Abstract
Aim
This study evaluated the correlation between retinopathy of prematurity (ROP), anaemia and blood transfusions in extremely preterm infants.
Methods
We included 227 infants born below 28 weeks of gestation at King Edward Memorial Hospital, Perth, Australia, from 2014–2016. Birth characteristics and risk factors for ROP were retrieved, and anaemia and severe anaemia were defined as a haemoglobins of <110 g/L and <80 g/L, respectively. Logistic regression was used for the analysis.
Results
Retinopathy of prematurity treatment was needed in 11% of cases and the mean number of blood transfusions (p < 0.01), and mean number of weeks of anaemia (p < 0.001) and of severe anaemia (p < 0.05), had positive associations with ROP cases warranting treatment. In the multivariate logistic regression analysis, the best-fit model of risk factors included anaemic days during first week of life, with an odds ratio (OR) of 1.46% and 95% confidence interval (CI) of 1.16–1.83 (p < 0.05), sepsis during the first 4 weeks of life (OR 3.14, 95% CI 1.10–9.00, p < 0.05) and days of ventilation (OR 1.03, 95% CI 1.01–1.06, p < 0.05).
Conclusion
The duration of anaemia during the first week of life was an independent risk factor for ROP warranting treatment and preventing early anaemia may decrease this risk.
Keywords: Anaemia, Blood transfusions, Erythropoietin, Preterm infants, Retinopathy of prematurity
INTRODUCTION
Retinopathy of prematurity (ROP) is a disease that is caused by abnormal vascular development and it affects the way that the retina develops in preterm infants (1). The hypothesis of oxygen toxicity, and the concept of ROP as a two-phase disease, was first presented by Ashton in 1954 (2). In phase one, hyperoxia suppresses the production of growth factors, such as vascular endothelial growth factor (VEGF) and erythropoietin, which delays normal retinal vessel growth, leading to retinal hypoxia as the neural retina matures and increases its metabolic demands. In phase two, the hypoxic avascular retina stimulates large increases in VEGF and erythropoietin, resulting in uncontrolled retinal neovascularisation (3). Without timely treatment, neovascularisation can lead to retinal detachment and blindness. Phase one occurs within the infants’ first weeks of life, and phase two ROP develops weeks to months after birth.
Prematurity and, or, low birthweights are known risk factors for ROP (2). It has been suggested that the risk factors for ROP may be phase-dependent and that they only have an impact during the early or late postnatal period, or in both (4). The overall health status of infants also affects the risk for ROP and other complications of preterm birth, such as bronchopulmonary dysplasia, necrotising enterocolitis, intraventricular haemorrhage and sepsis, is often seen in association with ROP (5–7).
Anaemia of prematurity is a common condition in preterm infants, especially in extremely preterm infants born before 28 weeks of gestation (8). It is caused by immaturity of the haematopoietic system and is due to inadequate production of erythropoietin and iatrogenic blood loss due to frequent blood sampling (9). Most extremely preterm infants receive blood transfusions for anaemia at some point during their hospitalisation (10), based on haemoglobin levels and clinical indications, including oxygen requirements (11).
Whether anaemia and blood transfusions are risk factors for ROP has been unclear. Some studies have suggested that anaemia was protective for ROP (12,13), whereas others have suggested that timely correction of anaemia with blood transfusions may have initiated the regression of ROP (14). Anaemia at birth has been associated with ROP development (15). However, prospective studies have shown that neither a liberal nor restrictive approach to blood transfusions in preterm infants affected ROP incidence or severity (16–19).
We aimed to evaluate the correlation between ROP, anaemia and blood transfusions in extremely preterm infants.
PATIENTS AND METHODS
In this retrospective cohort study, all extremely preterm infants born at less than 28 weeks of gestational age (GA), admitted to the level three neonatal intensive care unit at King Edward Memorial Hospital and Princess Margaret Hospital in Perth, Australia, between January 1, 2014 and September 1, 2016, were eligible for enrolment. Infants who died before 40 weeks of postmenstrual age (PMA) were excluded.
