Neurodevelopmental Outcome After Fetal Neonatal AlloImmune Thrombocytopenia
Conditions: Fetal and Neonatal Alloimmune Thrombocytopenia, Long Term Adverse Effects, Neurodevelopmental Abnormality, Intravenous Immunoglobulin Adverse Reaction
Sponsor: Leiden University Medical Center

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Neurodevelopmental Outcome after Fetal Neonatal AlloImmune 
Thrombocytopenia 
 
NO FNAIT 
 

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NEURODEVELOPMENTAL OUTCOME AFTER FNAIT 
 
Protocol ID 
NL70410.058.19 
Short title 
NO FNAIT 
EudraCT number 
Not applicable 
Version 
3 
Date 
20-09-2019 
Coordinating investigator 
 
 
 
 
Drs. T.W. de Vos 
Department of Pediatrics  
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
Tel. 071-5262748/06-52665280 
t.w.de_vos@lumc.nl  
Project leader 
 
Dr. J.M.M. van Klink 
Department of Pediatrics  
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
Tel. 071-5263925 
j.m.m.van_klink@lumc.nl 
Principal investigators 
Prof. Dr. E. Lopriore 
Department of Pediatrics  
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
Tel. 071-5262965 
e.lopriore@lumc.nl  
 
Prof. Dr. M. de Haas 
Stichting Sanquin Bloedvoorziening 
Plesmanlaan 125 
1066 CX Amsterdam 
Tel. 020-5123000 
m.dehaas@sanquin.nl 
 
 
 
 
 
 

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Sponsor 
Head of Department of Pediatrics 
Prof. Dr. E.H.H.M Rings  
Department of Pediatrics  
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
E.H.H.M.Rings@lumc.nl  
Subsidising party 
Stichting Sanquin Bloedvoorziening 
Plesmanlaan 125 
1066 CX Amsterdam 
Tel. 020-5123000 
Independent expert 
Dr. V.E.H.J. Wintjes 
Department of Pediatrics  
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
Tel. 071-5262965 
V.E.H.J.Smits-Wintjens@lumc.nl 
Laboratory sites 
Not applicable 
Statistical constulant 
Dr. S. Böhringer 
Department of Biomedical Data Sciences 
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
 
Tel. 071-5269743 
S.Boehringer@lumc.nl 
Pharmacy 
Not applicable 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Head of Department of Pediatrics 
Prof. Dr. E.H.H.M Rings  
Department of Pediatrics  
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
e.h.h.m.rings@lumc.nl  
 
20-09-2019  
Principal Investigator: 
Dr. J.M.M. van Klink 
Department of Pediatrics  
Leiden University Medical Center 
Albinusdreef 2 
2333 ZA Leiden 
Tel. 071-5263925 
j.m.m.van_klink@lumc.nl 
 
20-09-2019 
 
 

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TABLE OF CONTENTS 
 
1. 
SUMMARY ..................................................................................................................... 9 
2. 
INTRODUCTION AND RATIONALE .............................................................................11 
3. 
OBJECTIVES ................................................................................................................13 
3.1 
Primary objective(s) ................................................................................................13 
3.2 
Secondary Objective(s) ..........................................................................................13 
3.3 
Other study parameters ..........................................................................................13 
4. 
STUDY DESIGN ...........................................................................................................16 
5. 
STUDY POPULATION ..................................................................................................18 
5.1 
Population (base) ...................................................................................................18 
5.2 
Inclusion criteria .....................................................................................................18 
5.3 
Exclusion criteria ....................................................................................................18 
5.4 
Sample size calculation ..........................................................................................18 
6. 
TREATMENT OF SUBJECTS .......................................................................................20 
7. 
INVESTIGATIONAL PRODUCT ....................................................................................20 
8. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................20 
9. 
METHODS ....................................................................................................................21 
9.1 
Study parameters/endpoints ...................................................................................21 
9.1.1 
Main study parameter/endpoint .......................................................................21 
9.1.2 
Secondary study parameters/endpoints ..........................................................21 
9.1.3 
Other study parameters ...................................................................................22 
9.2 
Randomisation, blinding and treatment allocation ..................................................27 
9.3 
Study procedures ...................................................................................................27 
9.4 
Withdrawal of individual subjects ............................................................................28 
9.4.1 
Specific criteria for withdrawal .........................................................................29 
9.4.2 
Replacement of individual subjects after withdrawal ........................................29 
9.4.3 
Follow-up of subjects withdrawn from treatment ..............................................29 
9.5 
Premature termination of the study .........................................................................29 
10. 
SAFETY REPORTING ...............................................................................................30 
10.1 
Temporary halt for reasons of subject safety ..........................................................30 
10.2 
AEs, SAEs and SUSARs ........................................................................................30 
10.2.1 
Adverse events (AEs) ......................................................................................30 
10.2.2 
Serious adverse events (SAEs) .......................................................................30 
10.3 
Follow-up of adverse events ...................................................................................31 
10.4 
Data Safety Monitoring Board (DSMB) ...................................................................31 
11. 
STATISTICAL ANALYSIS ..........................................................................................32 
12. 
ETHICAL CONSIDERATIONS ...................................................................................33 
12.1 
Regulation statement .............................................................................................33 
12.2 
Recruitment and consent........................................................................................33 
12.3 
Objection by minors or incapacitated subjects ........................................................33 
12.4 
Benefits and risks assessment, group relatedness .................................................34 
12.5 
Compensation for injury .........................................................................................34 

