INTRODUCTION:

With case fatality rates of 20–30%¹, necrotizing enterocolitis is a significant cause of mortality in very preterm newborns. In recent years, there has been renewed interest in possible adverse events following the administration of blood products, particularly in light of the previously reported association between RBC transfusions and necrotizing enterocolitis (NEC)². These infants also make up a population that receives a lot of transfusions. Packet red blood cell (pRBC) transfusions and necrotizing enterocolitis (NEC) seem to be related in a number of observational studies³.

Both anemia and RBCs infusions have the potential to alter intestinal perfusion and exacerbate damage in preterm newborns. The splanchnic vascular bed's immaturity, re-oxygenation damage in the anaemic gut, and immunological responses akin to those described in transfusion-related lung injury (TRALI) are a few potential explanations⁴. Because of a developmental sensitivity to neovascularization and oxygen toxicity at this time, presumably connected to increased expression of angiogenic markers in the anaemic gastrointestinal tract, Blau et al. hypothesize that NEC may peak during the postmenstrual age of 31–32 weeks. In preterm newborns with birth weights under 1250grammes, Krimmel et al. demonstrated that RBC transfusions may reduce the postprandial rise in mesenteric blood flow that is often seen⁵.

Necrotizing enterocolitis (NEC) after 48hours of a pRBC transfusion is referred to as transfusion associated necrotizing enterocolitis (TANEC). In a recent study, within 48hours following a transfusion, 7 out of 18 cases (38.9%) of NEC in the first period occurred. None of the NEC cases in the second period (after the switch to feed withholding) occurred within 48hours of a PRBC transfusion. Since then, a large number of research have evaluated the effect of restricting meals during the peri-transfusion interval on the prevalence of TANEC⁶. The aim of this study is to determine the incidence of occurrence of NEC in preterms after red blood cell transfusion with different feeding protocols and to assess the value of withholding feeds around the pRBCs transfusion in decreasing the incidence of TANEC.

METHODOLOGY:

A prospective randomized control comparative study, which was carried out by enrolling 90 preterms < 36weeks gestation who received pRBCs transfusion and were divided into 2 groups: group (A) which consists of 45 preterms where only one feed was withheld during pRBCs transfusion and group (B) which consists of 45 preterms where feeds were withheld 4 hours before till 4 hours after pRBCs transfusion to neonatal intensive care unit (NICU) of hospitals of department of Pediatrics, Cairo University throughout a period from February, 2018 and till March 2020.

Ethical consideration:

The study was approved by the department of Pediatrics, Faculty of medicine, Cairo University held on May 2018. Ethical committee approval was obtained through a member of the Pediatrics department of the committee.

The inclusion criteria were as follow:

Preterms, ≤36 weeks gestational age (GA), delivered by cesarean section or vaginal delivery, necessitates pRBCs due to anemia, including anemia of prematurity and hemolysis from ABO incompatibility.

We excluded preterms with anemia due to other causes as pulmonary hemorrhage, massive bleeding, intracranial or ventricular hemorrhage or sepsis, fulminant sepsis, apparent congenital cardiac diseases, perinatal asphyxia, congenital malformations and previous feeding intolerance or suspected NEC.

A total of 90 preterms met the inclusion criteria and gave informed consent from all the patients’ guardians was taken prior to data collection and sample withdrawal. They were randomly divided to two groups Group (A): 45 preterms where only one feed was withheld during pRBCs transfusion Group (B): 45 preterms where feeds were withheld 4 hours before till 4 hours after pRBCs transfusion. Participants were divided according to computer-generated block-randomization sequence with random block sizes were used. Preterms were randomized into the study by a random number table sequence after informed parental consent were obtained. The allocations was contained in opaque sequentially numbered sealed envelopes.

Full History Taking:

Perinatal history from our participants was obtained such as maternal medical disorders during pregnancy especially preeclampsia and diabetes mellitus, antenatal corticosteroids, premature prolonged rupture of membranes (PPROM). Natal history as mode of delivery, perinatal asphyxia and meconium aspiration and Postnatal history: Birth weight, resuscitation data and delivery room interventions and low Apgar score which is considered if less than 7 at 5 minutes ⁶.

