BACKGROUND AND OBJECTIVES:

Thrombocytopenia is associated with late closure of patent ductus arteriosus (PDA). There are few studies evaluating platelet transfusions to treat PDA. We compared liberal platelet-transfusion criteria (to maintain a platelet count >100 000 per µL) versus standard criteria achieve earlier PDA closure among thrombocytopenic preterm neonates (<35 weeks’ gestation) with hemodynamically significant PDA (hs-PDA) presenting within the first 2 weeks of life.

METHODS:

Thrombocytopenic (<100 000 per µL) preterm neonates with hs-PDA were enrolled and randomly allocated to the liberal and standard transfusion groups: 22 in each arm. They underwent echocardiography daily until closure of PDA, completion of 120 hours follow-up, or death. All subjects received standard cotreatment with nonsteroidal antiinflammatory drugs. Primary outcome of time to PDA closure was compared by survival analysis. Multivariate Cox proportional hazard regression was performed with randomization group, baseline platelet count, gestational age, and age at enrollment as predictor variables.

RESULTS:

Median time to PDA closure was 72 (95% confidence interval [CI] 55.9–88.1) versus 72 (95% CI 45.5–98.4) hours in the liberal versus restrictive transfusion groups, respectively (unadjusted hazard ratio 0.88 [95% CI 0.4–1.9]; P = .697). Despite adjusting for potential confounders, there was no significant difference in time to PDA closure. In the liberal transfusion group, 40.9% of infants had any grade of intraventricular hemorrhage compared with 9.1% in the restrictive group (P = .034).

CONCLUSIONS:

Attempting to maintain a platelet count >100 000 per µL by liberally transfusing platelets in preterm thrombocytopenic neonates with hs-PDA does not hasten PDA closure.

What’s Known on This Subject:

Previous studies have demonstrated that thrombocytopenia is associated with delayed closure of ductus arteriosus. There are no trials evaluating platelet transfusions (to maintain the platelet count above a threshold) on the closure of patent ductus arteriosus (PDA) in preterm infants.

What This Study Adds:

Liberal criteria for platelet transfusion (to maintain a platelet count >100 000 per µL) in preterm thrombocytopenic neonates with hemodynamically significant PDA do not result in earlier closure of PDA compared with standard platelet-transfusion criteria.

A common complication of prematurity is patent ductus arteriosus (PDA). In recent years, the role of platelets in PDA closure has been studied. Animal studies have revealed that within minutes after birth, activated platelets adhere to the wall of the ductus arteriosus (DA) and accumulate in the lumen, leading to thrombus formation, which undergoes remodeling and leads to the permanent closure of the DA.1 Also, mice with defective platelet-adhesion properties had high rates of persistent DA even after treatment with indomethacin. These findings suggest that platelet plug formation is a critical link between initial reversible constriction and final anatomic closure of DA.1 Thereafter, many human studies tried to explore the effect of platelet count on the DA closure rates. A meta-analysis of retrospective observational studies revealed an association between thrombocytopenia and patency of the DA.2 Our group published a prospective study in this journal that showed that thrombocytopenia (defined as <100 000 per μL) within the postnatal age of 24 hours independently predicts delayed closure of DA in preterm infants and is associated with hemodynamically significant patent ductus arteriosus (hs-PDA).3 Thus, there are reasonable grounds to suspect that maintaining a higher platelet count by liberally transfusing platelets may facilitate the formation of a clot in the DA and subsequent closure of hs-PDA.

There is a paucity of data regarding platelet transfusions as a therapy to affect PDA closure. In a randomized controlled trial (RCT), Andrew et al4 studied the effect of platelet transfusions on intracranial hemorrhage as a primary outcome. PDA, which is a secondary outcome in this RCT, had a similar incidence in transfused and control groups.

We hypothesized that the administration of platelet concentrates to maintain a platelet count >100 000 per μL among thrombocytopenic preterm infants with hs-PDA presenting within the first 14 days of life would result in an earlier closure of the PDA. Therefore, we planned an RCT to determine if liberal platelet-transfusion criteria achieve earlier PDA closure compared with standard platelet-transfusion criteria among the above infants.

