Changes in Red Blood Cell Distribution Width in Very Low Birth Weight Infants for Predicting Bronchopulmonary Dysplasia


 It is unknown whether RDW can be used to predict the severity and prognosis of various diseases in children, especially newborns. This study aimed to investigate the RDW values of preterm infants born at < 30 weeks’ gestation with a birth weight < 1500 g and evaluate whether the RDW values in the early days of life can predict bronchopulmonary dysplasia (BPD) development. The mean RDW values on day 1 (D1), day 7 (D7), and day 28 (D28) after birth were 16.2 ± 1.4%, 17.5 ± 2.4%, and 17.6 ± 1.7%, respectively. The RDW at birth was lower in the infants born at < 28 weeks’ gestational age than in those born at ≥ 28 weeks’ gestational age (15.7 ± 0.8 vs 16.4 ± 1.5, P = 0.003). The RDW values of both groups increased during the first week after birth and did not differ significantly. The levels remained similar levels at 1 month of life. The RDW values examined at D1, D7, D28 and the changes of RDW from D1 to D7 were not correlated with the development of BPD independent of severity. The usefulness of RDW as a predictor of BPD development remains questionable and requires further study.


Introduction
Red blood cell distribution width (RDW) as part of complete blood count (CBC) has traditionally been used with mean corpuscular volume (MCV) to determine the cause of anemia. RDW values increase in circumstances of ineffective erythropoiesis in the bone marrow such as iron de ciency anemia, folate and vitamin B12 de ciency or shortening of the red blood cell (RBC) life span by destruction such as in sickle cell anemia. [1] Many recent studies reported that RDW is related to in ammation [2][3][4] and hypoxemia [5], and an easily available parameter that can predict the severity [4,6,7] and prognosis of various diseases in adults [3,[7][8][9][10][11][12][13][14][15][16][17]. However, studies of the same in children are limited [18][19][20][21]. Additional blood sampling is not required to determine the RDW values, as CBC is performed relatively frequently and requires only a small amount of blood. Therefore, RDW might be a useful tool for assessing the medical conditions of newborns, especially preterm infants. Nevertheless, this remains unknown and the normal range of RDW values in preterm infants has yet to be determined. [22][23][24][25] Bronchopulmonary dysplasia (BPD) occurs when premature lung tissue and vessels are injured and their development and differentiation are disrupted by the factors causing perinatal in ammation, such as chorioamnionitis, hyperoxia, mechanical ventilation, and infection. The authors investigated the changes in RDW values in very low birth weight infants born before 30 weeks' gestation and whether the RDW values measured in the early days of life can predict BPD development.

Clinical characteristics
Of the 171 infants eligible for this study, 63 were excluded. The mean gestational age (GA) and birth weight of the remaining 108 patients were 28.4 ± 1.4 weeks' gestation and 1165.6 ± 212.9 g. Eleven infants (10.2%) were small for gestation. Four infants died in the rst month of life.

RDW values in preterm infants
The mean RDW values checked at day 1 (D1), day 7 (D7), and day 28 (D28) after birth were 16.2 ± 1.4%, 17.5 ± 2.4%, and 17.6 ± 1.7%, respectively. The RDW increased during the rst week after birth (P < 0.001) and did not change signi cantly from D7 to D28 (P = 0.658) ( Table 1).  Table 2). The RDW of both groups increased in the rst week of life (P < 0.001 both) and then stayed at the similar levels for a month after birth (P = 0.639, P = 0.772, respectively) ( Table 1, Fig. 1). White blood cell count (WBC) and C-reactive protein measured at birth were higher in the lower gestational group (P < 0.001 and P = 0.003, respectively)