Clinical examination: we assessed the clinical examination for all participants as birth date, gestational age, gender, birth weight, vital Signs: heart rate, respiratory rate and core temperature, chest examination, cardiac examination, abdominal examination and neurological examination.

We documented the blood pressure measurements, use of vasopressors therapy, presence of patent dutus arteriosus (PDA) or need for medical closure, mode of ventilation and duration on oxygen, surfactant administration at birth, retinopathy of prematurity, chronic lung disease and duration of hospitalization in days.

Investigations:

Laboratory: Hemoglobin and hematocrit at birth, C–Reactive protein (CRP), blood chemistry including serum potassium, sodium, blood urea nitrogen and serum creatinine and blood culture indicating early onset sepsis.

Medications given in the NICU:

Antibiotics, antacids, iron therapy and postnatal steroids in chronic lung disease.

Feeding data: Expressed breast milk or formula feedings and its type, achievement of full feeds prior to onset, quantity of feed in ml per feed and number of feeds per day, route of feeding: oral/ nasogastric tube/ nasogastric drip and total parenteral nutrition parameters at time of pRBCs transfusion.

Intervention:

Our included participants were received pRBCs transfusion due to anemia of

prematurity or hemolysis from ABO or RH incompatibility according to

the unit guidelines.

Transfusion Practice: All transfusion used packed red cells preserved in AS-5 or As-1. Both preservatives are SAGM based (saline, adenine, glucose and mannitol).

Preserved units are leuko-reduced. Irradiated units are available upon request.

The preterms received pRBCs according to the criteria of pRBC transfusion we followed in our NICU

Diagnosis of TANEC:

Diagnosis of NEC was made according to the modified Bell's staging criteria by a neonatologist when infants had both systemic and radiographic signs of NEC, infants with stage II and greater will be defined as the NEC. TANEC is occurrence of signs of NEC within 48 hours after pRBC transfusion.

Statistical Methods:

Data were analyzed using IBM© SPSS© Statistics version 23 (IBM© Corp., Armonk, NY). Continuous numerical variables were presented as mean and SD and inter-group differences were compared using the unpaired t-test. Categorical variables were presented as number and percentage and differences were compared using Fisher’s exact test. Ordinal data were compared using the chi-squared test for trend. Two-sided p-values <0.05 were considered statistically significant.

RESULTS:

We approached 112 participants to join in the study. We excluded 12 of them; 12 did not meet inclusion criteria, finally 90 patients included in our study.

Table 1: Comparison between negative TANEC and positive TANEC in group (A) as regard; Perinatal history, Natal history, Postnatal history, Infant data and clinical examinations before pRbcs transfusion, Complications of prematurity, Medications given in the NICU, Feeding data, Suggested cause for transfusion and laboratory tests before pRbcs transfusion.

