Monitoring Outcome in Neonatal Thrombocytopenia

Brief Title

Monitoring Outcome in Neonatal Thrombocytopenia

Official Title

Monitoring Outcome in Neonatal Thrombocytopenia

Brief Summary

      Rationale: Approximately 10% of neonates admitted to neonatal intensive care units develop a
      major hemorrhage. In an attempt to avert this severe complication various preventive measures
      have been implemented. One of these is the transfusion of platelets to premature neonates
      with low platelet counts. However, this practice is not supported by scientific evidence.
      Most neonates with low platelet counts never experience a major bleeding and platelet
      transfusions may carry risks of volume overload or infection. Therefore, it is important to
      treat only those patients that truly benefit from this intervention. We urgently need a
      scientifically based tool to predict which premature neonates are at risk for major bleeding.
      A few prediction models do exist, but these only allow assessment of bleeding risk at
      baseline, and do not correct for changes in clinical status during the admission period. We
      believe that adding this feature to our prediction model will significantly improve our
      ability to predict bleeding. The prediction model will also be helpful in developing
      individualized transfusion guidelines as it helps us to predict which neonates would benefit
      from prophylactic platelet transfusions.

      Main objective: to develop a dynamic prediction model for bleeding in preterm neonates with
      low platelet counts.

      Study design: retrospective observational cohort study.

      Study population: neonates with a gestational age at birth of < 34 weeks admitted to a
      neonatal intensive care unit (NICU), with a thrombocyte count of less than 50x109/L will be
      included.

      Assessments: only data generated through standard care will be collected. This includes
      platelet counts, cerebral ultrasounds, information about bleeding and transfusions, and
      multiple clinical variables.

      Main study endpoint: major bleeding during admission

      Statistical analyses: dynamic prediction model using landmarking.
    

Detailed Description

      2. INTRODUCTION AND RATIONALE

      2.1 The relationship between thrombocytopenia and bleeding A complex relation exists between
      thrombocytopenia in preterm neonates and bleeding. This is illustrated by a recent
      observational study that demonstrated that only 9% of neonates with a very low platelet count
      developed major bleeding.(1) Moreover, patients with normal platelet counts bleed quite
      frequently, as evidenced by another study in which 25-38% of the patients with an IVH did not
      have thrombocytopenia.(2,3) Several recent reviews have highlighted that the fact that
      neonatal bleeding and neonatal thrombocytopenia often occur in the same timeframe, does not
      necessarily imply a causal relationship.(4,5) It is difficult to identify the role of
      thrombocytopenia in bleeding, because bleeding is a multifactorial process, and because there
      are a lot of interactions between bleeding, thrombocytopenia and clinical variables.
      Moreover, neonatal platelets appear to be different from adult platelets in many ways, which
      complicates our understanding of the effect of low platelet counts on bleeding risk, or the
      effect of transfusion of (adult) platelets in the neonatal system.(6)

      2.2 potential prognostic variables The most important known risk factor for bleeding is low
      gestational age.(1) In the specific case of IVH, it is thought that the prematurity of the
      brain - which has a highly vascularized germinal matrix that can easily be damaged - is an
      important causal factor. However, several other factors have been associated with an
      increased risk of bleeding, for example low Apgar scores, acidosis, vaginal birth, need for
      mechanical ventilation, disordered coagulation,NEC, DIC, indomethacin or surfactant
      treatment, low oxygen saturation levels, a low Score for Neonatal Acute Physiology (SNAP),
      and many more. But many of these studies have severe limitations such as lack of multivariate
      analysis, unclear selection of controls, small numbers and different study populations. Most
      are also limited to a baseline risk assessment, without a possibility to correct the risk
      assessment as the clinical status of the child changes. Therefore there is no clarity as to
      which factors are really relevant in clinical practice when assessing neonatal bleeding in
      neonates with thrombocytopenia.

      2.3 Current prediction models A few prediction models for neonatal bleeding have been
      published, but to our understanding, none of these is used regularly in clinical
      practice.(7-9) The main disadvantage of these models is that they only allow assessment of
      bleeding risk at baseline, and do not correct for changes in clinical status during the
      admission period. We believe that adding this feature to our prediction model will
      significantly improve our ability to predict bleeding.

      2.4 The MONET study The MONET study is a retrospective, multicenter, observational cohort
      study that assesses risk factors for neonatal bleeding in thrombocytopenic preterm neonates.
      This population is chosen because these are the neonates that are currently being treated
      with prophylactic thrombocyte transfusions. The results of this study will allow us to
      identify neonates within this population that are at high risk of bleeding. These neonates
      may potentially benefit from different treatment strategies. Also, modifiable risk factors
      can be further explored as potential targets for preventing neonatal bleeding.

