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Published on in Vol 7 (2024)

Preprints (earlier versions) of this paper are available at https://preprints.jmir.org/preprint/60330, first published .
Red Blood Cell Transfusion for Incidence of Retinopathy of Prematurity: Prospective Multicenter Cohort Study

Red Blood Cell Transfusion for Incidence of Retinopathy of Prematurity: Prospective Multicenter Cohort Study

Red Blood Cell Transfusion for Incidence of Retinopathy of Prematurity: Prospective Multicenter Cohort Study

Authors of this article:

Xiaoling Wang1, 2 Author Orcid Image ;   Rui Rao2 Author Orcid Image ;   Hua Li2 Author Orcid Image ;   Xiaoping Lei2 Author Orcid Image ;   Wenbin Dong1, 2 Author Orcid Image
Article Authors Cited by Tweetations Metrics

    1Jinan University, , Guangzhou, , China

    2Department of Neonatology, Children’s Medical Center, The Affiliated Hospital of Southwest Medical University, , Luzhou, , China

    *these authors contributed equally

    Corresponding Author:

    Wenbin Dong, MD


    Background: Retinopathy of prematurity (ROP) is a leading cause of visual impairment and blindness in preterm infants.

    Objective: This study sought to investigate the association between red blood cell (RBC) transfusion and ROP in very preterm infants (VPIs) to inform clinical strategies for ROP prevention and treatment.

    Methods: We designed a prospective multicenter cohort study that included VPIs and follow-up data from January 2017 to December 2022 at 3 neonatal clinical medicine centers. They were categorized into a transfusion group (infants who received an RBC transfusion within 4 wk) and a nontransfusion group. The relationship between RBC transfusion and ROP incidence was assessed using binary logistic regression, with subgroup analyses based on gestational age, birth weight, sex, and sepsis status. Inverse probability of treatment weighting and propensity score matching were applied to account for all potential confounding factors that could affect ROP development, followed by sensitivity analysis.

    Results: The study included 832 VPIs, including 327 in the nontransfusion group and 505 in the transfusion group. The transfusion group had a lower average birth weight and gestational age and a greater incidence of ROP, ≥stage 2 ROP, and severe ROP. Logistic regression analysis revealed that the transfusion group had a significantly greater risk of ROP (adjusted odds ratio [aOR] 1.70, 95% CI 1.14‐2.53, P=.009) and ≥stage 2 ROP (aOR 1.68, 95% CI 1.02‐2.78, P=.04) but not severe ROP (aOR 1.75, 95% CI 0.61‐5.02, P=.30). The trend analysis also revealed an increased risk of ROP with an increasing number of transfusions and a larger volume of blood transfused (P for trend<.001). Subgroup analyses confirmed a consistent trend, with the transfusion group at a higher risk for ROP across all subgroups. Inverse probability of treatment weighting and propensity score matching analyses supported the initial findings.

    Conclusions: For VPIs, RBC transfusion significantly increases the risk of ROP, and the risk increases with an increasing number of transfusions and volume of blood transfused.

    JMIR Pediatr Parent 2024;7:e60330

    doi:10.2196/60330

    Keywords

    red blood cell transfusion; retinopathy of prematurity; VPI; very preterm infants; ROP; visual impairment; blindness; RBC; red blood cell 


    Retinopathy of prematurity (ROP) is a retinal vasoproliferative disease that occurs in premature and low-birth-weight infants and is the most common cause of blindness and low vision in infants [1,2]. Early detection and treatment are essential for preventing irreversible visual impairment and blindness. The main pathophysiological factor in ROP is an imbalance between proangiogenic and antiangiogenic factors released locally in the retina, resulting in abnormal neovascularization [3].

    In premature infants, anemia is caused by multiple factors, including insufficient iron reserves from the mother, nutritional deficiency, a short red blood cell (RBC) lifespan, an immature hematopoietic system, and iatrogenic blood loss. RBC transfusion is one of the main treatments for anemia in premature infants. More than half of premature infants with a gestational age of less than 30 weeks and more than 80% of extremely low-birth-weight infants receive at least 1 RBC transfusion during hospitalization [4]. Although RBC transfusion can significantly improve oxygenation status and promote weight gain in anemic premature infants, the adverse reactions caused by RBC transfusion cannot be ignored. Previous studies have reported that RBC transfusion in premature infants is closely related to the development of necrotizing enterocolitis, bronchopulmonary dysplasia, and abnormal neurological outcomes [5]. However, whether RBC transfusion leads to the development of ROP remains controversial. Prospective and retrospective studies have not provided consistent results [6,7]. ROP may regress naturally or progress to stage 3 or higher, with severe cases requiring laser treatment or intravitreal anti–vascular endothelial growth factor (VEGF) injections [8]. Even for infants with ROP who receive timely treatment and those with ROP below the treatment threshold, there is still a risk of permanent visual impairment [9]. Identifying risk factors that can lead to the development and progression of ROP is crucial for its prevention.

    Therefore, the purpose of this study was to determine the correlation between RBC transfusion and the occurrence of ROP, providing new insights for the prevention and treatment of ROP.


