Abstract
Aim
The aim of this study is to examine possible associations between the transfusion of RBC or platelets (PLTs) and the development of retinopathy of prematurity (ROP) in infants.
Methods
This retrospective, national, case-control study included all live births in Switzerland between 2013 and 2018. We investigated preterm infants at a gestational age of <28 weeks, who developed higher stage ROP (≥stage 2, n = 178). Each case infant was matched to another of the same sex who did not develop ROP (n = 178, control group).
Results
When compared with the control group, we observed higher numbers of RBC transfusions per infant and higher percentages of infants receiving PLT transfusions in the case group. An adjusted logistic regression analysis revealed that both RBC (odds ratio [OR] 1.081, 95% confidence interval [CI] 1.020–1.146) and PLT transfusions (OR = 2.502, 95% CI 1.566–3.998) numbers were associated with ROP development.
Conclusions
Multiple RBC and PLT transfusions are associated with higher stage ROP development. Prospective studies are required to determine their potential as risk factors.
Keywords: Platelet transfusion, Red blood cell transfusion, Retinopathy of prematurity
Introduction
As mortality of extremely preterm infants has decreased in recent years [1], comorbidities such as retinopathy of prematurity (ROP) are of growing concern. ROP is the most common and potentially preventable cause of blindness or visual impairment in childhood and is associated with worse neurological and cognitive long-term developmental outcomes [2]. In Switzerland, 1.8% of infants born below 32 weeks gestation require ROP treatment, representing an internationally low incidence [3, 4].
Postnatally, partial oxygen (O2) pressure levels are higher when compared to in utero. This hyperoxic state leads to delayed vascularization of the immature retina, due to vascular endothelial growth factor (VEGF) suppression. Without adequate blood supply, the metabolically active retina becomes increasingly hypoxic over time, resulting in VEGF and other pro-angiogenic factor upregulation, and leading to aberrant vascularization [5].
To prevent these serious complications, it is crucial to identify factors increasing their risk. Established risk factors include low gestational age (GA) and low birth weight, especially for infants who have a body weight < the 10th percentile [5]. Similarly, O2 administration and hyperoxia [5] are further risk factors, while the role of sepsis [6] is equivocal. Currently, there is debate on whether RBC or platelet (PLT) transfusion increases the risk of developing ROP.
Studies have shown that high percentages of preterm infants receive blood transfusions [7], with some side effects including allergic or haemolytic reactions, and the release of pro-inflammatory and immunomodulatory mediators such as cytokines or VEGF [8]. However, a possible association between RBC transfusions and an increased ROP risk remains a subject of controversy, as neither prospective [9, 10, 11] nor retrospective [12, 13, 14] data analyses have provided consistent, unambiguous results. Similarly, other studies have suggested links between thrombocytopenia, PLT transfusions, and ROP development [15, 16, 17, 18]. Our aim was to investigate whether associations existed between RBC and PLT transfusions and ROP in Switzerland.
Patients and Methods
This was a retrospective, national, case-controlled study in all 9 neonatal intensive care units in Switzerland. We included all Swiss preterm infants (n = 178) born between 2013 and 2018 at a GA <28 weeks, who developed stage 2 ROP at least, as defined by the International Classification of Retinopathy of Prematurity [19].
Each infant in the case group was matched to another of the same sex, who did not develop ROP (control group, n = 178). Other matching criteria included treatment at the same perinatal centre, GA (same week) and birth weight (same quartile).
Infants were excluded if they had severe congenital malformations, documented parental refusal to consent, incomplete medical records or transfusion data, or the infant died before ROP screening could be performed. No case infants were lost due to incomplete data or parental refusal to consent.
Patient Data and Definitions
Patient characteristics and outcomes were extracted from SwissNeoNet. RBC and PLT transfusion data were gathered by local investigators from infant medical notes. Major brain lesions (defined as intraventricular haemorrhage grade 3 or higher, or cystic periventricular leukomalacia, MBL), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, and late-onset neonatal sepsis were defined as previously published [20]. Outborn was defined as a birth outside the perinatal centre. Days on additional O2 were defined as the number of days where FiO2 > 0.21 was provided for at least 12 h per day.