We conducted an open-label RCT in a level III NICU in North-Western India from March 2016 to April 2017. The institute’s ethics committee approved the study protocol. We registered this trial at www.clinicaltrials.gov (identifier NCT03022253) and with the Clinical Trials Registry–India (identifier CTRI/2017/01/007660).

We performed an echocardiogram in extremely low birth weight neonates in the first 48 hours per unit policy, and for the rest, we performed echocardiography only when there were clinical signs of PDA. Our screening criteria were all inborn and outborn preterm (age ≤34 + 6/7 weeks’ gestation) neonates with PDA detected at <14 days of postnatal age. We performed an echocardiogram (MicroMaxx Portable Ultrasound Machine; SonoSite, Inc, Bothell, WA) and a platelet count (Sysmex KX-21 Coulter) in infants who met the screening criteria and included them if they had a platelet count <100 000 per μL and hs-PDA. We diagnosed hs-PDA on the basis of standard validated criteria.5,6 We suspected clinically significant PDA in the presence of 2 or more of the following: (1) heart murmur, (2) hyperdynamic precordium, (3) bounding pulses, (4) persistent tachycardia (>160 beats per minute), (5) wide pulse pressure, (6) new-onset or increase in ventilator requirements, or (7) systemic hypoperfusion (poor pulses, prolonged capillary refill time, decreased urine output, or hypotension). We defined echocardiographic hs-PDA as the presence of transductal diameter ≥1.5 mm at the pulmonary end plus 1 of the following: (1) left-atrium/aorta ratio ≥1.4, (2) ductal velocity <2 meters per second, (3) antegrade left pulmonary artery diastolic flow >30 centimeters per second, (4) E-wave/A-wave ratio >1, (5) isovolemic relaxation time ≤45 milliseconds, or (6) absent or reversed diastolic blood flow pattern in the descending thoracic aorta.

We excluded infants with echocardiographically proven structural congenital heart diseases, major life-threatening malformations, and syndromes associated with PDA and those who had received platelet concentrates between the last platelet count and the point of randomization. We enrolled eligible neonates after obtaining written informed consent from a parent.

We allocated subjects by a stratified, block randomization design with the following strata: (1) platelet count <50 000 per μL and (2) platelet count 50 000 to 100 000 per μL. One of the investigators (S.D.) generated the randomization sequence and constructed randomly varying, permuted, even-numbered blocks for each stratum. He concealed the block sizes until the end of the study and was not involved in subject recruitment. We ensured concealment of allocation using serially numbered, opaque, sealed envelopes that contained a slip of paper with the allocation group. The first investigator (J.K.) enrolled subjects and allocated them to the intervention and control arms. We treated subjects in both arms with nonsteroidal antiinflammatory drugs (NSAIDs), starting immediately after diagnosis of hs-PDA. We administered oral Ibuprofen (10 mg/kg followed by 2 doses of 5 mg/kg at 24-hour intervals). We administered intravenous Paracetamol (15 mg/kg per dose every 6 hours for a total of 12 doses) if there were any contraindications to the use of Ibuprofen (blood urea >60 mg/dL, serum creatinine >1.6 mg/dL, platelet count <60 000/μL, contraindications to oral intake, clinical bleeding from any site, or recent-onset intraventricular hemorrhage [IVH] grade III or IV).

Transfusion criteria in the intervention arm were “liberal.” Subjects in this arm received repeated platelet concentrates with the intention of maintaining a platelet count >100 000 per μL until the first of the following end points was met: (1) PDA closed or (2) 120 hours after randomization. We monitored platelet counts in the intervention group at an interval of 24 ± 6 hours. Whenever the platelet count was <50 000 per μL, 2 back-to-back platelet concentrates were transfused without checking the platelet count between transfusions because there was little chance that the platelet count would rise to >100 000 per μL with a single platelet transfusion. Whenever the platelet count ranged from 50 000 to 100 000 per μL, a platelet count was performed after a single transfusion.