    Study Participants

    Inclusion and Exclusion Criteria

    A multicenter cohort study of very preterm infants (VPIs) who were admitted to 3 neonatal intensive care units in Sichuan was conducted from January 1, 2017, to December 31, 2022. The exclusion criteria for infants were as follows: (1) severe lethal congenital malformations (such as central nervous system malformations, congenital facial malformations, or congenital heart malformations); (2) participation refusal by parents or guardians; (3) incomplete hospitalization and transfusion records; (4) discharge or death before ROP screening; and (5) irregular follow-up after discharge.

    Definitions and Diagnostic Criteria for Related Diseases

    Early-onset sepsis (≤3 d after birth) and late-onset sepsis (>3 d after birth) were classified based on the timing of onset. The clinical diagnosis of sepsis was based on clinical manifestations and positive results for ≥2 nonspecific blood tests, cerebrospinal fluid examination results consistent with bacterial meningitis, or the detection of bacterial DNA in the blood. A confirmed diagnosis required clinical manifestations and positive blood or cerebrospinal fluid (or other sterile body fluid) cultures [10,11].

    Premature rupture of membranes refers to the spontaneous rupture of fetal membranes before labor or before the onset of the first stage of labor [12].

    Hypertensive disorders of pregnancy are specific and common diseases in pregnant women and include gestational hypertension, preeclampsia (mild and severe), eclampsia, chronic hypertension with preeclampsia, and chronic hypertension with superimposed gestational hypertension [13].

    Gestational diabetes mellitus was defined as meeting any one of the following criteria: a random blood glucose level ≥5.1 mmol/L, a postprandial 1-hour blood glucose level ≥10.0 mmol/L, or a postprandial 2-hour blood glucose level ≥8.5 mmol/L [14].

    Small for gestational age (SGA) was defined as a birth weight below the 10th percentile of the average birth weight for infants of the same gestational age and sex according to the Chinese birth weight curve for different gestational ages created by Zhu et al [15,16] in 2018.

    Apnea of prematurity was defined as a respiratory pause ≥20 seconds or <20 seconds accompanied by a decrease in heart rate or oxygen saturation [17].

    Transfusion Criteria for Premature Infants

    There is no unified transfusion guideline for anemia in premature infants. The timing and volume of transfusions are usually determined by physicians based on the clinical manifestations, laboratory parameters, and transfusion standards set by each department. Clinical manifestations include poor weight gain or slow growth, irregular breathing, and hemodynamic disturbances. The laboratory parameters include the RBC count, hematocrit level, hemoglobin content, and central and peripheral oxygen saturation. The transfusion dose is 15‐20 mL/kg per session, and if repeated transfusions are needed, blood from the same donor should be used whenever possible.

    ROP Screening, Diagnosis, and Follow-Up

    The initial screening for preterm infants was scheduled between 4 and 5 weeks after birth or at a corrected gestational age of 31 to 32 weeks. The examination was conducted by an experienced ophthalmologist using a RetCam III (Natus Medical Inc), an American-made, wide-angle digital pediatric retinal camera, following a systematic order: the posterior pole, macula, temporal, superior, nasal, and inferior regions.

    All the examinations were performed by the same ophthalmologist, who diagnosed and staged ROP according to the severity of the condition; ROP was categorized into stages 1 to 5 [18]. Severe ROP was defined as stage 3 to stage 5 ROP or plus disease in zone I or II [19]. Infants with immature retinal development and no ROP undergo retinal re-examinations every 3 to 4 weeks before peripheral vascularization. The follow-up interval for infants with established ROP was determined according to the severity of the condition.

    Methodology

    A standardized questionnaire for obtaining basic information for preterm infants was developed, and data from the infants’ hospital records were documented. All the data were entered independently by 2 individuals using EpiData software (version 3.1; The EpiData Association), with discrepancies resolved by a third party. The following data were collected: (1) maternal information: mode of delivery, gestational diabetes status, hypertensive disorders of pregnancy status, chorioamnionitis status, and premature rupture of membrane status (defined as rupture occurring more than 18 h before delivery); (2) infant information: gestational age, birth weight, 5-minute Apgar score, and SGA status; (3) postnatal conditions: duration of nasal continuous positive airway pressure (nCPAP), use of invasive mechanical ventilation, highest oxygen concentration (sustained for more than 2 h), apnea status, early-onset sepsis status, late-onset sepsis status, invasive ventilation status, and duration of invasive ventilation; (4) transfusion-related indicators: transfusion status, age at first transfusion, number of transfusions, and total blood volume transfused within the first 4 weeks of hospitalization; and (5) outcomes: ROP status, ≥stage 2 ROP status, and severe ROP status.

    Statistical Analysis

    Statistical software was used for data description and inference. Categorical data are represented by frequencies and percentages, while continuous data are represented by the mean and SD (for normally distributed data) or median and IQR (for nonnormally distributed data). Chi-square tests were used for group comparisons of categorical data, and independent 2-tailed t tests or Mann‒Whitney U tests were used for continuous data. Multivariate binary logistic regression was used to adjust for potential confounders and calculate the adjusted odds ratio (aOR) of RBC transfusion in premature infants with ROP. Trend tests (P for trend) were used to assess the association between the number of transfusions and the volume of blood transfused in infants with ROP. Subgroup analysis was performed based on gestational age, birth weight, sex, and sepsis status. Forest plots were generated to analyze the impact of RBC transfusions on the incidence of ROP in each subgroup.

