Selective prophylactic solvent-detergent plasma and cryoprecipitate transfusion to prevent intraventricular hemorrhage in extreme preterm infants: A case-historical control

Abstract

BACKGROUND:

Contradictory evidence exists whether a prophylactic coagulation factor transfusion in the first hours of life (HOL) prevents intraventricular hemorrhage (IVH) in extreme preterm infants (EPI, <28 weeks gestation). We aimed to determine whether selective prophylactic solvent-detergent plasma and cryoprecipitate transfusion within 12 hours of life (SP-SDP/Cryoprecipitate-T) could prevent IVH in EPI.

METHOD:

This is a retrospective analysis, case-historical control, of prospectively collected data from a pre-existing electronic neonatal database at a Saudi tertiary neonatal intensive care unit. We compared the IVH rate in EPI born in the first 4 years (Jan 2010–Dec 2013) of the SP-SDP/Cryoprecipitate-T period with that of EPI born during the last 4 years (Jan 2006–Dec 2009) of the rescue SDP/Cryoprecipitate-T period.

RESULTS:

The IVH rate was lower in the SP compared to the rescue- SDP/Cryoprecipitate-T period (30.8% versus 51.2%, odds ratio 0.42, 95% confidence interval 0.21, 0.88, p = 0.02). This difference remained significant after controlling for six other IVH risk factors.

CONCLUSIONS:

Early SP-SDP/Cryoprecipitate-T may reduce the IVH rate in EPI. A large multicenter clinical trial is required for confirm the short and long-term benefit and risk of this intervention. Until then, early SP-SDP/Cryoprecipitate-T may be considered by an institution with a persistently high IVH rate.

Keywords

Extreme preterm infant intraventricular hemorrhage coagulopathy solvent-detergent plasma cryoprecipitate fresh frozen plasma

1 Introduction

About one-third to one-half of extreme preterm infants (EPI, <28 weeks gestation) develop intraventricular hemorrhage (IVH) that has acute and long-term serious sequelae [1 –5]. About one-half of the IVH occurs within the first 6 hours of life (HOL) [6]. The pathogenesis of IVH is multifactorial which is classically grouped into intravascular, vascular, and extravascular factors [2].

The level of coagulation factors is directly proportional to both the gestational and postnatal ages [7, 8]. Thus, EPIs are physiologically in a remarkable hypocoagulable state [7, 8]. Their activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) in the first 24 HOL are on average 4-times lower than that of full-term infants [7 , 10]. However, this hypocoagulability in not consistently linked to the development of IVH [2 , 12]. Several studies have shown that the reduced activity of one or more coagulation factor is associated with IVH [13 –20], but other studies have not found such an association [21 –23].

Dani et al., in a case-historical control study has found that selective prophylactic fresh frozen plasma transfusion (SP-FFP-T) within the first 6 HOL reduced the IVH rate in 58 EPI born at 23–26 weeks gestation [24]. However, this result was contradicted in a retrospective study by Tran et al [25]. Tran et al. compared rate of IVH among 47 EPIs who had coagulation testing and SP-FFP-T within first 48 HOL (early) with that among 55 EPIs who had coagulation testing and SP-FFP-T after 48 HOL (late). They have found that rate of IVH grade 3-4 was higher in the early group than the late group (34% versus 9%, p = 0.002) [25]. These contradictory results might be due to the difference in the time the SP-FFP-T (6 HOL vs 48 HOL) was administrated. No randomized control trial (RCT) has yet investigated whether SP-FFP-T in early life can prevent IVH in EPI.

The rate of IVH continued to be high among EPI admitted to our tertiary neonatal intensive care unit (NICU) even after implementing potentially better evidence-based practices, with the exception of prophylactic indomethacin, for the prevention of IVH [26, 27]. In 2010, we have implemented SP Octaplas^® solvent-detergent plasma (SDP) and cryoprecipitate transfusion within the first 12 HOL (SP-SDP/Cryoprecipitate-T) to prevent IVH. Prior to that, we used SDP/Cryoprecipitate-T as a rescue treatment for active significant bleeding only. We report our results after initiating SP-SDP-T as the results of the two previous studies are conflicting. Besides, both previous studies used fresh frozen plasma (FFP) and SDP, which replacing FFP worldwide, contains a lower Factor VII and VIII concentration than FFP [28, 29].

