Blood products transfusion and retinopathy of prematurity: A cohort study

e294 | Acta Ophthalmologica. 2023;101:e294–e301. wileyonlinelibrary.com/journal/aos 1 | INTRODUCTION Retinopathy of prematurity (ROP) is a fibrous vasculoproliferative vitreoretinopathy that occurs as a consequence of abnormal retinal vascularization in premature infants (<1500 g weight at birth, or <32 weeks' gestation). It can cause a loss of visual acuity or even blindness (Recchia & Capone, 2004). The increased survival of children of low gestational age (GA) is accompanied by a corresponding increase in cases of severe ROP among newborns of lower GA, who also present more comorbidities (sepsis, ductus and apnoea) and have a greater need of supplemental oxygen to achieve a proper oxygenation (Chan et al., 2018; Gilbert,2008). Red blood cell transfusions are more frequently given to premature newborns, being indicated for approximately 40% of those with low birth weight and in 90% of those weighing <1000 g at birth. Although red blood cell transfusion may be crucial to the survival of these infants, it is also associated with higher rates of complications, such as necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), ROP and, possibly, abnormal neurological development (Villeneuve et al.,2021). In preterm infants, diminished foetal haemoglobin is related to the number of transfusions received. In these ORIGINAL ARTICLE Blood products transfusion and retinopathy of prematurity: A cohort study JoseUberos1 | ElisabethFernandezMarin1 | AnaCamposMartínez1 | AidaRuizLópez1 | Jose LuisGarcíaSerrano2 Received: 23 April 2022 | Accepted: 24 September 2022 DOI: 10.1111/aos.15269 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation. 1Neonatal Intensive Care Unit, Medicine Faculty, San Cecilio Clinical Hospital, Granada, Spain 2Ophthalmology Service, San Cecilio Clinical Hospital, Granada, Spain Correspondence Jose Uberos, Medicine Faculty. San Cecilio Clinical Hospital, Avda. de la Investigación 11, Granada 18016, Spain. Email: [email protected] Abstract Aim: The aim of the study was to assess the influence of blood product transfusions on the development and severity of retinopathy of prematurity (ROP). Methods: A retrospective cohort study was conducted of very low birth weight (VLBW) newborns with less than 32 weeks gestational age (GA) admitted to the neonatal unit of a tertiary care hospital during the period from 1 January 2008 to 31 December 2021. Data on the degree of ROP and the transfusions received were obtained and analysed. Both univariate and multivariate analyses were performed, by logistic regression. Results: A total of 565 VLBW newborns were recruited, of whom 263 received a red blood cell transfusion prior to 36 weeks corrected GA. The newborns with ROP received significantly more red blood cell transfusions than those not presenting this condition. After adjusting for oxygen therapy and GA, the risk of ROP was found to be 2.77 times higher (95% CI 1.31– 5.88) after receiving three or more transfusions, with a 3.95 times higher risk (95% CI 1.40– 11.1) of developing severe ROP. Having received the first red blood cell transfusion before 32 weeks corrected GA is associated with an increased risk of ROP (OR 2.18; 95% CI: 1.09– 4.36). Conclusion: In VLBW neonates, the number of red blood cell transfusions and their administration before 32 weeks corrected GA are important risk factors for ROP. KEYWORDS platelets, red blood cells, retinopathy of prematurity, transfusion | e295UBEROS et al. situations, there is an increase in haemoglobin A, which has lower affinity for oxygen and greater capacity to release oxygen, possibly exposing immature tissues to higher concentrations of oxygen and posing a greater risk of endothelial injury from the toxicity of oxygen free radicals (De Halleux et al.,2002). Stored red blood cells contain both proand antiinflammatory mediators that could play a role in the pathophysiology of certain comorbidities in premature newborns (Collard et al.,2005; Patel et al.,2019), and there is a higher risk of this occurring when larger volumes of transfused blood are received. Increased oxygen pressure after birth can trigger ROP in very low birth weight (VLBW) infants through two consecutive phases. The first phase, vasoobliterative, is initiated at birth with supplemental oxygen treatment, which usually occurs at 32 weeks corrected GA. After delivery, the newborn loses growth factors of maternal and placental origin and is exposed to high extrauterine oxygen tension. Hyperoxia suppresses the expression of angiogenic factors that maintain physiological angiogenesis. Phase 