Relationship between RDW and BPD
After four patients who died in the rst month of life were excluded, the remaining 104 patients were evaluated the relationship between RDW and BPD development. In multivariable logistic regression, the RDW values examined at D1, D7, D28 and the changes in RDW from D1 to D7 did not differ between the infants with BPD and those without BPD independent of severity (Table 3). Although it is known that the RDW levels of newborns are higher than those of children or adults due to active erythropoiesis and physiologic reticulocytosis, [26,27] [30] Looking into the data, we noticed that the RDW in 26-28 weeks' GA and 29-31 weeks' GA groups were higher than that in the 23-25 weeks' GA group, although these were no signi cant differences. It appears that erythropoiesis increased in the fetal period and peaked at 32-34 weeks' gestation.
The RDW values in the < 28 weeks' and ≥ 28 weeks' GA groups increased during the rst week of life, while the gap of RDW level between the groups disappeared. Christensen et al. [26] explained that the increase of RDW in the early days of life in preterm infants was secondary to that induced by a previous RBC transfusion. However, the RDW showed similar trends in the present study, although the infants who received RBC transfusions in the rst week of life were excluded. The increase in RDW seems to be partially due to physiologic anemia of preterm accompanied by reticulocytosis. White blood cell counts and C-reactive protein levels were higher in the < 28 weeks' GA than in the ≥ 28 weeks' GA group. It seems relevant that early preterm labor was induced by perinatal in ammation/infection. [31] In adult studies, a number of studies were reported in terms of the role of RDW as indicators of severity or predictors of outcome for various diseases including sepsis, respiratory disease, cardiovascular disease and critical illness. [3,6,8,9,[12][13][14][15][16][17][32][33][34][35] Even though the mechanism of RDW increase was not fully determined, it was suggested that chronic hypoxia, malnutrition and in ammation cause an increase in RDW values. [4,5,36] Hypoxia induces erythropoietin release, which leads to release immature reticulocyte into circulation. [5] Injured RBC by in ammation aggravates the progress of disease through decrease of oxygen transfer to organs and tissues. [4] RDW values were higher in patients with COPD than healthy people [33] and associated with its severity and outcomes including mortality and readmission rates. [8,[32][33][34] The pathophysiology of BPD and COPD are similar. [37] Both are resulted of the impairment of alveolarization/vascularization after in ammation and oxidative stress that can present as chronic hypoxia. However, in this study, the RDW values measured in the rst month of life were not related to development of BPD. It appeared that other clinical conditions affected the relationship during the period from RDW measurement to BPD presentation. Garofoli et al. reported that the RDW at 1 month of life was higher in the BPD group than in non-BPD group, whereas the RDW within the rst 3 days of life did not differ between groups. [28] However, the GA range was too broad and other contributing factors were not considered in the previous study.
There were some limitations in this study. First, it could not evaluate whether the infants with an evaluated RDW were likely to develop BPD because the normal RDW range has not yet been established in preterm infants yet. Second, chorioamnionitis was not evaluated as a perinatal factor because pathologic exam data of placenta were not available.
In conclusion, the RDW values at birth were higher in infants born at 28-29 weeks' GA than in those born at The patients who were born at GA < 30 weeks and birth weight < 1500 g were included in this study. Patients with 1) a chromosomal abnormality or major congenital anomaly; 2) culture-proven early onset sepsis; 3) a recent RBC transfusion (within 1 week after birth); or 4) maternal anemia (Hemoglobin < 8g/dL) were excluded.
RDW values measured at D1, D7 and D28 were reviewed. The RDW levels according to GA and the associations between RDW and BPD development were analyzed. RDW were determined as part of a CBC, which was checked within 1 h after birth (D1), at D7, D28, and per the local routine protocol as necessary. The 0.3-0.5 mL of blood sample was taken from radial or umbilical artery and placed in ethylenediaminetetraacetic acid-containing tube. CBC was measured by automated hematology analyzer (Sysmex, Kobe, Japan) and their quality controls and calibrations were performed regularly following standard rules. WBC, hemoglobin, MCV, platelet count were also collected with the RDW from the CBC.
BPD was diagnosed if the patient required arti cial respiratory support providing positive airway pressure or oxygen for more than 28 days but was discontinued before 36 weeks' postmenstrual age or discharge, whichever comes rst. Moderate or severe BPD was diagnosed if the patient needed arti cial respiratory support or oxygen at 36 weeks' postmenstrual age or at discharge.