2 Subjects and methods

This is a case-historical control study in a Saudi tertiary NICU comparing IVH rates in the SP-SDP/Cryoprecipitate-T period (hereafter called SP-period) and rescue SDP/Cryoprecipitate-T period (hereafter called rescue-period). EPI born within the first 4 years (Jan 2010–Dec 2013) of the SP-period constituted the case group and EPI born during the last 4 years (Jan 2006–Dec 2009) of the rescue-period constituted the historical control group. Inclusion criteria for the SP-period was EPI who were inborn and received both SP-SDP/Cryoprecipitate-T and a screening head ultrasound (SHUS). The inclusion criteria for the rescue-period was EPI who were inborn and had SHUS to detect IVH. There was only one small for gestation age EPI in entire cohort who was born during rescue-period and was not excluded. Data related to the included EPI was extracted from our pre-existing electronic database in which data has been collected prospectively. A description of our electronic database and NICU has been published previously [30]. The majority of the variables in our database are analogous with those of the National Institute of Children Health and Human Development and Neonatal Research Network [30]. We defined bronchopulmonary dysplasia (BPD) as supplemental oxygen at 36 weeks’ postmenstrual age [30]. We defined patent ductus arteries (PDA) as echocardiographic evidence of PDA regardless of ductal size, shunt, or clinical signs [30]. Only hemodynamically (transductal diameter >1.5 mm) or clinically significant PDAs were treated [30]. The retinopathy of prematurity (ROP) was defined according to the International Classification of ROP [31]. Postnatal potential risk or protective factors for the development of IVH were collected until 7 day of life (DOL) for EPI who did not develop IVH and until the time of IVH diagnosis for those who developed IVH. The Institutional Ethics Review Board of the Ministry of National Guard Health Affairs approved this study with waiver of informed consent as it was a retrospective study.

2.1 Protocol of SP-SDP/Cryoprecipitate-T

Our practice is to administer at least one SP-SDP/Cryoprecipitate-T within the first 12 HOL for all EPI with prolonged coagulation tests. Thus, all inborn EPI are tested for aPTT, PT, INR and fibrinogen level as soon as possible after birth. Two ml of blood is withdrawn using an umbilical catheter (UC) primed with non-heparinized normal saline to avoid having a factitious prolonged aPTT or a peripheral blood vessel if no UC was inserted. The blood is collected in a 3.2 % Sodium Citrate tube and sent to our laboratory to measure the aPTT, PT, INR and fibrinogen level. The laboratory uses a Siemens BCS/BCS XP fully automated coagulation analyzer to perform the coagulation tests with a turnaround time of about one hour on average. We interpret the results according to the reference range of Andrew et al. for preterm infants born at 30–36 weeks’ gestation [32]. Thus, 15 ml/kg SDP is infused over two hours if the aPTT >79.4 seconds, or the PT >16.2 seconds, or the INR >1.7 and 7 ml of cryoprecipitate is infused over one hour if the fibrinogen level <1.5 g/L. Abnormal tests is repeated at the discretion of the physicians. We use SDP (Octaplas^®, Octapharma AG, Ziegelbrücke, Switzerland) instead of FFP because of its advantage in terms of a lower risk of infectious disease transmission, immunological reactions and lower batch-to-batch variations of the coagulation factor concentrations [11, 33].

2.2 Screening for IVH

During the study period, SHUS was performed according to our established IVH screening guidelines: 1) HUS examination was routinely performed at 5–7 DOL for stable preterm infants≤32 weeks, 2) subsequent HUS follow-up examinations were performed at 14 and 28 DOL or before discharge, 3) the HUS examination was performed as soon as the clinical suspicion of IVH is raised, 4) if IVH is detected, a second HUS examination is repeated 5–7 days later and 5) prior to the commencement of medical treatment of a patent ductus arteriosus (PDA) [34]. The IVH is graded according to the grading system of Papile et al. [35]. The HUS of the study infants were reviewed to calculate Abdi’s IVH severity score which is equal to the square of the highest IVH grade, plus the IVH grade on the contralateral side, plus 5 for each hemisphere when more than two of its territories are involved, and plus 5 when there is a midline shift of the brain [5, 36].

2.3 Statistical analysis

Mean±standard deviation and median (first, third quartile) was used to describe normally and non-normally distributed data, respectively. A Student t-test was used to analyze parametric and a Mann-Whitney test was used to analyze nonparametric continuous variables. A Chi-square test or Fisher exact test was used to analyze dichotomous variables when appropriate. An unconditional multivariable logistic regression analysis was used to adjust for available potential risk or protective factors for IVH development that differed statistically between the two periods. We used the likelihood ratio test to assess the significance and the Hosmer-Lemeshow test to assess the goodness-of-fit of the model. Two-sided p < 0.05 was accepted as statistically significant for all the tests. The analysis was performed using IBM SPSS Statistics 20 (Chicago, IL, USA). We report the results of the coagulation tests of EPI born during the SP-period as endorsed by the International Federation of Clinical Chemistry (IFCC) and the Clinical and Laboratory Standards Institute (CLSI) for reference interval estimation [37, 38]. As our sample size was small in the SP-period (n = 52), we performed a non-parametric bootstrap method with 500 iterations via the RefVal 4.11 program [37, 39].