Data collection
Data on birth characteristics and risk factors for ROP, including sepsis, duration of oxygen requirement and ventilation, anaemia and blood transfusions, were collected. Sepsis was defined as a positive blood culture, and isolating the same organism from another blood culture within 7 days of the initial positive blood culture was considered to be one episode of sepsis. Anaemia and severe anaemia were defined as haemoglobin levels of <110 g/L and <80 g/L, respectively. The mean haemoglobin level and number of blood transfusions for each week during the postnatal period was calculated based on the laboratory records. Data on all eligible infants were collected from admission until 35 weeks of PMA.
ROP screening
Eye examinations were performed according to Australian and New Zealand ROP screening guidelines. ROP classifications were based on the International Classification of Retinopathy of Prematurity revisited guidelines (20). Treatment was based on the recommendations of the Early Treatment for Retinopathy of Prematurity Cooperative Group (21).
Blood transfusion and anaemia of prematurity
Routine blood samples were drawn according to local guidelines and clinical indications. All available values for haemoglobin levels were retrieved. Mean haemoglobin level per day was calculated for each infant, and, when multiple haemoglobin values were available for the same day, mean haemoglobin was calculated using the minimum and maximum haemoglobin for that day. The mean weekly haemoglobin was calculated for each infant based on the mean daily haemoglobin. Anaemia was defined as haemoglobin <110 g/L and severe anaemia as <80 g/L (11,13,22,23). The lowest haemoglobin value per day was recorded to indicate whether anaemia or severe anaemia was present or not that day. A week was designated as one with anaemia or severe anaemia if either condition were present for one or more days during that week. The date and number of blood transfusion were recorded, and the decisions for blood transfusions were based on local guidelines and clinical indications.
Statistical considerations
The independent samples t-test, Mann–Whitney U test and chi-square test were used to explore the relationships between the variables. Univariate and multivariate logistic regression analyses were applied to evaluate the impact of different risk factors for ROP warranting treatment. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for each risk factor. We assessed the impact of the risk factors over the entire study period, as well as during specific time periods as follows: the first week of life, the first 4 weeks of life and after the first 4 weeks. The level of significance was set as a p value of <0.05. Pearson’s correlation test was used to estimate correlations between the risk factors. The fit of the models was checked with the Hosmer–Lemeshow goodness-of-fit test. All analyses were carried out with IBM SPSS Statistics 20 for Microsoft Windows (IBM, Armonk, NY, USA).
Ethical considerations
The study was approved by the governance committee of the hospital and the institutional research screening committee at the women and newborn health service.
RESULTS
Clinical characteristics
A total of 235 extremely preterm infants were admitted over the study period, and eight infants were excluded because they died before 40 weeks of PMA. Data on 227 infants were analysed. The median GA and birthweight were 26 + 3 weeks of GA and 880 g, respectively. A total of 25 of 227 (11.0%) infants developed ROP warranting treatment. These infants were more immature at birth (23 + 1 versus 26 + 3, p < 0.001) and had a lower birthweight (694 versus 908 g, p < 0.001) compared to those who did not warrant ROP treatment (Table 1). The characteristics of the enrolled infants are shown in Table 1.
Table 1.
Birth characteristics and postnatal morbidities in 227 infants born at less than 28 weeks of GA who underwent ROP screening
| All infants (n = 227) | No ROP treatment (n = 202) | ROP treatment (n = 25) | p value | |
|---|---|---|---|---|
| Birth characteristics | ||||
| Birthweight (g), median (min–max) | 880 (420–1450) | 908 (420–1450) | 694 (490–1080) | <0.001 |
| Gestational age (weeks + days), median (min–max) | 26 + 3 (23 + 1 – 27 + 6) | 26 + 3 (23 + 1–27 + 6) | 24 + 3 (23 + 3 – 27 + 1) | <0.001 |
| Male sex, % (n) | 63.0% (143/227) | 61.9% (125/202) | 72.0% (18/25) | 0.30 |
| Postnatal morbidities | ||||
| Anaemia (<110 g/L), % (n) | 99.6% (226/227) | 99.5% (201/202) | 100% (25/25) | 0.72 |
| Severe anaemia (<80 g/L), % (n) | 56.8% (129/227) | 53.5% (108/202) | 84.0% (21/25) | <0.01 |
| Blood transfusion, % (n) | 86.6% (192/227) | 83.2% (168/202) | 96.0% (24/25) | 0.14 |
| Sepsis, % (n) | 26.0% (59/227) | 24.3% (49/202) | 40.0% (10/25) | 0.07 |
ROP, retinopathy of prematurity.