2, vasoproliferative, begins with hypoxia of the retina due to the increasing metabolism of the growing retina, usually from 32 weeks corrected GA. During this phase, there is hypoxia in the avascular retina, which increases vascular growth factor (VEGF) which causes increased vascularization at the edge of the vascularized and avascular retina (Sarlos et al., 2003). The transfusion of red blood cells may expose premature newborns to a higher risk of developing ROP (Bas et al.,2018), the severity of which is related to the number of transfusions (Valieva et al.,2009), while the need for transfusion is associated with the clinical severity of the newborn. Platelets are of crucial importance to tissue repair, endothelial maintenance and vascular tone. Among other functions, they accumulate, transport and release various key regulators of angiogenesis, such as vascular endothelial growth factor (VEGF), insulinlike growth factor1 (IGF1) and plateletderived growth factor (PDGF) in locations of pathological angiogenesis (Italiano et al.,2008; Klement et al.,2009). Furthermore, Freshfrozen plasma (FFP) from adult donors may be an actual source of IGF1 and play a main role in the pathogenesis of ROP (Dani et al.,2014). We hypothesize that the number of transfusions of blood products, or the early transfusion of such products for VLBW infants, might be associated with the development of ROP (moderate or severe). The objective of this study is to evaluate the impact of blood product transfusions on the development and severity of ROP in this population of infants. 2 | METHODS A retrospective observational cohort study was conducted of newborns with GA <32 weeks or birth weight <1500 g, born between January 2008 and December 2021. The dependent variable in this analysis is the degree of ROP, and the independent variables are the moment at which a red blood cell transfusion was performed and the numbers of red blood cell, platelet and fresh plasma transfusions performed. The maternal and perinatal variables shown in Table1 are taken as adjustment variables. 2.1 | Assessment of ROP Screening programmes for the early detection of ROP began in 1988 after the publication of a multicentre study of cryotherapy for ROP (Cryotherapy for Retinopathy of Prematurity Cooperative Group,1988). This study defined the presence of one or more of the following as an unfavourable structural outcome: retinal fold involving the macula, retinal detachment affecting zone I in the posterior pole or retrolental tissue or mass. The aim of these programmes was to identify preterm infants who needed treatment for ROP or to facilitate shortand longterm followup (Ferrer Novella et al.,2013; Palmer,1990). It has been suggested that the initial examination should be based on the child's postmenstrual age, since the onset of ROP correlates better with this parameter than with GA. Accordingly, the Ophthalmology Service and the Neonatal Unit at the San Cecilio University Hospital (Granada, Spain) jointly prepared a schedule to begin examining premature infants weighing ≤1500 g at birth or with GA ≤30 weeks. Infants weighing 1500– 2000 g or with GA >30 weeks were also screened if they presented an unstable clinical course (including those needing cardiorespiratory support) or who, according to paediatric criteria, were considered at high risk of developing ROP (ChavesSamaniego et al.,2020). A weekly examination was recommended if any of the following were observed: the presence of immature vascularization in zone I, the absence of vascularization in the retina, the vessels only reaching central zone II or zone I, stage 1 or 2 ROP in zone I, stage 3 ROP in zone II or the suspicion or presence of aggressive posterior ROP. Finally, examinations were performed every 2– 3 weeks if stage 1 or 2 or signs of ROP regression were observed in zone III (Lad et al.,2009; International Committee for the Classification of Retinopathy of Prematurity,2005). We define severe ROP as the existence of stage 3– 5 and/or Plus disease in zone I or II. 2.2 | Blood product transfusions For the present study, the timing and number of blood transfusions performed were obtained from the Granada Provincial Blood Bank database. This information is also documented in the clinical history of each newborn. In all cases, blood product transfusion was performed with prior informed consent. We define ‘early red cell transfusion’ such as that carried out with adult donor red blood cells in the first 7 postnatal days and ‘late red cell transfusion’ such as the one carried out after 7 days of postnatal life. In our analysis, the control group was composed of the newborns with no ROP. According