Whenever possible, we clubbed the posttransfusion platelet count (performed in a window period of 2 hours after transfusion) with blood sampling for other clinical indications. The posttransfusion platelet count was available within a turnaround time of 2 hours. If a subject in the intervention arm had a platelet count <100 000 per μL, we repeatedly administered platelet transfusions, subject to a maximum volume of 40 mL/kg per day of platelet concentrates in a 24-hour period (defined as 8 am to 8 am the next day) and adjusted the total fluid intake accordingly. We temporarily withheld transfusing platelet concentrates once we got a value of >100 000 per μL. We also performed platelet counts in the presence of clinical bleeds (any visible fresh oral, nasal, endotracheal, gastrointestinal, or skin bleed) and routinely once every 24 hours until PDA closed or 120 hours postrandomization provided that a posttransfusion platelet count was not already available within a preceding window period of 4 hours.

Transfusion criteria in the control arm were “restrictive.” In this arm, we transfused platelet concentrates per standard criteria: (1) platelet count <20 000 per μL, (2) clinical bleed, or (3) platelet count <50 000 per μL and requiring a major nonneurosurgical interventional procedure7 or (4) platelet count <100 000 per μL and required a neurosurgical procedure.7 We performed a platelet count per our standard unit practice (ie, whenever the subject was next sampled for a clinical indication or with routine samples).

In both groups, the volume of each platelet-concentrate transfusion depended on the pretransfusion platelet count. Subjects with a platelet count <50 000, 50 000 to 75 000, and 75 000 to 100 000 per μL were transfused 20, 15, and 10 mL/kg per transfusion, respectively. Diuretics were administered only if the treating team felt that the patient had already developed or was likely to develop congestive cardiac failure.

An investigator (J.K.) performed serial echocardiograms at intervals of 24 ± 6 hours from enrollment until 120 hours postrandomization, closure of PDA, discharge, or death, whichever was earlier. All echocardiographic findings were confirmed by a neonatal echocardiography expert (V.S. and S.S.S.) after masking patient identity on the video clips.

DA was considered open if the flow was detected across it on color Doppler. If DA was patent, an investigator recorded standard parameters on color Doppler modes to determine hemodynamic significance. To minimize variability, each parameter was measured twice, and the average was recorded. In situations in which 2 readings differed >20%, we repeated all the measurements and immediately reconfirmed with 1 of the experts. Clinical and echocardiographic hs-PDA was defined per standard criteria. Infants in whom ductus was closed, echocardiogram was repeated 24 hours later to ensure that the DA remained closed.

The primary outcome was the time between randomization and closure of the DA during the study period of 120 hours. Secondary outcomes included proportion with any PDA and hs-PDA at 24 hours after the last dose of the NSAID, proportion with hs-PDA at 120 hours after randomization, cumulative volume of platelet concentrate received within the study period, clinical bleeds during the study period, new-onset IVH of any grade and grades III and IV IVH during the study period, mortality during the study period, mortality during the hospital stay, duration of hospital stay, and reopening of closed PDA.

Our study had a fixed follow-up time of 5 days for all subjects. Therefore, the accrual interval was 0 days. Assuming the median time for closure of PDA among thrombocytopenic preterm infants with hs-PDA receiving NSAIDs to be 5 days, we needed 22 subjects in each arm to be able to detect a true hazard ratio (HR) of 0.35 with a 5% α error and 80% power.

We described categorical variables as percentages, normally distributed numerical variables as means (with SDs), and those with skewed distributions as medians (first and third quartiles). We determined skewness by using the Shapiro-Wilk test and Q-Q plot. The primary outcome was compared by using Kaplan-Meier curves (censoring variables were death, discharge, or completion of 120 hours postrandomization). We performed a multivariate Cox proportional hazard regression with time to PDA closure as the outcome and the group of allocation (control arm being the reference group), baseline platelet count (expressed in multiples of 10 000 per μL), gestational age, and postnatal age as covariates decided a priori. We compared categorical outcome variables by using the χ2 test or Fisher’s exact test as appropriate. We compared numerical variables by using the Student’s t test or Mann–Whitney U test as applicable. We used SPSS version 22 (IBM SPSS Statistics, IBM Corporation) for statistical analysis. We analyzed by intention to treat.

Figure 1 shows the flow of the study subjects. We enrolled 44 neonates and analyzed all for the primary outcome. None of the enrolled infants had ever received a platelet transfusion before study entry. The baseline characteristics were similar across groups except for maternal platelet count, which was lower (P = .04) in the liberal transfusion group (Table 1).