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12.6 
Incentives ...............................................................................................................34 
13. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................35 
13.1 
Handling and storage of data and documents ........................................................35 
13.2 
Monitoring and Quality Assurance ..........................................................................35 
13.3 
Amendments ..........................................................................................................36 
13.4 
Annual progress report ...........................................................................................36 
13.5 
Temporary halt and (prematurely) end of study report ............................................36 
13.6 
Public disclosure and publication policy ..................................................................37 
14. 
STRUCTURED RISK ANALYSIS...............................................................................38 
15. 
REFERENCES ..........................................................................................................39 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
AR 
Adverse Reaction 
ASQ 
Ages and Stages Questionnaire  
BSID 
Bayley Scales of Infant and Toddler Development 
CARAT 
Control of Allergic Rhinitis and Asthma Test 
CITO 
Centraal Instituut voor Toetsontwikkeling 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
eCRF 
Electronic case report form 
FNAIT 
Fetal and Neonatal Alloimmune Thrombocytopenia 
GCP 
Good Clinical Practice 
GMFCS 
Gross Motor Function Classification System 
HLA 
Human Leukocyte Antigen 
HPA 
Human Platelet Antigens 
HRQoL 
Health related Quality of Life 
IC 
Informed Consent 
ICH 
Intracranial hemorrhages  
IBM 
International Business Machines 
Ig 
Immunoglobulins 
IUT 
Intrauterine transfusions 
IUPT 
Intra uterine platelet transfusions 
IVIg 
Intravenous Immunoglobulin 
IQ 
Intelligence Quotient 
IQR 
Interquartile range 
LUMC 
Leiden University Medical Center 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
NDI 
Neurodevelopmental Impairment 
(S)AE 
(Serious) Adverse Event  
SD 
Standard deviation  
 

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Sponsor 
The sponsor is the party that commissions the organisation or performance of 
the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
SPSS 
Statistical Package for the Social Sciences 
WISC 
Wechsler Intelligence Scale for Children 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
WPPSI 
Wechsler Preschool and Primary Scale of Intelligence 
 
 
 

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1. SUMMARY 
 
Rationale: 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. Although treatment with 
IVIg is nowadays considered as the golden standard for the management of FNAIT, the 
exact mechanism of action of IVIg is still under debate. Most importantly, the long-term 
effects and safety of IVIg treatment in FNAIT have not yet been evaluated. The use of IVIg 
during pregnancy for FNAIT is therefore still ‘off-label’. The medication leaflet of IVIg 
continues to state that there is insufficient knowledge on the use of this product during 
pregnancy, despite all the years of experience and implementation in virtually all international 
guidelines.  
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. 
A greater understanding of the long-term outcome and the effects of IVIg on child 
development is necessary.  
Objective: To evaluate the long-term neurodevelopmental outcome in two groups of children 
with FNAIT. First, children with unanticipated disease ‘index cases’ that were born without 
maternal IVIg administration during pregnancy. Second, children with anticipated disease; 
their mothers were treated with IVIg during pregnancy. 
Study design: Observational cohort study. 
Study population: The study population consists of two different cohorts of FNAIT children 
born in the Netherlands between 2002 and 2017.  
- 
Cohort 1: The first cohort of children will consist children with unanticipated disease, 
‘index cases that were born without maternal IVIg administration during pregnancy.  
- 
Cohort 2: Second cohort will consist of children with anticipated disease; their 
mothers were treated with IVIg during pregnancy. 
Methods: Neurodevelopmental evaluation of the children will be performed, at a minimum age 
of 24 months. This includes an assessment of neurologic, motor and cognitive development 
using standardized psychometric tests appropriate for age and parent-report questionnaires 
on Health Related Quality of Life (HRQoL) and behavioral functioning. Academic trajectories 
of FNAIT children will be assessed by collecting test scores from the Dutch pupil monitoring 
system. We will assess allergies and the course of infections by questionnaires. 
Main study parameters/endpoints: The primary outcome is  cognitive development i.e., 
cognitive test score or Intelligence Quotient (IQ). Secondary outcome is neurodevelopmental 
impairment (NDI); a composite outcome including cerebral palsy Gross Motor Functioning 