Anaemia and blood transfusion
We found that 226 of the 227 infants had anaemia during their nursery stay. The infant without anaemia was a boy, born at 27 + 5 weeks of GA with a birthweight of 1210 g, who did not develop ROP. Severe anaemia was noted in 129 of 227 (56.8%) of the infants and was more frequent (84.0% versus 53.5%, p < 0.01) in those with ROP warranting treatment (Table 1). The number of infants receiving at least one blood transfusion was 189 of 227 (83.2%), and the total number of blood transfusions was significantly higher (4.24 versus 2.32, p < 0.001) in infants warranting treatment for ROP than in those that did not (Tables 1 and 2). The frequencies of anaemia, severe anaemia, blood transfusions and need for ROP treatment in all infants, stratified by gestation at birth, are shown in Figure 1. Figure 2 shows the mean number of blood transfusion per week of age in infants with ROP who did and did not warrant treatment.
Table 2.
Potential risk factors for any ROP treatment, associated with postnatal age in crude and adjusted logistic regression analysis Logistic regression
| Variable | Category | No ROP treatment (n = 202) | ROP treatment (n = 25) | p value | Logistic regression | p value | OR adjusted† (95% CI) | p value |
|---|---|---|---|---|---|---|---|---|
| OR crude (95% CI) | ||||||||
| Haemoglobin (g/L) | ||||||||
| Mean ± SD Median (min–max) | Birth to PMA | 115 (17) | 115 (14) | 0.37 | ||||
| 35 weeks | 113 (68–193) | 114 (72–179) | ||||||
| 0–7 days | 138 (25) | 125 (21) | <0.001 | 0.64 (0.48–0.86)b | <0.01 | 0.08 | ||
| 136 (84–222) | 120 (186 209) | |||||||
| 1–4 weeks | 123 (18) | 120 (13) | 0.41 | |||||
| 120 (87–193) | 118 (79–182) | |||||||
| >4 weeks | 109 (14) | 112 (13) | <0.05 | 1.18 (1.05–1.33) | <0.01 | 0.26 | ||
| 108 (68–171) | 110 (85–145) | |||||||
| Anaemia, haemoglobin <110 g/L (weeks or days*) | ||||||||
| Mean ± SD Median (min–max) | Birth to PMA | 7.07 (2.32) | 9.16 (1.82) | <0.001 | 1.61 (1.27–2.03) | <0.001 | 0.14 | |
| 35 weeks | 7 (0–13) | 10 (5–12) | ||||||
| 0–7 days | 1.89 (2.18)* | 4.08 (2.04)* | <0.001 | 1.49 (1.23–1.79) | <0.001 | 1.38 (1.12–1.69) | <0.01 | |
| 1 (0–8)* | 4 (0–7)* | |||||||
| 1–4 weeks | 2.77 (1.21) | 3.60 (0.76) | <0.001 | 2.41 (1.36–4.29) | <0.01 | 0.09 | ||
| 3 (0–4) | 4 (1–4) | |||||||
| >4 weeks | 4.31 (1.62) | 5.60 (1.38) | <0.001 | 1.69 (1.27–2.26) | <0.001 | 0.45 | ||
| 4 (0–9) | 6 (3–8) | |||||||
| Severe anaemia, haemoglobin <80 g/L (weeks or days*) | ||||||||
| Mean ± SD Median (min–max) | Birth to PMA | 0.89 (1.04) | 1.36 (1.04) | <0.05 | 1.46 (1.02–2.10) | <0.05 | 0.21 | |
| 35 weeks | 1 (0–4) | |||||||
| 0–7 days | 0.09 (0.10)* | 0.28 (0.46)* | >0.01 | 3.27 (1.28–8.40) | <0.05 | 0.12 | ||
