants with a lower gestational age (26 weeks) and birth weight (793 g) after adjusting for multiple confounders.\u003c/p\u003e \u003cp\u003eIn our study, ROP treatment was significantly associated with Hb levels of \u0026lt;\u0026thinsp;16.7 g/dL at birth; however, after adjusting for confounders, there was no statistically significant difference. Lundgren et al. found that Hb levels during the first week of life were significantly lower in infants requiring ROP treatment than in those who did not require treatment (12.5 g/dL vs. 13.8 g/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Furthermore, they determined that the number of days with anemia during the first week of life is an independent risk factor for ROP, warranting treatment even after adjusting for gestational age. \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e In another prospective study of 78 infants born below a gestational age of 28 weeks in Sweden, Lundgren et al. found that infants who required ROP treatment developed anemia more frequently than those who did not require treatment during the first (42.9% vs. 8.0%, p\u0026thinsp;=\u0026thinsp;0.003) and second (40.9% vs. 6.3%, p\u0026thinsp;=\u0026thinsp;0.002) postnatal week. \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In our study, the Hb cut-off values at birth were routinely measured prior to ROP treatment; however, anemia at birth or the number of early postnatal days with anemia might be important factors affecting ROP treatment. At our institution, blood samples are routinely collected at birth and on DOL 28; however, they are not routinely collected during the early postnatal period. Therefore, we could not evaluate the relationship between anemia during early postnatal weeks and ROP development.\u003c/p\u003e \u003cp\u003eA two-phase hypothesis regarding the development of ROP has been proposed. In phase 1, immediately following birth, there is delayed physiological retinal vascularization, vaso-attenuation, and obliteration, which are thought to be related to premature neonatal physiological stressors, extrauterine hyperoxia, low levels of insulin-like growth factor 1, and delayed expression of VEGF receptor 2. In phase 2 (approximately 4\u0026ndash;8 weeks after birth), there is abnormal proliferation of retinal vascular cells and neovascularization of the retina and vitreous. This is stimulated by the increased VEGF levels in the peripheral avascular retina in response to local hypoxia induced by metabolic cellular demands. \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Therefore, preventing hyperoxia during resuscitation and up to 30\u0026ndash;32 weeks of postmenstrual age decreases the risk of ROP. In contrast, preventing hypoxia beyond 32 weeks of postmenstrual age decreases the risk of ROP. This is consistent with our findings that Hb values\u0026thinsp;\u0026lt;\u0026thinsp;9.9 g/dL and Hct values\u0026thinsp;\u0026lt;\u0026thinsp;31.0% on DOL 28 are independent risk factors for ROP treatment, which can lead to hypoxia beyond DOL 28.\u003c/p\u003e \u003cp\u003eThe main strength of our study is the use of logistic regression to control for multiple confounders. Additionally, cut-off values were calculated using a wide range of RBC parameters. The limitations of our study include its single-center retrospective nature, the small number of treated infants, and lack of comparison between RBC parameters other than those at birth and on DOL 28.\u003c/p\u003e \u003cp\u003eIn conclusion, our study showed that infants born at \u0026lt;\u0026thinsp;30 weeks of gestation with Hb values\u0026thinsp;\u0026lt;\u0026thinsp;9.9 g/dL and Hct values\u0026thinsp;\u0026lt;\u0026thinsp;31.0% on DOL 28 had an increased risk of developing ROP, warranting treatment. Large prospective studies are required to validate the association between RBC parameters and ROP treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e This single-center, retrospective cohort study was conducted at the neonatal intensive care unit (NICU) of Fukushima Medical University Hospital in Fukushima, Japan, between January 1, 2011, and July 31, 2022. Preterm infants born at \u0026lt;\u0026thinsp;30 weeks\u0026rsquo; gestation were included in this study. Infants with congenital anomalies, missing data, and those who died or were transferred to another hospital within one month of life were excluded. The Ethics Committee of Fukushima Medical University, guided by local policy, national law, and the World Medical Association Declaration of Helsinki, approved this study without requiring informed consent from guardians, but consent could be rescinded in the form of opt-out.