to the transfusion protocol applied by the Neonatal Unit, the transfusion of packed red blood cells during the neonatal period is indicated when Hb values are <10 g/dl, prior to major surgery, on observing 17553768, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/aos.15269 by Readcube (Labtiva Inc.), Wiley Online Library on [22/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License e296 | UBEROS et al. moderate cardiopulmonary disease or during the first week of life when clinical disease is observed; when Hb values are <13 g/dl and severe cardiopulmonary disease requires mechanical ventilation and/or supplemental oxygen with FiO2 ≥ 0.4; when Hb values are <8g/dl and there is symptomatic anaemia (apnoea, tachycardia, tachypnoea, poor weight curve, decreased activity); or in the presence of acute bleeding with the loss of ≥25% of blood volume or with persistent clinical symptoms of hypoxia after the correction of blood volume with crystalloids/colloids. The transfusion of packed red blood cells, previously irradiated, is performed at a ratio of 10– 15 ml/kg body weight. Indications for platelet transfusion in newborns include a platelet count <50 000 in the absence of other risk factors for bleeding. The following dosage is applied: 1 platelet concentrate for every 5kg of body weight (approximately 10ml/kg). Freshfrozen plasma transfusion is considered in newborns whenever there is massive haemorrhage and multifactorial deficit, as is the case in disseminated intravascular coagulation. The dosage used is 10ml per kg of body weight. 2.3 | Neonatal morbidity In accordance with the thresholds proposed by the National Institute of Child Health and Human TABLE 1 Pregnancy, neonatal and nutritional characteristics in very low birth weight neonates with and without ROP Characteristics No ROP n=375 ROP n=97 p Maternal IVF (n, %) 65 (17.3) 16 (16.5) NS PIH (n, %) 46 (12.2) 9 (9.2) NS Chorioamnionitis (n, %) 53 (14.1) 21 (21.6) <0.05 Antibiotics (n, %) 147 (39.2) 36 (37.1) NS Glucocorticoids (n, %) 365 (97.3) 90 (92.7) NS PPROM (n, %) 91 (24.2) 28 (28.8) NS Gestation (w)a30 (28, 3) 27 (26, 2) <0.001 Gestation ≤27 w (n, %) 75 (20.0) 61 (62.8) <0.001 Twin birth (n, %) 173 (46.1) 40 (41.23) NS Caesarean section 327 (87.2) 81 (83.5) NS IUGR 85 (22.6) 20 (20.6) NS Neonatal Birth weight (g)a1242 (1032, 1455) 932 (758, 1118) NS Birth weight (zscore)a−0.51 (−1.15, 0.27) −0.41 (−1.04, 0.16) NS Male gender (n, %) 227 (60.5) 53 (54.6) NS Apgar<5, 5min (n, %) 45 (12.0) 19 (19.5) <0.05 CRIB indexa2 (1, 5) 4 (1, 8) <0.01 Milk breastfeedingb (n, %) 242 (64.5) 46 (47.4) NS Probiotics 148 (39.4) 29 (29.9) NS Early red blood cell transfusion (n, %) 56 (14.9) 12 (12.3) NS Late red blood cell transfusión (n, %) 121 (32.2) 49 (50.5) <0.001 Red blood cell transfusion (n, %) 184 (49.0) 79 (81.4) <0.001 Platelet transfusión (n, %) 35 (9.3) 27 (27.8) <0.001 Plasma trnsfusion (n, %) 50 (13.3) 22 (22.6) <0.01 Oxygena14 (4, 37) 48 (23, 78) <0.001 Neonatal comorbidities BPD 117 (31.2) 72 (74.2) <0.001 PDA 53 (14.13) 39 (40.2) <0.001 IVH (Grade III) 43 (11.4) 20 (20.6) <0.01 IVH (Grade IIIIV) 25 (6.6) 7 (7.2) NS NEC (Grade ≥2) 30 (8.0) 19 (19.5) <0.001 Early sepsis 38 (10.1) 23 (23.7) <0.001 Late onset sepsis 78 (20.8) 49 (50.5) <0.001 Abbreviations: BPD, Bbronchopulmonary dysplasia; CRIB, cClinical risk index for babies; IUGR, Iintrauterine growth restriction (decrease in the rate of weight increase that manifests in weight below the 10th percentile for gestational age); IUGR, iIntrauterine growth retardation; IVF, iIn vVitro fFertilization; IVH, iIntraventricular haemorrhage; NEC, necrotizing enterocolitis; PDA, pPatent ductus arteriosus; PIH, pPregnancy induced hypertension; PPROM, pPreterm prelabour rupture of membranes; ROP, Retinopathy of prematurity. aMedian (IQR). bSupplemented in <25% of the weekly volume with premature formula milk. 17553768, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/aos.15269 by Readcube (Labtiva Inc.), Wiley Online Library on [22/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | e297UBEROS et al. Development (NIHCD; Doyle et al.,2005) and by Jobe and Bancalari (2001), bronchopulmonary dysplasia (BPD) is defined as a need for supplemental oxygen >21% at 28 days of life and/or a need for supplemental oxygen >21% or for positive airway pressure at 36 weeks' corrected GA, similarly to that reported in previous works (Uberos et al.,2020). Chorioamnionitis is acute inflammation of the chorion with or without involvement of the amnion and is evidence of a maternal immunological response to infection, with a history of foulsmelling amniotic fluid, fever, increased acutephase