3 Results

In total, 64 EPIs were born in our hospital during the SP-period and 98 during the rescue-period. Eleven (17.2%) EPI died within the first 7 DOL during the SP-period and 25 (25.5%) during the rescue-period (χ² p = 0.21). In each period, two of these early neonatal deaths were due to lethal congenital malformations. A total of 52 (81%) EPI from the SP-period was included; 12 EPI were excluded because they had no screening coagulation tests and/or no SHUS. In total, 84 (86.0%) of the EPI from rescue-period met the inclusion criteria. Table 1 shows the basic characteristics of the samples in both periods.

Table 1
Basic characteristics and clinical outcomes of study extreme preterm infants in selective polylactic (SP) and rescue solvent-detergent plasma (SDP)/Cryoprecipitate transfusion periods

Characteristics SP-
SDP/cryoprecipitate
transfusion period
(n = 52) Rescue
SDP/cryoprecipitate
transfusion period
(n = 84) P value

Gestational age (weeks), mean±SD 25.5±1.4 25.7±1.2 0.42

Birth weight grams, mean±SD 752.9±156.7 774.1±166.6 0.46

Discharge home 45 (86.5%) 66 (78.6%) 0.24

Male 30 (57.7%) 49 (58.3%) 0.94

Assisted reproductive technology 5 (9.6%) 22 (26.2%) 0.02

Multiple pregnancy 9 (17.3%) 30 (35.7%) 0.02

Antenatal dexamethasone 45 (86.5%) 68 (81.0%) 0.40

Cesarean section 16 (30.8%) 41 (48.8%) 0.04

Maternal preeclampsia 4 (7.7%) 3 (3.6%) 0.29

Preterm premature rupture of membranes 13 (25.0%) 38 (45.2%) 0.02

Antenatal antibiotics 15 (28.8%) 24 (50.0%) 0.02

Histological chorioamnionitis without funisitis 5 (9.6%) 10 (11.9%) 0.68

Histological chorioamnionitis with funisitis 1 (1.9%) 1 (1.2%) 0.73

5-minutes Apgar score, median (first, third quartile) 7.0 (7.0, 8.0) 7.0 (7, 7) 0.39

Cord pH, median (first, third quartile) 7.3 (7.2, 7.4) 7.3 (7.2, 7.4) 0.26

Admission temperature, median (first, third quartile) 36.4 (36.1, 36.7) 36.5 (36.2, 36.8) 0.82

Conventional mechanical ventilation 48 (92.3%) 82 (97.6%) 0.14

High frequency oscillation ventilation 4 (7.7%) 12 (14.3%) 0.25

Surfactant 43 (82.7%) 76 (90.5%) 0.18

Inhaled nitric oxide 1 (1.9%) 2 (2.4%) 0.99

Pneumothorax 6 (11.5%) 6 (7.1%) 0.38

Massive pulmonary hemorrhage 4 (8.3%) 7 (8.3%) 0.99

Platelet count <50000/μL 15 (28.8%) 27 (31.8%) 0.72

Confirmed sepsis 9 (17.3%) 10 (11.9%) 0.38

Vasopressors/hydrocortisone for mean blood pressure less than gestational age in weeks (hypotension) 22 (66.7%) 47 (57.3%) 0.36

Echocardiography (ECHO) 39 (75.0%) 69 (82.1%) 0.32

Patent ductus arteriosus (PDA) 39 (100%) 62 (89.9%) 0.047

Treated Patent ductus arteriosus 23 (59.0%) 32 (51.6) 0.47

Total intraventricular hemorrhage 16 (30.8%) 43 (51.2%) 0.02

Grade 1 3 (5.8%) 11 (13.1%) 0.17

Grade 2 4 (7.7%) 8 (9.5%) 0.71

Grade 3 5 (9.6%) 13 (15.5%) 0.33

Grade 4 4 (7.7%) 11 (13.1%) 0.33

Abdi Score 5 and 6 3 (5.8%) 2 (2.4%) 0.31

Abdi score≥11 9 (17.3%) 19 (22.6%) 0.46

Ventriculoperitoneal shunt 4 (7.7%) 2 (2.4%) 0.20

Thrombosis 2 (3.8%) 5 (6.0%) 0.71

Necrotizing enterocolitis (Bell’s stage II and III) 5 (9.6%) 10 (11.9%) 0.68

Bronchopulmonary dysplasia (required supplemental oxygen at 36 weeks’ postmenstrual age) 15 (28.8%) 29 (34.5%) 0.49