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eWe extracted the following data from medical records: gestational age; birth weight; small for gestational age (SGA); sex; antenatal steroid use; a history of chorioamnionitis, premature rupture of membrane (PROM) or hypertensive disorders of pregnancy; Apgar score at 1 min and 5 min; the presence of respiratory distress syndrome or patent ductus arteriosus; a history of inhaled nitric oxide (iNO) use, oxygen supplementation on day of life (DOL) 28, mechanical ventilation on DOL 28, or RBC transfusion before DOL 28; laboratory values; and a history of ROP. Blood samples (approximately 250 \u0026micro;L) were collected in EDTA tubes from the peripheral veins of premature infants at birth and on DOL 28. Complete blood counts, including hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCH), and red blood cell distribution width (RDW), were measured using a coagulation analyzer (Sysmex XE-5000; Sysmex, Kobe, Japan). SGA was defined as both birth weight and length below the 10th percentile for gestational age or birth weight or length of \u0026le; -2.0 standard deviation scores (SDS), which was calculated according to sex-specific standards for birth weight and length or height during infancy in a Japanese population, for gestational age. \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e In this study, we included premature infants treated with iNO in the first 28 days of life for hypoxic respiratory failure (defined as the need for mechanical ventilation with an oxygenation index score of \u0026ge; 10) or pulmonary hypertension identified on echocardiography. Indications for RBC transfusion in the NICU were Hb values\u0026thinsp;\u0026lt;\u0026thinsp;7 g/dL, Hb values\u0026thinsp;\u0026lt;\u0026thinsp;11 g/dL for infants requiring oxygen supplementation, and Hb values\u0026thinsp;\u0026lt;\u0026thinsp;12 g/dL within 24 h of birth.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eROP screening\u003c/h2\u003e \u003cp\u003eAll infants were screened and diagnosed with ROP by three ophthalmologists with sufficient knowledge and experience to accurately locate and identify sequential changes in ROP. Infants were examined during the study period using the International Classification of Retinopathy of Prematurity Revised (ICROP). \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e The initial screening was performed at 31\u0026ndash;33 weeks of gestation for infants born before 28 weeks and 4\u0026ndash;6 weeks after birth for those born after 28 weeks. The ophthalmologists decided on follow-up examinations and treatments with laser photocoagulation or anti-vascular endothelial growth factor (VEGF) injections based on the ICROP findings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and confounding factors\u003c/h2\u003e \u003cp\u003eThe study outcome was the association between ROP treatment and RBC parameters at birth and on DOL 28. Infants were assigned to ROP treatment or non-ROP treatment groups based on the need for ROP treatment. The following factors were considered as possible confounders in the regression analyses: gestational age, birth weight, SGA, oxygen supplementation on DOL 28, mechanical ventilation on DOL 28, and RBC transfusion before DOL 28. \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe characteristics of the mothers and their children were summarized according to the ROP treatment. Receiver operating characteristic (ROC) curve analysis was performed to determine the RBC parameter cut-off values according to ROP treatment. Cut-off values were determined using Youden\u0026rsquo;s index analysis. The sensitivity and specificity of the cut-off values and the area under the curve (AUC) were also calculated. Chi-square test and one-way analysis of variance were used to compare categorical and continuous variables. Multiple logistic regression analysis was performed