Group (A)		Negative TANEC	Positive TANEC	P-value	Negative TANEC	Positive TANEC	P-value
Group (A)		No. = 33	No. = 12	P-value	No. = 38	No. = 7
Perinatal history
Maternal preeclampsia		6 (18.2%)	2 (16.7%)	0.906	9 (23.7%)	2 (28.6%)	0.782
Maternal diabetes mellitus		2 (6.1%)	1 (8.3%)	0.787	4 (10.5%)	0 (0.0%)	0.368
PROM		17 (51.5%)	8 (66.7%)	0.366	12 (31.6%)	5 (71.4%)	0.046
Antenatal corticosteroids		20 (60.6%)	7 (58.3%)	0.891	17 (44.7%)	3 (42.9%)	0.927
Natal history
Mode of delivery	VD	11 (33.3%)	4 (33.3%)	1	17 (44.7%)	2 (28.6%)	0.426
Mode of delivery	CS	22 (66.7%)	8 (66.7%)	1	21 (55.3%)	5 (71.4%)	0.426
Perinatal asphyxia		2 (6.1%)	0 (0.0%)	0.383	0 (0.0%)	0 (0.0%)	–
Meconium aspiration		4 (12.1%)	1 (8.3%)	0.721	8 (21.1%)	1 (14.3%)	0.681
Low APGAR		4 (12.1%)	6(50.0%)	0.007	9 (23.7%)	5 (71.4%)	0.012
Postnatal history
Gestational age (wks.)		32.06 ± 1.58	29.67 ± 1.61	0.001	31.5 ± 1.69	29.86 ± 1.77	0.024
Gender	Female	16 (48.5%)	4 (33.3%)	0.366	20 (52.6%)	2 (28.6%)	0.242
Gender	Male	17 (51.5%)	8 (66.7%)	0.366	18 (47.4%)	5 (71.4%)	0.242
Age at pRBCs transfusion (days)	Mean ± SD	7.7 ± 2.89	8.58 ± 1.51	0.319	8.61 ± 2.63	8.71 ± 2.69	0.92
Birth weight (kg)	Mean ± SD	1.62 ± 0.34	1.06 ± 0.18	< 0.001	1.53 ± 0.42	1.04 ± 0.15	0.004
Infant data and clinical examinations pRBCs transfusion
HR		146.21 ± 13.41	150.83 ± 17.48	0.352	145.13 ± 13.92	153.57 ± 11.41	0.139
RR		53.48 ± 5.14	56.5 ± 6.08	0.105	52.82 ± 5.83	54.43 ± 3.55	0.485
Temp		36.97 ± 0.25	37.07 ± 0.37	0.34	36.95 ± 0.17	36.87 ± 0.25	0.295
SBP		79.85 ± 9.62	67.17 ± 12.13	0.001	75.03 ± 10.06	79.86 ± 11.5	0.259
DBP		49.32 ± 8.73	39.33 ± 9.9	0.002	59.42 ± 9.25	63.14 ± 12.42	0.359
Mode of ventilation	MV	28 (84.8%)	12 (100.0%)	0.153	30 (78.9%)	7 (100.0%)	0.181
Mode of ventilation	PPV	5 (15.2%)	0 (0.0%)	0.153	8 (21.1%)	0 (0.0%)	0.181
Complications of prematurity
Duration of oxygen therapy (days) Mean ± SD		15.7 ± 6.01	36.92 ± 16.8	<0.001	16.92 ± 8.1	29.71 ± 12.05	0.001
BPD		1 (3.0%)	4 (33.3%)	0.004	2 (5.3%)	3 (42.9%)	0.004
Pneumothorax		3 (9.1%)	2 (16.7%)	0.475	2 (5.3%)	2 (28.6%)	0.046
Intracranial Hge		5 (15.2%)	5 (41.7%)	0.058	4 (10.5%)	3 (42.9%)	0.03