| 0 (0–2)* | 1 (0–2)* | |||||||
| 1–4 weeks | 0.40 (0.66) | 0.80 (0.58) | <0.001 | 2.14 (1.25–3.68) | <0.01 | 0.21 | ||
| 0 (0–3) | 1 (0–2) | |||||||
| >4 weeks | 0.50 (0.71) | 0.56 (0.82) | 0.67 | |||||
| 0 (0–3) | 0 (0–3) | |||||||
| Blood transfusions (n) | ||||||||
| Mean ± SD Median (min–max) | Birth to PMA | 2.32 (1.82) | 4.24 (1.88) | <0.001 | 1.67 (1.32–2.10) | <0.001 | 1.40 (1.06–1.84) | <0.05 |
| 35 weeks | 2 (0–8) | 4 (0–7) | ||||||
| 0–7 days | 0.43 (0.69) | 1.00 (0.83) | <0.001 | 2.30 (1.40–3.79) | <0.01 | 1.72 (1.01–2.95) | <0.05 | |
| 0 (0–4) | 1 (0–3) | |||||||
| 1–4 weeks | 1.53 (1.18) | 2.79 (1.02) | <0.001 | 2.25 (1.55–3.28 | <0.001 | 1.82 (1.20–2.78) | <0.01 | |
| 1 (0–6) | 3 (1–5) | |||||||
| >4 weeks | 0.99 (0.91) | 1.54 (0.93) | <0.001 | 1.84 (1.18–2.87) | <0.01 | 0.26 | ||
| 1 (0–4) | 1.5 (0–3) | |||||||
| Sepsis (n) | ||||||||
| Mean ± SD Median (min–max) | Birth to PMA | 0.22 (0.45) | 0.48 (0.77) | 0.40 | ||||
| 35 weeks | 0 (0–2) | 0 (0–3) | ||||||
| 0–7 days | 0.04 (0.20) | 0.04 (0.20) | 0.63 | |||||
| 0 (0–1) | 0 (0–1) | |||||||
| 1–4 weeks | 0.13 (0.34) | 0.40 (0.50) | <0.001 | 4.51 (1.84–11.10) | <0.01 | 3.01 (1.54–7.85) | <0.05 | |
| 0 (0–1) | 0 (0–1) | |||||||
| >4 weeks | 0.06 (0.24) | 0.08 (0.28) | 0.55 | |||||
| 0 (0–1) | 0 (0–1) | |||||||
| Ventilator support (days) | ||||||||
| Mean ± SD Median (min–max) | Birth to PMA | 10.52 (16.29) | 31.61 (23.13) | <0.001 | 1.05 (1.03–1.07) | <0.001 | 1.03 (1.00–1.06) | <0.05 |
| 35 weeks | 1.98 (0–72.38) | 32.04 (0–99.50) | ||||||
| 0–7 days | 3.32 (2.92) | 5.94 (2.37) | <0.001 | 1.42 (1.18–1.72) | <0.001 | 0.08 | ||
| 1.97 (0–7) | 7 (0–7) | |||||||
| 1–4 weeks | 7.99 (10.44) | 420.60 (10.86) | <0.001 | 1.10 (1.06–1.14) | 0.001 | 1.07 (1.02–1.12) | <0.05 | |
| 1.98 (0–28) | 28 (0–28) | |||||||
| >4 weeks | 2.54 (7.38) | 11.00 (15.74) | <0.001 | 1.07 (1.03–1.11) | <0.001 | 0.13 | ||
| 0 (0–4) | 4.04 (0–71.50) | |||||||
| Oxygen supplementation (days) | ||||||||
| Mean ± SD Median (min–max) | Birth to PMA | 48.22 (44.01) | 84.42 (51.69) | <0.01 | 1.02 (1.01–1.02) | <0.001 | 0.12 | |
| 35 weeks | 39.14 (0–184.58) | 85.62 (0.04–165.71) | ||||||
| 0–7 days | 5.78 (2.44) | 6.72 (1.39) | 0.09 | |||||
| 7 (0–7) | 7 (0.04–7) | |||||||
| 1–4 weeks | 19.54 (11.24) | 24.56 (7.49) | <0.05 | 1.06 (1.00–1.11) | <0.05 | 0.56 | ||
| 28 (0–28) | 28 (0.04–28) | |||||||
| >4 weeks | 28.68 (36.37) | 59.86 (46.76) | <0.01 | 1.02 (1.01–1.03) | <0.001 | 0.11 | ||
| 11.14 (0–156.58) | 57.62 (0–137.71) | |||||||
Days.
Adjusted for gestational age week at birth.
OR, odds ratio; ROP, retinopathy of prematurity; SD, standard deviation.
Figure 1.
