1 Pediatric Hematology-Oncology Fellow, Department of Pediatrics, Division of Pediatric Hematology-Oncology, Montreal Children’s Hospital, McGill University, Montreal, Québec, Canada
2 Pediatric Intensivist, Department of Pediatrics, Division of Pediatric Intensive Care, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada
3 Neonatologist, Department of Pediatrics, Division of Neonatology, CHU Sainte-Justine, Université de Montréal, Montreal, Québec, Canada
4 Emergency Physician, Department of Emergency Medicine, Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montreal, Québec, Canada
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Article ID: 100072Z02AZ2022
Aims: Platelet transfusions are common in the neonatal intensive care unit (NICU), yet practices vary substantially. This study aims to determine platelet transfusion incidence, determinants, and justifications in neonatology.
Methods: Single-center prospective cohort study, including all patients consecutively admitted to the CHU Sainte-Justine Hospital NICU over a 5-month period in 2013. Data were collected by chart review and transfusion justifications were assessed using a questionnaire.
Results: A total of 401 participants were included. Mean birth weight (BW) was 2.34±1.01 kg and gestational age (GA) was 34.4±4.5 weeks. Thirty-seven neonates (9.2%) received at least one platelet transfusion. Platelet-transfused neonates were mostly extremely preterm (40.5%) or term (24.3%). The median pre-platelet transfusion count was 57 × 109/L (9–285 × 109/L). Compared to non-transfused patients, those who received at least one platelet transfusion had a significantly lower BW and GA, higher CRIB-II and SNAPPE-II scores (all p <0.001) and were more frequently admitted for respiratory disease (p <0.001), hypoxic-ischemic encephalopathy (p=0.009), and hemolytic disease of the newborn (p <0.001). Gestational age <28 weeks (p<0.001), mechanical ventilation requirements (p=0.008), and platelet nadir ≤150 × 109/L (p<0.001) upon admission were independently associated with a higher risk of platelet transfusion in this cohort. Most frequent justifications for ordering a first platelet transfusion were low platelet counts (86.5%), underlying disease (78.4%) and illness severity (37.8%).
Conclusion: Pre-transfusion platelet counts in neonates varied widely and were higher than the thresholds proposed in the literature. Several factors other than platelet count predicted risk of platelet transfusion in this cohort.
Keywords: Neonatology, Platelet, Thrombocytopenia, Transfusion
Thrombocytopenia, defined as platelet count < 150 × 109/L, affects 20–45% of infants in the neonatal intensive care unit (NICU) ,. Studies linking thrombocytopenia to neonatal outcomes have yielded conflicting results. While some raised concerns about a potential association between thrombocytopenia, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and higher mortality ,,, others found no such association ,,,, or on the contrary have linked platelet transfusions in the NICU with adverse outcomes such as a higher risk of sepsis, NEC, and hyporegenerative thrombocytopenia ,, as well as increased IVH and mortality ,,,. Notably, the large multicenter randomized controlled trial PlaNeT-2  reported worse outcomes in preterm neonates transfused at a threshold of 50 versus 25 × 109 platelets/L. Additionally, platelet transfusions are associated with a seven-fold increased risk of acute transfusion reaction compared to red blood cells, and neonates experience a disproportionately high number of transfusion adverse events compared with pediatric and adult patients . Whereas until recently the clinical consequences of a more liberal versus a more restrictive transfusion approach were unclear, the latest publications advocate for the use of lower platelet transfusion thresholds, even in extremely preterm infants ,.
Reported platelet transfusion practices in the NICU vary widely, with transfusion thresholds ranging from 150 × 109/L ,,,,. This implies that factors other than the platelet count influence platelet transfusion decisions. There are scarce reports in the literature addressing what these additional influences might be. Characterizing these variables will aid the evaluation and optimization of platelet transfusions in the NICU to achieve a rational and safe use of platelets in this vulnerable population.
The primary aim of this study was to describe the epidemiology of platelet transfusions in the NICU of a tertiary university-affiliated pediatric hospital. The secondary aim was to characterize the determinants and justifications for platelet transfusions in neonatology. We hypothesized that there would be substantial variability in the transfusion practices in this cohort and that a significant proportion of infants would receive platelet transfusions at thresholds higher than supported by current evidence.
All patients consecutively admitted to the NICU of the Centre Hospitalier Universitaire (CHU) Sainte-Justine from May 30 to November 4, 2013 were enrolled into this prospective observational cohort study. Extracorporeal membrane oxygenation was the only exclusion criteria. The Research Ethics Board of CHU Sainte-Justine Hospital approved this study and waived consent.