ROP		0 (0.0%)	1 (8.3%)	0.094	0 (0.0%)	2 (28.6%)	0.001
PDA		12 (36.4%)	9 (75.0%)	0.022	12 (31.6%)	5 (71.4%)	0.046
Medications given in the NICU
Surfactant		21 (63.6%)	11 (91.7%)	0.067	21 (55.3%)	5 (71.4%)	0.426
Vasopressors		30 (90.9%)	11 (91.7%)	0.937	30 (78.9%)	7 (100.0%)	0.181
Antibiotics		33 (100.0%)	12 (100.0%)	1	38 (100.0%)	7 (100.0%)	1
Antacids		4 (12.1%)	7 (58.3%)	0.001	4 (10.5%)	3 (42.9%)	0.03
Iron therapy		0 (0.0%)	0 (0.0%)	–	0 (0.0%)	0 (0.0%)	–
Postnatal steroid		7 (21.2%)	8 (66.7%)	0.004	14 (36.8%)	5 (71.4%)	0.089
Feeding data
Type of feeding	Formula	11 (33.3%)	9 (75.0%)	0.013	15 (39.5%)	7 (100.0%)	0.003
Type of feeding	EBM	22 (66.7%)	3 (25.0%)	0.013	23 (60.5%)	0 (0.0%)	0.003
Amount of feeding cc/fed		17.33 ± 9.13	11.08 ± 4.42	0.029	20.89 ± 9.16	15.43 ± 7.61	0.145
TPN		21 (63.6%)	12 (100.0%)	0.015	16 (42.1%)	7 (100.0%)	0.005
Suggested cause for transfusion
Anemia of prematurity		28 (84.8%)	8 (66.7%)	0.178	34 (89.5%)	5 (71.4%)	0.197
Intracranial Hge		5 (15.2%)	4 (33.3%)	0.178	4 (10.5%)	2 (28.6%)	0.197
CBC
Hb		9.61 ± 1.01	9.77 ± 0.92	0.646	9.39 ± 0.79	8.94 ± 0.45	0.159
Hct		28.78 ± 2.57	28.74 ± 3.4	0.971	27.83 ± 2.65	25.00 ± 2.43	0.012
Plt		215 (179 – 319)	280 (211 – 340)	0.248	289.5 (214 – 389)	285 (248 – 530)	0.481
TLC		12.8 (10.3 – 15.3)	10.75 (8.75 – 21.25)	0.827	12.95 (10.5 – 18.5)	14.1 (8.8 – 20.3)	0.707
Positive CRP		11 (33.3%)	6 (50.0%)	0.308	11 (28.9%)	4 (57.1%)	0.146
Positive Blood culture		4 (12.1%)	5 (41.7%)	0.028	5 (13.2%)	2 (28.6%)	0.301
Serum sodium		138.03 ± 4.38	139.67 ± 4.83	0.287	138.84 ± 4.85	136.86 ± 1.35	0.293
Serum potassium		4.71 ± 0.64	4.34 ± 0.78	0.116	4.53 ± 0.76	4.51 ± 0.73	0.963
Urea		25 (20 – 32)	39.5 (28 – 71.5)	0.011	27 (19 – 35)	32 (22 – 50)	0.355
Creatinine		0.57 ± 0.15	0.65 ± 0.19	0.13	0.58 ± 0.18	0.49 ± 0.09	0.181
ABG
PH		7.33 ± 0.05	7.33 ± 0.04	0.722	7.32 ± 0.07	7.31 ± 0.05	0.711
PCO2		38.3 ± 6.46	36.56 ± 7.87	0.454	39 ± 9.75	43.57 ± 5.97	0.239
HCO3		19.98 ± 3.29	19.33 ± 2.92	0.549	19.53 ± 3.57	22.13 ± 1.81	0.069
BE		-6.6 (-8.5 – -4.1)	-5.25 (-7.85 – -4.7)	0.959	-2.2 (-3.8 – -1.5)	-4.7 (-5.8 – -2.8)	0.04