      3. OBJECTIVE

      To develop a dynamic prediction model for bleeding in preterm neonates with low platelet
      counts.

      4. STUDY DESIGN

      Retrospective observational cohort study. Timeframe in which data will be collected is 5
      years (2010-2014).

      5. STUDY POPULATION

      5.1 Population (base) Neonates will be selected based on inclusion and exclusion criteria
      defined below.

      5.2 Inclusion criteria

        1. Admission to a neonatal intensive care unit (NICU) in the Netherlands, including
           postnatal transfers;

        2. Gestational age at birth < 34 weeks;

        3. A platelet count of <50 x109/L;

      5.3 Exclusion criteria

      A potential subject who meets any of the following criteria will be excluded from
      participation in this study:

        1. Severe congenital malformations;

        2. High suspicion of spurious platelet count (e.g. clots in the sample, or very rapid
           'recovery' to previous non-severely thrombocytopenic levels);

        3. Thrombocytopenia which occurred exclusively in the context of exchange transfusion;

        4. Prior admission to a NICU (only first admissions to NICU's will be included. Postnatal
           transfers from non-NICU's will be included).

      5.4 Sample size calculation Data on the frequency of bleeding outcomes in severely
      thrombocytopenic neonates are available from the PlaNeT-1 survey in which 15/169 or 9% of
      neonates experienced a major bleed while on study.(1) However, this proportion applies to
      neonates of all gestational ages. Other studies show incidences in premature neonates of
      7-11%, depending on the type of population studied.(3,10,11) Assuming an event rate of
      approximately 10%, we calculated that for testing 5 variables we will need a sample size of
      500 neonates, because we will need approximately 10 events per tested variable. Each year,
      4000 neonates are admitted to the neonatal intensive care unit, of which approximately 5%
      have severe thrombocytopenia. Therefore, we expect 200 eligible neonates each year, and a
      total sample size of 1000 neonates, which will allow us to include a maximum of 10 variables.

      6. METHODS

      6.1 Main study endpoint

      Major or severe bleeding during admission is the primary outcome. This has been defined as
      either one of the following:

        1. Intraventricular hemorrhage grade 3 (>50% of ventricle filled with blood)

        2. Intraventricular hemorrhage of any grade in combination with parenchymal involvement.
           Information about dimensions will be collected: maximum diameter of <1 cm, or 1-2 cm or
           >2 cm.

        3. Parenchymal hemorrhage (without IVH) visible on ultrasound (contrary to small bleeds
           visible only on MRI). Information about size will be collected: maximum diameter <1 cm,
           1-2 cm or >2 cm.

        4. Cerebellar hemorrhage visible on ultrasound (contrary to small bleeds visible only on
           MRI). The maximum diameter of the bleeding will be collected.

        5. Other types of intracranial hemorrhage. The maximum diameter will be recorded.

        6. Pulmonary hemorrhage, defined as fresh blood from the endotracheal tube in combination
           with increased ventilatory requirements

        7. Any other type of hemorrhage, if major. A bleeding was considered major if it required
           or was related to either one of the following:

             1. Red cell transfusion

             2. Volume boluses

             3. Need for inotropes (either start of inotrope therapy, or increased dose of current
                therapy)

             4. Significant drop in blood pressure The first time a major bleed was diagnosed is
                the endpoint for this study. Date and time of first major bleed will be recorded,
                if the exact time cannot be retrieved from the medical file, an estimate will be
                computed based on what is known about the timing (for example, that it occurred in
                an evening shift, or that it occurred after 16:00).

                6.2 Clinical variables The initial strategy was to select clinical variables
                through a systematic review of the literature in combination with expert advice.
                The review was started, but yielded over 8000 abstracts, and over 1000 included
                full texts, and was therefore considered too large for the scope of this project.
                However, an overview of the clinical variables assessed in these papers was made,
                and will be taken into account during the variable selection process. Clinical
                variables will be selected based on literature in combination with expert advice.
                Exclusion of a variable will be considered when the variable is not not
                consistently documented in medical records, when few studies concerning this
                variable have been published, when multiple published studies show a weak
                association with bleeding, when a strong interaction with another variable is
                expected (e.g. birth weight and IUGR), or when the variable is difficult to measure
                regularly (e.g. blood parameters that need large blood samples).

                6.3 study procedures Data will be collected by study personnel, including research
                nurses, datamanagers and medical students under supervision of the principal
                investigator. Data will be collected from the hospital's written or online patient
                record files, recorded imaging reports and nurses records. Data collection ends
                when a neonate is transferred out of the neonatal intensive care unit, when a major
                bleed occurs, or when a neonate dies.