FIGURE 1

Flow of the study.

FIGURE 1

Flow of the study.

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TABLE 1

Baseline Characteristics in Liberal and Restrictive Transfusion Groups

CharacteristicLiberal Transfusion Group (N = 22)Restrictive Transfusion Group (N = 22)Pa
Gestational age, completed wk    
 Mean ± SD 29.30 ± 2.4 30.01 ± 2.0  
 Median (first–third quartile) 29 (27–31) 30 (28–32) .2 
Birth wt, g    
 Mean ± SD 1074.73 ± 307.5 1149.14 ± 303.1  
 Median (first–third quartile) 1057.50 (826.0–1243.5) 1093.50 (962.2–1298.5) .3 
Male sex, n (%) 11 (50) 13 (59.1) .5 
Cesarean delivery, % 9 (40.9) 12 (54.5) .3 
Birth asphyxia,bn (%) 10 (45.5) 10 (45.5) .9 
Baseline platelet count    
 Mean ± SD 64 272.73 ± 21 752.2 68 045.45 ± 21 261.3 .5 
 Median (first–third quartile) 66 000 (45 500–91 250) 67 500 (47 250–91 500)  
Age at enrollment, d    
 Mean ± SD 3.36 ± 1.5 3.55 ± 1.9 .7 
 Median (first–third quartile) 3 (2–4.2) 3 (2–4.2)  
Wt at enrollment, g    
 Mean ± SD 1033.18 ± 317.4 1099.82 ± 271.9 .2 
 Median (first–third quartile) 983.50 (807.5–1171.2) 1060.00 (912.5–1275.0)  
Maternal platelet count n = 13 n = 17  
 Median (first–third quartile) 180 000 (100 500–246 500) 247 000 (183 500–304 000) .044 
Maternal essential hypertension, n (%) 3 (13.6) 6 (27.2) .4 
Maternal pregnancy-induced hypertension, n (%) 10 (45.5) 11 (50.0) .5 
Suspect sepsis before enrollment, n (%) 1 (4.5) 2 (9.0) .9 
Culture-positive sepsis before enrollment, n (%) 2 (9.0) 3 (13.6) .9 
IVH before enrollment (any grade), n (%) 4 (18.2) 3 (13.6) .9 
CharacteristicLiberal Transfusion Group (N = 22)Restrictive Transfusion Group (N = 22)Pa
Gestational age, completed wk    
 Mean ± SD 29.30 ± 2.4 30.01 ± 2.0  
 Median (first–third quartile) 29 (27–31) 30 (28–32) .2 
Birth wt, g    
 Mean ± SD 1074.73 ± 307.5 1149.14 ± 303.1  
 Median (first–third quartile) 1057.50 (826.0–1243.5) 1093.50 (962.2–1298.5) .3 
Male sex, n (%) 11 (50) 13 (59.1) .5 
Cesarean delivery, % 9 (40.9) 12 (54.5) .3 
Birth asphyxia,bn (%) 10 (45.5) 10 (45.5) .9 
Baseline platelet count    
 Mean ± SD 64 272.73 ± 21 752.2 68 045.45 ± 21 261.3 .5 
 Median (first–third quartile) 66 000 (45 500–91 250) 67 500 (47 250–91 500)  
Age at enrollment, d    
 Mean ± SD 3.36 ± 1.5 3.55 ± 1.9 .7 
 Median (first–third quartile) 3 (2–4.2) 3 (2–4.2)  
Wt at enrollment, g    
 Mean ± SD 1033.18 ± 317.4 1099.82 ± 271.9 .2 
 Median (first–third quartile) 983.50 (807.5–1171.2) 1060.00 (912.5–1275.0)  
Maternal platelet count n = 13 n = 17  
 Median (first–third quartile) 180 000 (100 500–246 500) 247 000 (183 500–304 000) .044 
Maternal essential hypertension, n (%) 3 (13.6) 6 (27.2) .4 
Maternal pregnancy-induced hypertension, n (%) 10 (45.5) 11 (50.0) .5 
Suspect sepsis before enrollment, n (%) 1 (4.5) 2 (9.0) .9 
Culture-positive sepsis before enrollment, n (%) 2 (9.0) 3 (13.6) .9 
IVH before enrollment (any grade), n (%) 4 (18.2) 3 (13.6) .9 
a

χ2 or Fisher’s exact tests were used for categorical outcomes. Independent-sample Student’s t tests were used for normal distribution, and independent-sample Mann–Whitney U tests were used for skewed distribution.

b

Apgar score <6 at 1 min of life.