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Classification System (GMFCS) ≥ II, cognitive and/or motor test score of less than 70 (-2 
SD), hearing loss requiring amplification or visual impairment (legally certifiable as blind or 
partially sighted). Other secondary outcome parameters are HRQoL and behavioral 
functioning and the academic performance. The course and incidence of infections and 
allergies will be assessed. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness 
The burden of neurodevelopmental assessment tests is minimal (e.g. 120 minutes at 2 to 6 
years and 150 minutes at 7 to 17 years follow-up). Neurodevelopmental assessment is 
generally experienced as enjoyable for children. Parents will complete a HRQoL- and a 
behavioral questionnaire for their children. Academic performance will be evaluated by scores 
that were obtained at school. Participation does not result in any direct benefit. 

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2. INTRODUCTION AND RATIONALE 
 
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of 
thrombocytopenia in otherwise healthy term-born neonates. [1] FNAIT is a rare disease with 
an incidence estimated around 1 per 1000 live newborns. [2] 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. [2] [3]  
 
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. [4] Intervention with immune 
modulation in the semi -allogenic environment of the fetus by administration of 
immunoglobulins (Ig) is successful, especially in preventing ICH. [5] 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. [6] 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. [6]  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. [7] 
 
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 [8] [9]. It 

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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 [10], 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 
we 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. In our opinion we have a 
duty as a national expertise center 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.  
 
 

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3. OBJECTIVES 
3.1 Primary objective(s) 
The primary objective is to determine the cognitive test score of children diagnosed with 
FNAIT without and with antenatal treatment. We will assess the neurodevelopmental 
outcome, with IQ score as outcome measure, of two groups: 
Cohort 1: To evaluate the natural history of FNAIT, we will include in this first cohort all 
FNAIT survivors without antenatal treatment. Our hypothesis is that the cognitive test score 
in this cohort will be lower compared to the general population.  
Cohort 2: To evaluate the safety and benefit of IVIg treatment, the IQ score in all FNAIT 
survivors treated with antenatal IVIg treatment will be determined. Our hypothesis is that the 
cognitive test score in this cohort is similar to the general population. 
3.2 Secondary Objective(s) 
In both groups we will assess the incidence of neurodevelopmental impairment (NDI). NDI is 
a composite outcome including cerebral palsy (GMFCS ≥ II), cognitive or motor test score of 
less than 70, hearing loss requiring amplification or visual impairment (legally certifiable as 
blind or partially sighted). Other secondary outcomes will be HRQoL and behavioral problem 
score. In both cohorts we will assess academic performance by evaluation of test scores on 
three domains; arithmetic and spelling performance and reading comprehension. [11-13]  
 
We will also focus on potential long-term side effects of IVIg treatment and  determine the 
prevalence of allergies, eczema, asthma and the course of infections.  
3.3 Other study parameters 
We will gather the data about the following data of our cases; age and sex of the child, 
obstetric medical data and neonatal characteristics and morbidity of the study population. 
Parents will be asked to complete a questionnaire to assess the highest level of education of 
the parents. We use this data to describe our study population and correct for potential 
confounding of these factors on neurodevelopmental outcome as described in chapter 11. 
Study parameters are summarized in Table 1, a list of definitions can be found in Table 3.  
 
Possible confounding factors for allergies are the family history for asthma, allergies or 
eczema. For evaluation of the infections it is important to assess smoking at home and day-
care visit as possible confounding factors. 
 
 

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Study parameters 
Obstetric data 
Maternal characteristics 
Age mother at delivery 
Obstetric history 
Medication usage during pregnancy 
 
Pregnancy characteristics 
Gravidity/Parity 
Pregnancy induced hypertension 
Pre-eclampsia 
Signs of bleeding in the fetus at ultrasound 
 
FNAIT related therapy 
IVIg treatment 
Intra-uterine transfusions 
Treatment with corticosteroids 
 
Labour characteristics 
Mode parturition 
Gestational age at delivery 
 
Placental features 
Placenta weight 
Neonatal data 
Birth data 
Gestational age at birth 
Birthweight 
Apgar score 
 
Severe neonatal morbidity 
Respiratory distress syndrome 
Perinatal asphyxia 
Proven early onset neonatal sepsis 
Retinopathy of prematurity 
Necrotizing enterocolitis 
 