The NICU of CHU Sainte-Justine in Montreal, Canada, is a tertiary care (level 3B) university-affiliated mother–child health center. Approximately 1000 patients are admitted yearly into this 65-bed NICU.
Platelet transfusions and local practices
Decisions regarding blood product transfusions were at the discretion of the attending physicians and medical team; there was no local transfusion protocol at the time of the study. All blood products were obtained from the Héma-Québec Blood Bank and were leukoreduced by pre-storage filtration. Neonates with BW ≤1200 g were transfused with cytomegalovirus (CMV)-negative and gamma irradiated products. Decisions regarding any additional processing (e.g., washing) was at the discretion of the medical team.
Data abstraction and data entry were performed by research assistants using validated case report forms. Baseline characteristics were collected at time zero for each patient, corresponding to their admission day to the NICU. In transfused patients, daily monitoring of potential determinants of platelet transfusions started at time zero and ended upon receiving their first transfusion. In non-transfused patients, daily monitoring ended upon patient death, NICU discharge, or 44 weeks of corrected age, whichever occurred first. Validated scores to estimate the severity of illness in NICU patients were recorded upon admission, including the Clinical Risk Index for Babies (CRIB)-II score  and the Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE)-II .
Determinants of platelet transfusions
A list of potential determinants of platelet transfusions in neonates was generated based on a literature review and in collaboration with local experts in neonatology and transfusion medicine. They included patients’ baseline characteristics and data on the day of their admission and throughout their NICU stay.
Justifications of red blood cell (RBC) transfusions
Justifications for each first platelet transfusion were collected within 48 hours of the transfusion using a printed validated questionnaire generated by local experts’ consensus (Supplementary Information). The transfusion-requesting clinician could check one or more justifications from a list, as well as sort them by order of relative importance.
Descriptive statistics included the number and proportion of patients (%), mean±standard deviation (SD) and median with interquartile range (IQR). Comparisons between transfused and non-transfused patients were performed using the Chi square statistic or the Fisher exact probability test for categorical variables. The Student t test or Wilcoxon test for continuous variables was used if the distribution was normal or not, respectively. Univariate analysis was performed for possible determinants using logistic regression, the odds ratio (OR), and 95% confidence interval (95% CI) were reported. All continuous variables were analyzed using categories, which were separated according to clinically relevant thresholds or quartiles. Multivariate analysis was performed using multiple logistic regressions. A multivariable logistic regression was then constructed, including as many clinically relevant covariables as was allowed by the number of events. The predictive ability of this model was compared to the model obtained by a forward stepwise selection based on the likelihood ratio with receiver operating characteristic (ROC) curve. All statistical analyses were performed using the SPSS statistical software program (IBM SPSS Statistics, Version 26, 2019).
A total of 401 consecutively admitted patients were included during the 5-month study period. None were excluded. Neonates in this cohort were born with a mean GA of 34.4±4.5 weeks and birth weight of 2.34±1.01 kg. At least one platelet transfusion was given to 37 patients (9.2%) during their NICU stay (median: 2 platelet transfusions, 1st–3rd IQR 1–4). Baseline characteristics of the study population are presented in Table 1.
Extremely preterm neonates, defined as those born before 28 weeks GA, accounted for 40.5% of the cohort transfused in platelets, followed by 24.3% of term patients, defined as born after 37 weeks GA (Table 2). Figure 1 depicts the proportion of platelet-transfused patients according to their GA category.
Statistically significant baseline characteristics between the transfused versus non-transfused patients included lower birth weight (1.72±1.18 vs 2.41±0.97 kg, p<0.001), lower gestational age (29.6±5.2 vs 35.1±3.8 weeks, p<0.001), and the following admission diagnoses: respiratory disease (81.5 vs 57.9%, p=0.001), hypoxic-ischemic encephalopathy (10.8 vs 1.6%, p=0.009) and hemolytic disease of the newborn (13.5 vs 0.3%, p<0.001).
Platelet transfusion data
The median platelet nadir within 24 hours before transfusion was 57 × 109/L, ranging from 9 to 285 × 109/L (25–75th percentiles 36–82 × 109/L, mean 64±46 × 109/L). The highest proportion of transfused patients received one platelet transfusion (35.1%); 21.6% received two transfusions and another 21.6% received five or more transfusions. Of the transfused infants, 62.2% were exposed to multiple donors. Table 3 summarizes the number of platelet transfusions per patient and their donor exposure.
Determinants of platelet transfusion
On the day of NICU admission
On univariate analysis, the associations between the following determinants recorded on the day of NICU admission and future platelet transfusion were statistically significant (Table 2): GA at birth <28 weeks, BW ≤ 1500 g, CRIB-II score ≥10, SNAPPE-II score ≥24, mechanical ventilation requirements (high frequency or conventional), and seizures.