The median time to closure of PDA in the liberal transfusion group was 72.00 (95% confidence interval [CI] 55.9–88.1) hours versus 72.00 (95% CI 45.5–98.4) hours in the restrictive transfusion group (unadjusted HR 0.88 [95% CI 0.4–1.9]; P = .697; Fig 2). On Cox proportional hazard regression, there was no statistically significant difference in time to PDA closure between the groups (Table 2). None of the enrolled patients were discharged from the hospital, taken by caregivers against medical advice, or had consent withdrawn before the closure of PDA. Figure 3 shows the median (95% CI) of the maximum platelet count in each 24-hour epoch from baseline until 120 hours postrandomization in the liberal versus the restrictive transfusion groups. Except for the values in the 0-to-24–hour epoch, values at other time points showed a wide overlap between the groups.

FIGURE 2

Kaplan-Meier survival curves comparing liberal and restrictive transfusion groups for time to PDA closure. Censoring variables were death, discharge, or completion of 120 hours of life.

FIGURE 2

Kaplan-Meier survival curves comparing liberal and restrictive transfusion groups for time to PDA closure. Censoring variables were death, discharge, or completion of 120 hours of life.

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TABLE 2

Multivariable Analysis by Cox Proportional Hazard Regression for Time to PDA Closure

Predictor VariableAdjusted HR95% CI of Adjusted HRP
Liberal transfusion groupa 1.4 0.57–3.47 .46 
Baseline platelet count in multiples of 10 000 1.12 0.91–1.37 .28 
Gestational age, wk 0.79 0.62–1.002 .052 
Age at enrollment, d 1.005 0.77–1.31 .97 
Sepsis at baselineb 1.47 0.48–4.46 .5 
Predictor VariableAdjusted HR95% CI of Adjusted HRP
Liberal transfusion groupa 1.4 0.57–3.47 .46 
Baseline platelet count in multiples of 10 000 1.12 0.91–1.37 .28 
Gestational age, wk 0.79 0.62–1.002 .052 
Age at enrollment, d 1.005 0.77–1.31 .97 
Sepsis at baselineb 1.47 0.48–4.46 .5 

Censoring variables were death, discharge, and completion of 120 h postrandomization.

a

Restrictive transfusion group was the reference group.

b

No sepsis was the reference group.

FIGURE 3

Comparison of the median of maximum platelet counts in 24-hour epochs. Error bars represent 95% CIs.

FIGURE 3

Comparison of the median of maximum platelet counts in 24-hour epochs. Error bars represent 95% CIs.

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In the liberal transfusion group, 40.9% of infants had any grade of IVH versus 9.1% of those in the restrictive group (P = .034; Table 3). However, new-onset grade III or IV IVH was similar in both groups (P = .6). In light of this finding, we performed a multivariate regression analysis to determine if liberal platelet transfusion was an independent predictor of any grade of IVH after adjusting for gestational age, suspected or proven sepsis at baseline, Pco2 at baseline, mechanical ventilation, and persistence of hs-PDA (Table 4). The cumulative volume of platelet concentrate transfused in 120 hours after randomization was a statistically significant independent predictor of any grade of IVH (P = .019). Each extra milliliter per kilogram transfused increased the odds by 4.5%.