Perinatal Centre Guidelines
All infants were screened for ROP. Infants with a haemorrhage received a PLT transfusion (10–20 mL/kg of body weight) if their PLT levels were <50 G/L and those without haemorrhage if their PLT levels reached <20 G/L, respectively. RBC transfusions (10–20 mL/kg of body weight) were administered depending on haematocrit/haemoglobin levels, the need for O2, cardiopulmonary disease, and clinical symptoms. Preterm infants routinely received erythropoietin (EPO) for treatment of anaemia of prematurity at 3 perinatal centres involving 3 intravenous/subcutaneous administrations of 250–400 IU EPO per week. They were evenly distributed among cases (N = 49) and controls (N = 51). Target blood oxygenation levels averaged 87–95%.
Statistics
The χ2 test or Fisher's exact test was used for categorical and the Mann-Whitney U test for metric variables. Effect sizes (r) were determined by calculating Phi and Cramer's V for the χ2 test and the rank-biserial correlation for the Mann-Whitney U test. An adjusted ordinal logistic regression tested for links between blood transfusions and ROP development. We adjusted for GA, birth weight (Z scores), sepsis, MBL, and days on additional O2. p values <0.05 were considered statistically significant. Statistical analyses were performed using the IBM SPSS Statistics 25 USA programme.
Results
Baseline characteristics between case and control groups were similar (Table 1), apart from a slightly lower mean GA and birth weight, a poorer clinical health in case infants with MBL (18 vs. 8%, p = 0.008, r = 0.14), a statistical tendency towards a higher number of days on additional O2 (71 vs. 68 days, p = 0.074, r = 0.1), a higher rate of severe BPD (25 vs. 12%, p = 0.006, r = 0.17), and a more frequent administration of BPD steroid treatments (28 vs. 19%, p = 0.046, r = 0.11). The distribution of these characteristics was reflected by older postmenstrual age upon hospital discharge from hospital (42 1/7 weeks of pregnancy vs. 41 2/7 weeks of pregnancy, p = 0.004, r = 0.16). In the case group, 87 infants (49%) developed severe ROP (≥stage 3) of which 50 (57%) were treated.
Table 1.
Case population demographic data and the Swiss population as a whole
| Demographic data | Cohort, n = 1,365 | Case group, n = 178 | Control group, n = 178 | p value | Effect size, r | |
|---|---|---|---|---|---|---|
| Male, n (%) | 717 (52) | 103 (58) | 103 (58) | |||
| GA (weeks of pregnancy) | 26 1/7 | 25 3/7 | 25 5/7 | 0.003 | 0.16 | |
| (25 2/7–27 1/7) | (24 4/7–26 1/7) | (24 6/7–26 3/7) | ||||
| Birth weight, g | 800 (680–950) | 703 (588–792) | 737 (620–740) | 0.009 | 0.14 | |
| SGA, n (%) | 166 (12) | 35 (20) | 27 (15) | 0.264 | 0.06 | |
| Deceased infants, n (%) | 220 (16) | 4 (2) | 3 (2) | 0.703 | 0.02 | |
| Outborn, n (%) | 73 (5) | 1 (1) | 4 (2) | 0.177 | 0.07 | |
| Multiples, n (%) | 382 (28) | 61 (34) | 46 (26) | 0.083 | 0.08 | |
| Section, n (%) | 1,084 (79) | 155 (87) | 145 (82) | 0.145 | 0.08 | |
| Surfactant, n (%) | 1,124 (82) | 162 (91) | 158 (89) | 0.482 | 0.04 | |
| Antenatal steroids, n (%) | 1,261 (93) | 171 (96) | 167 (94) | 0.333 | 0.05 | |