All retinopathy of prematurity 12 (23.1%) 24 (28.6%) 0.48

Characteristics	SP- SDP/cryoprecipitate transfusion period (n = 52)	Rescue SDP/cryoprecipitate transfusion period (n = 84)	P value
Gestational age (weeks), mean±SD	25.5±1.4	25.7±1.2	0.42
Birth weight grams, mean±SD	752.9±156.7	774.1±166.6	0.46
Discharge home	45 (86.5%)	66 (78.6%)	0.24
Male	30 (57.7%)	49 (58.3%)	0.94
Assisted reproductive technology	5 (9.6%)	22 (26.2%)	0.02
Multiple pregnancy	9 (17.3%)	30 (35.7%)	0.02
Antenatal dexamethasone	45 (86.5%)	68 (81.0%)	0.40
Cesarean section	16 (30.8%)	41 (48.8%)	0.04
Maternal preeclampsia	4 (7.7%)	3 (3.6%)	0.29
Preterm premature rupture of membranes	13 (25.0%)	38 (45.2%)	0.02
Antenatal antibiotics	15 (28.8%)	24 (50.0%)	0.02
Histological chorioamnionitis without funisitis	5 (9.6%)	10 (11.9%)	0.68
Histological chorioamnionitis with funisitis	1 (1.9%)	1 (1.2%)	0.73
5-minutes Apgar score, median (first, third quartile)	7.0 (7.0, 8.0)	7.0 (7, 7)	0.39
Cord pH, median (first, third quartile)	7.3 (7.2, 7.4)	7.3 (7.2, 7.4)	0.26
Admission temperature, median (first, third quartile)	36.4 (36.1, 36.7)	36.5 (36.2, 36.8)	0.82
Conventional mechanical ventilation	48 (92.3%)	82 (97.6%)	0.14
High frequency oscillation ventilation	4 (7.7%)	12 (14.3%)	0.25
Surfactant	43 (82.7%)	76 (90.5%)	0.18
Inhaled nitric oxide	1 (1.9%)	2 (2.4%)	0.99
Pneumothorax	6 (11.5%)	6 (7.1%)	0.38
Massive pulmonary hemorrhage	4 (8.3%)	7 (8.3%)	0.99
Platelet count <50000/μL	15 (28.8%)	27 (31.8%)	0.72
Confirmed sepsis	9 (17.3%)	10 (11.9%)	0.38
Vasopressors/hydrocortisone for mean blood pressure less than gestational age in weeks (hypotension)	22 (66.7%)	47 (57.3%)	0.36
Echocardiography (ECHO)	39 (75.0%)	69 (82.1%)	0.32
Patent ductus arteriosus (PDA)	39 (100%)	62 (89.9%)	0.047
Treated Patent ductus arteriosus	23 (59.0%)	32 (51.6)	0.47
Total intraventricular hemorrhage	16 (30.8%)	43 (51.2%)	0.02
Grade 1	3 (5.8%)	11 (13.1%)	0.17
Grade 2	4 (7.7%)	8 (9.5%)	0.71
Grade 3	5 (9.6%)	13 (15.5%)	0.33
Grade 4	4 (7.7%)	11 (13.1%)	0.33
Abdi Score 5 and 6	3 (5.8%)	2 (2.4%)	0.31
Abdi score≥11	9 (17.3%)	19 (22.6%)	0.46
Ventriculoperitoneal shunt	4 (7.7%)	2 (2.4%)	0.20
Thrombosis	2 (3.8%)	5 (6.0%)	0.71
Necrotizing enterocolitis (Bell’s stage II and III)	5 (9.6%)	10 (11.9%)	0.68
Bronchopulmonary dysplasia (required supplemental oxygen at 36 weeks’ postmenstrual age)	15 (28.8%)	29 (34.5%)	0.49
All retinopathy of prematurity	12 (23.1%)	24 (28.6%)	0.48

The EPI from the SP-period had coagulation tests performed at a median (first, third quartile) age of 2 (1, 4) HOL. The coagulation tests results are shown in Table 2. During SP-period, 30 (57.7%) EPI had SP-SDP/Cryoprecipitate-T: 16 had SDP only, 1 had cryoprecipitate only, and 13 had both SDP and cryoprecipitate transfusions. A total of 56 transfusions was performed during the first 168 HOL as 10 EPI had multiple SDP or cryoprecipitate transfusions. The first SP-SDP/Cryoprecipitate-T had been transfused at a median (first, third quartile) age of 7 (6, 9) HOL. During the rescue-period, 20 (23.8%) EPI had rescue SDP/Cryoprecipitate-T within the first 168 HOL: 15 had SDP only, 5 had both SDP and cryoprecipitate transfusions. A total of 46 transfusions was performed during the first 168 HOL as 16 EPI had multiple SDP or cryoprecipitate transfusions. The first rescue SDP/Cryoprecipitate-T had been transfused at median (first, third quartile) age of 33 (12, 46) HOL. The rate of multiple transfusions of SDP or cryoprecipitate within the first 168 HOL was the same in both periods (19.2% versus 19.0%, p = 0.98). The rate of multiple SDP/Cryoprecipitate-T was significantly lower in the SP- than the rescue-period among EPI who had transfusions within the first 168 HOL (33.3% versus 80.8%, p = 0.001).