reactants and/or spontaneous onset preterm labour (Hall et al.,2022). A diagnosis of lateonset sepsis is made when a nosocomial sepsis (NOSEP1) score >8 is recorded. On this scale, the presence of CRP > 0.014 g/L is assigned five points; that of neutrophils >50%, three points; that of thrombocytopaenia <150 × 109/L, five points; and that of fever >38.2°C, five points (Mahieu et al.,2000). Earlyonset sepsis is considered when a vertical mother– child transmission mechanism can be demonstrated. (Simonsen et al.,2014). Persistent ductus arteriosus (PDA) is diagnosed by Doppler ultrasound and treated when clinical repercussions are observed or when the diameter is greater than 2 mm. The diagnosis of intraventricular haemorrhage (IVH) is based on Papile's classification (Papile et al., 1978). All neonates in this study received a transfontanellar ultrasound examination on the third day of life and every week thereafter. For the diagnosis of NEC, patients are classified according to Bell's criteria (Caplan & Jilling,2001). Cases classified as spontaneous intestinal perforations were excluded from this diagnosis. 2.4 | Statistical analysis of the results The descriptive data are summarized using medians and the interquartile range for the continuous values and the frequency distribution for the categorical variables. The Mann– Whitney Utest was used to make univariate comparisons of the continuous variables, and the chisquare test was applied for the categorical ones. Association analysis was performed using multinomial logistic regression. The degree of ROP was considered a dependent variable, since it is a categorical variable, and multinomial analysis was conducted to determine the risk associated with each category. The number of transfusions received and the day on which the first transfusion was performed (early transfusion was defined as that performed during the first 7 days of life) were considered as independent variables. Being transfused for the first time before or after 32 postmenstrual weeks was also considered an independent variable. Oxygen therapy (days) and GA were taken as adjustment variables. All statistical analyses were carried out using the IBM spss® 20.0 for Windows package (IBM). 3 | RESULTS Between January 2008 and December 2021, 565 VLBW newborns with GA <32 weeks or weight at birth <1500 g were treated in our NICU. Of these, 74 died before 36 weeks' corrected GA. In 14 cases, transfusion data were not available, and five infants were not included in the ROP programme (Figure1). Of the patients who developed ROP, 37 did not receive any red cell transfusion. Fortynine newborns received their first transfusion with a corrected GA <32 weeks, and 11 newborns FIGURE 1 Patient flow chart. 17553768, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/aos.15269 by Readcube (Labtiva Inc.), Wiley Online Library on [22/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License e298 | UBEROS et al. received their first red cell transfusion with ≥32 weeks corrected GA. Thirty newborns developed ROP grade 1 and 17 developed ROP grade 2. Fifty newborns developed severe ROP requiring laser treatment. Although only 14.4% received a red blood cell transfusion during the early neonatal period, 55.7% of the study cohort received a red blood cell transfusion before 36 weeks' corrected GA. Moreover, 83.3% of those under 27 weeks' GA received a red blood cell transfusion before 36 weeks' corrected GA. Having received the first red blood cell transfusion before 32 weeks of corrected GA is associated with an increased risk of ROP (OR 2.18; 95% CI 1.09– 4.36), while we did not observe a significant association between early red blood cell transfusion and ROP (Table2). Severe ROP was not significantly associated with early transfusion or receiving the first transfusion before 32 weeks of corrected GA (Table3). Overall, 263 of the newborns in our study cohort received a red blood cell transfusion prior to 36 weeks' corrected GA (Figure1). 