Neurodevelopmental Outcome After Fetal Neonatal AlloImmune Thrombocytopenia

Neurodevelopmental Abnormality Clinical Trial

— NOFNAIT  

Official title:

Neurodevelopmental Outcome After Fetal Neonatal AlloImmune Thrombocytopenia

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04529382
• Other study ID #: P19.069
• Status: Enrolling by invitation
• Start date: December 17, 2019
• Est. completion date: December 17, 2021

Study information

• Verified date: August 2020
• Source: Leiden University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 78
• Est. completion date: December 17, 2021
• Est. primary completion date: December 17, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Months to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fetal and Neonatal Alloimmune Thrombocytopenia
• Intravenous Immunoglobulin Adverse Reaction
• Long Term Adverse Effects
• Neurodevelopmental Abnormality
• Thrombocytopenia

Intervention

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.

Locations

Country	Name	City	State
Netherlands	Leiden University Medical Center	Leiden

Sponsors (2)

Lead Sponsor	Collaborator
Leiden University Medical Center	Sanquin-LUMC J.J van Rood Center for Clinical Transfusion Research

Country where clinical trial is conducted

Netherlands, 

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* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Maternal characteristics	Age mother at delivery	Measured at delivery of the child that is assessed. Calculated in years.
Other	Obstetric history	History of pre-eclampsia, miscarriages or intra uterine fetal demise	Measured at delivery of the child that is assessed.
Other	Gravidity/Parity	Gravidity/Parity	Measured at delivery of the child that is assessed.
Other	Mode parturition	Mode parturition	Measured at delivery of the child that is assessed.
Other	Gestational age at birth	Gestational age at birth in days	Measured at delivery of the child that is assessed. Gestational age expressed in days.
Other	Birthweight	Birthweight in grams	Measured at delivery of the child that is assessed, measurement directly after birth.
Other	Apgar score	Apgar score	Measured at delivery of the child that is assessed, measured at 1, 5 and 10 minutes after birth.
Other	anti-HPA specificity	HPA specificity of the antibody found in the presence of an HPA incompatibility between mother and fetus.	Measured at diagnosis of FNAIT, during pregnancy or until 1 week after birth.
Other	Platelet count	Lowest platelet count	Lowest platelet count measured between birth and 7 days after birth.
Other	Platelet transfusion	Any platelet transfusion.	Platelet transfusion between birth and 7 days after birth.
Other	Neonatal IVIG treatment	Any administration of IVIG after birth.	Between birth and 7 days after birth.
Other	Skin bleeding manifestations	Petechiae, purpura or hematoma diagnosed by the caretaker at neonatal period (gynecologist, pediatrician or midwife).	Between birth and 7 days after birth.
Other	Intracranial hemorrhage	Any intracranial hemorrhage	Between birth and 7 days after birth.
Other	Convulsions	Any paroxysmal, repetitive or stereotypical events interpreted as neonatal convulsions by a pediatrician.	Between birth and 7 days after birth.
Other	Organ bleeding	Bleeding in any organ located in the thorax or abdomen	Between birth and 7 days after birth.
Other	Respiratory distress syndrome	Requiring mechanical ventilation and/or surfactant.	Between birth and 7 days after birth.
Other	Perinatal asphyxia	One of the following criteria; Apgar score < 7 and/or umbilical cord pH = 7.0.	Diagnosed within 24 hours after birth.
Other	Proven early onset neonatal sepsis	Positive blood culture within 72 hours postpartum and clinical suspicion of a neonatal sepsis.	Between birth and 7 days after birth.
Other	Necrotizing enterocolitis	Bells Stage 2 or higher.	Between birth and 28 days after birth.
Other	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.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Other	Ethnic origin of the parents	Ethnic origin of mother and father.	Asked at study enrollment.
Other	Parent smoking	Any person living in the household of the child smoking one or more cigarettes a day.	Within 1 month before study enrollment.
Other	Day-care visit	When child is in day care at least one day a week.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Other	Educational level of the parents	Highest level of graduation of the parents.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Primary	Cognitive test score	IQ test score calculated from a standardized cognitive test.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	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	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Health Related Quality of Life	Health Related Quality of Life score calculated from the PedsQol questionnaire.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Cerebral Palsy	Spastic bilateral, spastic unilateral or mixed Classification by European CP Network	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Bilateral blindness	Blind or partially sighted.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Bilateral deafness	Needing hearing aids.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Behaviour test score	Behaviour test score bases on Child Behavior Checklist	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	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.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Prevalence of eczema	Number of children that suffer from eczema.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Prevalence of allergies	Number of children that suffer from allergies	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Patient reported anaphylaxis	Serious allergic reaction, requiring urgent medical treatment with epinephrine.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Poor control of allergic rhinitis	CARAT score of upper airways < 8	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	Poor control of asthma	CARAT score of lower airways < 16.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.
Secondary	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.	From birth until study enrollment. Average age of the participants is expected to be 8 years old.