| Steroids for BPD, n (%) | 188 (14) | 50 (28) | 34 (19) | 0.046 | 0.11 | |
| EPO to prevent anaemia, n (%) | na | 49 (28) | 51 (29) | 0.814 | 0.01 | |
| Postmenstrual age in weeks of pregnancy upon discharge from hospital | 38 6/7 | 42 1/7 | 41 2/7 | 0.004 | 0.16 | |
| (36 2/7–41 1/7) | (39 4/7–43 5/7) | (38 1/7–42 4/7) | ||||
| Sepsis, n (%) | 321 (24) | 56 (32) | 47 (26) | 0.293 | 0.06 | |
| MBLs, n (%) | 189 (14) | 32 (18) | 15 (8) | 0.008 | 0.14 | |
| Necrotizing enterocolitis, n | (%) | 95 (7) | 15 (8) | 11 (6) | 0.415 | 0.04 |
| BPD, n (%) | ||||||
| Moderate | 217 (16) | 55 (31) | 59 (33) | 0.006 | 0.17 | |
| Severe | 119 (9) | 44 (25) | 21 (12) | |||
| Days on additional O2 | 37 (10–62) | 71 (52–88) | 68 (48–80) | 0.074 | 0.1 | |
| ROP stage, n (%) | ||||||
| Stage 2 | 91 (51) | |||||
| Stage 3 | 85 (48) | |||||
| Stage 4 | 1 (1) | |||||
| Stage 5 | 1 (1) | |||||
| ROP therapy, n (%) | ||||||
| Anti-VEGF | 15 (8) | |||||
| Laser/cryotherapy | 35 (20) |
ROP, retinopathy of prematurity; BPD, bronchopulmonary dysplasia; MBL, major brain lesion; EPO, erythropoietin; VEGF, vascular endothelial growth factor; SGA, small for gestational age; O2, oxygen. Values in parenthesis show the interquartile range. p values and the effect size related to case and control groups.
In comparison with the overall Swiss source population (Table 1), mortality was higher in the source population (16%) than in the case and control populations (2% each). This concerns infants who died prior to being screened for ROP. They were, therefore, excluded. Case and control populations comprised patients in poorer clinical health than the source population. They had lower GA and birth weights, higher rates of severe BPD, more days on additional O2, and longer hospital stays.
We observed statistically significant differences between transfused infants in the case and the control groups. The latter received a higher number of RBC transfusions per infant (4 vs. 3; p < 0.001, r = 0.26) and higher volumes of RBCs per transfusion (57.3 vs. 40.3 mL; p < 0.001, r = 0.21). They also received transfusion treatments earlier (at 3 days postnatal age vs. 5 days, p < 0.001, r = 0.19) (Table 2). A higher number of infants from the case group received 1 or more PLT transfusions (39 vs. 18%, p < 0.001, r = 0.23) (Table 3), but there was no difference between groups in terms of the numbers of transfusions per infant, transfusion volumes, and the timing of transfusions.
Table 2.
RBC transfusion analysis between the case and control groups
| RBC transfusion parameters | Case group, n = 178 | Control group, n = 178 | p value | Effect size, r |
|---|---|---|---|---|
| Infants receiving transfusions, n (%) | 162 (91) | 154 (87) | 0.179 | 0.07 |
| Transfusions per infant, n | 4 | 3 | 0.001 | 0.26 |
| Transfusion volume, mL | 57.3 (32.4–97.9) | 40.3 (23.8–64.9) | <0.001 | 0.21 |
| Timing of 1st transfusion (postnatal age in days) | 3 | 5 | <0.001 | 0.19 |
The median is shown for transfusion analysis; the value in parentheses reflects the interquartile range.
Table 3.