Neonatal neurologic 
sequelae 
Intracranial haemorrhage 
Cystic periventricular leukomalacia 
Ventricular dilatation 
Porencephalic or parenchymal cysts 
Convulsions 
Any cerebral lesions associated with 
adverse neurologic outcome 
 
Signs of bleeding 
Skin manifestations 
Intracerebral bleeding 
Organ bleeding  
Increased bleeding tendency, reported by 
the caregiver 
 
Therapy 
Platelet transfusions 
IVIg treatment 
 
 
 
 
 
 
Table 1: Study parameters 

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Table 1: Study parameters 
Study parameters 
Laboratory 
data 
HPA 
HPA incompatibility 
HPA genotyping 
Anti-HPA-titre 
 
Platelet count 
Directly after birth 
Nadir 
 
Other 
Presence of HLA class I antibodies 
Outcome 
Neurodevelopmental 
scores 
Cognitive test score 
 
 
Motor test score 
 
 
Cerebral palsy 
 
Neurodevelopmental 
impairment 
Impaired cognitive or motor development 
 
 
Impaired functioning in communication 
 
 
Bilateral blindness 
 
 
Bilateral deafness 
 
Quality of life 
Health related quality of life score 
 
Behavior 
Behavioural test score 
 
Academic performance 
Arithmetic test score at primary school 
 
 
Spelling test score at primary school 
 
 
Reading comprehension test score at 
primary school 
 
Immunology 
Prevalence of allergies 
 
 
Patient reported anaphylaxis 
 
 
Poor control of allergic rhinitis 
 
 
Poor control of asthma 
Patient reported eczema 
Course and incidence of infections 
Potential 
confounders 
Demographic 
characteristics 
Age and gender of the child 
Family history (first degree) of allergy, 
astma or eczema 
Highest level of education of the parents 
Smoking at home 
Day-care visit 
 
 
Ethnic origin of the parents 
 
 

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4. STUDY DESIGN 
We 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. A summary of our study design is presented in Figure 1. 
 
Enrollment in our 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 according to the 
procedures described in paragraph 12.2.  
 
After informed consent, child cognitive functioning will be assessed with a formal 
psychological test of cognitive functioning described in table 2, chapter 9. 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 
[14]. 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.  

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Figure 1: Study design  

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5.  STUDY POPULATION 
 
5.1 Population (base)  
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).  
 
The retrospective study design might bias the results (e.g. survival and recall bias). 
However in our opinion this is the only feasible way to perform a long term development 
study in this disease. Between 2002 and 2017 the NOICH trail was performed, after this 
trial the dosage regime of IVIg treatment was reduced from 1.0 g/kg/week to 0.5 
gr/kg/week. We do not think this will have important effects on the results of our study but 
will verify this effect by description of the maternal treatment dosage. 
 
5.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
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. 
 
5.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
▪ 
Children born with congenital and/or chromosomal abnormalities. 
▪ 
Children that passed away before inclusion. 
 
5.4 Sample size calculation  
Of note, performing sample size calculations in the context of this rare disease is difficult 
since literature is scarce and heterogeneous.  
 

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We performed two different sample size calculations for the two cohorts. 
Cohort 1: Using the literature to date we estimated that the IQ score of FNAIT survivors 
without antenatal treatment is lower, that is 92 versus average (100) in the normal 
population. To show a difference in IQ score between FNAIT survivors without IVIg treatment 
compared to a fixed average of 100, we performed a sample size calculation for a one-
sample t-test. We calculated that a minimum group size of 39 was needed to show a mean 
difference of 7 IQ points with a power of 0.8 and a significance of 0.05. We assume a 
standard deviation (SD) of 15 for the IQ score. 
 
Cohort 2: In the FNAIT survivors with antenatal treatment we expect no difference in IQ 
score between cases and the national average. To show that there is no difference IQ score 
in anticipated IVIg treatment compared to the Dutch average we perform a non-inferiority 
calculation by a one-sample t-test. In this case we need a sample size of 39 children with a 
non-inferiority margin of 7 IQ points, with a power of 0.8 and a significance level of 0.025. We 
assume a standard deviation (SD) of 15 for the IQ score. 
 
 

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6. TREATMENT OF SUBJECTS 
 
Not applicable. 
 
7. INVESTIGATIONAL PRODUCT  
 
Not applicable. 
 
8. NON-INVESTIGATIONAL PRODUCT 
 
Not applicable. 

