Neurodevelopmental Outcome After Fetal Neonatal AlloImmune Thrombocytopenia

Brief Title

Neurodevelopmental Outcome After Fetal Neonatal AlloImmune Thrombocytopenia

Official Title

Neurodevelopmental Outcome After Fetal Neonatal AlloImmune Thrombocytopenia

Brief Summary

      Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease caused by
      allo-immunisation during pregnancy. If left untreated, FNAIT can lead to severe fetal
      intracranial haemorrhage. This complication can be prevented by weekly administration of
      intravenous immunoglobulin (IVIg) to the mother during pregnancy. Knowledge on long-term
      development of FNAIT survivors with or without IVIg treatment is very limited but an
      important subject in the counselling of parents of newly diagnosed cases. To evaluate the
      long-term neurodevelopmental outcome in two groups of children with FNAIT will be asked to
      participate in our study in an outpatient clinic setting.

Detailed Description

      INTRODUCTION AND RATIONALE Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most
      common cause of thrombocytopenia in otherwise healthy term-born neonates. FNAIT is a rare
      disease with an incidence estimated around 1 per 1000 live newborns. During pregnancy
      alloimmunization can occur due to incompatibility of the Human Platelet Antigens (HPA) on the
      maternal and fetal platelets. Alloimmunization and maternal production of antibodies directed
      against the HPA-positive fetal platelets, leads to thrombocytopenia and an increased risk of
      intracranial hemorrhages (ICH) in the fetus. Clinical presentation can vary from skin
      bleedings to severe ICH leading to lifelong neurologic sequelae or intrauterine death.

      In the past, FNAIT was managed with invasive and high-risk interventions including
      intrauterine platelet transfusion (IUPT). Since the end of the 20th century, invasive
      intrauterine transfusions (IUT) were replaced by a new, non-invasive therapy: maternal
      administration of intravenous immunoglobulin (IVIg). This novel therapy resulted in a
      significant lower risk of intrauterine fetal death and ICH. Intervention with immune
      modulation in the semi -allogenic environment of the fetus by administration of
      immunoglobulins (Ig) is successful, especially in preventing ICH. However antenatal treatment
      with IVIg has been implemented as standard of care without strong methodological follow-up
      research of children from mothers treated with IVIg. To date, only two follow-up studies have
      been published in children with anticipated FNAIT cases. The first study of a FNAIT cohort
      treated with IVIg was done by Ward et al. in 2006. They concluded that development of
      children treated for FNAIT was better compared to their non-treated siblings. Their
      conclusions were based on non-validated questionnaires taken by telephone, assessing the
      behavioral outcome of the children and were limited by a ~40% lost-to-follow-up rate. A
      second follow-up study including 39 children was published by a research group from our
      center in 2004. This research stated that the outcome in children with FNAIT and exposed to
      maternal IVIg treatment was similar to the normal population. However, this study included a
      heterogenic group of children with different treatment strategies including IUT, hampering
      definitive conclusions and substantiating the need for more research.

      No long-term standardized follow-up studies were performed on FNAIT cases without antenatal
      treatment and/or ICH. The natural course of the disease and long-term effects of
      thrombocytopenia on the developing fetus and newborn are unknown. FNAIT is defined as a
      disease caused by alloantibodies, resulting in thrombocytopenia and a risk of bleeding in the
      neonate. In the last years, evidence is increasing that the maternal alloantibodies can also
      bind to the fetal endothelium and may impair angiogenesis in the developing fetuses It is not
      known at which moment in pregnancy the developing brain is most vulnerable for damage induced
      by these kind of alloantibodies. The timing in fetal life FNAIT associated ICH ranges from 23
      to 42 weeks, but small bleeding may not be diagnosed. It may also be that these type of
      alloantibodies not lead to ICH but to other type of cerebral damage. These lesions can remain
      subclinical directly after birth but lead to developmental delay on the long term. This
      knowledge can be of great interest when counseling parents with a risk of FNAIT or in writing

      For 3 decades a nationwide screening on FNAIT to detect pregnancies with alloantibodies in
      time and start treatment to prevent bleedings is being discussed. If alloantibodies lead to
      cerebral damage on the long term also in patients without large ICH this might have large
      implications in the debate on the introduction of a national screening programme. Therefore
      the investigators want to underline that more knowledge about the long-term development of
      FNAIT survivors is required.