PLT transfusion analysis between the case and control groups
| PLT transfusion parameters | Case group, n = 178 | Control group, n = 178 | p value | Effect size, r |
|---|---|---|---|---|
| Infants receiving transfusion, n (%) | 69 (39) | 32 (18) | <0.001 | 0.23 |
| Transfusions per infant | 2 | 3 | 0.776 | 0.03 |
| Transfusion volume, mL | 27.5 (12.5–63.2) | 31.1 (12.5–64.6) | 0.710 | 0.04 |
| Timing of 1st transfusion (postnatal age in days) | 5 | 4 | 0.205 | 0.13 |
PLT, platelet. The median is shown for transfusion analysis; the value in parentheses reflects the interquartile range.
Using a univariable approach, we observed an association between ROP and the amount (number/volume) of RBC transfusions for infants receiving transfusions and for ROP and PLT transfusions. We further tested these associations using a logistic regression approach, adjusting for major differences in baseline characteristics, that is, sepsis, MBL and days on additional O2 (Tables 4−6). As matching does not necessarily control for confounding by matching factors, both GA and birth weight were included in logistic regression analyses [21].
Table 4.
Ordinal logistic regression of RBC transfusion volumes/infant receiving a transfusion
| Parameter | OR | CI (95%) | p value |
|---|---|---|---|
| RBC transfusion volume | 1.001 | 1.000–1.002 | 0.182 |
| GA | 0.957 | 0.930–0.985 | 0.003 |
| Birth weight (Z score) | 1.000 | 1.000–1.000 | 0.053 |
| Sepsis | 1.072 | 0.685–1.678 | 0.762 |
| MBLs | 2.100 | 1.183–3.728 | 0.011 |
| Days on additional O2 | 1.002 | 0.996–1.007 | 0.544 |
MBL, major brain lesion; GA, gestational age; OR, odds ratio, CI, confidence interval; O2, oxygen.
Table 6.
Ordinal logistic regression for PLT transfusions for all infants
| Parameter | OR | CI (95%) | p value |
|---|---|---|---|
| Receiving a transfusion (yes/no) | 2.502 | 1.566–3.998 | <0.001 |
| GA | 0.959 | 0.932–0.987 | 0.005 |
| Birth weight (Z score) | 1.000 | 1.000–1.000 | 0.094 |
| Sepsis | 0.934 | 0.591–1.475 | 0.769 |
| MBLs | 1.899 | 1.058–3.408 | 0.032 |
| Days on additional O2 | 1.000 | 0.994–1.006 | 0.933 |
MBL, major brain lesion; OR, odds ratio, CI, confidence interval; O2, oxygen.
The development of severe ROP was associated with the number of RBC transfusions per infant (odds ratio [OR] = 1.081, 95% confidence interval [CI] 1.020–1.146, p = 0.008) and the number of infants who received at least 1 PLT transfusion (OR = 2.502, 95% CI 1.566–3.998, p < 0.001). RBC transfusion volumes were less strongly associated (OR = 1.001, 95% CI 1.000–1.002, p = 0.182) and were, therefore, a worse predictor than the number of RBC transfusions.
Discussion
In our retrospective, national, 1:1 matched case-control study, RBC and PLT transfusions were associated with the development of severe ROP, both in primary analysis and adjusted logistic regression. Infants in the case group were less healthy than the corresponding Swiss source population <28 weeks gestation. This may indicate either a selection bias or confounding. A selection bias would apply if both case and control groups were comparably less healthy than the overall Swiss national cohort, and both groups had an increased need for transfusions. The link between RBC/PLT transfusions and ROP could, therefore, be more pronounced than our study suggests if the case group were compared to the overall Swiss cohort. Confounding would apply if sicker infants had a higher risk for developing ROP, and at the same time, a higher need for transfusions without transfusions being an intermediate step in the causal pathway to ROP. However, the degree of illness of cases and controls was similar in comparison with the overall collective, the association between transfusions and ROP was consistent in primary and adjusted analyses, and the literature discussed below indicates association. This leads us to believe that our study warrants further, prospective investigation of the association between transfusions and ROP.