26.4% of all red blood cell transfusions were performed between 24 and 26 weeks' corrected GA (Figure2). This age group accounted for 33.6% of all the cases of ROP detected and had a threefold greater need of oxygen therapy. Table1 shows the maternal and neonatal characteristics of our study cohort, revealing significant differences with respect to GA at birth and clinical history of chorioamnionitis. As expected, ROP was more prevalent at earlier gestational ages. Regarding the distribution of cases with IUGR, the study cohort presented no significant differences between newborns with or without ROP. The duration of oxygen therapy differed significantly between these groups. The raw data analysis revealed higher prevalences of red blood cell, platelet and plasma transfusions, together with a greater frequency of other neonatal comorbidities among the patients who developed ROP (Table1). TABLE 2 Logistic regression model for ROP risk OR (CI 95%) Unadjusted OR (CI 95%) Adjusted Early red cell transfusion 3.37 (2.03– 5.60)¶¶¶ 1.25 (0.68– 2.30) Late red cell transfusion 17.7 (6.82– 46.1)¶¶¶ 2.05 (0.51– 8.21) Red cell transfusion 1– 2 transfusions 1.66 (0.91– 3.02) 0.85 (0.43– 1.67) More than 3 10.8 (6.11– 19.1)¶¶¶ 2.77 (1.31– 5.88)¶¶ First red cell transfusion <32 weeks PMA 1.97 (1.19– 3.24)¶¶¶ 2.18 (1.09– 4.36)¶ ≥32 weeks PMA 0.90 (0.43– 1.92) 1.37 (0.62– 3.02) Platelet transfusion 4.71 (2.64– 8.38)¶¶¶ 1.86 (0.87– 3.98) Plasma transfusion 2.35 (1.33– 4.17)¶¶ 0.86 (0.40– 1.84) Chorioamnionitis 1.80 (1.03– 3.15)¶0.83 (0.40– 1.73) Apgar < 5, 5 min 2.00 (1.11– 3.63)¶0.91 (0.41– 2.01) BPD 6.03 (3.66– 9.94)¶¶¶ 1.18 (0.57– 2.44) PDA 4.33 (2.64– 7.08)¶¶¶ 1.15 (0.61– 2.18) IVH (Grade III) 2.16 (1.20– 3.90)¶0.81 (0.37– 1.76) IVH (Grade IIIIV) 1.30 (0.54– 3.139 1.08 (0.34– 3.39) NEC (Grade ≥ 2) 3.54 (1.93– 6.90)¶¶¶ 1.56 (0.70– 3.48) Early sepsis 2.98 (1.68– 5.28)¶¶¶ 1.66 (0.80– 3.44) Late onset sepsis 4.10 (2.59– 6.49)¶¶¶ 1.95 (1.13– 3.38)¶ Note: Adjusted for gestational age (weeks) and oxygen therapy (days). Abbreviations: BPD, bronchopulmonary dysplasia; IVH, intraventricular haemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PMA, postmenstrual age; ROP, retinopathy of prematurity. ¶p < 0.05; ¶¶p < 0.01; ¶¶¶p < 0.001. TABLE 3 Logistic regression model for severe ROP risk OR (CI 95%) Unadjusted OR (CI 95%) Adjusted Early red cell transfusion 6.86 (2.91– 16.1)¶¶¶ 1.60 (0.58– 4.37) Late red cell transfusion 4.56 (1.53– 13.5)¶¶¶ 1.07 (0.27– 4.19) Red cell transfusion 1– 2 transfusions 2.64 (1.00– 6.97)¶1.37 (0.48– 3.87) More than 3 16.9 (7.17– 39.8)¶¶¶ 3.95 (1.40– 11.1)¶¶ First red cell transfusion <32 weeks PMA 4.08 (2.17– 7.66)¶¶¶ 1.39 (0.60– 3.19) ≥32 weeks PMA 0.72 (0.23– 2.21) 1.22 (0.37– 4.04) Platelet transfusion 6.60 (3.26– 13.3)¶¶¶ 2.43 (0.98– 6.04) Plasma transfusion 2.02 (0.94– 4.37) 0.77 (0.29– 2.01) Chorioamnionitis 2.70 (1.38– 5.31)¶¶ 1.10 (0.48– 2.54) Apgar <5, 5min 2.71 (1.32– 557)¶¶ 1.10 (0.75– 2.73) BPD 8.37 (3.96– 17.7)¶¶¶ 1.36 (0.51– 3.61) PDA 4.83 (2.63– 8.87)¶¶¶ 1.20 (0.56– 2.85) IVH (Grade III) 3.14 (1.54– 6.38)¶¶ 1.35 (0.56– 3.28) IVH (Grade IIIIV) 2.24 (0.80– 6.21) 2.22 (0.63– 7.76) NEC (Grade ≥ 2) 4.13 (1.90– 8.99)¶¶¶ 1.75 (0.68– 4.49) Early sepsis 2.81 (1.37– 5.75)¶¶ 1.29 (0.55– 2.98) Late onset sepsis 3.34 (1.84– 6.06)¶¶¶ 1.45 (0.72– 2.91) Note: Adjusted for gestational age (weeks) and oxygen therapy (days). Abbreviations: BPD, bronchopulmonary dysplasia; IVH, intraventricular haemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PMA, postmenstrual age; ROP, retinopathy of prematurity. ¶p < 0.05; ¶¶p < 0.01; ¶¶¶p < 0.001. FIGURE 2 Histogram displaying the mean (95% CI) number of transfusions given at each gestational age. Note that most transfusions occurred before 28 weeks of gestational age. 17553768, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/aos.15269 by Readcube (Labtiva Inc.), Wiley Online Library on [22/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | e299UBEROS et al. However, the association analysis did not allow us to observe significant associations between ROP or severe ROP and the history of having received platelet transfusions or FFP. Table2 shows that having had lateonset sepsis is associated with an increased risk of ROP (OR 1.95; 95% CI 1.13– 3.38). However, lateonset sepsis is not significantly associated with severe ROP (Table3). History of having received more than 3 red blood cell transfusions (OR 2.77; 95% CI 1.31– 5.88) was a risk factor for ROP. After adjustment, severe ROP was also found to be associated with a history of having received three or more red blood cell transfusions (OR 3.95; 95% CI 1.40– 11.1). In this cohort, all cases of severe ROP were treated with laser. 4 | DISCUSSION According to the study data obtained, both the number of red blood cell transfusions and having received the first transfusion before 32 weeks corrected gestational age are important factors in determining the risk of ROP in VLBW preterm infants. Having suffered lateonset sepsis is another relevant factor for the risk of ROP. Red blood cell transfusion during the early neonatal period has been associated with the development of severe Lust et al.(2019) related the use of transfusions during the first 10 days of life with the development of severe ROP. Similarly, Schecter et al.