Table 2: Comparison between negative TANEC and positive TANEC in group (A),(B) as regard diagnosis of NEC.

group (A)	Negative TANEC Group A	Positive TANEC Group A	P-value	Negative TANEC Group B	Positive TANEC Group B	P-value
group (A)	No. = 33	No. = 12		No. = 38	No. = 7	P-value
Within 6-12 hr. after pRBCs transfusion
Hb	12.89 ± 1.13	12.83 ± 1.14	0.881	12.84 ± 1.6	12.63 ± 1.44	0.746
Hct	37.68 ± 3.24	37.2 ± 4.56	0.693	37.1 ± 4.72	37.31 ± 4.38	0.912
Reaction during transfusion	0 (0.0%)	0 (0.0%)	–	0 (0.0%)	0 (0.0%)	–
Clinical
Apnea	0 (0.0%)	3 (25.0%)	0.003	3 (7.9%)	3 (42.9%)	0.012
Bradycardia	0 (0.0%)	2 (16.7%)	0.016	0 (0.0%)	1 (14.3%)	0.018
Resp distress	3 (9.1%)	7 (58.3%)	0.022	4 (10.5%)	2 (28.6%)	0.197
Abd distension	9 (27.3%)	12 (100.0%)	0.027	8 (21.1%)	7 (100.0%)	0.029
Vomiting	2 (6.1%)	6 (50.0%)	0.001	2 (5.3%)	5 (71.4%)	0.004
Gastric residual	1 (3.0%)	9 (75.0%)	<0.001	2 (5.3%)	4 (57.1%)	0.015
CBC after 48 hrs of p RBCs transfusion
Hb	12.69 ± 1.15	11.31 ± 0.96	0.001	12.37 ± 1.48	11.44 ± 1.71	0.145
Hct	37.14 ± 3.5	33.07 ± 2.7	0.001	36.06 ± 4.33	33.56 ± 5.65	0.187
TLC	12 (9.1 – 16)	16 (10.9 – 20.9)	0.111	12.6 (8.9 – 16.6)	20.4 (9.3 – 24.9)	0.145
Plt	285 (205 – 342)	146 (128.5 – 202)	0.001	268.5 (211 – 309)	148 (134 – 280)	0.02
Positive CRP	5 (15.2%)	6 (50.0%)	0.016	7 (18.4%)	5 (71.4%)	0.004
Na	139.7 ± 3.72	132.5 ± 4.23	0.001	140.74 ± 4.25	129.57 ± 2.07	0.001
K	4.7 ± 0.52	4.53 ± 0.95	0.434	4.83 ± 0.59	4.34 ± 1	0.079
Urea	18 (14 – 29)	60.5 (44 – 74)	0	19.5 (17 – 27)	52 (33 – 73)	0.001
Creat	0.53 ± 0.14	0.71 ± 0.18	0.001	0.56 ± 0.13	0.49 ± 0.13	0.178
ABG
PH	7.35 ± 0.03	7.26 ± 0.04	<0.001	7.36 ± 0.05	7.37 ± 0.19	0.88
PCO2	38.99 ± 5.99	36.64 ± 9.07	0.318	39.76 ± 7.14	34.43 ± 5.86	0.07
HCO3	21.51 ± 2.78	17.43 ± 5.44	0.002	23.22 ± 4.6	17.14 ± 2.22	0.001
BE	-4 (-5 – -1.6)	-11.35 (-13.3 – -8.35)	<0.001	-2.75 (-5.1 – 1.1)	-8.8 (-11.4 – -6.7)	<0.001
Radiological after 48 hrs of pRBCs transfusion
Positive Pneumatosis intestinalis	0 (0.0%)	7 (58.3%)	<0.001	1 (2.6%)	5 (71.4%)	0.001
Positive Dilated thickened fixed intestinal loop	5 (15.2%)	4 (33.3%)	0.178	8 (21.1%)	3 (42.9%)	0.217

According to Perinatal history in group (A): there was no statistically significant difference according to perinatal history= >0.05.

According to natal history; there was no statistically significant difference in the term of Mode of delivery, Perinatal asphyxia, Meconium aspiration, p-value >0.05. on the other hand, there was no statistically significant difference in the term of Low APGAR, p-value=0.007

According to Postnatal history; There was no statistically significant difference in the term of Gender and Age at pRBCs transfusion (days), p-value > 0.05 . on the other hand, there was statistically significant difference in the term of Gestational age (wks.) and Birth weight (kg), p-value <0.001.

According to Infant data and clinical examinations pRBCs transfusion; There was no statistically significant difference in the term of HR, RR, Temp and mode of ventilation, p-value > 0.05 . on the other hand, there was statistically significant difference in the term of SBP, DBP and MABP, p-value<0.05.

According to Complications of prematurity; There was no statistically significant difference in the term Duration of oxygen therapy (days), BPD and PDA, p-value > 0.05. on the other hand, there was statistically significant difference in the term of Pneumothorax, Intracranial He and ROP, p-value <0.05.

According to Medications given in the NICU; There was no statistically significant difference in the term of Surfactant, Vasopressors and Antibiotics, p-value > 0.05 . on the other hand, there was statistically significant difference in the term of Antacids and Postnatal steroid, p-value <0.05.

According to Feeding data: there was statistically significant difference according to Feeding data p-value < 0.05.

According to Suggested cause for transfusion: there was no statistically significant difference according to Suggested cause for transfusion (anemia of prematurity and intracranial hge) p-value=0.178.

According to CBC: There was no statistically significant difference in the term Hb, Hct, Plt, TLC, Positive CRP, Na, K and creat, p-value > 0.05. on the other hand, there was statistically significant difference in the term of , Positive Blood culture and Urea, p-value <0.05.

According to ABG: there was no statistically significant difference according to ABG (PH, PCO2, HCO3 and BE) p-value >0.05. Table 3

According to Perinatal history in group (B): there was no statistically significant difference according to Maternal preeclampsia, Maternal diabetes mellitus, PROM and Antenatal corticosteroids= >0.05. there was statistically significant difference in the term of Abnormal end diastolic placental flow, p-value=0.001.

