Categorization and Frequency of Indications for Packed Cell Transfusion in the Preterm Newborn during the Initial Hospital Stay at a Tertiary Care Hospital: A Cross-Sectional Study

Introduction: Packed cell transfusion is a lifesaving procedure in premature babies as they have more complications as compared to babies who are born at term. Complications related to prematurity increase as gestational age de-creases and anemia is one of the complications of prematurity which needs packed cell transfusions. To date, when to transfuse preterm babies and what would be the threshold for hemoglobin and hematocrit is still a point of ar-gument as well as liberal versus restrictive transfusion protocols have been developed but what should be followed still needs more data. In our study, we have observed frequencies of different indications of packed cell transfusion in the neonatal intensive care unit of a tertiary care hospital. This endeavor will help in the establishment of guidelines regarding transfusion and the threshold on which any intervention should be done also it would be a step towards the identification of preventable causes that lead to transfusion and transfusion-related risks and hazards. Objective: To determine the indication of packed cell transfusion and their frequencies in preterm neonates. Study Design: This was a cross-sectional study. Setting: The study was carried out in the neonatal intensive care unit (NICU). Study Duration: The duration of the study was 1 year. Material and Methods: A total of 246 preterm neonates admitted to Aga Khan University Hospital (AKUH) neonatal intensive care unit in the tenure of 1 year, fulfilling the inclusion criteria and requiring packed cell transfusion were included. After the approval from ethical review matological causes, other causes of hemorrhage and other causes) were observed and recorded. Pre-transfusion hemoglobin levels (g/dL) and hematocrit levels were also recorded. Other information like number and volume of transfusion and day of life on which transfusion was administered was also documented. Results: A total of 246 critically ill children were enrolled in this study. Of the total, 52.8% were baby boys and 47.2% were baby girls. 57% of babies were born via cesarean section and 43% were born via vaginal delivery. Out of total preterm newborns admitted in NICU, 22.8% were extremely preterm, 35.4% were very preterm and 41.9% were late preterm. Mean gestational age was observed to be 31 (±4) weeks and the mean birth weight of newborns was 1500 (±600) grams. Indications of packed cell transfusion observed in our study are intraventricular hemorrhage 10%, 26% sepsis/infection, 4% hematological disorders, 12.8% anemia of prematurity, 25.2% was related to increase in oxygen requirement, 13% other hematological causes and 9.3% other causes. Conclusion: An increase in oxygen requirement and anemia of prematurity were the indications that were observed in the extremely preterm a nd very preterm groups. Sepsis and increase oxygen requirement are some of the major causes of transfusions observed in the late preterm group. Preventable indications can be one of the areas that can be worked on and will reduce the need for transfusion in preterm babies with subsequent prevention of trans-fusion-associated risks.


Introduction
About 15 million babies are born prematurely worldwide every year. Out of these 1 million children are dying each year due to complications of preterm birth. Globally, prematurity is the leading cause of death in children under the age of 5. And in almost all countries with reliable data, preterm birth rates are increasing. Globally from the year 2000, the incidence of preterm was 9.7% which has risen to 10.4% in the year 2014 [1]. More than 60% of preterm deliveries are from Africa and South Asia. Pakistan is 4 th out of 10 countries with the greatest number of preterm births and 8 th with the highest rate of preterm birth per 100 live births i.e., 15.8/100 live births [2].
Packed red blood cell transfusion is a life-saving procedure in preterm neonates admitted to the neonatal intensive care unit. Approximately 90% of extremely low birth weight neonates of less than 1000 g will require at least one red blood cell transfusion [3]. 50% of all RBC transfusions administered to VLBW infants are given in the first 2 weeks after birth, and 70% are administered within the first month [4]. Anemia can also be one of the causes which can decrease oxygen delivery to tissues so to increase oxygen delivery packed RBC transfusion Open Journal of Pediatrics is an important measure.
A study done in 2008, evaluated the pathophysiology of anemia and showed that anemia of prematurity along with other factors like infection/sepsis (89.1%) [5], malnourishment, intraventricular hemorrhage grade II and IV (10.9%] [5] and cardiorespiratory disease are contributing factors. Phlebotomy losses (36.7%) are also one of the main culprits [2].
A multicenter study carried out in seven neonatal units found that phlebotomy blood loss of 10 mL/kg increased the number of RBC transfusions by 27% [5]. Another study done in 2010 elaborated that blood hemoglobin concentration falls to approximately 8 g/dL in infants with birth weights of 1000 g to 1500 g and to approximately 7 g/dL in infants with birth weights < 1000 g [3].
Neonatal specialists have long debated the indications and merits of strategies for use of transfusions to preserve oxygen delivery or to address a variety of adverse clinical associations with transfusion [6].
Delay of 30 -120 seconds in umbilical cord clamping is also one of the contributing factors in reducing the need for transfusion in the preterm neonate [7]. There is a certain risk associated with transfusions and known complications, which can be due to: 1) storage associated (due to reduced adenosine triphosphate, adenosine, potassium leak, increased hemolysis, free hemoglobin, formation of micro-particles, activation of white cells, and release of pro-inflammatory cytokines), 2) reduced red blood cells (RBC) deformability and increases in viscosity (altered rheology) as well as RBC lysis, 3) decreased (2,3-diphosphoglycerate) levels and reduced O 2 binding, 4) reduced capacity to transport and release nitric oxide, 5) oxidative injury due to free radicals and iron release, and 6) transmission of viral or bacterial infections. Complications that are associated with red blood cell transfusions in neonatal group are transfusion-associated gut injury, increased risk of necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity and intraventricular hemorrhage [4] [6] [8].
It has been observed that transfusion with packed red blood cells at a dose of 20 mL/kg is well tolerated and results in an overall decrease in the number of transfusions compared to transfusions done at 10 mL/kg. There is also a higher rise in hemoglobin with a higher dose of packed red blood cells.
The expected response after each transfusion of 9 mL/kg of body weight hemoglobin level should increase by 3 g/dL. Meticulous monitoring of input, output and vital signs are mandatory during blood transfusion [9].