Frequency of anaemia, severe anaemia, blood transfusion and ROP treatment in all infants (n = 227) and stratified by gestational age at birth.
Figure 2.
Comparisons between infants who did not develop ROP warranting treatment and infants who did warrant ROP treatment: (a) weekly mean number of blood transfusions during first seven (light grey bars = did not and dark grey bars = did); b) daily mean haemoglobin levels during the first 14 days of life (solid line = did not and dotted line = did); (c) weekly mean haemoglobin levels during the first seven weeks of life (solid line = did not and dotted line = did); (d) weekly mean haemoglobin levels from birth to a postmenstrual age 35 weeks (solid line = did not and dotted line = did), *p < 0.05, **p < 0.01, ***<0.001.
Haemoglobin levels
Haemoglobin values during the first week of life were available for 99.3% of the days in the first 4 weeks of life. There were no significant differences in the frequency of available haemoglobin levels between infants warranting versus not warranting treatment for ROP. Haemoglobin levels during the first week of life were significantly lower in infants warranting ROP treatment versus not warranting treatment (125 g/L versus 138 g/L, p < 0.001). In Figure 2, we present the daily mean haemoglobin levels during the first 2 weeks of life, and the mean haemoglobin level for each week thereafter, as per postnatal age week and PMA week in infants with ROP warranting versus not warranting treatment.
Sepsis and oxygen status
Sepsis was diagnosed in 59 of 227 (26%) of the infants. The number of sepsis episodes during the whole nursery stay was not a risk factor for ROP, but the number of sepsis episodes during the first 4 weeks of life was (0.04 versus 0.08, p < 0.001) (Tables 1 and 2). The duration of ventilator days (10.52 versus 31.61, p < 0.001) and oxygen supplementation days (48.22 versus 84.42, p < 0.01) was risk factors for ROP warranting treatment (Table 2).
Logistic regression analysis
Table 2 shows the results of the crude and adjusted univariate logistic regression analysis for the GA at birth and postnatal age. When adjusting for GA at birth and postnatal age, the variables of the duration of anaemia, blood transfusions, sepsis and ventilator support were found to be significant risk factors for ROP warranting treatment. The levels of significance, OR and 95% CI are presented in detail in Table 2. In the multivariate logistic regression analysis, the best-fit model of risk factors included anaemic days during first week of life (OR 1.46, 95% CI 1.16–1.83, p < 0.05), sepsis during the first 4 weeks of life (OR 3.14, 95% CI 1.10–9.00, p < 0.05) and days of ventilation from birth to a PMA of 35 weeks (OR 1.03, 95% CI 1.01–1.06, p < 0.05) (Table 3).
Table 3.
The best-fit model, created by stepwise forward multivariate logistic regression analysis and including potential risk factors for ROP warranting treatment
| Variable | OR adjusted (95% CI) | p value |
|---|---|---|
| Sepsis, 1–4 weeks (n) | 3.14 (1.10–9.00) | <0.05 |
| Anaemia <11 g/L, 0–7 days (n) | 1.46 (1.16–1.83) | <0.05 |
| Ventilation days from birth to PMA 35 weeks (n) | 1.03 (1.01–1.06) | <0.05 |
OR, odds ratio; PMA, postmenstrual age; ROP, retinopathy of prematurity.
This combination of variables explained between 15% (Cox & Snell R-squared) and 31% (Nagelkerke R-squared) of the infants’ risk for developing ROP warranting treatment and correctly classified 89% of the cases (Hosmer–Lemeshow goodness-of-fit 0.5).
DISCUSSION
Anaemia and blood transfusions have been implicated as risk factors for severe ROP and ROP warranting treatment. Our results showed that days with anaemia during the first week of life was an independent risk factor for ROP warranting treatment, even after adjusting for GA. To our knowledge, no changes in clinical practice occurred over the study period that may have influenced the outcomes.
The mean haemoglobin levels during the first week of life were significantly lower in infants who developed ROP that warranted treatment. However, this was not significant when adjusted for GA. The total number and timing of blood transfusions during the first 4 weeks of life were found to be independent risk factors for ROP warranting treatment in our cohort as well when the data were adjusted for GA. Our findings suggest that anaemia and blood transfusions may be risk factors for ROP warranting treatment. However, in this study, the best-fit model, created by stepwise forward multivariate logistic regression analysis, and variables such as the duration of anaemia during the first week of life, sepsis during the first 4 weeks of life and days of ventilator support during the nursery stay, was included. Our findings suggest that early anaemia, which may reflect the infant’s general condition, may be a risk factor for ROP warranting treatment rather than blood transfusions.