      The Leiden University Medical Center (LUMC), a national fetal therapy center in The
      Netherlands, has a close and long-lasting collaboration with Sanquin. This collaboration
      offers a unique opportunity to evaluate a large and complete cohort of children with FNAIT.
      LUMC and Sanquin are both nationwide referral centers for FNAIT and committed to improve
      timely detection of high-risk cases who need intra-uterine therapy. This research group from
      the national expertise centers are designated to assess long-term outcome in children with
      FNAIT and describe the natural history of children affected by FNAIT and the long term
      effects of a given therapy.

      OBJECTIVE The primary objective is to determine the cognitive test score of children
      diagnosed with FNAIT without and with antenatal treatment.

      STUDY DESIGN The investigators will perform an observational cohort study. The long-term
      neurodevelopmental outcome of children affected by FNAIT will be evaluated. All children born
      between 2002 and 2017 and diagnosed with FNAIT are eligible for follow-up assessment and will
      be invited for an assessment at our outpatient clinic. The FNAIT survivors will be collected
      in two cohorts; cohort 1 will consist of FNAIT survivors without antenatal treatment, cohort
      2 will consist of FNAIT survivors that were antenatally anticipated and therefore IVIg
      treatment to the mother was given.

      Enrollment in this study will take place via the LUMC and Stichting Sanquin Bloedvoorziening.
      The LUMC is national referral center for intrauterine therapy and Sanquin is national
      reference laboratory to diagnose FNAIT. Retrospectively FNAIT cases will be collected and
      asked for permission directly or via referring specialist.

      After informed consent, child cognitive functioning will be assessed with a formal
      psychological test of cognitive functioning. According to age, the parents will complete a
      standardized behavioral and HRQoL questionnaire. Academic performance will be assessed by
      collecting the most recent CITO test scores from the Dutch Pupil monitoring system developed
      by the National Institute for Educational Measurement. Assessment of the prevalence of
      possible late effects of IVIg on the immune system will be assessed by questionnaires about
      the prevalence of allergies, astma, eczema and course of infections by questionnaires.
      Parents and children, when 12 years old or older, are asked for consent to request the
      medical letters from the maternity or neonatology ward to obtain perinatal and neonatal data.

      No laboratory tests will be performed in this study, however data of the laboratory tests
      that were performed at timepoint of diagnosing FNAIT will be involved in this study.

      After assessment a report will be made from the observations and test results, this report
      will be sent to the parents.

Study Type


Primary Outcome

Cognitive test score

Secondary Outcome

 Neurodevelopmental injury (NDI)


Fetal and Neonatal Alloimmune Thrombocytopenia


Cognitive testing (Bayley III, WPPSI III and WISC V)

Study Arms / Comparison Groups

 Cohort 1: Unanticipated FNAIT cases
Description:  All children born between 2002 and 2017 and diagnosed with FNAIT are eligible for this study. Children in cohort 1 will be FNAIT cases that were not antenatally treated with by maternal IVIg administration (or other forms of fetal therapy).


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

Recruitment Information

Recruitment Status

Diagnostic Test

Estimated Enrollment


Start Date

December 17, 2019

Completion Date

December 17, 2021

Primary Completion Date

December 17, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  Children diagnosed with FNAIT during pregnancy or postnatal, at moment of inclusion 2
             to 16 years of age.

          -  Children living in the Netherlands.

          -  Parents or guardian aged ≥ 18 years old, with parental authority.

          -  Written informed consent form both parents with, form being approved by Ethic

        Exclusion Criteria:

          -  Children born with congenital and/or chromosomal abnormalities.

          -  Children that passed away before inclusion.




18 Months - 17 Years

Accepts Healthy Volunteers



Enrico Lopriore, Prof. MD PhD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

Leiden University Medical Center


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

Study Sponsor

Enrico Lopriore, Prof. MD PhD, Principal Investigator, Department of Neonatology, Leiden University Medical Center

Verification Date

August 2020