    To address potential baseline data bias in real-world studies, inverse probability of treatment weighting (IPTW) and 1:1 propensity score matching (PSM) methods were used to balance baseline differences between groups [20]. Sensitivity analysis was conducted using the calculated sample sizes obtained from these postrandomization methods to validate the stability of the results. All the statistical analyses were performed using open-source R packages and SPSS software (version 26.0; IBM Corp). A P value <.05 was considered to indicate statistical significance.

    Ethical Considerations

    The Clinical Trial Ethics Committee of the Affiliated Hospital of Southwest Medical University approved the study (approval number Y2024124). The study was in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from the legal guardians of all participants included in the study.


    Case Selection Process

    During the study period, a total of 1129 VPIs were admitted to 3 neonatal intensive care units. After excluding 297 infants, 832 were ultimately included. Since the initial screening for ROP occurs between 4 and 5 weeks after birth, infants who received RBC transfusions within 4 weeks after birth were defined as the transfusion group, and those who did not receive transfusions within 4 weeks or who received transfusions after 4 weeks were defined as the nontransfusion group. The nontransfusion group consisted of 327 (39.3%) infants, and the transfusion group included 505 (60.7%) infants (Figure 1).

    ‎
    Figure 1. Flowchart of the selection of the research participants. GA: gestational age.

    Study Results Before Random Matching

    Comparison of General Information Between the 2 Groups

    Table 1 shows that the preterm infants in the transfusion group had a younger gestational age (median 30.10, IQR 28.90-31.10 wk vs median 31.10, IQR 30.30-31.60 wk, z=−8.77, P<.001), a lower average birth weight (mean 1327, SD 251 g vs mean 1543, SD 231 g; t=12.50, df=830, P<.001), and a lower 5-minute Apgar score (median 8, IQR 7-9 points vs median 9, IQR 8-9 points, z=−6.73, P<.001). The highest oxygen concentrations required were greater (median 30%, IQR 28-40% vs median 28%, IQR 25-30%, z=−10.02, P<.001); the duration of nCPAP use was greater (median 11, IQR 6-18 d vs median 6, IQR 3-9 d, z=−12.03, P<.001); and the incidences of mechanical ventilation (156/505, 30.9% vs 16/327, 4.9%, χ21=81.80, P<.001), apnea (280/505, 55.5% vs 87/327, 26.6%, χ21=66.96, P<.001), early-onset sepsis (132/505, 26.1% vs 60/327, 18.4%, χ21=6.79, P=.009), late-onset sepsis (198/505, 39.2% vs 57/327, 17.4%, χ21=44.28, P<.001), and SGA (59/505, 11.7% vs 14/327, 4.3%, χ21=13.59, P<.001) were significantly greater in the transfusion group than in the nontransfusion group (Table 1).

    Table 1. Comparison of baseline characteristics between the 2 groups.
    General informationNontransfusion group (n=327)Transfusion group (n=505)z, chi-square (df), or t test (df)P value
    Maternal data, n (%)
    Vaginal delivery183 (56.0)264 (52.3)1.09(1).30
    Premature rupture of membrane143 (43.7)154 (30.5)15.15(1)<.001
    Hypertensive disorders of pregnancy38 (11.6)72 (14.3)1.20(1).27
    Gestational diabetes mellitus68 (20.8)125 (24.8)1.75(1).19
    Chorioamnionitis120 (36.7)177 (35.1)0.24(1).63
    Neonatal data
    Male, n (%)183 (56.0)282 (55.9)0.001(1).97
    Gestational age (weeks), median (IQR)31.10 (30.30-31.60)30.10 (28.90-31.10)−8.77<.001
    Birth weight (g), mean (SD)1543 (231)1327 (251)12.50(830)<.001
    5-min Apgar score, median (IQR)9 (8-9)8 (7-9)−6.73<.001
    nCPAPa duration (days), median (IQR)6 (3-9)11 (6-18)−12.03<.001
    Invasive ventilation, n (%)16 (4.9)156 (30.9)81.80 (1)<.001
    Invasive ventilation duration (days), median (IQR)0 (0-0)0 (0-2)−9.21<.001
    Maximum oxygen concentration (%), median (IQR)28 (25-30)30 (28-40)−10.02<.001
    Apnea, n (%)87 (26.6)280 (55.5)66.96 (1)<.001
    Early-onset sepsis, n (%)60 (18.4)132 (26.1)6.79 (1).009
    Late-onset sepsis, n (%)57 (17.4)198 (39.2)44.28 (1)<.001
    SGAb, n (%)14 (4.3)59 (11.7)13.59 (1)<.001

    anCPAP: nasal continuous positive airway pressure.

    bSGA: small for gestational age.

    The Impact of Transfusion Within 4 Weeks on ROP Incidence

    Using the results of univariate analysis as a basis, potential confounding factors were included in a multivariate binary logistic regression model. The results showed that the risk of ROP (aOR 1.70, 95% CI 1.14‐2.53; P=.009) and ≥stage 2 ROP (aOR 1.68, 95% CI 1.02‐2.78; P=.04) in the transfusion group was significantly greater than that in the nontransfusion group; however, there was no significant difference in the risk of severe ROP between the 2 groups (aOR 1.75, 95% CI 0.61‐5.02; P=.30) (Table 2).