The results of studies evaluating anaemia as a risk factor for ROP have been inconsistent. Bossi et al. reported no association between haemoglobin levels and any stage of ROP in their cohort of 639 infants (24). Englert et al. reported that infants with prolonged severe anaemia, with a haemoglobin of <80 g/L, developed milder ROP than those infants with anaemia with shorter duration who received frequent blood transfusions. That study showed that severe anaemia was associated with ROP severity (13). However, Banerjee et al. found that low haemoglobin levels at birth were associated with increased morbidities, including ROP (15). In a retrospective case series of 82 eyes who had milder ROP not warranting treatment, anaemia was found to be one of the predictive risk factor for delayed involution of ROP (25) and timely blood transfusions have been suggested as a way of initiating the regression of ROP (14).
The role of blood transfusions as a risk factor for ROP was first suggested by Shohat et al. (26) in a retrospective cohort of 65 infants from 1977 to 1980. In a prospective study, Dani et al. found that blood transfusions and iron load during the first week and first 2 months of life were independent risk factors for the development of ROP (12). In prospective nonrandomised studies, a restrictive blood transfusion policy did not affect ROP outcome, but these studies did not report longitudinal haemoglobin levels (16,18,19). Kirpalani et al. (17), who did report longitudinal haemoglobin levels, found no difference in severe ROP, defined as ROP stage ≥ 3, between infants randomised to low or high transfusion threshold groups based on their haemoglobin levels, postnatal age and need for respiratory support.
Our finding that the duration of anaemia in the first week of life, which persisted as a risk factor for ROP warranting treatment in the best-fit model in the multivariate logistic regression analysis, needs further research. We hypothesised that low levels of erythropoietin, an oxygen-regulated growth hormone responsible for increasing haematocrit, may play an important role in suppressing retinal vascularisation in the early weeks of life and lead to the later development of severe ROP. Deficiency of erythropoietin was reported in the first phase of ROP in an animal model (27), and this finding was confirmed in preterm infants who developed ROP (27–29). Early supplementation with erythropoietin has been reported to prevent vessel loss and ischaemia in phase one and thereby suppressed later retinal neovascularisation in phase two ROP in an animal model (27). Whether treatment with erythropoietin is preventative or a risk factor for ROP in preterm infants continues to be a matter of debate. Some researchers suggest that the timing of erythropoietin treatment might be an important factor in the pathogenesis of ROP (30).
To our knowledge, this was the first study to assess the impact of anaemia and blood transfusions at different postnatal ages on the development of ROP warranting treatment. Its strengths included the use of logistic regression to control for confounders, such as sepsis, the duration of ventilation and gestation at birth, and the data on daily haemoglobin values. The limitations of our study include its design, which made it difficult to control for all possible confounders and the small number of infants with ROP warranting treatment.
CONCLUSION
Our study showed that in extremely preterm infants, the duration of anaemia during the first week of life was associated with an increased risk of developing ROP warranting treatment. Large, prospective studies are required to assess whether the early identification and treatment of anaemia in high-risk infants is beneficial preventing ROP warranting treatment.
Key notes.
We evaluated the correlation between retinopathy of prematurity (ROP), anaemia and blood transfusions in 227 extremely preterm infants.
ROP treatment was needed in 11% of cases, and the mean number of blood transfusions and weeks with anaemia were positively associated with ROP.
The duration of anaemia during the first week of life was an independent risk factor for ROP warranting treatment and preventing early anaemia may decrease this risk.
Acknowledgments
FUNDING
This study was supported by The Swedish Society of Medicine, The Gothenburg Medical Society, The Fredrik and Ingrid Thurings Foundation and The Cronqvist Foundation.
Abbreviations
- GA
Gestational age
- PMA
Postmenstrual age
- ROP
Retinopathy of prematurity
- VEGF
Vascular endothelial growth factor
Footnotes
CONFLICT OF INTEREST
The authors have no conflict of interests to declare.
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