RBC Transfusions and Anaemia
Case infants received significantly more RBC transfusions and volumes, when compared to control infants. On average, they also received earlier transfusions. Various models have sought to explain the influence of RBC transfusions on ROP development from a pathogenic perspective. In preterm infants, RBC transfusions significantly increase adult haemoglobin levels in overall haemoglobin. Due to the lower O2 affinity of adult haemoglobin, this can lead to increased O2 transfer to the tissue, inducing hyperoxia of tissue [22]. Other studies have shown that multiple RBC transfusions also trigger iron overload, potentially contributing to ROP pathogenesis, due to increased pro-inflammatory cytokines and oxidative stress [23].
Prospective studies, comparing liberal and restrictive RBC transfusion guidelines and associated neonatal outcomes, have shown that liberal transfusion groups receive more transfusions, but no statistically significant differences are observed in ROP incidences between groups [9, 10, 11]. However, some retrospective studies have observed associations between RBC transfusions and ROP [12, 13, 14].
Our logistic regression analysis revealed a statistically significant association between MBL and ROP; however, there is little evidence in the literature to support this finding. However, the literature suggests that an increased need for additional O2 is a risk factor for ROP development, due to the potential effects of hyperoxia. In contrast, an increased O2 requirement plays an important role in defining RBC transfusion limits in preterm infants. Consequently, these infants tend to have higher transfusion limits, which translates to more RBC transfusions overall. We attempted to correct for this three-way relationship by including the number of days on additional O2 in our logistic regression analysis.
PLT Transfusions
More infants in the case group required 1 or more PLT transfusions, using primary and adjusted analyses; thus, more infants in this group presented with thrombocytopenia severe enough to indicate a PLT transfusion. As our study was retrospective, it was not possible to ascertain whether ROP associates with the PLT transfusion itself or with the condition of thrombocytopenia. However, the literature provides possible explanations for both.
For instance, PLT transfusion release cytokines, VEGF and other immunomodulatory mediators, and favours inflammatory and proliferative processes [8]. Other studies have shown associations between severe thrombocytopenia and ROP development [15, 16, 17, 18]. Thrombocytopenia in itself triggers the release of pro-inflammatory mediators [24]. Furthermore, PLTs carry both pro- and anti-angiogenic factors in their granules, which can be selectively released. Thus, this process could play an important role in ROP development [25]. As a result, thrombocytopenia could contribute to ROP pathogenesis in the initial phase, as reduced pro-angiogenic factors could restrict the development of new retinal blood vessels. In the 2nd phase of ROP development, PLT transfusions could inhibit VEGF-induced neovascularization because of anti-angiogenic factor release from transfused PLTs. Larger prospective studies are required to assess true causal relationships.
Strengths and Limitations
Our national study included all premature infants with at least stage 2 ROP, in a defined geographical area. Patient characteristics and comorbidities were clearly defined, well-recorded, and comparable between participating perinatal centres. As limitations, we list the retrospective nature of the study and the differences between clinics in terms of transfusion guidelines and targets for O2 saturation limits. As each infant in the case group was matched to another from the same, there were no differences in treatment approaches between groups.
Conclusions
We observed an association between RBC or PLT transfusion and ROP development. Prospective studies are required to examine possible causal relationships between these parameters.
Statement of Ethics
This study was approved by the Ethikkommission Zurich (References; 2014-0551, 2014-0552 and 2019-01205). Participating centres were obliged to inform parents about the scientific use of anonymized data at the time of data collection. No data were recorded upon documented parental refusal to consent.
Conflict of Interest Statement
Mark Adams receives a salary as network coordinator for the Swiss Neonatal Network. The remaining authors declare no conflicts of interest.
Funding Sources
The authors received no specific funding for this work.
Author Contributions
Tobias Hengartner and Mark Adams: data collection, analysis, interpretation, literature search, and manuscript writing; Romaine Arlettaz Mieth: supervision, study design, data collection and interpretation of analysis, and manuscript revision; remaining authors: data collection and proofreading of the manuscript; all authors agree to the final version of the manuscript.