    Table 2. The impact of red blood cell (RBC) transfusion within 4 wk on retinopathy of prematurity (ROP) incidence.
    Nontransfusion group (n=327), n (%)Transfusion group (n=505), n (%)ORa (95% CI)P valueaORb (95% CI)P value
    ROP58 (17.7)239 (47.3)4.17 (2.99-5.81)<.0011.70 (1.14-2.53).009
    ≥Stage 2 ROP30 (9.2)159 (31.5)4.55 (2.99-6.92)<.0011.68 (1.02-2.78).04
    Severe ROP5 (1.5)51 (10.1)7.23 (2.86-18.33)<.0011.75 (0.61-5.02).30

    aOR: odds ratio.

    baOR: adjusted odds ratio. Adjusted for gestational age, birth weight, 5-min Apgar score, mechanical ventilation use, maximum oxygen concentration, early-onset sepsis, late-onset sepsis, apnea, and small for gestational age.

    The Impact of Different Transfusion Frequencies Within 4 Weeks on ROP Incidence

    To clarify the impact of different transfusion frequencies within 4 weeks on ROP incidence, preterm infants in the transfusion group were further divided into a single transfusion group (339 infants) and a multiple transfusion group (166 infants) and compared with those in the nontransfusion group. A single transfusion within 4 weeks increased the risk of ROP (aOR 1.79, 95% CI 1.20‐2.68; P=.005) but did not increase the risk of ≥stage 2 ROP or severe ROP; multiple transfusions within 4 weeks increased the risk of ROP (aOR 2.95, 95% CI 1.67‐5.21; P<.001) and ≥stage 2 ROP (aOR 2.84, 95% CI 1.47‐5.47; P=.002) but did not increase the risk of severe ROP (Multimedia Appendix 1). As the number of transfusions increased, the risk of ROP, ≥stage 2 ROP, and severe ROP gradually increased, with trend test results all less than 0.001, indicating that the higher the number of transfusions was, the greater the risk of ROP.

    The Impact of Different Transfusion Volumes Within 4 Weeks on ROP Incidence

    To clarify the impact of different transfusion volumes within 4 weeks on ROP incidence, preterm infants in the transfusion group were further divided based on the total volume of blood transfused. Due to the nonnormal distribution of the total transfusion volume within 4 weeks, the infants in the transfusion group were divided into the following 3 groups according to the IQR and compared with those in the nontransfusion group: the ≤34 mL/kg group (176 infants), 34‐42 mL/kg group (159 infants), and ≥42 mL/kg group (170 infants). A total transfusion volume ≤34 mL/kg within 4 weeks did not increase the risk of ROP, ≥stage 2 ROP, or severe ROP; a total transfusion volume of 34‐42 mL/kg within 4 weeks increased the risk of ROP (aOR 1.67, 95% CI 1.02‐2.72, P=.04) but did not increase the risk of ≥stage 2 ROP or severe ROP; and a total transfusion volume ≥42 mL/kg within 4 weeks increased the risk of ROP (odds ratio [OR] 2.88, 95% CI 1.54‐5.39, P<.001) and ≥stage 2 ROP (OR 3.08, 95% CI 1.53‐6.23, P=.002) but did not increase the risk of severe ROP (Multimedia Appendix 2). As the total transfusion volume increased, the risk of ROP, ≥stage 2 ROP, and severe ROP gradually increased, with trend test results all less than 0.001, indicating that the greater the total transfusion volume was, the greater the risk of ROP.

    The Impact of Transfusion on ROP Incidence in Various Subgroups of Preterm Infants

    To clarify the impact of transfusion within 4 weeks on ROP incidence in different preterm infant populations, the included preterm infants were divided into 3 subgroups based on gestational age (>30 weeks ≤30 weeks), birth weight (>1500 g, ≤1500 g), sex (male, female) and sepsis status (yes, no). Although there were no significant differences in some outcome indicators between the subgroups, the overall trend was consistent, with the risk of ROP in the transfusion group being greater than that in the nontransfusion group (Figure 2, Multimedia Appendices 3, 4, and 5).

    ‎
    Figure 2. Forest plot of the effect of red blood cell transfusion within 4 wk on the occurrence of retinopathy of prematurity (ROP) in preterm infants in each subgroup. BW: birth weight; GA: gestational age.

    Sensitivity Analysis Results After IPTW and PSM

    Given the numerous factors influencing ROP incidence and the significant imbalance in the baseline data in this real-world study, as shown in Table 2, the ROP data showed considerable changes before and after adjusting for confounding factors, suggesting potential selection bias in the study results. Therefore, the IPTW and PSM methods were applied in this study to evaluate all factors that could affect ROP incidence between the 2 groups. Sensitivity analysis was performed using the calculated sample sizes obtained after IPTW and PSM to validate the stability of the impact of RBC transfusions on ROP incidence. The balance between the groups was significantly improved after IPTW and PSM (Multimedia Appendices 6 and 7). The results obtained after IPTW and PSM were consistent with the original results (Multimedia Appendices 8 and 9).


    Principal Findings

    Previous studies on the association between RBC transfusion and ROP incidence have used a retrospective case-control design to investigate risk factors for ROP development. This is the first prospective multicenter cohort study in which infants were categorized based on whether they received RBC transfusions within the first 4 weeks after birth. The study included all VPIs who were admitted to 3 centers over nearly 6 years, and the correlation between RBC transfusion and ROP incidence was explored. The results indicated that RBC transfusion within the first 4 weeks significantly increases the risk of ROP in VPIs, and this correlation remained consistent across different groups of preterm infants.