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9. METHODS 
9.1 Study parameters/endpoints 
9.1.1 Main study parameter/endpoint 
To determine the cognitive and motor development score in children diagnosed with 
FNAIT without and with antenatal treatment. This will be evaluated using formal 
neurologic examination [15] and Bayley scales of Infant and Toddler Development 
third edition (Bayley III) at 2-3 years,[16] Wechsler Preschool and Primary Scale of 
Intelligence third edition (WPPSI III) at 4 to 6 years,[17] and Wechsler Intelligence 
Scale for Children fifth edition (WISC V) at 7 to 16 years [18]. 
9.1.2 Secondary study parameters/endpoints 
NDI is a composite outcome of: 
▪ 
Cerebral palsy ≥ grade II according to Gross Motor Classification System 
(GMFCS) [19] 
▪ 
Impaired cognitive, language and/or motor development (test scores <70) 
▪ 
Bilateral blindness and/or bilateral deafness 
▪ 
Bilateral deafness requiring amplification 
 
The Health Related Quality of life will be assessed with PedsQL and behavioral 
problem score will be assessed using the Child Behavior Checklist [20, 21].  
 
Academic performance will be evaluated by obtaining test scores from the Dutch 
Pupil monitoring system. [14] The latest test scores from primary school will be 
requested. If children are in high school grades from grade 6 in primary school will 
be used in our evaluation to obtain uniform test scores. Three academic domains 
will be assessed; arithmetic and spelling performance and measurements on 
reading comprehension. Of these three domains the following scores will be 
obtained from the monitoring system; the raw test scores, standardized test scores 
and the level of the child.  
 
To assess long-term effects of maternal IVIg treatment on the immune system of the 
child we will assess two outcome parameters: 
▪ 
The prevalence of allergies, asthma and eczema will be evaluated by a 
questionnaire composed in collaboration with an allergist. The severity and 
control of the allergic rhinitis will be assessed by the CARATkids 
questionnaire [22]. 

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▪ 
The prevalence of children with an abnormal incidence or frequency of 
infections will be assessed by a questionnaire based on the guideline; 
‘Richtlijn diagnostiek naar onderliggende aandoeningen bij kinderen met 
recidiverende luchtweginfecties’ [23] and the 10 warning signs of PI of the 
Jeffrey Model Foundation. [24] 
9.1.3 Other study parameters 
An inventory will be made of the following confounders gender, obstetrical and 
neonatological complications and education level of the parents according to the 
International Classification of Education. [25] We will assess the family history of 
allergies asthma and eczema to obtain information about possible confounding 
factors in our study groups. Also smoking and day-care visit will be questioned. 
 
 

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Study assessments 
 
Age group 
Name assessment tool 
Abbreviati
on 
Outcome 
Cognitive development 
2-3 years 
Bayley scales of infant and 
toddler development third 
edition. 
Bayley III 
IQ score 
 
4-6 years 
Wechsler Preschool and 
Primary Scale of Intelligence 
third edition. 
WPPSI III 
IQ score 
 
7-16 years 
Wechsler Intelligence Scale for 
Children fifth edition 
WISC V 
IQ score 
 
Motor development 
2-3 years 
Bayley scales of infant and 
toddler development third 
edition 
Bayley III 
Motor test score 
 
2-18 years 
Neurologic Examination 
According to Touwen.  
Touwen 
Gross Motor Function 
Classification System 
Quality of life 
5-7 years 
Pediatric Quality of Life 
Inventory 
PedsQoL 
Health related quality 
of life score 
 
8-12 years 
Pediatric Quality of Life 
Inventory 
PedsQoL 
Health related quality 
of life score 
 
Behaviour 
1.5-5 years 
Child Behavior Checklist 
CBCL 
Behaviour test score 
6-18 years 
Child Behavior Checklist 
CBCL 
Behaviour test score 
Course of infections 
2-18 years 
Questionnaire based on ‘Richtlijn diagnostiek 
naar onderliggende aandoeningen bij 
kinderen met recidiverende luchtweginfecties’ 
Indication for 
diagnostic evaluation 
by immunologist; 
Yes/No. 
 
 
 
Table 2: Overview assessments 

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Study assessments 
 
Age group 
Name assessment tool 
Abbreviation 
Outcome 
Atopic constitution 
2-18 years 
Questionnaire composited in collaboration with 
allergist (Dr. H. de Groot). 
(Parent reported) 
Allergy 
Anaphylaxis 
Asthma 
Eczema  
Severity of asthma and hay fever 
6-18 years 
Control of allergic rhinitis and 
asthma test. 
CARATkids 
CARATkids score 
 
