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Predicting bleeding in thrombocytopenic neonates
assess whether platelet counts are causally related to major bleeding, or whether platelet transfusions reduce bleeding risk in thrombocytopenic preterm neonates.3 Despite this lack of evidence, platelet transfusions are given to approximately 75% of thrombocytopenic preterm neonates.4,5
Recently, the results of the first randomized trial assess- ing currently used platelet count thresholds in preterm infants was published. The trial showed that giving pro- phylactic transfusions of platelets at a platelet count threshold of 50x109/L was associated with an increased risk of bleeding and mortality compared to a lower thresh- old of 25x109/L, within 28 days after randomization.6 These results highlight the need for improved and individ- ualized guidelines on platelet transfusion in neonates.
In addition to lack of evidence regarding transfusion thresholds and identification of platelet transfusion-related harm, indications for platelet transfusions are based prima- rily on platelet count. However, two neonates with similar platelet counts but different clinical conditions may have very different risks of bleeding, and benefit differently from platelet transfusions.7 We need to be able to predict which neonates will develop major bleeding and quantify this bleeding risk, using a model that includes not only platelet count but also a set of relevant clinical variables. Such a prediction model could be used to define indica- tions for transfusion in future studies, which is a first step towards individualized platelet transfusion therapy.
Some prediction models for bleeding in neonates have already been developed, but these models were not derived specifically for neonates with thrombocytopenia, and only allow for a risk assessment at baseline.8–15 The disadvantage of baseline prediction models is that they do not take into account the clinical course of the neonate, which can change substantially over time, and may have a profound impact on bleeding risk. In dynamic predic- tions, the clinical course can be incorporated into the model. The objective of this study was, therefore, to develop a dynamic prediction model for major bleeding in thrombocytopenic preterm neonates.
Methods
The study protocol was published online at www.clinicaltrials.gov (NCT03110887). The institutional review board of the Academic Medical Center Amsterdam approved the study and waived the need for informed consent. The study was conducted in accor- dance with the Declaration of Helsinki and reported according to The Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines.16 An extended methods section is available in the Online Supplementary Materials, including the procedure for predictor selection, outcome definitions, a list of participating centers with an overview of their clinical practice, description of the data acquisition process, sam- ple size calculations, details on statistical methods and the role of the funding source.
Population
We performed a cohort study among consecutive preterm neonates with thrombocytopenia admitted to any one of seven participating neonatal intensive care units in the Netherlands between January 2010 and January 2015. The cohort comprised all neonates with a gestational age at birth <34 weeks and at least one platelet count <50x109/L. We excluded patients: (i) with severe
congenital malformations; (ii) for whom there was a high suspi- cion of spurious platelet count (e.g. clots in the sample, or sponta- neous platelet count recovery within 6 h, or a platelet count labeled as spurious in the medical file); (iii) with thrombocytope- nia occurring exclusively in the context of exchange transfusion; (iv) with a prior admission to another neonatal intensive care unit or readmission; and (v) who had major bleeding prior to severe thrombocytopenia. Neonates with major bleeding after the end of the follow-up were not excluded, but registered as not having experienced major bleeding during the study.
Model development and statistics
The core research team drafted and approved a statistical analy- sis plan prior to the data analysis. We developed a proportional baseline landmark supermodel, with bleeding within the subse- quent 3 days as the outcome.17 Variables included in the model were gestational age, intrauterine growth retardation (IUGR), mechanical ventilation, platelet count, platelet transfusion, postna- tal age at inclusion, and necrotizing enterocolitis (NEC) and/or sepsis (combined).
Model validation
We validated the model by internal calibration using the heuris- tic shrinkage factor described by van Houwelingen et al.18 We eval- uated the model’s accuracy in correctly discriminating between patients with and without major bleeding using the dynamic cross-validated c-index. A c-index of 1.0 indicates perfect discrim- ination, while a c-index of 0.5 is obtained when the model per- forms as well as chance. We calculated a c-index at each 2 h time- point, and reported this series of c-indices as a graph. Analyses were carried out using SPSS (version 24.0), Stata (version 14.1) and R (version 3.4.2).
Clinical applicability of the model
Our study is a first, basic prediction model for major bleeding in preterm neonates with severe thrombocytopenia. Due to the dynamic nature of the model, it cannot be fully summarized in one table, but once validation studies have been performed, we will develop an online calculator. We have chosen not to publish the calculator along with this paper, in order to prevent inappro- priate premature use of the model in clinical practice. The model is available upon request for researchers looking to perform model validation and impact studies.
Results
Baseline characteristics
Of 9,333 neonates with a gestational age <34 weeks, 927 had at least one platelet count <50x109/L. Of these, 67 were excluded due to spurious platelet counts and 29 because thrombocytopenia occurred only during a read- mission. Of the remaining 831 neonates, 191 were exclud- ed based on major bleeding prior to thrombocytopenia (n=55), previous admission to another neonatal intensive care unit (n=51), congenital malformations (n=47), missing medical files (n=35) and because thrombocytopenia occurred exclusively during exchange transfusion (n=3). The remaining 640 neonates (7%) were included in the study (Figure 1). The median gestational age at birth was 28.1 weeks, the median birth weight was 900 grams (Table 1 and Online Supplementary Figures S1 and S2) and 73% of the neonates received at least one platelet transfu- sion. No cases of fetal and neonatal alloimmune thrombo- cytopenia were identified. The lowest platelet counts dur-
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