TABLE 3

Comparison of Secondary Outcome Parameters Between Liberal and Restrictive Transfusion Groups

CharacteristicLiberal Transfusion Group (N = 22)Restrictive Transfusion Group (N = 22)Pa
Proportion with PDA open at 24 h after last dose of medication, n (%) n = 15 n = 14 .9 
 2 (13.3) 2 (14.3)  
Proportion with echocardiographic hs-PDA at 24 h after last dose of medication, n (%) n = 15 n = 14 .9 
 2 (13.3) 1 (7.1)  
Proportion with echocardiographic hs-PDA at 120 h after randomization, n (%) n = 15 n = 14 .9 
 2 (13.3) 1 (7.1)  
Cumulative volume of platelet concentrate received within 120 h after randomization, mL/kg, median (first–third quartile) 30 (15–55) 0 (0–15) <.001 
Any clinical bleed within 120 h,bn (%) 10 (45.5) 10 (45.5) .9 
New-onset IVH of any grade within 120 h, n (%) 9 (40.9) 2 (9.1) .034 
New-onset IVH grade III or IV within 120 h, n (%) 4 (18.2) 2 (9.1) .6 
Mortality in 120 h, n (%) 7 (31.8) 8 (36.4) .9 
Mortality at any time during hospital stay, n (%) 8 (36.4) 9 (40.9) .9 
Culture-positive sepsis, n (%) 8 (36.3) 2 (9.1) .07 
Duration to discharge among survivors, d n = 15 n = 14 .1 
 Median (first–third quartile) 50 (23–72) 29 (15.5–46.5)  
Reopening rate of PDA, n (%) — 
Highest platelet count between 0 and 24 h after enrollment, ×105 per µL n = 18 n = 17 .012 
 Median (first–third quartile) 1.09 (1.05–1.23) 0.78 (0.52–1.10)  
Highest platelet count between 24 and 48 h after enrollment, ×105 per µL n = 18 n = 16 .1 
 Median (first–third quartile) 1.24 (1.02–1.43) 0.98 (0.57–1.28)  
CharacteristicLiberal Transfusion Group (N = 22)Restrictive Transfusion Group (N = 22)Pa
Proportion with PDA open at 24 h after last dose of medication, n (%) n = 15 n = 14 .9 
 2 (13.3) 2 (14.3)  
Proportion with echocardiographic hs-PDA at 24 h after last dose of medication, n (%) n = 15 n = 14 .9 
 2 (13.3) 1 (7.1)  
Proportion with echocardiographic hs-PDA at 120 h after randomization, n (%) n = 15 n = 14 .9 
 2 (13.3) 1 (7.1)  
Cumulative volume of platelet concentrate received within 120 h after randomization, mL/kg, median (first–third quartile) 30 (15–55) 0 (0–15) <.001 
Any clinical bleed within 120 h,bn (%) 10 (45.5) 10 (45.5) .9 
New-onset IVH of any grade within 120 h, n (%) 9 (40.9) 2 (9.1) .034 
New-onset IVH grade III or IV within 120 h, n (%) 4 (18.2) 2 (9.1) .6 
Mortality in 120 h, n (%) 7 (31.8) 8 (36.4) .9 
Mortality at any time during hospital stay, n (%) 8 (36.4) 9 (40.9) .9 
Culture-positive sepsis, n (%) 8 (36.3) 2 (9.1) .07 
Duration to discharge among survivors, d n = 15 n = 14 .1 
 Median (first–third quartile) 50 (23–72) 29 (15.5–46.5)  
Reopening rate of PDA, n (%) — 
Highest platelet count between 0 and 24 h after enrollment, ×105 per µL n = 18 n = 17 .012 
 Median (first–third quartile) 1.09 (1.05–1.23) 0.78 (0.52–1.10)  
Highest platelet count between 24 and 48 h after enrollment, ×105 per µL n = 18 n = 16 .1 
 Median (first–third quartile) 1.24 (1.02–1.43) 0.98 (0.57–1.28)  

—, not applicable.

a

χ2 test or Fisher’s exact test for categorical outcomes. Independent-sample Student’s t tests were used for normal distribution, and independent-sample Mann–Whitney U tests were used for skewed distribution.

b

Clinical bleed was any visible fresh oral, nasal, endotracheal, gastrointestinal, or skin bleed.