Table 5.
Ordinal logistic regression of the number of RBC transfusions/infant receiving a transfusion
| Parameter | OR | CI (95%) | p value |
|---|---|---|---|
| RBC transfusions | 1.081 | 1.020–1.146 | 0.008 |
| GA | 0.965 | 0.937–0.994 | 0.018 |
| Birth weight (Z score) | 1.000 | 1.000–1.000 | 0.090 |
| Sepsis | 0.932 | 0.587–1.480 | 0.765 |
| MBLs | 1.939 | 1.084–3.468 | 0.026 |
| Days on additional O2 | 0.999 | 0.993–1.005 | 0.841 |
MBL, major brain lesion; GA, gestational age; OR, odds ratio, CI, confidence interval; O2, oxygen.
Acknowledgements
We thank Rachel Scholkmann for assistance in translating the manuscript. We thank the following units for their collaboration: Cantonal Hospital Aarau, Children's Clinic, Department of Neonatology (Ph. Meyer, R. Kusche); University of Basel Children's Hospital (UKBB), Department of Neonatology (S. Schulzke); University Hospital Berne, Department of Neonatology (M. Nelle), Department of Paediatric Intensive Care and Neonatology (T. Humpl); Cantonal Hospital Graubuenden, Department of Paediatrics (T. Riedel), Department of Child and Adolescent; University Hospital (HUG), Neonatology Units (R.E. Pfister); University Hospital (CHUV), Department of Neonatology (J.F. Tolsa, M. Roth-Kleiner); Children's Hospital of Lucerne, Neonatal and Paediatric Intensive Care Unit (M. Stocker); Cantonal Hospital St. Gallen, Department of Neonatology (A. Malzacher); Children's Hospital of Eastern Switzerland, Neonatal and Paediatric Intensive Care Unit (B. Rogdo); University Hospital Zurich (USZ), Department of Neonatology (D. Bassler); and University Children's Hospital Zurich, Department of Neonatology (V. Bernet).
Joint first authorship: Tobias Hengartner and Mark Adams contributed equally to the publication.
References
- 1.Grandi C. Neonatal mortality in the framework of the Millennium Development Goals and new post-2015 goals. Arch Argent Pediatr. 2018;116((4)):238–40. doi: 10.5546/aap.2018.eng.238. [DOI] [PubMed] [Google Scholar]
- 2.Molloy CS, Anderson PJ, Anderson VA, Doyle LW. The long-term outcome of extremely preterm (<28 weeks' gestational age) infants with and without severe retinopathy of prematurity. J Neuropsychol. 2016;10((2)):276–94. doi: 10.1111/jnp.12069. [DOI] [PubMed] [Google Scholar]
- 3.Gerull R, Brauer V, Bassler D, Laubscher B, Pfister RE, Nelle M, et al. Incidence of retinopathy of prematurity (ROP) and ROP treatment in Switzerland 2006–2015: a population-based analysis. Arch Dis Child Fetal Neonatal Ed. 2018;103((4)):F337–f42. doi: 10.1136/archdischild-2017-313574. [DOI] [PubMed] [Google Scholar]
- 4.Darlow BA, Lui K, Kusuda S, Reichman B, Håkansson S, Bassler D, et al. International variations and trends in the treatment for retinopathy of prematurity. Br J Ophthalmol. 2017;101((10)):1399–404. doi: 10.1136/bjophthalmol-2016-310041. [DOI] [PubMed] [Google Scholar]
- 5.Hellstrom A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet. 2013;382((9902)):1445–57. doi: 10.1016/S0140-6736(13)60178-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Huang J, Tang Y, Zhu T, Li Y, Chun H, Qu Y, et al. Cumulative evidence for association of sepsis and retinopathy of prematurity. Medicine. 2019;98((42)):e17512. doi: 10.1097/MD.0000000000017512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Howarth C, Banerjee J, Aladangady N. Red blood cell transfusion in preterm infants: current evidence and controversies. Neonatology. 2018;114((1)):7–16. doi: 10.1159/000486584. [DOI] [PubMed] [Google Scholar]