 
Table 2: Overview assessments 

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Definitions of outcome                                                                                       (1/3) 
Outcome parameter 
Definition 
Obstetric medical data 
Pregnancy induced 
hypertension 
De novo hypertension (blood pressure above 140/90 mmHg) 
after gestational week 20.[26] 
Pre-eclampsia 
De novo hypertension after gestational week 20 and new 
onset of one of the following; proteinuria (>300 mg/day), renal 
insufficiency, liver disease, neurological problems, 
hematological disturbances or fetal growth restriction. [26] 
Signs of bleeding in the 
fetus at ultrasound 
For instance intraventricular hemorrhages or ventricular 
dilatation. 
Antentatal IVIg-treatment 
Administration during pregnancy from 28 weeks gestational 
age or 16-18 weeks gestational age in high risk pregnancies 
according to the protocol of the LUMC.[27] 
Intra-uterine transfusions 
Any platelet transfusions of the fetus during pregnancy. 
Treatment with 
corticosteroids 
Maternal treatment with corticosteroids to prevent burden or 
worsening of alloantigen production. 
Mode parturition 
Type of parturition (e.g. caesarean section and instrumental 
delivery). 
Gestational age at birth 
Gestational age: completed weeks and additional days since 
the first day of the last menstruation period of the mother. 
Placenta weight 
Weight of placenta after birth in grams. 
Neonatal data (part 1) 
Respiratory distress 
syndrome 
Requiring mechanical ventilation and/or surfactant. 
Perinatal asphyxia 
One of the following criteria; Apgar score < 7 and/or umbilical 
cord pH ≤ 7.0. 
Proven early onset 
neonatal sepsis 
Positive blood culture within 72 hours postpartum and clinical 
suspicion of a neonatal sepsis.  
Retinopathy of 
prematurity 
Staging according to ICROP [28] 
Neonatal morbidity 
Scored positive if one of the following conditions were 
present: Respiratory distress syndrome, Perinatal asphyxia, 
Proven early onset neonatal sepsis, NEC, Retinopathy of 
prematurity. 
Table 3: Definitions of outcome 

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Definitions of outcome                                                                                       (2/3) 
Outcome parameter 
Definition 
Neonatal data (part 2) 
Necrotizing enterocolitis 
Stage 2 or higher [29] 
Intracranial hemorrhage 
Any cranial hemorrhage 
Intraventricular 
hemorrhage 
Grading according to Volpe [30] 
Cystic periventricular 
leukomalacia 
Grade 2 or higher [31] 
Ventricular dilatation 
Above 97th percentile [32] 
Porencephalic or 
parenchymal cysts 
Presence of porencephalic or parenchymal cysts. 
Porencephalic cyst: focal area of encephalomalacia that 
communicates with the ventricular system and/or the 
subarachnoid space. 
Parenchymal cyst: smooth rounded borders and minimal-to-
no surrounding signal intensity abnormality. 
Convulsions 
Any paroxysmal, repetitive or stereotypical events interpreted 
as neonatal convulsions by a pediatrician. 
Signs of bleeding 
 
Intracerebral bleeding 
Any bleeding in the cerebral cavity.  
Organ bleeding  
Bleeding in any organ located in the thorax or abdomen.  
Postpone bleeding 
Postpone bleeding that was noted as sign of bleeding by the 
caretaker. 
Skin manifestations 
Petechiae, purpura or hematoma diagnosed by the caretaker 
at neonatal period (gynecologist, pediatrician or midwife).  
Neonatal IVIG treatment 
Any administration of IVIG after birth. 
Platelet transfusion 
Any platelet transfusion. 
Neurodevelopmental impairment 
Cerebral Palsy 
Spastic bilateral, spastic unilateral or mixed Classification by 
European CP Network [19]. 
Impaired cognitive or 
motor development 
Score < 70 (2 SD below the mean) as assessed by Bayley 
Scales of Infant and Toddler Development version 3 (BSID III) 
[16] 
Bilateral blindness 
Blind or partially sighted. 
Bilateral deafness 
Needing hearing aids. 
 
 
 

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Definitions of outcome                                                                                      (3/3) 
Outcome parameter             Definition 
Secondary outcomes 
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. [23] 
Prevalence of allergies 
Parent reported allergy.  
Patient reported 
anaphylaxis 
Serious allergic reaction, requiring urgent medical treatment 
with epinephrine.  
Poor control of allergic 
rhinitis 
CARAT score of upper airways < 8.[22, 33] 
Poor control of asthma 
CARAT score of lower airways < 16.[22, 33] 
Prevalence of eczema 
Parent reported eczema. 
 
Demographic characteristics 
Ethnic origin of the 
parents 
Ethnic origin of mother and father. 
Educational level of the 
parents 
Highest level of graduation of the parents. 
Smoking 
Any person living in the household of the child smoking one or 
more cigarettes a day. 
Day-care visit 
When child is in day care at least one day a week. 
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. 
 