According to natal history; there was no statistically significant difference in the term of Mode of delivery, Perinatal asphyxia, Meconium aspiration, p-value >0.05. on the other hand, there was statistically significant difference in the term of Low APGAR, p-value=0.012

According to Postnatal history; There was no statistically significant difference in the term of Gender and Age at pRBCs transfusion (days), p-value > 0.05. on the other hand, there was statistically significant difference in the term of Gestational age (wks.) and Birth weight (kg), p-value <0.05.

According to Infant data and clinical examinations pRBCs transfusion; There was no statistically significant difference in the Infant data and clinical examinations pRBCs transfusion, p-value > 0.05.

According to Complications of prematurity; there was statistically significant difference in the term of Complications of prematurity, p-value <0.05.

According to Medications given in the NICU; There was no statistically significant difference in the term of Surfactant, Vasopressors and Antibiotics and Postnatal steroid p-value > 0.05 . on the other hand, there was statistically significant difference in the term of Type of feeding and TPN p-value <0.05.

According to Feeding data: there was statistically significant difference according to Amount of feeding cc/fed p-value < 0.05. on the other hand, there was statistically significant difference in the term of Antacids p-value <0.05.

According to CBC; There was no statistically significant difference in the term Hb, Plt, TLC, Positive CRP, Na, K, creat Positive Blood culture and Urea, p-value > 0.05. on the other hand, there was statistically significant difference in the term of Hct p-value <0.05.

According to ABG: there was no statistically significant difference according to ABG (PH, PCO2 and HCO3) p-value >0.05. on the other hand, there was statistically significant difference in the term of BE p-value <0.05. Table 5

In group (A) There was highly statistically significant difference in positive TANEC patients of group A as regard clinical diagnosis of NEC with occurrence of apnea, respiratory distress, abdominal distension, vomiting, gastric residual, Hb level, Hct level, Plt count, Na level, blood urea level, blood creatinine level, PH, Hco3 level, base excess and presence of pneumatosis intestinalis, there was significant difference as regard occurrence of bradycardia and positive CRP level but there was no significant difference between two groups as regard other parameters of diagnosis of NEC.

In group (B) There was statistically significant difference in positive TANEC patients of group B as regard clinical diagnosis of NEC with occurrence of abdominal distension, vomiting, gastric residual, positive CRP, Na level, blood urea level, Hco3 level, base excess and positive pneumatosis intestinalis, there was significant difference in TANEC positive patients as regard apnea, bradycardia and Plt count. There was no significant difference of other parameters as regard diagnosis of NEC.

This table showed univariate logistic regression were associated with positive TANEC in group A and multivariate shows that the most associated variable was birth weight (kg) >1.12. Table 3.

This table showed univariate logistic regression were associated with positive TANEC in group B and multivariate shows that the most associated variables were birth weight (kg) > 1.1 and low APGAR score. Table 4 .

DISCUSSION:

Necrotizing enterocolitis (NEC) is a serious inflammatory condition of the intestine that affects up to 10% of very low birth weight (VLBW) infants, leading to increased risk for mortality and significant morbidities⁷.

Transfusion-associated NEC (TANEC) refers to NEC episodes that are temporally related to the transfusion of packed red blood cells, typically within 48 hours after transfusion⁸. In a meta-analysis of observational studies, exposure to blood transfusion was reported to double the risk of NEC⁹. One intervention that has been suggested to reduce the risk of TANEC is stopping feeds around the time of a blood transfusion ¹⁰. Types of alterations to feeding during blood transfusions include the following: withholding feeding hours before blood transfusion, during the transfusion, and after transfusion¹¹. Gordon and Swanson et al found that postmenstrual age is correlated with the development of NEC, the peak age being 29-31 weeks (peak 31 weeks) based on last menstrual period or conception ¹². Fanaroff et al found that NEC is seen in 7% of very low birth weight infants (birth weight<1500 g) and up to 5% of admissions to the neonatal intensive care unit (NICU) ¹³. This agreed with Ted and Shelley et al who found that NEC is more prevalent in premature infants, with incidence inversely related to birth weight and gestational age ¹⁴. Been et al found that PROM leading to chorioamnionitis, has been suggested as a risk factor of NEC ¹⁵. A case control study by Ahle et al found that there was no association between male sex and increased risk of NEC¹⁶. Iliodromiti et al found that low Apgar scores (<7) measured at 5 minutes can predict short term infant mortality¹⁷. Ongun et al found that low Apgar score were identified as the leading cause of acquiring NEC and its severe consequences (intestinal perforation) in their study ¹⁸. Sellmer et al have described a case series of full fed preterms with PDA who developed NEC after receiving a RBC transfusion, thus raising concerns on the simultaneous presence of PDA and RBCs administration as a possible risk factor for adverse intestinal outcomes¹⁹.