    Despite various available measures to prevent anemia in preterm infants, the use of RBC transfusion remains inevitable [21]. Studies show that more than 90% of extremely low-birth-weight infants receive at least 1 RBC transfusion during their hospital stay, with the risk of transfusion increasing for infants with younger gestational ages, lower birth weights, and greater immaturity [22,23]. Puia-Dumitrescu et al’s [24] study, which included 54 preterm infants with a gestational age of 30 weeks and a birth weight less than 1000 g, revealed that the average number of RBC transfusions during a 10-week hospital stay was 8. For extremely preterm infants with a gestational age of 23‐24 weeks, the average number of transfusions was 11, and for those with a gestational age of 27‐28 weeks, the number could reach 6. Our study revealed that 505 (60.7%) preterm infants with a gestational age ≤32 weeks received at least 1 RBC transfusion within 28 days of hospitalization, with a greater likelihood of transfusion in infants with a younger gestational age. The proportion of transfusions decreased with increasing gestational age and birth weight, which is consistent with previous findings.

    ROP is a common complication in preterm infants, and its incidence and severity decrease as gestational age and birth weight increase. In this study, the incidence of ROP in preterm infants with a gestational age ≤32 weeks was 297 (35.6%), and the incidence of severe ROP was 56 (6.7%). The incidence of ROP is greater in infants with younger gestational ages, with those born at less than 28 weeks having an incidence rate of approximately 70%, which is consistent with the reports by Dai et al [25].

    The pathogenesis of ROP is multifactorial, with low gestational age, low birth weight, and prolonged exposure to oxygen therapy being the main risk factors for ROP [26]. In addition to these risk factors, RBC transfusion has been suggested to be a risk factor for ROP development in numerous case-control studies [27-29]. However, Lundgren et al [30] reported that the duration of anemia in the first week after birth was an independent risk factor for ROP, while RBC transfusion was not. Given the inconsistent results of retrospective studies, our prospective cohort study aimed to clarify the association between RBC transfusion and ROP incidence. The results indicated that after adjusting for confounding factors such as gestational age at birth, birth weight, and nCPAP use, RBC transfusion within the first 4 weeks of hospitalization significantly increased the risk of ROP and ≥stage 2 ROP in VPIs. However, there was no significant difference in the incidence of severe ROP between the 2 groups, which may have been due to the low incidence of severe ROP and the small sample size. Given that this study was observational, many factors influence ROP development, and there is potential selection bias due to the imbalance of baseline data, we applied the IPTW and PSM methods to account for all potential confounding factors that could affect ROP development. The results still suggested that RBC transfusion increases the risk of ROP in VPIs, and this association remained consistent across different groups of preterm infants.

    The risk of ROP increases with an increasing number of RBC transfusions and volume of blood transfused. Ghirardello et al’s [31] study, which included 641 preterm infants with very low birth weight, showed that RBC transfusion is an independent risk factor for ROP development in very low-birth-weight infants, and the risk of complications increases with an increasing number of transfusions, with 3 or more transfusions increasing the risk of bronchopulmonary dysplasia and ROP by 4.88 times. Hengartner et al’s [32] retrospective study of 178 extremely preterm infants showed that infants with ≥stage 2 ROP received more transfusions, had larger volumes transfused, and received earlier treatment. Additionally, Uberos et al’s [19] data indicate that the relationship between the number of RBC transfusions and the risk of ROP and severe ROP is more significant than that between early RBC transfusion (within the first 7 d of life) and the risk of ROP and severe ROP. Our study revealed that the risk of ROP and ≥stage 2 ROP increases with an increasing number of RBC transfusions and volume of blood transfused, which is consistent with the findings of the aforementioned studies.

    The mechanism by which RBC transfusion leads to ROP development is not yet fully understood, but it may be related to the replacement of fetal hemoglobin (HbF) with adult hemoglobin after transfusion, which leads to changes in the type and quantity of hemoglobin [33]. Since adult hemoglobin has a decreased affinity for oxygen, developing retinal tissue is exposed to high oxygen levels, leading to oxidative damage to vascular endothelial cells, downregulation of VEGF expression, and stagnation of retinal vascular development [34]. This results in retinal hypoxia, increased VEGF and erythropoietin expression, pathological proliferation of vessels in the retina and vitreous, and the development of ROP [35]. Jiramongkolchai et al’s [36] prospective cohort study showed that infants with the lowest percentage of HbF at a corrected age of 31 weeks had a 7.6-fold increased risk of mild and severe ROP, and this risk increased to 12.3 times by the corrected age of 34 weeks, indicating that a lower HbF percentage is associated with a greater risk of ROP. Prasad et al [37,38] conducted 2 prospective studies to explore the correlation between HbF concentration and ROP, and the results showed that preterm infants with lower HbF levels were at higher risk of developing ROP, and preterm infants with higher HbF concentration were more likely to have ROP spontaneously subside. HbF may play a protective role in the occurrence and development of ROP. Teofili et al investigated the relationship between transfusion-free survival and ROP [39]. The study found that preterm infants receiving RBC transfusions before 28 weeks of gestational age were associated with an increased risk of developing severe ROP, that gestational age at second transfusion was a better predictor of developing severe ROP than gestational age at first transfusion, and that maintaining higher levels of HbF may help reduce the risk of ROP [39].