9.2 Randomisation, blinding and treatment allocation 
Not applicable. 
 
9.3 Study procedures 
After informed consent is obtained, assessment will be planned at the outpatient clinic of 
the LUMC. Questionnaires considering HRQoL, behaviour, allergies or infections will be 
send  home with the request to fill in the forms and bring them at the planned visit. We will 

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provide parents with a letter to request the most recent academic test scores from the 
teacher. 
 
When parents visit the outpatient clinic with their children, the assessment will take place.  
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. To 
gather important patient data from the pregnancy and neonatal period parents will be 
asked permission to obtain the medical letters from referral hospital of the child. Secondly 
mothers will be asked for informed consent to obtain the medical letter from the 
gynaecologist. 
 
After assessment a report will be made from the observations during psychological 
testing. 
 
 
 
9.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
urgent medical reasons during the assessment. 
Figure 2: Study procedures 

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9.4.1 
Specific criteria for withdrawal  
Not applicable 
9.4.2 
Replacement of individual subjects after withdrawal 
Not applicable 
9.4.3 
Follow-up of subjects withdrawn from treatment 
Not applicable 
9.5 Premature termination of the study 
In case of premature termination of the study the project leader will notify the accredited  
METC within 15 days, including the reasons for the premature termination.  
 
 

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10. SAFETY REPORTING 
 
10.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
10.2 AEs, SAEs and SUSARs 
10.2.1 
Adverse events (AEs) 
The risk on adverse events in this study negligible, therefore AEs will not be reported. 
If parents notify psychological burden of the assessments and notify this burden to 
the researchers in writing, this will be recorded and reported to the METC.   
10.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the METC without undue delay after obtaining 
knowledge of the events. 
 
The investigator will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 

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period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
10.3 Follow-up of adverse events 
 The risk of AE in this study is negligible, therefore follow-up of AEs is not applicable. 
Unexpected findings or study results that might be of importance for the development or 
health of our subjects will be reported to the general physician. 
 
10.4 Data Safety Monitoring Board (DSMB) 
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11. STATISTICAL ANALYSIS 
Continuous parametric data will be presented with mean ± standard deviation (SD) or 
median with interquartile range (IQR) as appropriate. Categorical data will be presented as 
counts and percentages within each study group.  
 
The cognitive test score of both cohorts will be compared with the Dutch average by using a 
lineair regression model. The following potential confounders for cognitive development (IQ 
score) identified in earlier research will be used in the analysis; 
▪ 
Sex 
▪ 
Gestational age at birth 
▪ 
Small for gestational age 
▪ 
Neonatal morbidity 
▪ 
Level of education of the parents 
 
In second cohort; the FNAIT survivors with IVIg treatment atopic constitution and the course 
of infections will be assessed in a secondary analysis. 
 
In the assessment of course of infections the following confounders will be used in the 
analysis by using a lineair regression model; 
▪ 
Day-care visit 
▪ 
Smoking in a household  
▪ 
Time of the year that the questionnaire was filled in 
 
In the analysis of allergies and asthma the following confounders will be used in the analysis 
by using a lineair regression model; 
▪ 
Presence of a first degree family member with asthma eczema or allergy 
▪ 
Smoking in a household 
 
All data is analysed with IBM SPSS Statistics version 24 (IBM Software, NY, USA, 2016). 
 

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12. ETHICAL CONSIDERATIONS 
12.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki 
(64th WMA General Assembly, Fortaleza, Brazil, October 2013; version 2013; 
www.wma.net) and in accordance with the Medical Research Involving Human Subjects 
Act (WMO). 
12.2 Recruitment and consent 
The investigator will identify potential subjects according to the aforementioned criteria. 
Eligible patients are informed about the study and are asked for their participation. 
Enrolment in will take place in two ways;  
- 
First directly via the LUMC, the LUMC is national referral center for intrauterine 
therapy. Parents of children that survived FNAIT will be invited to participate by sending a 
patient information letter and information leaflet for children. In this way, the parents will 
be informed that they will be contacted by phone approximately two weeks after sending 
the information letter.  
- 
Secondly patients will be asked via Stichting Sanquin Bloedvoorziening, Sanquin is 
the national reference laboratory to diagnose FNAIT. Retrospectively all FNAIT cases are 
collected in the Laboratory of platelet and leukocyte serology of Sanquin. Referring 
specialists (mostly pediatricians) will be asked to obtain permission from the parents to 
inform them about our study by letter enclosed by the patient information leaflet. If 
parents do not object to be informed they will be contacted by our research team 
approximately two weeks after sending this letter.  
 