Keir et al found that RBCT at 21 days or more of life in previously transfusion preterm infants were associated with increased odds of chronic lung disease (CLD) and found a statistically significant longer duration of mechanical ventilation in this group, which would clearly contribute to the increased odds of CLD²⁰. As well as²¹ Wang et al report that the number of RBCT within 7 days of life was associated with severe IVH (odds ratio: 1.53; 95% CI: 1.09- 2.16) ²¹. Retinopathy of prematurity (ROP) is a Vaso proliferative retinal disorder sharing the same cascade as that of NEC, we found that there was significant association in positive TANEC patients in group B than those with negative TANEC patients in the same group where the occurrence of ROP was (28.6%) in positive TANEC patients and (0.0%) in negative TANEC patients with a high significant P-value (0.001).

Dani et al showed that RBCT volume was associated with ROP (odds ratio = 1.16 for the first week of life and 2.92 for the first 60 days of life) in infants with a birth weight of < 1,250 g ²². More et al showed a significantly increased risk of NEC with acid-suppression medications (OR: 1.78; 95% CI: 1.4–2.27; two studies, 11,346 infants)²³. A meta-analysis of timing of postnatal corticosteroids, dosing regimens, and methods suggests that postnatal steroid use is not a risk factor for NEC²⁴, while Doyle et al found that although early corticosteroid treatment reduces risk of bronchopulmonary dysplasia and patent ductus arteriosus but gastrointestinal bleeding and intestinal perforation were important adverse effects²⁵. Cotten et al show a correlation between prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants²⁶. A meta-analysis of 343 infants showed that those receiving human milk were 3 times less likely to develop NEC when compared to those who were formula fed²⁷. Several studies evaluating slow versus fast feeding advancement found faster feeding advancements were safe without an increased risk of NEC ²⁸. Delaying feeds in preterm infants is not a recommended strategy for the prevention of NEC, as delayed feeds have been shown to result in delayed gut development, increased central catheter days, and increased risk of central line associated bloodstream infections²⁹. Several studies have shown no increase in mortality or NEC recurrence with early feeding regimens (defined as 5-7 days), Two retrospective studies have shown a significant increase in time to full enteral feeds and an increased rate of central line associated bloodstream infections (CLABSIs) in patients who received delayed feeding³⁰. Morgan et al in another Cochrane review found no difference in the risk of NEC when feeds were advanced slowly (15–20 ml/kg/day) versus when advanced at the rate of 30–35 ml/kg/day ³¹.Early sepsis confirmed by positive blood culture before pRBCs transfusion was found in positive TANEC patients among group A (41.7%) with significant P-value (0.028) in comparison with negative TANEC patients (12.1%) in the same group. Drenckpohl et al found that Sepsis places an infant at risk for NEC. Another finding from two multivariable analyses an association between diagnosis and treatment of sepsis and NEC, which was defined as blood culture proven late onset sepsis in one study and undefined sepsisprior to NEC in the other ¹⁸. Vermont Oxford Network (2018) has also established a less ambiguous classification system for defining the disease and requires 1 clinical and 1 radiographic finding. These clinical findings include bilious emesis or gastric aspirate, abdominal distention, or gross blood in the stool, while radiographic findings include pneumatosis intestinalis, pneumoperitoneum, or portal venous gas, and correspond to Bell’s stage II or higher³². Niemarkt et al. (2015) stated that proinflammatory cytokines and acute phase reactants like TNFα, and C-reactive protein also show promise in diagnosing NEC and may even predict the need for surgical intervention³³. Zani et al found that A survey amongst pediatric surgeons concluded that the most commonly used biochemical tests in the diagnosis and progression of NEC include platelet count, C-reactive protein, white blood cell count, and lactate level ³⁴. Krimmel et al suggested that withholding feeds in the peritransfusion period may prevent TANEC by reducing postprandial mesenteric ischemia ⁵. Perciaccante and Young (2008) found that after a cluster of cases of transfusion-associated NEC, a change from a practice of no disruption of feeding schedules to a practice of withholding feedings from 4h before the start of the transfusion until 4h after the completion of the transfusion. Before introducing the practice of withholding feedings, a history of an RBC transfusion in the preceding 48h prior to onset of NEC in 7 out of 18 cases of NEC. Following the change in feeding practices there was no record of any cases of NEC that occurred within 48 h of an RBC transfusion⁶. These findings are similar to those reported by El-Dib et al who also used a pre-vs post-practice change design and detected a significant reduction in the incidence of transfusion-associated NEC after instituting the feeding policy change ¹⁰. As part of a multicenter quality improvement (QI) initiative in 8 NICUs, Talavera et al. (2016) implemented withholding of feedings during transfusions (but not before or after) and allowed no changes in fortification or volume advancement on the day of transfusion coupled with standardized human milk feeding^35-37. The only concern about withholding feeds is that it may affect the caloric intake, disruption to feeding progress, and metabolic instability of the infant. Studies and protocols have also considered altering types of milk feed and fortifications during the period of blood transfusion ³⁸^-⁴⁷.