    Preventing anemia and reducing the risk of RBC transfusion are pressing issues for neonatologists. Delayed cord clamping [40], reduced iatrogenic blood loss, and iron supplementation are beneficial interventions for preventing anemia. Research on the RBC source, storage time, and different transfusion thresholds is currently ongoing, but there are no unified results. Kirpalani et al [41] reported that restrictive transfusion strategies did not reduce the incidence of ROP; Glaser et al’s [42] large cohort study revealed that restrictive transfusion strategies could reduce the risk of ROP, while liberal transfusion strategies increased the risk. In recent years, umbilical cord blood (UCB) transfusion has gained increasing attention. The use of UCB from healthy newborns has been proposed to prevent ROP in preterm infants. The main potential advantage of UCB is that it contains the same amount of HbF as newborns in utero. Thus, autologous UCB transfusions would maintain a physiological concentration of HbF during the first weeks of life, which has a greater affinity for oxygen and is more stable in an oxidative environment, maintaining similar oxygen transportation and tissue delivery as in the fetal stage. This fact could optimize the postnatal development of different immature tissues [43].

    Limitations

    This study has certain limitations. First, as a multicenter observational study spanning 6 years, there may have been changes in the treatment and transfusion strategies for preterm infants across centers, leading to potential bias in the results. Second, although the IPTW and PSM methods were used to control for known confounding factors, unknown confounding factors and other intermediate factors may still have affected the results. Therefore, considering the potential impact of unknown confounding factors, we believe that well-designed, larger-sample randomized clinical trials are needed to further validate the effects of RBC transfusion, different RBC storage times, transfusion intervals, and anemia status on the development of ROP. We also need to learn from the work of Schallmoser et al [44], integrating the medical profession with machine learning to construct a predictive model for the risk of retinopathy of ROP occurrence.

    Conclusions

    Based on our study results, RBC transfusion increases the risk of ROP, and this effect is consistent across different groups of preterm infants. For VPIs, RBC transfusions are strongly associated with an increased risk of ROP, which escalates alongside the number and volume of transfusions. We recommend that for VPIs with small gestational age, low birth weight, and high risk of sepsis, the indications for RBC transfusion in preterm infants should be strictly controlled and that the number of transfusions and volume of blood transfused should be limited to reduce adverse consequences.

    Acknowledgments

    The research was supported by the National Natural Science Foundation of China (82371710).

    Data Availability

    The data that support the findings of this study are available from the corresponding author upon reasonable request.

    Authors' Contributions

    XW was responsible for collecting data, completing data curation, following up with patients, and writing the original draft. RR contributed by collecting data, performing statistical analysis, and revising the manuscript. HL was involved in collecting data and following up with patients. XL and WD conceived the research idea, supervised the research work, and approved and edited the manuscript. All authors read and approved the final manuscript.

    Conflicts of Interest

    None declared.

    Multimedia Appendix 1

    The impact of different transfusion frequencies within 4 weeks on retinopathy of prematurity incidence.

    DOCX File, 18 KB
    Multimedia Appendix 2

    The impact of different transfusion volumes within 4 weeks on retinopathy of prematurity incidence.

    DOCX File, 18 KB
    Multimedia Appendix 3

    The impact of red blood cell transfusion within 4 weeks on retinopathy of prematurity incidence for different gestational ages.

    DOCX File, 17 KB
    Multimedia Appendix 4

    The impact of red blood cell transfusion within 4 weeks on retinopathy of prematurity incidence for different birth weights.

    DOCX File, 17 KB
    Multimedia Appendix 5

    The impact of red blood cell transfusion within 4 weeks on retinopathy of prematurity incidence for each sex.

    DOCX File, 17 KB
    Multimedia Appendix 6

    Change in standardized mean difference (SMD) values before and after inverse probability of treatment weighting (IPTW) and propensity score matching (PSM). (A) Change in SMD values before and after IPTW; (B) change in SMD values before and after PSM.

    PNG File, 88 KB
    Multimedia Appendix 7

    Propensity score value distribution between groups before and after probability of treatment weighting (IPTW) and propensity score matching (PSM). (A) Propensity score value distribution between groups before random matching; (B) propensity score value distribution between groups after IPTW; (C) propensity score value distribution between groups after PSM.

    PNG File, 65 KB
    Multimedia Appendix 8

    The impact of red blood cell transfusion within 4 weeks on retinopathy of prematurity incidence after inverse probability of treatment weighting.

    DOCX File, 16 KB
    Multimedia Appendix 9

    The impact of red blood cell transfusion within 4 weeks on retinopathy of prematurity incidence after propensity score matching.