On the day of admission, significant determinants for platelet transfusion throughout the NICU stay were: Hb nadir ≤ 150 g/L, platelet nadir ≤ 150 × 109/L, blood lactate >5 mmol/L and base excess ≤−10.
After the first day in the NICU
After the first day in the NICU, significant determinants of platelet transfusion on univariate analysis were: Hb nadir ≤ 96 g/L, platelet nadir ≤ 150 × 109/L, clinically evident hemorrhage, NEC, sepsis, or ibuprofen treatment.
Multivariate logistic regression model to predict the platelet transfusion risk for a neonate admitted in the NICU identified GA < 28 weeks at birth, mechanical ventilation requirements on day one in the NICU and platelet nadir ≤150 × 109/L on the first day in the NICU. The area under the ROC curve was 0.856 (95% CI 0.799–0.914). This was similar to the area under the ROC curve of the model obtained by a forward stepwise selection [0.917 (95%CI 0.878–0.956)].
Stated justifications for a first platelet transfusion
All caregivers who ordered a first platelet transfusion filled the questionnaire (Appendix 1) on their justification to prescribe a platelet transfusion (Table 4). The most frequently declared reasons were: (1) low platelet levels (86.5%), (2) underlying disease (78.4%), (3) severity of the illness (37.8%), and (4) active bleeding (32.4%). When underlying illness justified a transfusion (29 patients out of 37), the main reported conditions were sepsis (with or without shock) (N=7) and gastrointestinal issues such as NEC and/or intestinal perforation (N=5). A subgroup of 14 patients received platelet transfusions despite having platelet counts ≥150 × 109/L. The stated justifications for transfusing these non-thrombocytopenic patients are also reported in Table 4. Low platelet counts remained the most frequent physician justification in this subgroup (42.9%). Reasons stated as “other” were exchange transfusion (N=1), disseminated intravascular coagulation post-operatively (N=1), and an administration error where plasma was prescribed but platelets were given (N=1).
This prospective cohort study reports the platelet transfusion practices in 401 consecutively admitted preterm and term neonates admitted in a tertiary care NICU. At least one platelet transfusion was administered to 9.2% of this population. Among the GA subgroups, extremely preterm neonates (<28 weeks GA) were the most likely to be transfused, followed by term ill neonates. Extreme prematurity, mechanical ventilation, and a low platelet count were associated with platelet transfusion. Main reasons given by physicians for ordering a platelet transfusion in neonates were a low platelet count, underlying disease, and severity of illness. The pre-platelet transfusion threshold varied substantially, from severe thrombocytopenia to normal platelet levels.
We observed transfusion rates consistent with other studies in the NICU, where the proportion of patients who receive at least one platelet transfusion ranges from 2% to 9.4% ,,,. Extremely preterm neonates of less than 28 weeks GA were proportionally the highest transfused sub-group in this cohort. This concords with a recent large observational study of transfusion practices in newborns (N=60,243) with an overlapping timeline with our study, where neonates <27 weeks GA proportionally received the most platelet transfusions (34%, 95%CI 29–39%) compared with other GA groups in newborns . In our study, term neonates were the second most transfused sub-group, an unexpected result, especially given that in the aforementioned report platelet transfusions decreased with GA . However, our study selects for term infants ill enough to be admitted to the NICU, thus it represents a subgroup of term infants with a higher illness severity and/or more comorbidities at baseline.
Platelet transfusions in our study were strongly associated with extreme prematurity, as well as mechanical ventilation requirements and platelet nadir ≤ 150 × 109/L on the first day in the NICU. This makes clinical sense and is consistent with other reports ,,,. Other previously found risk factors that our study corroborates were hemorrhage ,, treatment with non-steroidal anti-inflammatory drugs ,, critical illness (often sepsis) ,,,, as well as low BW and hypoxic ischemic encephalopathy . Additionally, our study demonstrated that anemia and a diagnosis of hemolytic disease of the newborn on admission were associated with a higher risk of platelet transfusion, which, to the best of our knowledge, has not been reported previously. This was an unexpected result and the direct clinical correlation between anemia and platelet transfusion is unclear. A hypothetical explanation might be that physicians might be concerned about the effects of a potential bleed due to untreated thrombocytopenia on further lowering the hemoglobin in an already anemic patient. This is an example of a potential target for improvement when looking to decrease unnecessary or irrational use of platelet transfusions in this population.