to determine the association between the need for ROP treatment and RBC parameters by calculating the odds ratio (OR), which was adjusted for the confounders and 95% confidence intervals (CIs). All the statistical analyses were performed using Stata (version 15.0; Stata StataCorp LLC, College Station, TX, USA). \u003cem\u003ep\u003c/em\u003e-values of \u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eH.M. had primary responsibility for protocol development, patient screening, enrollment, outcome assessment, preliminary data analysis and writing the manuscript. H.G. and H.I. participated in the development of the protocol and analytical framework for the study and contributed to the writing of the manuscript. S.H., H.I., Y.S., and K.O. contributed in the same ways as HG and HI and was responsible for patient screening. N.M., T.S., and M.H. supervised the design and execution of the study, performed the final data analyses and contributed to the writing of the manuscript.\u003c/p\u003e\n\u003ch2\u003eData availability\u003c/h2\u003e\n\u003cp\u003eThe datasets analyzed during the current study are not publicly available, because the consent obtained from the participants specified that the data can be used only for research purposes at our institution. The datasets can only be available from the corresponding author upon reasonable request and after the approval of the ethics committee of Fukushima Medical University.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSabri, K., Ells, A. L., Lee, E. Y., Dutta, S. \u0026amp; Vinekar, A. Retinopathy of Prematurity: A Global Perspective and Recent Developments. \u003cem\u003ePediatrics\u003c/em\u003e \u003cstrong\u003e150\u003c/strong\u003e, doi:10.1542/peds.2021-053924 (2022).\u003c/li\u003e\n\u003cli\u003eBlencowe, H., Lawn, J. E., Vazquez, T., Fielder, A. \u0026amp; Gilbert, C. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. \u003cem\u003ePediatr Res\u003c/em\u003e \u003cstrong\u003e74 Suppl 1\u003c/strong\u003e, 35-49, doi:10.1038/pr.2013.205 (2013).\u003c/li\u003e\n\u003cli\u003eCudjoe, G. A.\u003cem\u003e et al.\u003c/em\u003e National trends in the incidence and management of retinopathy of prematurity in the United States, 2009 -2018. \u003cem\u003eJ Neonatal Perinatal Med\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 553-557, doi:10.3233/npm-210826 (2022).\u003c/li\u003e\n\u003cli\u003eIsayama, T. The clinical management and outcomes of extremely preterm infants in Japan: past, present, and future. \u003cem\u003eTransl Pediatr\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 199-211, doi:10.21037/tp.2019.07.10 (2019).\u003c/li\u003e\n\u003cli\u003eIsayama, T.\u003cem\u003e et al.\u003c/em\u003e Comparison of mortality and morbidity of very low birth weight infants between Canada and Japan. \u003cem\u003ePediatrics\u003c/em\u003e \u003cstrong\u003e130\u003c/strong\u003e, e957-965, doi:10.1542/peds.2012-0336 (2012).\u003c/li\u003e\n\u003cli\u003eKim, S. J.\u003cem\u003e et al.\u003c/em\u003e Retinopathy of prematurity: a review of risk factors and their clinical significance. \u003cem\u003eSurv Ophthalmol\u003c/em\u003e \u003cstrong\u003e63\u003c/strong\u003e, 618-637, doi:10.1016/j.survophthal.2018.04.002 (2018).\u003c/li\u003e\n\u003cli\u003eAli, A. A., Gomaa, N. A. S., Awadein, A. R., Al-Hayouti, H. H. \u0026amp; Hegazy, A. I. Retrospective cohort study shows that the risks for retinopathy of prematurity included birth age and weight, medical conditions and treatment. \u003cem\u003eActa Paediatr\u003c/em\u003e \u003cstrong\u003e106\u003c/strong\u003e, 1919-1927, doi:10.1111/apa.14019 (2017).\u003c/li\u003e\n\u003cli\u003eChen, M. L., Guo, L., Smith, L. E., Dammann, C. E. \u0026amp; Dammann, O. High or low oxygen saturation and severe retinopathy of prematurity: a meta-analysis. \u003cem\u003ePediatrics\u003c/em\u003e \u003cstrong\u003e125\u003c/strong\u003e, e1483-1492, doi:10.1542/peds.2009-2218 (2010).\u003c/li\u003e\n\u003cli\u003eDi Fiore, J. M.\u003cem\u003e et al.\u003c/em\u003e A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity. \u003cem\u003eJ Pediatr\u003c/em\u003e \u003cstrong\u003e157\u003c/strong\u003e, 69-73, doi:10.1016/j.jpeds.2010.01.046 (2010).