LIMITATION:

We acknowledge some drawbacks in our study, our sample size might be small and we need to take a larger scale, and following up weight strictly of the preterm daily, nutritional laboratory parameters after withholding feeds to see the impact of withholding feeds on them. We recommend withholding feeds before, during, and after pRBCs, as it showed a less number for TANEC even if it wasn’t statistically significant if it was not affecting the weight.

CONCLUSION:

The Incidence of transfusion related NEC in preterm neonates in group (B) where feeds were withheld before, during and after pRBCs transfusion (15.6%) were less than those in group (A) where only one feed was withheld during pRBCs transfusion (26.7%). Incidence of other complications of prematurity in group (A) were relatively higher where: ICH Incidence was (22.2%), BPD was (11.1%), PDA was (46.7%), ROP was (2.2%) and pneumothorax was (11.1%), while that in group (B): ICH Incidence was (15.6%), BPD was (11.1%), PDA (37.8%) was ROP (4.4%) was and pneumothorax was (8.9%). Risk factors that increase NEC incidence are PDA, lower birth weight, lower gestational age, low APGAR score at 5 minutes and feeding of preterm before pRBCs transfusion.

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Received on 12.06.2023 Modified on 09.09.2023

Research J. Pharm. and Tech 2024; 17(2):834-842.

DOI: 10.52711/0974-360X.2024.00129

	Univariate				Multivariate
			95% CI				95% CI
	P-value	Odds ratio (OR)	Lower	Upper	P-value	Odds ratio (OR)	Lower	Upper
Low APGAR	0.012	7.25	1.553	33.837	0.051	6.299	0.991	40.049
Gestational age (wks.) £ 30	0.001	14.5	2.952	71.222	–	–	–	–
Birth weight (kg) £ 1.12	0	77.5	9.628	623.799	0.003	19.677	2.78	139.269
Antacids	0.003	10.15	2.149	47.936	–	–	–	–

	Univariate				Multivariate
			95% CI				95% CI
	P-value	Odds ratio (OR)	Lower	Upper	P-value	Odds ratio (OR)	Lower	Upper
Low APGAR	0.006	13.333	2.081	85.413	0.041	14.205	1.121	179.978
Gestational age (wks.) £ 31	0.062	8.25	0.903	75.414	–	–	–	–
Birth weight (kg) £ 1.1	0.003	32	3.242	315.852	0.005	49.502	3.19	768.094
Antacids	0.046	6.375	1.032	39.365	–	–	–	–