The most frequently stated justifications for transfusion were a low platelet level, underlying disease, and severity of illness. The median platelet nadir within 24 hours before transfusion was 57 × 109/L, ranging from 9 to 285 × 109/L. This is similar to the variability reported by Patel et al. , where the median pre-transfusion platelet count in newborns of all GA was 71 × 109/L (10–90th percentiles 26–135 × 109/L) and 70 × 109/L (33–100 × 109/L) in newborns <27 weeks GA. Prior to this study, there was already a growing awareness in the neonatal community about potential overuse of platelet products due to overly liberal transfusion thresholds . For example, as early as in 2007, British national guidelines recommended a transfusion threshold of 20–30 × 109 platelets/L for neonates . Although the randomized controlled trial demonstrating the superiority of the 25 × 109 platelets/L threshold for neonates postdates the study period , at the time of the study the generally accepted threshold was of 50 × 109 platelets/L ,. However, many transfusions were given above this threshold, highlighting that platelet transfusion practices may not always be guided by evidence.
Of note, in 14 patients, platelet transfusions were given to infants who were not thrombocytopenic. This represents 37.8% of the platelet-transfused subgroup. It is puzzling that the most frequently stated justification for platelet transfusion in this subgroup remained low platelet count (42.9%) and brought on the question of whether at times physicians may be administering blood products without waiting for complete blood count results.
Until recently, there were limited reports describing neonatal transfusion practices. Most platelet transfusions in the NICU are prophylactic, with widely ranging pretransfusion thresholds ,,,. Even when local guidelines do exist, they are not always followed: up to 36% of platelet transfusions are given in the NICU outside of such guidelines  in practice, most American and Canadian neonatologists surveyed reported a platelet transfusion threshold of 50 × 109/L for premature neonates with no medication and this threshold increased to 100 × 109/L in the United States and 50–100 × 109/L in Canada if the patient was on indomethacin . A similar observational study reported a wide variety of practices in Europe and the United States, with thresholds ranging from 10 to 150 × 109/L .
The study had some limitations. It was a unicentric, limiting its external validity. Physicians were aware that their transfusion habits were monitored throughout the research project, potentially affecting their practices. Similarly, the stated justifications for transfusions could have been influenced by the multiple choice questionnaire. Only the reasons for the first platelet transfusion were assessed in this study, thus the justifications for the entirety of platelet transfusions may have differed. Among the study’s strengths was the inclusion of all consecutive admissions, minimizing selection bias. No patients were excluded, enhancing result generalizability. Also favoring generalizability is that this NICU is a typical multidisciplinary unit, treating preterm and term surgical and medical patients. The prospective design limited the risk of information bias. The use of a validated case report form optimized the quality and integrity of our data. A notable strength of this study was its design in which only data observed before the first platelet transfusion in NICU were considered possible determinants of platelet transfusion, which addressed any protopathic bias.
This analysis may help review and optimize platelet transfusion practices to achieve safer use of platelets in the NICU, and potentially improve outcomes for neonates, reduce healthcare costs, and decrease blood bank resources. In our center, the observations from this study, along with current evidence from the literature, have promoted a review of local platelet transfusion practice among the neonatology group and have already incited the implementation of guidelines favoring more restrictive transfusion thresholds in neonates. A study is currently ongoing in our NICU to evaluate whether these efforts have resulted in a change in platelet transfusion practice locally.
See Supplementary Information at: http://www.ijbti.com/archive/2022/100072Z02AZ2022/100072Z02AZ2022_SI.pdf
This article was published previously as a preprint. The citation is: Zabeida A, Lacroix J, Lapointe A, Lachance C, Cournoyer A, Villeneuve A. Platelet transfusion practices in neonatology: A single-center observational study. Available at SSRN: https://ssrn.com/abstract=3963638 or http://dx.doi.org/10.2139/ssrn.3963638
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We would like to thank Miguel Chagnon for his contribution to the statistical analysis, as well as the Fonds Fonds de la Recherche du Québec—Santé for funding this project.Author Contributions
Alexandra Zabeida - Acquisition of data, Analysis of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Jacques Lacroix - Conception of the work, Design of the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Anie Lapointe - Conception of the work, Design of the work, Acquisition of data, Analysis of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Christian Lachance - Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Alexis Cournoyer - Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Andréanne Villeneuve - Conception of the work, Design of the work, Acquisition of data, Analysis of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.Guarantor of Submission
The corresponding author is the guarantor of submission.Source of Support
Written informed consent was obtained from the patient for publication of this article.Data Availability
All relevant data are within the paper and its Supporting Information files.Conflict of Interest
Authors declare no conflict of interest.Copyright
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