Table 2

Results of coagulation tests of 52 extreme preterm infants of solvent-detergent plasma/Cryoprecipitate transfusion period

	Activated partial thromboplastin time(second)	Prothrombin time (second)	International normalized ratio	Fibrinogens (g/L) (g/L)
Mean (95% confidence interval)	98.1 (86.0, 111.3)	20.2 (18.8, 21.6)	1.7 (1.6, 1.9)	2.3 (1.7, 3.0)
2.5th percentile (95% confidence interval)	44.8 (43.5, 53.2)	11.7 (11.5, 13.8)	0.9 (0.9, 1.1)	0.1 (0.1, 0.4)
5th percentile (95% confidence interval)	48.9 (43.5, 55.2)	12.7 (11.5, 14.4)	1.1 (0.9, 1.2)	0.1 (0.1, 0.6)
50th percentile (95% confidence interval)	88.0 (73.0, 103.4)	19.3 (17.9, 20.8)	1.7 (1.5, 1.8)	1.5 (1.2, 2.5)
95th percentile (95% confidence interval)	221 (140.1, 250.0)	32.3 (26.5, 34.2)	2.8 (2.3, 3.1)	7.8 (5.0, 9.8)
97.5th percentile (95% confidence interval)	250.0 (141.4, 250.0)	33.9 (29.5, 34.2)	3.0 (2.7, 3.1)	9.2 (5.5, 9.8)

The rate of IVH was the lower in the SP- compared to the rescue-period (30.8% versus 51.2%, odds ratio 0.42, 95% confidence interval 0.21, 0.88, p = 0.02). The number needed to treat (NNT) would be 5.0 as the absolute risk reduction is 0.20. During the SP-period, 18.2 % (4/22) of EPI with normal coagulation tests developed IVH versus 40.0% (12/30) who received SDP/Cryoprecipitate-T developed IVH (p = 0.09). However, the EPI who received SDP/Cryoprecipitate-T were born at smaller gestational age (25 versus 26 weeks, p = 0.06) and at lower birth weight (702 grams versus 823 grams, p = 0.005) than EPI with normal coagulation tests.

The rates of five other potential risk/protective factors for IVH development were statistically different between the two periods (Table 1). These were assisted reproductive technology, multiple pregnancies, Caesarian sections, preterm premature rupture of membranes, and a patent ductus arteriosus (Table 1). The association between the IVH rate and SP-period remained significant after controlling for these five factors (Table 3).

Table 3

Result of logistic regression analysis

Variables	Adjusted odds ratio of intraventricular hemorrhage	(95% confidence interval)
Selective prophylactic solvent-detergent	0.37 (0.17, 0.81)
plasma/Cryoprecipitate transfusion period
Assisted reproductive technology	3.44 (0.99, 11.85)
Multiple pregnancies	0.68 (0.23, 2.03)
Caesarian sections	0.50 (0.23, 1.10)
Preterm premature rupture of membranes	0.56 (0.25, 1.24)
Patent ductus arteriosus	0.88 (0.38, 2.05)

The rate of Grade 2 IVH decreased by 19%, but contrarily, the Abdi score of 5 and 6 increased by 142% in SP-period as compared to rescue-period (Table 1). The rate of Severe IVH (grade 3 and 4) reduced by 40% but an Abdi score≥11 reduced by only 23% in SP-period as compared to rescue-period (Table 1). As there were only 12 EPI with these Abdi scores in the SP-period, the small sample size precluded further meaningful analysis that could provide more delineation. Rate of ROP, thrombosis, BPD, treated PDA, and Bell’s stage II and III necrotizing enterocolitis (NEC) were the same in both periods (Table 1).

4 Discussion

This study provided evidence that after SP-SDP/Cryoprecipitate-T within the first 12 HOL, the IVH rate reduced by about 40% and NNT of 5.0 but SDP and cryoprecipitate transfusions increased two folds in the first 168 HOL in the study NICU. It suggested that SP-SDP/Cryoprecipitate-T might reduce multiple administering rescue SDP/Cryoprecipitate-T if required later in life. However, this intervention has several challenges including the lack of a robust reference limit (RL) for coagulation tests and strong supporting evidence.

Dani et al., and we treated EPIs with abnormal coagulation tests much earlier than Tran et al. (within 6–12 HOL versus within 48 HOL) [24, 25]. This could be the reason why our study and Dani et al., found that SP-FFP-T or SP-SDP/Cryoprecipitate-T reduced the IVH rate whereas Tran et al. did not. In recent work, Dani et al., suggested that SP-FFP-T might have another clinical benefit. They showed for the first time that the SP-FFP-T might prevent ROP [40]. They proposed that this effect is due to high concentration of insulin-like growth factor 1 (IGF-1) FFP [40]. However, our ROP rate was not affected by SP-SDP/Cryoprecipitate-T. This discrepancy might be due to our small sample size. We do not know if SDP contains a lower IGF-1 concentration than FFP. However, it has been shown that solvent/detergent treatment of platelet concentrates has not effect on IGF-1 concentration [41].