\u003c/li\u003e\n\u003cli\u003eHiggins, R. D. Oxygen Saturation and Retinopathy of Prematurity. \u003cem\u003eClin Perinatol\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 593-599, doi:10.1016/j.clp.2019.05.008 (2019).\u003c/li\u003e\n\u003cli\u003eLundgren, P.\u003cem\u003e et al.\u003c/em\u003e Low birth weight is a risk factor for severe retinopathy of prematurity depending on gestational age. \u003cem\u003ePLoS One\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, e109460, doi:10.1371/journal.pone.0109460 (2014).\u003c/li\u003e\n\u003cli\u003eYucel, O. E., Eraydin, B., Niyaz, L. \u0026amp; Terzi, O. Incidence and risk factors for retinopathy of prematurity in premature, extremely low birth weight and extremely low gestational age infants. \u003cem\u003eBMC Ophthalmol\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 367, doi:10.1186/s12886-022-02591-9 (2022).\u003c/li\u003e\n\u003cli\u003eJu, R. H.\u003cem\u003e et al.\u003c/em\u003e Spontaneous regression of retinopathy of prematurity: incidence and predictive factors. \u003cem\u003eInt J Ophthalmol\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 475-480, doi:10.3980/j.issn.2222-3959.2013.04.13 (2013).\u003c/li\u003e\n\u003cli\u003eLundgren, P.\u003cem\u003e et al.\u003c/em\u003e Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. \u003cem\u003eActa Paediatr\u003c/em\u003e \u003cstrong\u003e107\u003c/strong\u003e, 759-766, doi:10.1111/apa.14187 (2018).\u003c/li\u003e\n\u003cli\u003eLundgren, P.\u003cem\u003e et al.\u003c/em\u003e Erythropoietin serum levels, versus anaemia as risk factors for severe retinopathy of prematurity. \u003cem\u003ePediatr Res\u003c/em\u003e \u003cstrong\u003e86\u003c/strong\u003e, 276-282, doi:10.1038/s41390-018-0186-6 (2019).\u003c/li\u003e\n\u003cli\u003eNguyen, T. T. B., Bui, V. T., Pham, V. P. T. \u0026amp; Pham, T. N. Retinopathy of Prematurity: A Study of Incidence and Risk Factors in a Tertiary Hospital in Vietnam. \u003cem\u003eClin Ophthalmol\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, 3361-3367, doi:10.2147/opth.S386808 (2022).\u003c/li\u003e\n\u003cli\u003eRekha, S. \u0026amp; Battu, R. R. Retinopathy of prematurity: incidence and risk factors. \u003cem\u003eIndian Pediatr\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, 999-1003 (1996).\u003c/li\u003e\n\u003cli\u003eUgurbas, S. C.\u003cem\u003e et al.\u003c/em\u003e Comparison of UK and US screening criteria for detection of retinopathy of prematurity in a developing nation. \u003cem\u003eJ aapos\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 506-510, doi:10.1016/j.jaapos.2010.07.012 (2010).\u003c/li\u003e\n\u003cli\u003eYau, G. S.\u003cem\u003e et al.\u003c/em\u003e Incidence and Risk Factors of Retinopathy of Prematurity From 2 Neonatal Intensive Care Units in a Hong Kong Chinese Population. \u003cem\u003eAsia Pac J Ophthalmol (Phila)\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 185-191, doi:10.1097/apo.0000000000000167 (2016).\u003c/li\u003e\n\u003cli\u003eAky\u0026uuml;z \u0026Uuml;nsal, A.\u003cem\u003e et al.\u003c/em\u003e Can Complete Blood Count Parameters Predict Retinopathy of Prematurity? \u003cem\u003eTurk J Ophthalmol\u003c/em\u003e \u003cstrong\u003e50\u003c/strong\u003e, 87-93, doi:10.4274/tjo.galenos.2019.45313 (2020).\u003c/li\u003e\n\u003cli\u003eFevereiro-Martins, M., Santos, A. C., Marques-Neves, C., Guimar\u0026atilde;es, H. \u0026amp; Bicho, M. Complete blood count parameters as biomarkers of retinopathy of prematurity: a Portuguese multicenter study. \u003cem\u003eGraefes Arch Clin Exp Ophthalmol\u003c/em\u003e, doi:10.1007/s00417-023-06072-7 (2023).\u003c/li\u003e\n\u003cli\u003eTandon, M., Ranjan, R., Muralidharan, U. \u0026amp; Kannan, A. Influence of Anaemia on Multifactorial Disease Retinopathy of Prematurity: A Prospective Observational Study. \u003cem\u003eCureus\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, e27877, doi:10.7759/cureus.27877 (2022).\u003c/li\u003e\n\u003cli\u003eDammann, O., Hartnett, M. E. \u0026amp; Stahl, A. Retinopathy of prematurity. \u003cem\u003eDev Med Child Neurol\u003c/em\u003e \u003cstrong\u003e65\u003c/strong\u003e, 625-631, doi:10.1111/dmcn.15468 (2023).\u003c/li\u003e\n\u003cli\u003eHartnett, M. E. \u0026amp; Penn, J. S. Mechanisms and management of retinopathy of prematurity. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e367\u003c/strong\u003e, 2515-2526, doi:10.1056/NEJMra1208129 (2012).\u003c/li\u003e\n\u003cli\u003eFujita, K.\u003cem\u003e et al.\u003c/em\u003e Prevalence of small for gestational age (SGA) and short stature in children born SGA who qualify for growth hormone treatment at 3\u0026thinsp;years of age: Population-based study. \u003cem\u003ePediatr Int\u003c/em\u003e \u003cstrong\u003e58\u003c/strong\u003e, 372-376, doi:10.1111/ped.12859 (2016).\u003c/li\u003e\n\u003cli\u003eFierson, W. M. Screening Examination of Premature Infants for Retinopathy of Prematurity. \u003cem\u003ePediatrics\u003c/em\u003e \u003cstrong\u003e142\u003c/strong\u003e, doi:10.1542/peds.2018-3061 (2018).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3872014/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3872014/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRetinopathy of prematurity (ROP) is a major cause of preventable blindness in preterm infants. The association between red blood cell (RBC) parameters and the development of ROP remains unclear. The objectives of the present study were to evaluate the association between RBC parameters and ROP treatment. This single-center, retrospective cohort study included preterm infants born at \u0026lt;\u0026thinsp;30 weeks of gestation. Data pertaining to RBC parameters and ROP treatment were obtained from the medical records. A receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of the RBC parameters according to the need for ROP treatment. Multiple logistic regression analyses assessed the association between ROP treatment and RBC parameters at birth and on day of life (DOL) 28. We included 202 infants, and 44.1% were treated for ROP. After adjusting for confounders, associations between ROP treatment and hemoglobin (Hb) values of \u0026lt;\u0026thinsp;9.9 g/dL (adjusted odds ratio [aOR]:3.0; 95% confidence intervals [CI]:1.4\u0026ndash;6.7) and hematocrit (Hct) values of \u0026lt;\u0026thinsp;31.0% (aOR:2.7; 95% CI:1.3\u0026ndash;5.6) on DOL 28 were detected. In conclusion, our study showed that infants born at \u0026lt;\u0026thinsp;30 weeks of gestation with Hb\u0026thinsp;\u0026lt;\u0026thinsp;9.9 g/dL and Hct\u0026thinsp;\u0026lt;\u0026thinsp;31.0% on DOL 28 had an increased risk of receiving ROP-warranting treatment.\u003c/p\u003e","manuscriptTitle":"Red blood cell parameters as biomarkers of retinopathy of prematurity in preterm infants born before 30 weeks of gestation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-24 18:52:45","doi":"10.21203/rs.3.rs-3872014/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-03T05:35:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-28T07:21:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35530c22-7a17-40ea-b650-35e67609446d_SNPRID","date":"2024-04-06T16:05:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-23T11:13:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"74bc7b9c-f01f-4db9-9c3c-db4e7c555a77","date":"2024-03-11T19:40:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-09T06:13:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-30T14:40:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-01-22T04:44:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-22T04:42:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-01-17T05:59:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3c419bd4-d231-431b-aa69-fb3d33503558","owner":[],"postedDate":"January 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28286596,"name":"Health sciences/Biomarkers"},{"id":28286597,"name":"Health sciences/Diseases"},{"id":28286598,"name":"Health sciences/Medical research"},{"id":28286599,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-01-06T15:59:54+00:00","versionOfRecord":{"articleIdentity":"rs-3872014","link":"https://doi.org/10.1038/s41598-024-84030-x","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-01-02 15:57:12","publishedOnDateReadable":"January 2nd, 2025"},"versionCreatedAt":"2024-01-24 18:52:45","video":"","vorDoi":"10.1038/s41598-024-84030-x","vorDoiUrl":"https://doi.org/10.1038/s41598-024-84030-x","workflowStages":[]},"version":"v1","identity":"rs-3872014","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3872014","identity":"rs-3872014","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}