(2021) observed that the number of red blood cell transfusions during the neonatal period in VLBW newborns is related to the development of more severe forms of ROP. Our own data show that the number of transfusions received is more significantly related to the risk of ROP and severe ROP than to that of early red blood cell transfusion. However, we observed that the administration of the first red blood cell transfusion during the vasoobliterative phase of ROP (<32 weeks of corrected GA) is significantly associated with an increased risk of ROP. We did not observe a significant association with the risk of ROP when the first transfusion is performed in the early neonatal period. Bas et al.(2018) reported that transfusions of packed red blood cells were closely related to the development of ROP. In the retina of the premature newborn, vessel growth that would occur in utero slows or ceases after birth and exposure to the relatively hyperoxic environment. As the newborn matures and retinal metabolism increases, local tissue hypoxia causes abnormal vessel growth and the development of retinopathy (Recchia & Capone Jr.,2004). Transfusions of adult red blood cells in the premature newborn increase the concentration of HbA, shifting the oxygen dissociation curve to the right and increasing oxygen delivery to the retinal tissue at a time when it is susceptible to hyperoxia. Moreover, repeated transfusions can lead to an accumulation of free iron, and hydroxyl radicals, which, as revealed by the Fenton reaction, can produce retinal damage (Wardle et al., 2002). Studies have also shown that blood transfusions in very premature newborns may drastically modify HbF levels (De Halleux et al.,2002; Stutchfield et al.,2017). Bas et al.(2018) suggest that limiting the number of transfusions can reduce the prevalence of ROP. Strategies such as late clamping of the umbilical cord and limiting the use of venipuncture for laboratory tests may reduce the need for red blood cell transfusion (Venancio et al.,2007; Widness et al.,2005). Platelet alpha granules include IGF1, IGFbinding protein 3 (the major serum binding protein for IGF1), VEGF and PDGF. IGF1 and VEGF levels are critically associated with the development of ROP (Yenice et al.,2013). IGF1 is necessary for VEGFinduced vessel growth, while low platelet count at an early GA slows vasculogenesis and leads to the development of ROP. In our cohort, the indication for transfusion was always made after confirming platelet values <50 000/μl. In this respect, Sahinoglu Keskek et al.(2020) noted that a low platelet count in the first week of life is an independent risk factor for ROP. Dani et al. (2014) observed that two or more FFP transfusions in the first week of life reduce the risk of developing any degree of ROP in premature infants with a GA of less than 29 weeks (Dani et al.,2014). We did not observe a significant association between ROP and FFP transfusion, although it is true that the newborns in whom it was indicated were critically ill newborns with consumptive coagulopathy. Some authors have related neonatal sepsis with the development of ROP possibly acting through the release of cytokines and endotoxins that would directly affect retinal angiogenesis. Neonatal sepsis can increase the duration of NICU care and of oxygen therapy required. Indeed, analysis of our data reveals an association with ROP in our study cohort. This study presents certain limitations, the most important of which is its retrospective nature. In addition, it is conceivable that the newborns whose condition is most serious are also most likely to require a transfusion. If this were so, the transfusions themselves would be mere confounding factors of another, unevaluated, condition. To address this possibility, we took into account the perinatal factors that are most frequently related to neonatal morbidity. We then considered the existence of an association between ROP and these factors, after adjusting for the variables known to influence the development of ROP, that is GA and oxygen therapy (ChavesSamaniego et al., 2020; Ng et al.,2020). 