                7. SAFETY REPORTING

                MONET is an observational study, therefore we consider reporting of adverse events
                or serious adverse events not applicable for this study.

                8. STATISTICAL ANALYSIS

                The development of the prediction model will take place in cooperation with several
                experts, including prof. dr. J.G. van der Bom, professor in clinical transfusion
                medicine, and prof dr. H. Putter, professor of medical statistics and an expert in
                dynamic prediction modelling. We will develop a dynamic prediction model using
                landmarking, as described elsewhere.(12) A statistical analysis plan will be
                written and signed prior to any analysis. Variables to be included in the model
                will be chosen prior to the statistical analyses.

                9. ETHICAL CONSIDERATIONS

                9.1 Regulation statement This study will be conducted according to the principles
                of the Declaration of Helsinki (version 59, oct 2008). The Medical Research
                Involving Human Subjects Act (WMO) does not apply.

                9.2 Recruitment and consent Informed consent does not need to be obtained for this
                study, as only retrospective data are being collected.

                10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION

                10.1 Handling and storage of data and documents Data will be held and processed in
                accordance with the Dutch Personal Data Protection Act. All study data will be held
                securely. It will not be disclosed to third parties. All staff working on the study
                owe a duty of confidentiality to the participants. Manual records will be held
                securely (for example in locked filing cabinets). Electronic records will be held
                on a secure network requiring user ID and password access. A fully anonymised data
                set will be used for data analysis. Individuals will not be identifiable from the
                results of the study. Neonates enrolled in the MONET study will receive a unique
                study code. Data will be send to the study manager and entered into a MONET
                database.

                10.2 Monitoring and Quality Assurance Because of the retrospective, observational
                nature of this study, monitoring was not deemed necessary.

                10.3 Public disclosure and publication policy The study will be registered in the
                website of the Dutch National Competent Authority, the 'Centrale Commissie
                Mensgebonden Onderzoek' (CCMO) and a public study registry. The results from the
                MONET study will be analyzed and published as soon as possible in peer-reviewed
                international scientific journals and presented at scientific meetings, unless the
                study was terminated prematurely and did not yield sufficient data for a
                publication. The responsibility for presentations and/or publications belongs to
                the investigators. No restriction regarding the public disclosure and publication
                of the research data have been, or will be made by the funding agencies. The final
                publication of the study results will be written by the principal investigators and
                the co-investigators. A draft manuscript will be submitted for review to all
                co-authors. Results will also be published in a PhD-thesis. Authors of the main
                manuscript will include the Principal Investigator, the co-investigators and,
                investigators who have included evaluable patients in the study. Others who have
                made a significant contribution to the study may also be included as author, or
                otherwise will be included in the acknowledgement.

                11. REFERENCES

                  1. Stanworth SJ, Clarke P, Watts T, Ballard S, Choo L, Morris T, et al.
                     Prospective, observational study of outcomes in neonates with severe
                     thrombocytopenia. Pediatrics [Internet]. 2009 Nov [cited 2013 May
                     27];124(5):e826-34. Available from:
                     http://www.ncbi.nlm.nih.gov/pubmed/19841111

                  2. von Lindern JS, Hulzebos C V, Bos AF, Brand A, Walther FJ, Lopriore E.
                     Thrombocytopaenia and intraventricular haemorrhage in very premature infants:
                     a tale of two cities. Arch Dis Child Fetal Neonatal Ed [Internet]. 2012 Sep
                     [cited 2014 Oct 1];97(5):F348-52. Available from:
                     http://www.ncbi.nlm.nih.gov/pubmed/22933094

                  3. von Lindern JS, van den Bruele T, Lopriore E, Walther FJ. Thrombocytopenia in
                     neonates and the risk of intraventricular hemorrhage: a retrospective cohort
                     study. BMC Pediatr [Internet]. BioMed Central Ltd; 2011 Jan [cited 2013 Jun
                     15];11(1):16. Available from:
                     http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3045959&tool=pmcentr
                     ez&rendertype=abstract

                  4. Stanworth SJ. Thrombocytopenia, bleeding, and use of platelet transfusions in
                     sick neonates. Hematology Am Soc Hematol Educ Program [Internet]. 2012
                     Jan;2012:512-6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23233627

                  5. Gunnink SF, Vlug R, Fijnvandraat K, van der Bom JG, Stanworth SJ, Lopriore E.
                     Neonatal thrombocytopenia: etiology, management and outcome. Expert Rev
                     Hematol [Internet]. 2014 Jun [cited 2014 Jun 12];7(3):387-95. Available from:
                     http://www.ncbi.nlm.nih.gov/pubmed/24665958