TABLE 4

Multivariate Logistic Regression Analysis of Predictors of Any Grade of IVH

Predictor VariablesRegression CoefficientaOR95% CI of aORP
Constant 6.87 964 — — 
Cumulative volume of platelet concentrate transfused in 120 h 0.044 1.045 1.007–1.084 .019 
Gestational age −0.37 0.69 0.35–1.35 .28 
Maximum Pco2 within 12 h before enrollment 0.009 1.009 0.93–1.09 .82 
Mechanically ventilated 1.04 2.82 0.14–56.9 .5 
hs-PDA persisting at 24 h after last dose of NSAIDs −0.26 0.07 0.001–7.86 .27 
Suspected or proven sepsis 0.37 1.45 0.06–38.06 .82 
Predictor VariablesRegression CoefficientaOR95% CI of aORP
Constant 6.87 964 — — 
Cumulative volume of platelet concentrate transfused in 120 h 0.044 1.045 1.007–1.084 .019 
Gestational age −0.37 0.69 0.35–1.35 .28 
Maximum Pco2 within 12 h before enrollment 0.009 1.009 0.93–1.09 .82 
Mechanically ventilated 1.04 2.82 0.14–56.9 .5 
hs-PDA persisting at 24 h after last dose of NSAIDs −0.26 0.07 0.001–7.86 .27 
Suspected or proven sepsis 0.37 1.45 0.06–38.06 .82 

aOR, adjusted odds ratio; —, not applicable.

Mortality during the first 120 hours postrandomization as well as during the hospital stay was comparable in both groups (P = 1.0). There was no reopening of PDA in either group. No participant in either group had an anaphylactic reaction, a transfusion-related acute lung injury, or transfusion-associated circulatory overload (any 4 of the following symptoms occurring within 6 hours of transfusion: [1] acute respiratory distress, [2] tachycardia, [3] hypertension, [4] acute or worsening pulmonary edema, and/or [5] evidence of positive fluid balance).

We did not find a statistically significant difference in time to closure of PDA or the proportion with DA closure between the liberal and restrictive transfusion groups. Hence, we were unable to prove the hypothesis that platelet transfusion to maintain a platelet count >100 000 per μL in thrombocytopenic preterm neonates will lead to early closure of hs-PDA. We observed that despite the liberal criteria for transfusion in the intervention arm, the actual average platelet counts achieved in the 2 arms were not significantly different. Despite a liberal transfusion policy, in 7 of 22 (31.8%) neonates, we were unable to achieve the target platelet count at 1 or another time postrandomization, probably because of ongoing consumption. The highest platelet counts between 0 and 24 hours postrandomization were significantly higher in the liberal group, but the difference did not persist thereafter until the end of the study period.

This coupled with the possibility that platelet dysfunction could play an important role (and dysfunction may not improve with platelet transfusion) could explain why the groups had similar outcomes.8,10 Studies have revealed that the platelet-aggregation capacity of transfused donor blood is lower than native blood, and there is potential developmental mismatch between native neonatal platelets and transfused adult platelets.11 Some authors have suggested that platelet mass, mean platelet volume, and impairment of platelet function in preterm infants due to sickness and prematurity, rather than platelet count, may be better predictors of PDA closure.8,9,12 Therefore, future studies should take into account not only the number of platelets but also platelet function.8 However, there are logistic issues in performing platelet-function tests because they require a large amount of blood, which may not be feasible in preterm infants. Also, studies on platelet function reveal that these tests poorly simulate in vivo primary hemostasis.13 

The increase in blood volume through more frequent platelet transfusions in the intervention arm may have offset any possible benefit of maintaining a higher platelet count when compared with the control group. Higher circulating blood volume is known to contribute to persistence of the PDA.14,15 

The mean gestational age in most of the previous observational studies on platelet counts and PDA closure was 25 to 34 weeks’ gestation.1,3,8,16,17 We chose a gestational age group of up to 34 weeks’ gestation and postnatal age of until 14 days because the chances of detecting hs-PDA of prematurity are less beyond 34 weeks’ gestation and beyond the first 14 days.3 We chose a cutoff of 100 000 per μL to define thrombocytopenia on the basis of a prospective study done from our own unit.3 On the basis of the current literature, we enrolled infants with clinical as well as echocardiographic hs-PDA except in the extremely low birth weight population, in which those with echocardiographical hs-PDA alone were also enrolled.18,20 

Andrew et al4 evaluated the role of the early use of platelet-concentrate transfusion in preterm infants in reducing the incidence of IVH. Among the secondary outcomes, they found no difference in the incidence of PDA (43.6% vs 45.9%). In the study by Andrew et al,4 there is no mention of the mode of diagnosis of PDA and its hemodynamic significance and treatment. Also, they did not enroll infants with an initial platelet count <50 000 per µL. Their transfusion criteria and the definition of thrombocytopenia differed from our study.