5 | CONCLUSIONS According to our findings, a history of having received more than three red blood cell transfusions or having been transfused before 32 weeks corrected gestational age is associated with an increase in the risk of developing severe ROP, although not with the risk of severe ROP. AUTHOR CONTRIBUTIONS J U designed the analysis and data interpretation procedures, cowrote the article and critically reviewed it for important intellectual content. He approves the present version for publication. He accepts responsibility for all aspects of the work, including the proper investigation 17553768, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/aos.15269 by Readcube (Labtiva Inc.), Wiley Online Library on [22/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License e300 | UBEROS et al. and resolution of questions related to its accuracy and completeness. J L GS performed the ophthalmological examinations. J L GS, A CM, A RL and E FM made substantial contributions to the conception and design of the study, cowrote the article and critically reviewed it for important intellectual content. They approve the present version for publication. They accept responsibility for all aspects of the work, including the proper investigation and resolution of questions related to its accuracy and completeness. ACKNOWLEDGEMENTS The authors thank the nursing staff of the Neonatal Unit involved for their invaluable collaboration with this study. Funding for open access charge: Universidad de Granada/CBUA. ETHICAL APPROVAL The study protocol was approved by the Ethics Committee of the hospital, and all current regulations regarding data confidentiality were respected. INFORMED CONSENT The consent of the parents or guardian of the patients was required. Informed consent was requested from all legal guardians. ORCID Jose Uberos https://orcid.org/0000-0002-3519-6678 REFERENCES Bas, A.Y., Demirel, N., Koc, E., Ulubas Isik, D., Hirfanoglu, I.M., Tunc, T. et al. (2018) Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TRROP study): a prospective, multicentre study in 69 neonatal intensive care units. The British Journal of Ophthalmology, 102, 1711– 1716. Caplan, M.S. & Jilling, T. (2001) New concepts in necrotizing enterocolitis. Current Opinion in Pediatrics, 13, 111– 115. Chan, H., CougnardGregoire, A., Korobelnik, J.F., Delyfer, M.N., Touboul, D., Coste, V. et al. (2018) Screening for retinopathy of prematurity by telemedicine in a tertiary level neonatal intensive care unit in France: review of a sixyear period. Journal Français d'Ophtalmologie, 41, 926– 932. ChavesSamaniego, M.J., Garcia Castejon, M., ChavesSamaniego, M.C., Solans Perez Larraya, A., Ortega Molina, J.M., Munoz Hoyos, A. et al. (2020) Risk calculator for retinopathy of prematurity requiring treatment. Frontiers in Pediatrics, 8, 529639. Collard, K.J., Godeck, S. & Holley, J.E. (2005) Blood transfusion and pulmonary lipid peroxidation in ventilated premature babies. Pediatric Pulmonology, 39, 257– 261. Dani, C., Poggi, C., Bresci, C., Corsini, I., Frosini, S. & Pratesi, S. (2014) Early freshfrozen plasma transfusion decreases the risk of retinopathy of prematurity. Transfusion, 54, 1002– 1007. De Halleux, V., Truttmann, A., Gagnon, C. & Bard, H. (2002) The effect of blood transfusion on the hemoglobin oxygen dissociation curve of very early preterm infants during the first week of life. Seminars in Perinatology, 26, 411– 415. Doyle, L.W., Halliday, H.L., Ehrenkranz, R.A., Davis, P.G. & Sinclair, J.C. (2005) Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics, 115, 655– 661. Ferrer Novella, C., Gonzalez Viejo, I., Pueyo Royo, V., Martinez Fernandez, R., Galdos Iztueta, M., Peralta Calvo, J. et al. (2013) Screening program for retinopathy of prematurity in Spain. Archivos de la Sociedad Española de Oftalmología, 88, 184– 188. Gilbert, C. (2008) Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control. Early Human Development, 84, 77– 82. Cryotherapy for Retinopathy of Prematurity Cooperative Group. (1988) Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Archives of Ophthalmology, 106, 471– 479. Hall, M., Hutter, J., Suff, N., Zampieri, C.A., Tribe, R.M., Shennan, A. et al. (2022) Antenatal diagnosis of chorioamnionitis: a review of the potential role of fetal and placental imaging. Prenatal Diagnosis, 42, 1049– 1058. Italiano, J.E., Jr., Richardson, J.L., PatelHett, S., Battinelli, E., Zaslavsky, A., Short, S. et al. (2008) Angiogenesis is regulated by a novel mechanism: proand antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood, 111, 1227– 1233. Jobe, A.H. & Bancalari, E. (2001) Bronchopulmonary dysplasia. American Journal of Respiratory and Critical Care Medicine, 163, 1723– 1729. Klement, G.L., Yip, T.T., Cassiola, F., Kikuchi, L., Cervi, D., Podust, V. et al. (2009) Platelets actively sequester angiogenesis regulators. Blood, 113, 2835– 2842. Lad, E.M., HernandezBoussard, T., Morton, J.M. & Moshfeghi, D.M. (2009) Incidence of retinopathy of prematurity in the United States: 1997 through 2005. American Journal of Ophthalmology, 148, 451– 458. Lust, C., Vesoulis, Z., Jackups, R., Jr., Liao, S., Rao, R. & Mathur, A.M. (2019) Early red cell transfusion is associated with development of