                  6. Sola-Visner M. Platelets in the neonatal period: developmental differences in
                     platelet production, function, and hemostasis and the potential impact of
                     therapies. Hematology Am Soc Hematol Educ Program [Internet]. 2012
                     Jan;2012(1):506-11. Available from:
                     http://www.ncbi.nlm.nih.gov/pubmed/23233626

                  7. Singh R, Visintainer P. Predictive models for severe intraventricular
                     hemorrhage in preterm infants. J Perinatol [Internet]. Nature Publishing
                     Group; 2014;34(10):802-802. Available from:
                     http://www.nature.com/doifinder/10.1038/jp.2014.152

                  8. Heuchan a M, Evans N, Henderson Smart DJ, Simpson JM. Perinatal risk factors
                     for major intraventricular haemorrhage in the Australian and New Zealand
                     Neonatal Network, 1995-97. Arch Dis Child Fetal Neonatal Ed [Internet]. 2002
                     Mar;86(2):F86-90. Available from:
                     http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1721387&tool=pmcentr
                     ez&rendertype=abstract

                  9. Luque MJ, Tapia JL, Villarroel L, Marshall G, Musante G, Carlo W, et al. A
                     risk prediction model for severe intraventricular hemorrhage in very low birth
                     weight infants and the effect of prophylactic indomethacin. J Perinatol
                     [Internet]. Nature Publishing Group; 2014 Jan [cited 2014 Sep 20];34(1):43-8.
                     Available from: http://www.ncbi.nlm.nih.gov/pubmed/24113396

                 10. Murray N a, Howarth LJ, McCloy MP, Letsky E a, Roberts I a G. Platelet
                     transfusion in the management of severe thrombocytopenia in neonatal intensive
                     care unit patients. Transfus Med [Internet]. 2002 Feb;12(1):35-41. Available
                     from: http://www.ncbi.nlm.nih.gov/pubmed/11967135

                 11. Honohan A, Van't Ende E, Hulzebos C, Lopriore E, Van't Verlaat E, Govaert P,
                     et al. Posttransfusion platelet increments after different platelet products
                     in neonates: a retrospective cohort study. Transfusion [Internet]. 2013 Feb 26
                     [cited 2013 Jul 1];53(12):3100-9. Available from:
                     http://www.ncbi.nlm.nih.gov/pubmed/23441721

                 12. Fontein DBY, Klinten Grand M, Nortier JWR, Seynaeve C, Meershoek-Klein
                     Kranenbarg E, Dirix LY, et al. Dynamic prediction in breast cancer: Proving
                     feasibility in clinical practice using the TEAM trial. Ann Oncol.
                     2015;26(6):1254-62.

                12. APPENDIX 1: names and contact information of participating NICUs

                NICU University Medical Center Groningen (UMCG) Local investigator: Chris Hulzebos,
                neonatologist

           [email protected]

           NICU Isala Klinieken Zwolle (Isala) Local investigator: Esther d'Haens, neonatologist
           [email protected]

           NICU University Medical Center Utrecht (UMCU) Local investigator: Daniël Vijlbrief,
           neonatologist [email protected]

           NICU Academic Medical Center Amsterdam (AMC) Wes Onland, neonatologist
           [email protected]

           NICU Leiden University Medical Center (LUMC) Local investigator: Enrico Lopriore,
           neonatologist [email protected]

           NICU Maxima Medical Center Veldhoven (MMC) Peter Andriessen, neonatologist
           [email protected]

           NICU Erasmus University Medical Center Rotterdam (Erasmus MC) Andre Kroon, neonatologist

           [email protected]
    


Study Type

Observational


Primary Outcome

Major hemorrhage


Condition

Neonatal Thrombocytopenia


Study Arms / Comparison Groups

 Preterm neonate with thrombocytopenia
Description:  Preterm neonates (GA<34 weeks) with severe thrombocytopenia

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

700

Start Date

November 20, 2015

Completion Date

November 9, 2016

Primary Completion Date

October 21, 2016

Eligibility Criteria

        Inclusion Criteria:

          -  gestational age <34 weeks at birth

          -  platelet count <50x10^9/L

        Exclusion Criteria:

          -  readmission to NICU (only first admissions are included. Postnatal transfers from
             non-NICU hospitals are included)

          -  major congenital malformations

          -  high suspicion of spurious platelet count

          -  thrombocytopenia exclusively in the context of exchange transfusion
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Karin Fijnvandraat, MD PhD prof, , 



Administrative Informations


NCT ID

NCT03110887

Organization ID

PPOC 12-012027


Responsible Party

Sponsor

Study Sponsor

Sanquin-LUMC J.J van Rood Center for Clinical Transfusion Research

Collaborators

 Leiden University Medical Center

Study Sponsor

Karin Fijnvandraat, MD PhD prof, Principal Investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)


Verification Date

August 2017