Dynamic prediction of bleeding risk in thrombocytopenic preterm neonates

Abstract

Over 75% of severely thrombocytopenic neonates receive platelet transfusions, though little evidence supports this practice, and only 10% develop major bleeding. In a recent randomized trial, giving platelet transfusions at a threshold platelet count of 50x10⁹/L compared to a threshold of 25x10⁹/L was associated with an increased risk of major bleeding or mortality. This finding highlights the need for improved and individualized guidelines on neonatal platelet transfusion, which require accurate prediction of bleeding risk. Therefore, the objective of this study was to develop a dynamic prediction model for major bleeding in thrombocytopenic preterm neonates. This model allows for calculation of bleeding risk at any time-point during the first week after the onset of severe thrombocytopenia. In this multicenter cohort study, we included neonates with a gestational age <34 weeks, admitted to a neonatal intensive care unit, who developed severe thrombocytopenia (platelet count <50x10⁹/L). The study endpoint was major bleeding. We obtained predictions of bleeding risk using a proportional baselines landmark supermodel. Of 640 included neonates, 71 (11%) had a major bleed. We included the variables gestational age, postnatal age, intrauterine growth retardation, necrotizing enterocolitis, sepsis, platelet count and mechanical ventilation in the model. The median cross-validated c-index was 0.74 (interquartile range, 0.69-0.82). This is a promising dynamic prediction model for bleeding in this population that should be explored further in clinical studies as a potential instrument for supporting clinical decisions. The study was registered at www.clinicaltrials.gov (NCT03110887).

Figure 1.

CONSORT flow chart. CONSORT: consolidated standards of reporting trials; NICU: neonatal intensive care unit.

Figure 2.

Number of neonates reaching the different study endpoints (major bleeding, death or discharge/transfer) in the first 10 days after the onset of severe thrombocytopenia. T₀ is the day on which the platelet count dropped below 50x10⁹/L for the first time. Neonates who developed a major bleed and then died were only registered as having major bleeding (no overlap between major bleeding and mortality).

Figure 3.

Dynamic, cross-validated c-index. This graph represents the dynamic, cross-validated c-index of the main model. A c-index of 1 resembles a model that discriminates perfectly between patients with and without major bleeding, while a c-index of 0.5 indicates that the prediction is as good as chance. For each time-point, the number at risk at the beginning of that day has been reported, as well as the total number of major bleeds that occurred during those 24 hours. For example, at the start of day 1, the number of patients still at risk was 604, and during this day 22 neonates developed a major bleed.

Figure 4.

Change in probability of having a major bleed within 3 days for two example patients. Day 0 is the day of onset of severe thrombocytopenia (T₀). Characteristics of child A: gestational age (weeks+days) 27+2, birthweight 1100 grams, 2 days old at T₀, sepsis, mechanical ventilation, two platelet transfusions, platelet counts (x10⁹/L): 41, 104, 47, and 88. Bilateral grade III intraventricular hemorrhage on day 2. Characteristics of child B: gestational age (weeks+days) 32+3, birth weight 1175 grams, 5 days old at T₀, sepsis, no mechanical ventilation, no platelet transfusions, platelet counts (x10⁹/L) 4, 53, 49, 63, 195 and 376. No major bleed. Days 3-7 not shown because no substantial change in bleeding risk occurred. During study days 1-3, the predicted risk of major bleeding within the subsequent 3 days is substantially higher in child A than in child B, indicating that the use of this prediction model during that time-period would have correctly identified child A as being at a high risk of bleeding.