An observational study in Fetal and Neonatal Alloimmune Thrombocytopenia, Long Term Adverse Effects and Neurodevelopmental Abnormality, sponsored by Leiden University Medical Center. Status unknown at 1 site in Netherlands. Open to participants aged 18 Months to 17 Years. Per ClinicalTrials.gov, last updated 2020-08-27.
Sponsored by Leiden University Medical Center · Observational
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.
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.
697 studies on the registry are indexed under Thrombocytopenia; 153 are open to participants now.
This study's planned enrollment of 78 is below the median of 120 across 183 observational studies indexed under Thrombocytopenia.
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All children born between 2002 and 2017 and diagnosed with FNAIT are eligible for this study. They will be invited for an assessment at our outpatient clinic. FNAIT cases that were not antenatally treated with IVIg will be eligible for the study (cohort 1), as well as FNAIT cases which were anticipated antenatally by materal IVIg administration (cohort 2).
Exclusion Criteria:
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).
Diagnostic Test: Cognitive testing (Bayley III, WPPSI III and WISC V)
All children born between 2002 and 2017 and diagnosed with FNAIT are eligible for this study. Children in cohort 2 will be FNAIT cases which were anticipated antenatally by maternal IVIg administration according to our local protocol.
Diagnostic Test: Cognitive testing (Bayley III, WPPSI III and WISC V)
Parents and children will be invited to come for an outpatient clinic visit where cognitive testing and neurologic examination will be performed. In addition to this parents will be asked to fill in questionnaires, provide latest school results and medical files will be requested from treating physicians.
Also known as: Pediatric Quality of Life Inventory, Child Behavior Checklist, Questionnaire based on 'Richtlijn diagnostiek naar onderliggende aandoeningen bij kinderen met recidiverende luchtweginfecties', Questionnaire composited in collaboration with allergist (Dr. H. de Groot)., Neurologic Examination
Cognitive test score
IQ test score calculated from a standardized cognitive test.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Neurodevelopmental injury (NDI)
NDI is a composite outcome of: * Cerebral palsy ≥ grade II according to Gross Motor Classification System (GMFCS) * Impaired cognitive, language and/or motor development (test scores \<70) * Bilateral blindness and/or bilateral deafness * Bilateral deafness requiring amplification
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Health Related Quality of Life
Health Related Quality of Life score calculated from the PedsQol questionnaire.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Cerebral Palsy
Spastic bilateral, spastic unilateral or mixed Classification by European CP Network
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Bilateral blindness
Blind or partially sighted.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Bilateral deafness
Needing hearing aids.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Behaviour test score
Behaviour test score bases on Child Behavior Checklist
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Abnormal course or incidence of infections
Need to refer to an immunologist or the need to preform diagnostics based on history taking according to the Dutch guidelines.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Prevalence of eczema
Number of children that suffer from eczema.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Prevalence of allergies
Number of children that suffer from allergies
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Patient reported anaphylaxis
Serious allergic reaction, requiring urgent medical treatment with epinephrine.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Poor control of allergic rhinitis
CARAT score of upper airways \< 8
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Poor control of asthma
CARAT score of lower airways \< 16.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Academic performance
The latest test scores from primary school will be requested. Three academic domains will be assessed; arithmetic and spelling performance and measurements on reading comprehension.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Maternal characteristics
Age mother at delivery
Time frame: Measured at delivery of the child that is assessed. Calculated in years.
Obstetric history
History of pre-eclampsia, miscarriages or intra uterine fetal demise
Time frame: Measured at delivery of the child that is assessed.
Gravidity/Parity
Gravidity/Parity
Time frame: Measured at delivery of the child that is assessed.
Mode parturition
Mode parturition
Time frame: Measured at delivery of the child that is assessed.
Gestational age at birth
Gestational age at birth in days
Time frame: Measured at delivery of the child that is assessed. Gestational age expressed in days.
Birthweight
Birthweight in grams
Time frame: Measured at delivery of the child that is assessed, measurement directly after birth.
Apgar score
Apgar score
Time frame: Measured at delivery of the child that is assessed, measured at 1, 5 and 10 minutes after birth.
anti-HPA specificity
HPA specificity of the antibody found in the presence of an HPA incompatibility between mother and fetus.
Time frame: Measured at diagnosis of FNAIT, during pregnancy or until 1 week after birth.
Platelet count
Lowest platelet count
Time frame: Lowest platelet count measured between birth and 7 days after birth.
Platelet transfusion
Any platelet transfusion.
Time frame: Platelet transfusion between birth and 7 days after birth.
Neonatal IVIG treatment
Any administration of IVIG after birth.
Time frame: Between birth and 7 days after birth.
Skin bleeding manifestations
Petechiae, purpura or hematoma diagnosed by the caretaker at neonatal period (gynecologist, pediatrician or midwife).
Time frame: Between birth and 7 days after birth.
Intracranial hemorrhage
Any intracranial hemorrhage
Time frame: Between birth and 7 days after birth.
Convulsions
Any paroxysmal, repetitive or stereotypical events interpreted as neonatal convulsions by a pediatrician.
Time frame: Between birth and 7 days after birth.
Organ bleeding
Bleeding in any organ located in the thorax or abdomen
Time frame: Between birth and 7 days after birth.
Respiratory distress syndrome
Requiring mechanical ventilation and/or surfactant.
Time frame: Between birth and 7 days after birth.
Perinatal asphyxia
One of the following criteria; Apgar score \< 7 and/or umbilical cord pH ≤ 7.0.
Time frame: Diagnosed within 24 hours after birth.
Proven early onset neonatal sepsis
Positive blood culture within 72 hours postpartum and clinical suspicion of a neonatal sepsis.
Time frame: Between birth and 7 days after birth.
Necrotizing enterocolitis
Bells Stage 2 or higher.
Time frame: Between birth and 28 days after birth.
Family history (first degree) of allergy, asthma or eczema
Positive when 1st degree of family members receive daily treatment for asthma or eczema. Or when a family member wears an epinephrine pencil because of a severe allergy.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Ethnic origin of the parents
Ethnic origin of mother and father.
Time frame: Asked at study enrollment.
Parent smoking
Any person living in the household of the child smoking one or more cigarettes a day.
Time frame: Within 1 month before study enrollment.
Day-care visit
When child is in day care at least one day a week.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Educational level of the parents
Highest level of graduation of the parents.
Time frame: From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Documents are hosted by the registry — open the source record to download them.
Plan to share: No — In principle we do not share individual participant data with other researchers. If there is a request on sharing data this request is first submitted to the project leader (J.M.M. van Klink) or the principal investigators (E. Lopriore or M. de Haas). If they agree upon sharing data this request will be sent to the scientific committee of the Department of Pediatrics. If the project leader or scientific committees give permission for access to the data, the request is sent to a the METC of the LUMC. The METC will evaluate whether the purpose of reuse is in line with the informed consent.
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