Study Setting
The study was conducted at the neonatal intensive care unit of the Aga Khan University Hospital, Karachi, Pakistan.

Duration of Study
This study was carried out over a period

Sample Size
50% -80% of the preterm babies admitted in a neonatal ICU receive red blood transfusion during their stay (3). The sample size was calculated to be 246 with a frequency of 80% with 5% precision and 95% confidence interval 1 .

Sampling Technique
Non-probability purposive sampling technique was used for the enrolment of the study participants.

Sample Selection
Inclusion Criteria: All newborn preterm babies > 24 weeks of gestation and less than 37 weeks require admission in the neonatal intensive care unit and red blood cell transfusion.
Exclusion Criteria: All neonates receiving packed cell transfusion outside AKUH will be excluded and whose code status has been decided as DNR for any reason will be excluded.

Study Design
Descriptive, cross-sectional study.

Data Collection
Preterm neonates admitted to AKUH neonatal intensive care unit, fulfilling the

Data Analysis
Collected data on proforma was entered, described and analyzed statistically in

Results
A total of 246 critically ill children were enrolled in this study. Of the total, 52.8% were late preterm ( Figure 3). Mean gestational age was observed to be 31 (±4) weeks and the mean birth weight of newborns was 1500 (±600) grams (Table 1).

Discussion
In Pakistan, a total of 8.39% of preterm babies were born in the year 2014 [1] Packed cell transfusion is a lifesaving procedure in newborns especially in extremely preterm newborns in whom the rate of complication of prematurity is more as compared to other preterm babies. In Asia in the year 2014, the incidence of extremely preterm babies was 3.4%, 10.8% were observed to be very preterm and 85.9% of babies were late preterm [1]. It was observed in multiple studies that as gestational age decreases, the rate of complications related to prematurity increases so gestational age is significantly related to administration of transfusions which was also evident in our study.
In our study, we have observed that mean pre-transfusion hemoglobin was 9.7 g/dL (range 2.0 g/dL-28 g/dL) and mean pre-transfusion hematocrit was 29.5 (range 12 -60). Large multicenter trials were done to assess whether preterm newborns need liberal packed cell transfusion or restrictive transfusion. In The Premature Infants in Need of In transfusion (PINT) study, [11] did a randomized controlled trial in 450 extremely preterm newborns weighing less than 1000 g and their thresholds for pre-transfusion hemoglobin and hematocrit in restrictive transfusion group were for infants requiring respiratory support (ventilation, CPAP, or oxygen): 115 g/L or 11.5 g/dL in the first post-natal week and in the liberal group were 135 g/L or 13.5 g/L. In another trial, [12] transfused 78 preterm babies according to clinical indication but in liberal group pre-transfusion hemoglobin threshold was <10 g/dL. [13] kept pre-transfusion hemoglobin in restrictive group to be less than 70 g/L but in the liberal group, the threshold was 100 g/L. In some studies level of respiratory support was important like a study done by [11] and [14]. low thresholds for packed cell transfusion were kept for intubated babies as compared to higher thresholds for babies who did not require any respiratory support [11] [14]. In our study, no guidelines for restrictive or liberal transfusions were followed.
As per WHO, the global prevalence of LBW is 15.5%, which amounts to about 20 million LBW infants born each year, 96.5% of them in developing countries.
The mean birth weight of all the preterm newborns under study was observed to be very low birth weight (1500 ± 600 grams). [15] observed in their study that at their facility inborn delivery rate is approximately 1500 births per year with 32% of these being of LBW (<2500 gm) and approximately 13% of these being of very low birth weight (<1500 g) as observed in our study as well. such as apathy, difficulty in suckling, poor growth, tachycardia, and tachypnea [16]. In another study, anemia of prematurity which is an exaggeration of physiological anemia was also an important cause of packed red cell transfusion in premature babies [3] and a similar finding was evident in our study as well.
One of the established complications in extremely low birth weight neonates is anemia secondary to phlebotomy losses [13] [17]. In one report, withdrawal of blood in excess of that required for laboratory studies contributed to iatrogenic blood loss by 2 to 4 mL/kg per week [18].

Limitations
It was a single-center study so we cannot generalize its findings.

Conclusions
As more newborn babies are born preterm, the rate of complications rises and the need for packed cell transfusion also increases. To reduce the number of packed cell transfusion, we need to work on its respective indications. It was evident from our study that in extremely preterm and very preterm newborns increase in oxygen requirement and anemia of prematurity were major causes of transfusion and in late preterm infections are the leading cause of red blood cell transfusion.
Preventable indications under study are infection and phlebotomy losses, therefore, we recommend endeavors for infection control and use of phlebotomy protocols in neonatal intensive care units.
Variability was observed in all three preterm categories so there is a need for a proper guideline to be followed.