We observed a discrepancy between changes in the rates of grade 2 and Abdi score 5 and 6. We observed that the magnitude of the reduction of Abdi score≥11 was less than that of severe IVH. These observations may have important inferences. The predictive ability of these scores for death or neurodevelopmental impairment is better than the Papile grading system [5]. There was also non-statistically significant increase in rate of ventriculoperitoneal shunt during SP-period. Consequently, the observed short-term benefit of SP-SDP/Cryoprecipitate-T will possibly not translate into a better long-term outcome.

The first step in administering SP-SDP/Cryopreci-pitate-T, is to correctly identify EPI with abnormal coagulation tests. Ideally, each laboratory should establish its own reference RL from at least 120 healthy subjects [37, 38]. As the hemostasis is developmental and gestational age dependent, ideally, we need 120 healthy EPI in each gestational age week. Obviously, this will be challenging to find and define such a sample size of healthy EPI. There is no clarity whether to use measures of central tendency or spread of dispersion as a RL for coagulation tests. It has been suggested to use 1.5 times mean, 1.5 times median, 95th percentile, or 97.5 percentile as the RL [42, 43]. As up to 50% of EPI develop IVH [1 –5], it may prudent to use the median level (50th percentile) as the RL.

Universal polylactic transfusion can be used to overcome the dilemma of the RL of coagulation tests. Intuitively, FFP transfusion will be higher in universal than selective transfusions. Systematic reviews including Cochrane reviews of RCTs evaluating universal prophylactic FFP transfusion (UP-FFP-T) have concluded that available evidence is not in favor of UP-FFP-T as only one small RCT by Beverley et al. (n = 73) has been reported [44 –48]. This conclusion should be taken with caution. The rate of IVH was a secondary outcome in the Northern Neonatal Nursing Initiative (NNNI) trial, the largest multicenter RCT on UP-FFP-T [49, 50]. The NNNI found that the IVH rate and 2-year neurological outcomes were similar in the UP-FFP-T (n = 201) and no UP-FFP-T group (n = 203) among preterm infant <32 weeks born in study centers performing SHUS [49, 50]. In this trial, two FFP doses were transfused over 15 minutes (20 ml/kg FFP within first 2 HOL followed by10 ml/kg). This is a very rapid infusion rate which is a risk factor for IVH [2]. The proportion of EPI, the group at the highest risk of developing IVH, was 25%. Accordingly, the NNNI trial included about 100 EPI and unfortunately, the IVH rate was not cross-tabulated by gestational age in its reports.

Our study has several limitations. It has a small size sample with a post-hoc power of 65%. As our study is a historical comparison, the reported improvement in IVH could be due to general improvement in the neonatal care. However, clinical care in our NICU during the study period did not change significantly apart from SP-SDP/Cryoprecipitate-T. Similar rates of NEC, BPD and ROP in the SP- and rescue-periods suggest that we did not have a global neonatal outcomes improvement. We used RLs that was extrapolated from another setting and older gestational ages. Results of the coagulation tests of EPI of the SP-period confirm (Table 2) they were higher than the used RL of Andrew et al. [32]. The small sample size precluded performing a propensity score matching to minimize inherited selection bias of observational studies [51]. It also preluded further analyzing the coagulation results, to establish the appropriate RL and which LR is associated with least NNT.

In conclusion, administering SP-SDP/Cryopreci-pitate-T within the first 12 HOL may reduce the IVH rate in EPI. We and others believe that a large multicenter clinical trial is required for confirm the short and long term benefit of this intervention [12]. Until then, early SP-SDP/Cryoprecipitate-T may be considered by an institution with a persistently high IVH rate.

Disclosure statement

All authors have no financial or non-financial competing interests to disclose. No funding has been received. The language editing of this manuscript by King Abdullah International Medical Research Center.

Human research statement

This study was conducted in accordance with the ethical standards of institutional committee and the World Medical Association’s Helsinki Declaration.

Footnotes

Acknowledgments

We dedicate this work to the great Saudi pediatric nephrologist Dr. Sadek Al-Omran (April 19, 1965–September 3, 2017) who recently died of metastatic rectal adenocarcinoma.

References

Synnes

, Chien

L-Y

, Peliowski

, Baboolal

, Lee

. Variations in intraventricular hemorrhage incidence rates among Canadian neonatal intensive care units. J Pediatr. 2001;138(4):525–31.

Volpe

JJ.

Intracranial Hemorrhage: Germinal Matrix–Intraventricular Hemorrhage of the Premature Infant. Neurology of the Newborn. 5th ed. Philadelphia (PA): Saunders/Elsevier. 2008:517–88.