    DOCX File, 16 KB
    1. Barry GP, Yu Y, Ying GS, et al. Retinal detachment after treatment of retinopathy of prematurity with laser versus intravitreal anti-vascular endothelial growth factor. Ophthalmology. Aug 2021;128(8):1188-1196. [CrossRef] [Medline]
    2. Dammann O, Hartnett ME, Stahl A. Retinopathy of prematurity. Dev Med Child Neurol. May 2023;65(5):625-631. [CrossRef] [Medline]
    3. Holmström G, Hellström A, Jakobsson P, Lundgren P, Tornqvist K, Wallin A. Five years of treatment for retinopathy of prematurity in Sweden: results from SWEDROP, a national quality register. Br J Ophthalmol. Dec 2016;100(12):1656-1661. [CrossRef] [Medline]
    4. Keir AK, Yang J, Harrison A, Pelausa E, Shah PS, Canadian Neonatal Network. Temporal changes in blood product usage in preterm neonates born at less than 30 weeks’ gestation in Canada. Transfusion. Jun 2015;55(6):1340-1346. [CrossRef] [Medline]
    5. Villeneuve A, Arsenault V, Lacroix J, Tucci M. Neonatal red blood cell transfusion. Vox Sang. Apr 2021;116(4):366-378. [CrossRef] [Medline]
    6. Chen HL, Tseng HI, Lu CC, Yang SN, Fan HC, Yang RC. Effect of blood transfusions on the outcome of very low body weight preterm infants under two differe NT transfusion criteria. Pediatr Neonatol. Jun 2009;50(3):110-116. [CrossRef] [Medline]
    7. Knee D, Knoop S, Davis AT, Rawson B, DiCarlo A, Olivero R. Outcomes after implementing restrictive blood transfusion criteria in extremely premature infants. J Perinatol. Aug 2019;39(8):1089-1097. [CrossRef] [Medline]
    8. Stahl A, Lepore D, Fielder A, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet. Oct 26, 2019;394(10208):1551-1559. [CrossRef] [Medline]
    9. Hellström A, Smith LEH, Dammann O. Retinopathy of prematurity. Lancet. Oct 26, 2013;382(9902):1445-1457. [CrossRef] [Medline]
    10. Investigators of the Delhi Neonatal Infection Study (DeNIS) collaboration. Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study. Lancet Glob Health. Oct 2016;4(10):e752-e760. [CrossRef] [Medline]
    11. Subspecialty Group of Neonatology, the Society of Pediatric, Chinese Medical Association, Professional Committee of Infectious Diseases, Neonatology Society, Chinese Medical Doctor Association. Expert consensus on the diagnosis and management of neonatal sepsis (version 2019). Zhonghua Er Ke Za Zhi. Apr 2, 2019;57(4):252-257. [CrossRef] [Medline]
    12. Kole-White MB, Nelson LA, Lord M, et al. Pregnancy latency after preterm premature rupture of membranes: oral versus intravenous antibiotics. Am J Obstet Gynecol MFM. May 2021;3(3):100333. [CrossRef] [Medline]
    13. Narang K, Szymanski LM. Multiple gestations and hypertensive disorders of pregnancy: what do we know? Curr Hypertens Rep. Nov 18, 2020;23(1):1. [CrossRef] [Medline]
    14. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. Mar 2010;33(3):676-682. [CrossRef] [Medline]
    15. Katz J, Lee AC, Kozuki N, et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. Lancet. Aug 3, 2013;382(9890):417-425. [CrossRef] [Medline]
    16. Zhu L, Zhang R, Zhang S, et al. Chinese neonatal birth weight curve for different gestational age. Zhonghua Er Ke Za Zhi. Feb 2015;53(2):97-103. [Medline]
    17. Erickson G, Dobson NR, Hunt CE. Immature control of breathing and apnea of prematurity: the known and unknown. J Perinatol. Sep 2021;41(9):2111-2123. [CrossRef] [Medline]
    18. Fierson WM, American Academy of Pediatrics Section on Ophthalmology, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Association of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. Jan 2013;131(1):189-195. [CrossRef] [Medline]
    19. Uberos J, Fernandez-Marin E, Campos-Martínez A, Ruiz-López A, García-Serrano JL. Blood products transfusion and retinopathy of prematurity: a cohort study. Acta Ophthalmol. May 2023;101(3):e294-e301. [CrossRef] [Medline]
    20. Haukoos JS, Lewis RJ. The propensity score. JAMA. Oct 20, 2015;314(15):1637-1638. [CrossRef] [Medline]
    21. Counsilman CE, Heeger LE, Tan R, et al. Iatrogenic blood loss in extreme preterm infants due to frequent laboratory tests and procedures. J Matern Fetal Neonatal Med. Aug 2021;34(16):2660-2665. [CrossRef] [Medline]
    22. Bowen JR, Patterson JA, Roberts CL, Isbister JP, Irving DO, Ford JB. Red cell and platelet transfusions in neonates: a population-based study. Arch Dis Child Fetal Neonatal Ed. Sep 2015;100(5):F411-F415. [CrossRef] [Medline]
    23. Scrivens A, Reibel NJ, Heeger L, et al. Survey of transfusion practices in preterm infants in Europe. Arch Dis Child Fetal Neonatal Ed. Jul 2023;108(4):360-366. [CrossRef] [Medline]
    24. Puia-Dumitrescu M, Tanaka DT, Spears TG, et al. Patterns of phlebotomy blood loss and transfusions in extremely low birth weight infants. J Perinatol. Dec 2019;39(12):1670-1675. [CrossRef] [Medline]
    25. Dai Y, Zhu L, Zhou Y, et al. Incidence of retinopathy of prematurity treatment in extremely preterm infants in China. Paediatr Perinat Epidemiol. May 2022;36(3):380-389. [CrossRef] [Medline]
