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
guidelines.
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
Observational
Primary Outcome
Cognitive test score
Secondary Outcome
Neurodevelopmental injury (NDI)
Condition
Fetal and Neonatal Alloimmune Thrombocytopenia
Intervention
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).
Publications
* 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
78
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
Committee.
Exclusion Criteria:
- Children born with congenital and/or chromosomal abnormalities.
- Children that passed away before inclusion.
Gender
All
Ages
18 Months - 17 Years
Accepts Healthy Volunteers
No
Contacts
Enrico Lopriore, Prof. MD PhD, ,
Location Countries
Netherlands
Location Countries
Netherlands
Administrative Informations
NCT ID
NCT04529382
Organization ID
P19.069
Responsible Party
Principal Investigator
Study Sponsor
Leiden University Medical Center
Collaborators
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