Stoll

, Hansen

, Bell

, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126(3):443–56.

Bolisetty

, Dhawan

, Abdel-Latif

, Bajuk

, Stack

, Lui

. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics Jan. 2014;133(1):55–62.

Al-Mouqdad

, Al-Abdi

, Scott

, et al. A New IVH Scoring System Based on Laterality Enhances Prediction of Neurodevelopmental Outcomes at 3 Years Age in Premature Infants. Am J Perinatol. 34(1):44–50.

Al-Abdi

, Al-Aamri

. A Systematic Review and Meta-analysis of the Timing of Early Intraventricular Hemorrhage in Preterm Neonates: Clinical and Research Implications. J Clin Neonatol. 3(2):76–88.

Andrew

, Paes

, Johnston

. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol. 1990;12(1):95–104.

Monagle

, Massicotte

. Developmental haemostasis: Secondary haemostasis. Semin Fetal Neonatal Med. 16(6):294–300.

Manco-Johnson

. Development of hemostasis in the fetus. Thromb Res. 2005;115(Suppl 1):55–63.

10.

Neary

, Okafor

, Al-Awaysheh

, et al. Laboratory coagulation parameters in extremely premature infants born earlier than 27 gestational weeks upon admission to a neonatal intensive care unit. Neonatology. 2013;104(3):222–27.

11.

Al-Abdi

. Virus-inactivated plasma and intraventricular hemorrhage in preterm neonates. J Matern Fetal Neonatal Med. 2014;27(12):1288.

12.

Kuperman

, Brenner

, Kenet

. Intraventricular haemorrhage in preterm infants–can we improve outcome by addressing coagulation? J Matern Fetal Neonatal Med. 2015;28(Suppl 1):2265–7.

13.

Setzer

, Webb

, Wassenaar

, Reeder

, Mehta

, Eitzman

. Platelet dysfunction and coagulopathy in intraventricular hemorrhage in the premature infant. J Pediatr. 1982;100(4):599–605.

14.

McDonald

, Johnson

, Rumack

, et al. Role of coagulopathy in newborn intracranial hemorrhage. Pediatrics. 1984;74(1):26–31.

15.

Beverley

, Chance

, Inwood

, Schaus

, O’Keefe

. Intraventricular haemorrhage and haemostasis defects. ArchDis Child. 1984;59(5):444–8.

16.

Amato

, Fauchere

, Hermann

Jr.

Coagulation abnormalities in low birth weight infants with peri-intraventricular hemorrhage.

Neuropediatrics. 1988;19(3):154–7.

17.

Shirahata

, Nakamura

, Shimono

, Kaneko

, Tanaka

. Blood coagulation findings and the efficacy of Factor XIII concentrate in premature infants with intracranial hemorrhages. Thrombosis Research. 1990;57(5):755–63.

18.

Salonvaara

, Riikonen

, Kekomaki

, et al. Intraventricular haemorrhage in very-low-birthweight preterm infants: Association with low prothrombin activity at birth. Acta Pediatr. 2005;94(6):807–11.

19.

Piotrowski

, Dabrowska-Wojciak

, Mikinka

, et al. Coagulation abnormalities and severe intraventricular hemorrhage in extremely lowbirth weight infants. J Matern Fetal Neonatal Med. 2010;23(7):601–6.

20.

White

, Twomey

, Donoghue

, et al. Decreased fibrinogen levels are associated with severe intraventricular hemorrhage in very lowbirth weight (VLBW) infants. J Neonatal Perinatal Med. 2011;4(2):133–6.

21.

Chessells

, Wigglesworth

. Coagulation studies in preterm infants with respiratory distress and intracranial haemorrhage. Arch Dis Child. 1972;47(254):564–70.

22.

Van de Bor

, Briet

, Van Bel

, Ruys

. Hemostasis and periventricular-intraventricular hemorrhage of the newborn. Am J Dis Chil. 1986;140(11):1131–4.

23.

Christensen

, Baer

, Lambert

, Henry

, Ilstrup

, Bennett

. Reference intervals for common coagulation tests of preterm infants (CME). Transfusion. 2014;54(3):627–32.

24.

Dani

, Poggi

, Ceciarini

, Bertini

, Pratesi

, Rubaltelli

. Coagulopathy screening and early plasma treatment for the prevention of intraventricular hemorrhage in preterm infants. Transfusion. 2009;49(12):2637–44.

25.

Tran

, Veldman

, Malhotra

. Does risk-based coagulation screening predict intraventricular haemorrhage in extreme premature infants? Blood Coagul Fibrinolysis. 2012;23(6):532–6.

26.

Carteaux

, Cohen

, Check

, et al. Evaluation and development of potentially better practices for the prevention of brain hemorrhage and ischemic brain injury in very lowbirth weight infants. Pediatrics. 2003;111(4 Pt 2):e489–496.