In our study, the liberal transfusion group had a higher incidence of any grade of IVH; however, the incidence of severe IVH was not significantly different. Higher rates of IVH may be due to a rapid increase in blood volume during platelet transfusion with a resultant fluctuation of cerebral blood flow and IVH.21,22 Similar results were shown in a previous RCT4 on the role of platelet-concentrate transfusion in preterm infants in the reduction of the incidence or extension of intracranial hemorrhage. Brunner et al23 studied the risk of IVH in thrombocytopenic, very low birth weight, preterm infants with PDA treated with NSAIDs. They found that in the presence of moderate thrombocytopenia (50 000–99 000 per µL), NSAIDs amplified the risk of IVH (odds ratio 3.40 [95% CI 1.13–10.29]) compared with those with platelets ≥100 000 per µL.

There is no consensus in the results from previous studies evaluating multiple platelet transfusions on the incidence of IVH. A few observational studies have pointed toward increased risk of any IVH in infants receiving multiple platelet transfusions.24,25 Bonifacio et al25 reported an incidence of any grade of IVH of 62% vs 32% (P not significant) in transfused versus nontransfused groups, respectively. One retrospective study comparing a liberal versus restrictive platelet-transfusion strategy did not find significant differences in the rates of any IVH (30% vs 29% in the restrictive and liberal group, respectively; P = .81) or severe IVH (8% vs 11% in the restrictive and liberal group, respectively; P = .38) between the 2 groups.26 The only RCT evaluating the role of platelet transfusion in the prevention of IVH concluded that the prophylactic transfusions of platelet concentrates do not decrease the incidence or extension of IVH in premature infants with mild thrombocytopenia (50 000–100 000 per μL).4 The upper safe limit for volume of platelet transfusion in neonates is not defined. Our study points toward an increased risk of IVH with a liberal platelet-transfusion strategy.

The strengths of our study were well-defined eligibility criteria, a detailed platelet transfusion and monitoring protocol, and daily echocardiography with a comprehensive set of parameters. Because of the nature of the intervention, it could not be blinded. We did not perform platelet-function studies because of nonfeasibility.

We conclude that liberal criteria for platelet transfusion in preterm thrombocytopenic neonates who are being treated with NSAIDs for hs-PDA do not affect PDA closure rates. The liberal transfusion group had higher rates of any grade of IVH; however, grade III or IV IVH was similar in both groups.

Dr Kumar participated in the study design, recruited patients, performed echocardiography, collected data, and drafted the manuscript; Dr Dutta conceptualized and designed the study, supervised the collection of and analyzed the data, and critically revised and finalized the manuscript; Drs Sundaram and Saini participated in the study design, reviewed the echocardiography, and participated in the revision of the manuscript; Dr Sharma participated in the study design and ensured that the interventions were administered per study protocol; Dr Varma participated in the study design, performed the platelet counts, and ensured that platelet reports were available per study protocol; and all authors approved the final manuscript as submitted.

Deidentified individual participant data (including data dictionaries) will be made available on publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to sourabhdutta1@gmail.com.

This trial has been registered at www.clinicaltrials.gov (identifier NCT03022253) and with the Clinical Trials Registry–India (http://ctri.nic.in) (identifier CTRI/2017/01/007660).

FUNDING: No external funding.

     
  • CI

    confidence interval

  •  
  • DA

    ductus arteriosus

  •  
  • HR

    hazard ratio

  •  
  • hs-PDA

    hemodynamically significant patent ductus arteriosus

  •  
  • IVH

    intraventricular hemorrhage

  •  
  • NSAID

    nonsteroidal antiinflammatory drug

  •  
  • PDA

    patent ductus arteriosus

  •  
  • RCT

    randomized controlled trial

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.