severe retinopathy of prematurity. Journal of Perinatology, 39, 393– 400. Mahieu, L.M., De Muynck, A.O., De Dooy, J.J., Laroche, S.M. & Van Acker, K.J. (2000) Prediction of nosocomial sepsis in neonates by means of a computerweighted bedside scoring system (NOSEP score). Critical Care Medicine, 28, 2026– 2033. Ng, T.R., Wong, I.B., Ngo, C.S., Niduvaje, K., Ngiam, X.Y., Sensaki, S. et al. (2020) Case control study of risk factors and ophthalmological outcomes of very low birth weight infants with type 1 retinopathy of prematurity. Singapore Medical Journal, 61, 426– 434. Palmer, E.A. (1990) Results of U.S. randomized clinical trial of cryotherapy for ROP (CRYOROP). Documenta Ophthalmologica, 74, 245– 251. Papile, L.A., Burstein, J., Burstein, R. & Koffler, H. (1978) Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. The Journal of Pediatrics, 92, 529– 534. Patel, R.M., Knezevic, A., Yang, J., Shenvi, N., Hinkes, M., Roback, J.D. et al. (2019) Enteral iron supplementation, red blood cell transfusion, and risk of bronchopulmonary dysplasia in verylowbirthweight infants. Transfusion, 59, 1675– 1682. International Committee for the Classification of Retinopathy of Prematurity. (2005) The international classification of retinopathy of prematurity revisited. Archives of Ophthalmology, 123, 991– 997. Recchia, F.M. & Capone, A., Jr. (2004) Contemporary understanding and management of retinopathy of prematurity. Retina, 24, 283– 292. Sahinoglu Keskek, N., Gulcan, H., Yilmaz, G. & Akkoyun, I. (2020) Impact of platelet count in retinopathy of prematurity. Turkish Journal of Ophthalmology, 50, 351– 355. Sarlos, S., Rizkalla, B., Moravski, C.J., Cao, Z., Cooper, M.E. & WilkinsonBerka, J.L. (2003) Retinal angiogenesis is mediated by an interaction between the angiotensin type 2 receptor, VEGF, and angiopoietin. The American Journal of Pathology, 163, 879– 887. Schecter, L.V., Medina, A.E., Alexander, J.L. & Sundararajan, S. (2021) Impact of early postnatal exposure of red blood cell transfusions on the severity of retinopathy of prematurity. Journal of NeonatalPerinatal Medicine, 14, 527– 535. Simonsen, K.A., AndersonBerry, A.L., Delair, S.F. & Davies, H.D. (2014) Earlyonset neonatal sepsis. Clinical Microbiology Reviews, 27, 21– 47. Stutchfield, C.J., Jain, A., Odd, D., Williams, C. & Markham, R. (2017) Foetal haemoglobin, blood transfusion, and retinopathy 17553768, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/aos.15269 by Readcube (Labtiva Inc.), Wiley Online Library on [22/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | e301UBEROS et al. of prematurity in very preterm infants: a pilot prospective cohort study. Eye, 31, 1451– 1455. Uberos, J., JimenezMontilla, S., MolinaOya, M. & GarciaSerrano, J.L. (2020) Early energy restriction in premature infants and bronchopulmonary dysplasia: a cohort study. British Journal of Nutrition, 123, 1024– 1031. Valieva, O.A., Strandjord, T.P., Mayock, D.E. & Juul, S.E. (2009) Effects of transfusions in extremely low birth weight infants: A retrospective study. The Journal of Pediatrics, 155(3), 331– 337.e1. Venancio, J.P., Santos, A.M., Guinsburg, R., Peres Cde, A., Shinzato, A.R. & Lora, M.I. (2007) Strict guideline reduces the need for RBC transfusions in premature infants. Journal of Tropical Pediatrics, 53, 78– 82. Villeneuve, A., Arsenault, V., Lacroix, J. & Tucci, M. (2021) Neonatal red blood cell transfusion. Vox Sanguinis, 116, 366– 378. Wardle, S.P., Drury, J., Garr, R. & Weindling, A.M. (2002) Effect of blood transfusion on lipid peroxidation in preterm infants. Archives of Disease in Childhood. Fetal and Neonatal Edition, 86, F46– F48. Widness, J.A., Madan, A., Grindeanu, L.A., Zimmerman, M.B., Wong, D.K. & Stevenson, D.K. (2005) Reduction in red blood cell transfusions among preterm infants: results of a randomized trial with an inline blood gas and chemistry monitor. Pediatrics, 115, 1299– 1306. Yenice, O., Cerman, E., Ashour, A., Firat, R., Haklar, G., Sirikci, O. et al. (2013) Serum erythropoietin, insulinlike growth factor 1, and vascular endothelial growth factor in etiopathogenesis of retinopathy of prematurity. Ophthalmic Surgery, Lasers & Imaging Retina, 44, 549– 554. How to cite this article: Uberos, J., FernandezMarin, E., CamposMartínez, A., RuizLópez, A. & GarcíaSerrano, J.L. (2023) Blood products transfusion and retinopathy of prematurity: A cohort study. Acta Ophthalmologica, 101, e294–e301. Available from: https://doi.org/10.1111/aos.15269 17553768, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/aos.15269 by Readcube (Labtiva Inc.), Wiley Online Library on [22/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License