    26. Thomas K, Shah PS, Canning R, Harrison A, Lee SK, Dow KE. Retinopathy of prematurity: risk factors and variability in Canadian neonatal intensive care units. J Neonatal Perinatal Med. 2015;8(3):207-214. [CrossRef] [Medline]
    27. Bas AY, Demirel N, Koc E, et al. Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR-ROP study): a prospective, multicentre study in 69 neonatal intensive care units. Br J Ophthalmol. Dec 2018;102(12):1711-1716. [CrossRef] [Medline]
    28. Lust C, Vesoulis Z, Jackups R Jr, Liao S, Rao R, Mathur AM. Early red cell transfusion is associated with development of severe retinopathy of prematurity. J Perinatol. Mar 2019;39(3):393-400. [CrossRef] [Medline]
    29. Dani C, Coviello C, Panin F, et al. Incidence and risk factors of retinopathy of prematurity in an Italian cohort of preterm infants. Ital J Pediatr. Mar 12, 2021;47(1):64. [CrossRef] [Medline]
    30. Lundgren P, Athikarisamy SE, Patole S, Lam GC, Smith LE, Simmer K. Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. Acta Paediatr. May 2018;107(5):759-766. [CrossRef] [Medline]
    31. Ghirardello S, Dusi E, Cortinovis I, et al. Effects of red blood cell transfusions on the risk of developing complications or death: an observational study of a cohort of very low birth weight infants. Am J Perinatol. Jan 2017;34(1):88-95. [CrossRef] [Medline]
    32. Hengartner T, Adams M, Pfister RE, et al. Associations between red blood cell and platelet transfusions and retinopathy of prematurity. Neonatology. Dec 8, 2020;117(5):1-7. [CrossRef] [Medline]
    33. Stutchfield CJ, Jain A, Odd D, Williams C, Markham R. Foetal haemoglobin, blood transfusion, and retinopathy of prematurity in very preterm infants: a pilot prospective cohort study. Eye (Lond). Oct 2017;31(10):1451-1455. [CrossRef] [Medline]
    34. Podraza W. A new approach to neonatal medical management that could transform the prevention of retinopathy of prematurity: theoretical considerations. Med Hypotheses. Apr 2020;137:109541. [CrossRef] [Medline]
    35. Rivera JC, Holm M, Austeng D, et al. Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies. J Neuroinflammation. Aug 22, 2017;14(1):165. [CrossRef] [Medline]
    36. Jiramongkolchai K, Repka MX, Tian J, et al. Lower foetal haemoglobin levels at 31- and 34-weeks post menstrual age is associated with the development of retinopathy of prematurity: PacIFiHER Report No. 1 PacIFiHER Study Group (Preterm Infants and Fetal Haemoglobin in ROP). Eye (Lond). Feb 2021;35(2):659-664. [CrossRef] [Medline]
    37. Prasad N, Kumar K, Dubey A. Fetal hemoglobin, blood transfusion, and retinopathy of prematurity in preterm infants: an observational, prospective study. Indian J Ophthalmol. Jul 2023;71(7):2803-2807. [CrossRef] [Medline]
    38. Prasad N, Dubey A, Kumar K, Shrivastava J. Role of fetal hemoglobin in the development and progression of retinopathy of prematurity in preterm infants. Indian J Ophthalmol. Nov 2023;71(11):3478-3483. [CrossRef] [Medline]
    39. Teofili L, Papacci P, Bartolo M, et al. Transfusion-free survival predicts severe retinopathy in preterm neonates. Front Pediatr. 2022;10:814194. [CrossRef] [Medline]
    40. Sundararajan S, Rabe H. Prevention of iron deficiency anemia in infants and toddlers. Pediatr Res. Jan 2021;89(1):63-73. [CrossRef] [Medline]
    41. Kirpalani H, Bell EF, Hintz SR, et al. Higher or lower hemoglobin transfusion thresholds for preterm infants. N Engl J Med. Dec 31, 2020;383(27):2639-2651. [CrossRef] [Medline]
    42. Glaser K, Härtel C, Dammann O, et al. Erythrocyte transfusions are associated with retinopathy of prematurity in extremely low gestational age newborns. Acta Paediatr. Dec 2023;112(12):2507-2515. [CrossRef] [Medline]
    43. Torrejon-Rodriguez L, Pinilla-Gonzalez A, Lara Cantón I, et al. Effect of autologous umbilical cord blood transfusion in the development of retinopathy of prematurity: randomized clinical trial - study protocol. Front Pediatr. 2023;11:1269797. [CrossRef] [Medline]
    44. Schallmoser S, Zueger T, Kraus M, Saar-Tsechansky M, Stettler C, Feuerriegel S. Machine learning for predicting micro- and macrovascular complications in individuals with prediabetes or diabetes: retrospective cohort study. J Med Internet Res. Feb 27, 2023;25:e42181. [CrossRef] [Medline]

    ‎
    aOR: adjusted odds ratio
    HbF: fetal hemoglobin
    IPTW: inverse probability of treatment weighting
    nCPAP: nasal continuous positive airway pressure
    OR: odds ratio
    PSM: propensity score matching
    RBC: red blood cell
    ROP: retinopathy of prematurity
    SGA: small for gestational age
    UCB: umbilical cord blood
    VEGF: vascular endothelial growth factor
    VPI: very preterm infant

    Edited by Sherif Badawy; submitted 08.05.24; peer-reviewed by Caterina Giovanna Valentini, Maria Bianchi; final revised version received 16.06.24; accepted 18.06.24; published 18.09.24.

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    © Xiaoling Wang, Rui Rao, Hua Li, Xiaoping Lei, Wenbin Dong. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 18.9.2024.

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