- 8.Stolla M, Refaai MA, Heal JM, Spinelli SL, Garraud O, Phipps RP, et al. Platelet transfusion: the new immunology of an old therapy. Front Immunol. 2015;6:28. doi: 10.3389/fimmu.2015.00028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.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 different transfusion criteria. Pediatr Neonatol. 2009;50((3)):110–6. doi: 10.1016/S1875-9572(09)60045-0. [DOI] [PubMed] [Google Scholar]
- 10.Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149((3)):301–7. doi: 10.1016/j.jpeds.2006.05.011. [DOI] [PubMed] [Google Scholar]
- 11.Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. 2005;115((6)):1685–91. doi: 10.1542/peds.2004-1884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.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. 2019;39((3)):393–400. doi: 10.1038/s41372-018-0274-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.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. 2019;39((8)):1089–97. doi: 10.1038/s41372-019-0408-8. [DOI] [PubMed] [Google Scholar]
- 14.Ghirardello S, Dusi E, Cortinovis I, Villa S, Fumagalli M, Agosti M, 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. 2017;34((1)):88–95. doi: 10.1055/s-0036-1584300. [DOI] [PubMed] [Google Scholar]
- 15.Cakir B, Liegl R, Hellgren G, Lundgren P, Sun Y, Klevebro S, et al. Thrombocytopenia is associated with severe retinopathy of prematurity. JCI Insight. 2018;3((19)):e99448. doi: 10.1172/jci.insight.99448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Jensen AK, Ying GS, Huang J, Quinn GE, Binenbaum G. Longitudinal study of the association between thrombocytopenia and retinopathy of prematurity. J Aapos. 2018;22((2)):119–23. doi: 10.1016/j.jaapos.2017.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Sancak S, Toptan HH, Gokmen Yildirim T, Karatekin G, Ovali F. Thrombocytopenia as a risk factor for retinopathy of prematurity. Retina. 2019;39((4)):706–11. doi: 10.1097/IAE.0000000000002028. [DOI] [PubMed] [Google Scholar]
- 18.Lundgren P, Lundberg L, Hellgren G, Holmström G, Hård AL, Smith LE, et al. Aggressive posterior retinopathy of prematurity is associated with multiple infectious episodes and thrombocytopenia. Neonatology. 2017;111((1)):79–85. doi: 10.1159/000448161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.International Committee for the Classification of Retinopathy of Prematurity The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123((7)):991–9. doi: 10.1001/archopht.123.7.991. [DOI] [PubMed] [Google Scholar]
- 20.Schlapbach LJ, Adams M, Proietti E, Aebischer M, Grunt S, Borradori-Tolsa C, et al. Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008. BMC Pediatr. 2012;12:198. doi: 10.1186/1471-2431-12-198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Pearce N. Analysis of matched case-control studies. 2016. [DOI] [PMC free article] [PubMed]
- 22.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. 2017;31((10)):1451–5. doi: 10.1038/eye.2017.76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Dani C, Reali MF, Bertini G, Martelli E, Pezzati M, Rubaltelli FF. The role of blood transfusions and iron intake on retinopathy of prematurity. Early Hum Dev. 2001;62((1)):57–63. doi: 10.1016/s0378-3782(01)00115-3. [DOI] [PubMed] [Google Scholar]
- 24.Sola-Visner M, Bercovitz RS. Neonatal platelet transfusions and future areas of research. Transfus Med Rev. 2016;30((4)):183–8. doi: 10.1016/j.tmrv.2016.05.009. [DOI] [PubMed] [Google Scholar]
- 25.Italiano JE, Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood. 2008;111((3)):1227–33. doi: 10.1182/blood-2007-09-113837. [DOI] [PMC free article] [PubMed] [Google Scholar]