27.

McLendon

, Check

, Carteaux

, et al. Implementation of potentially better practices for the prevention of brain hemorrhage and ischemic brain injury in very low birth weight infants. Pediatrics. 2003;111(4 Pt 2):e.497–503.

28.

Doyle

, O’Brien

, Murphy

, Fleming

, O’Donnell

. Coagulation factor content of solvent/detergent plasma compared with fresh frozen plasma. Blood Coagul Fibrinolysis. 2003;14(3):283–7.

29.

Liumbruno

, Franchini

. Solvent/detergent plasma: Pharmaceutical characteristics and clinical experience. J Thromb Thrombolysis. 2015;39(1):118–28.

30.

Al-Abdi

, Abou Mehrem

, Dabelah

, Al-Aghbari

, Al-Aamri

. The effect of low to moderate patient volume on very low-birth-weight outcomes in a level III-B neonatal intensive care unit. Am J Perinatol. 2011;28(3):219–26.

31.

Classification of Retinopathy of P. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123(7):991–9.

32.

Andrew

, Paes

, Milner

, et al. Development of the human coagulation system in the healthy premature infant. Blood. 1988;72(5):1651–7.

33.

Marietta

, Franchini

, Bindi

, Picardi

, Ruggeri

, De Silvestro

. Is solvent/detergent plasma better than standard fresh-frozen plasma? A systematic review and an expert consensus document. Blood Transfus. 2016;14(4):277–86.

34.

Al-Abdi

, Nojoom

, Alshaalan

, Al-Aamri

. Pilot-randomized study on intraventricular hemorrhage with midline versus lateral head positions. Saudi Med J. 2011;32(4):420–1.

35.

Papile

, Burstein

, Koffler

. Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529–34.

36.

Al-Abdi

. A severity score for intraventricular hemorrhage inpreterm neonates. Saudi Med J. 2011;32(12):1313–4.

37.

Horowitz

, Altaie

, Boyd

, et al. Defining, establishing, and verifying reference intervals in the clinical laboratory; Approved guideline. Wayne, PA; Clinical and Laboratory Standards Institute (CLSI); (Corrected 2010).

38.

Solberg

. International Federation of Clinical Chemistry (IFCC), Scientific Committee, Clinical Section, Expert Panel on Theory of Reference Values (EPTRV), and International Committee for Standardization in Haematology (ICSH), Standing Committee on Reference Values. Approved Recommendation (1987) on the Theory of Reference Values. Part 5. Statistical treatment of collected reference values. Determination of reference limits. J Clin Chem Clin Biochem. 1987;25(9):645–56.

39.

Solberg

. The IFCC recommendation on estimation of reference intervals. The RefVal program. Clin Chem Lab Med. 2004;42(7):710–14.

40.

Dani

, Poggi

, Bresci

, Corsini

, Frosini

, Pratesi

. Early fresh-frozen plasma transfusion decreases the risk of retinopathy of prematurity. Transfusion. 2014;54(4):1002–7.

41.

Burnouf

, Tseng

, Kuo

, Su

. Solvent/detergent treatment of platelet concentrates enhances the release of growth factors. Transfusion. 2008;48(6):1090–8.

42.

Cooper

, Bracey

, Horvath

, Shanberge

, Simon

, Yawn

. Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. JAMA. 1994;271(10):777–81.

43.

Stehling

, Luban

, Anderson

, et al. Guidelines for blood utilization review. Transfusion. 1994;34(5):438–48.

44.

Beverley

, Pitts-Tucker

, Congdon

, Arthur

, Tate

. Prevention of intraventricular haemorrhage by fresh frozen plasma. Arch Dis Child. 1985;60(8):710–3.

45.

Stanworth

, Brunskill

, Hyde

, McClelland

, Murphy

. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol. 2004;126(1):139–52.

46.

Osborn

, Evans

. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev. 2004(2):CD002055.

47.

Poterjoy

, Josephson

. Platelets, frozen plasma, and cryoprecipitate: What is the clinical evidence for their use in the neonatal intensive care unit? Semin Perinatol. 2009;33(1):66–74.

48.

Yang

, Stanworth

, Hopewell

, Doree

, Murphy

. Is fresh-frozen plasma clinically effective? An update of a systematic reviewof randomized controlled trials. Transfusion. 2012;52(8):1673–86; quiz 1673.

49.

Group TNNNINT. A randomized trial comparing the effect of prophylactic intravenous fresh frozen plasma, gelatin or glucose on early mortality and morbidity in preterm babies. EurJ Pediatr. 1996;155(7):580–8.

50.

Northern Neonatal Nursing Initiative [NNNI] Trial Group. Randomised trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: Outcome at 2 years. Lancet. 1996;348(9022):229–32.

51.

Austin

. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate BehavRes. 2011;46(3):399–424.