When parents wish not to be approached by our research team they can indicate this by 
responding by e-mail, phone or reply letter. Informed consent is obtained from all patients 
who are willing to participate. In case of minors both parents or their guardian will be 
asked for participation and informed consent. The patient information letter and informed 
consent form will be attached as a separate document. If informed consent is given, 
assessment will be planned. At most, 3 attempts will be made to contact parents by 
phone. It is expected that enrollment for this study will cover a period of one year. 
 
12.3 Objection by minors or incapacitated subjects 
Neuropediatric examination and neurodevelopmental tests are performed by trained 
personnel who are in close contact with the child and parents to detect any resistance. All 
tests have age related items and can be performed in a playful way to avoid stress. 
 

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The investigators will follow the guidelines of the Dutch pediatric society concerning 
resistance or anxiety in minors during investigation procedures and the CCMO code of 
conduct concerning research with minors. 
12.4 Benefits and risks assessment, group relatedness 
Participation in the study does not result in individual benefits. There is no risk associated 
with study participation.  
Our department has extensive experience in conducting neurodevelopmental assessment 
of children. The main part of the neurodevelopmental assessment and the completion of 
questionnaires are part of routine care for preterm children born with a gestational age 
<30 weeks and/or birth weight <1000 grams or <P10, for children treated with fetal 
therapy for children with documented severe neonatal brain injury. The examinations are 
performed according to the guidelines of the Dutch Neonatal follow-up (LNF) Study 
Group. Parents and children will receive a report of the test results and, if necessary, 
advice for further support and interventions.  
12.5 Compensation for injury 
A dispensation for the liability insurance was accredited by the METC Leiden Den Haag 
Delft. 
12.6 Incentives  
Children will receive a small present (to be determined, for example a stuffed animal) 
after the follow-up assessments. Parents receive a parking fee and  
travel allowance. 
 
 
 

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13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
13.1 Handling and storage of data and documents 
Data management will be implemented according to Good Clinical Practice (GCP)-
guidelines. Patient data will be entered by way of an eCRF in a central GCP proof 
internet-based database to facilitate on-site data-entry. Castor was chosen as our data 
management system. Data will be stored at the LUMC network. Security is guaranteed 
with login names, login codes and encrypted data transfer. The researchers will maintain 
the database and check the information in the database for completeness, consistency 
and plausibility with consultancy of the department advanced data management.  
 
The data of all subjects will be coded and this coding will not be retraceable to the 
individual patient. The key to this coding is safeguarded by the investigator. A limited 
number of people have access to the source data. These are the principal investigators, 
investigating personnel. Personal data are only processed by the researchers or by those 
who fall directly under their authority. In addition, the study monitor, quality assurance 
auditor, employees from the Health Care Inspectorate of the Ministry of Health, welfare 
and Sport (Nederlandse Inspectie voor de Gezondheidszorg) have access to the source 
data. All are subject to the pledge of confidentiality. Data will be stored for 15 years 
strictly confidential.  
 
Consent for our study or storage of personal data can be withdrawn at any time during 
our study. Research data that was collected till withdraw of permission will be used in our 
current study. The board of directors of the LUMC is responsible for processing data. The 
data protection officer, functionaris gegevensbescherming, of the LUMC or/and Sanquin 
can be contacted by participants when they have questions about the protection of their 
privacy.  
 
13.2 Monitoring and Quality Assurance  
The study will be monitored by the internal monitoring pool of the LUMC throughout its 
duration by means of personal visits to the investigator’s facilities and through other 
communications (e.g., telephone calls, written correspondence). Monitoring visits will be 
scheduled, conform to the risk classification, once throughout the study and at frequency 
deemed appropriate for the study. For details we refer to the monitoring plan of the study. 
 
This visit will be conducted to evaluate the progress of the study, ensure the rights and 
wellbeing of the subjects are protected, check that the reported clinical study data are 

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accurate, complete and verifiable from source documents, and the conduct of the study is 
in compliance with the approved protocol and amendments, GCP and applicable national 
regulatory requirements. A monitoring visit will include a review of the essential clinical 
study documents (regulatory documents, CRFs, source documents, subject informed 
consent forms, etc.) as well as discussion on the conduct of the study with the 
Investigator and staff. The Investigator and staff should be available during these visits to 
facilitate the review of the clinical study records and resolve/document any discrepancies 
found during the visit. 
 
13.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
13.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
13.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. In case the study is ended prematurely, the sponsor will 
notify the accredited METC within 15 days, including the reasons for the premature 
termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
In case the final study report will not be available within one year, another term should be 
defined including the reasons. 

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13.6 Public disclosure and publication policy 
The final publication of the study results will be written by the study coordinator(s). A draft 
manuscript will be submitted to co-authors for review. After revision the manuscript will be 
sent to a peer reviewed scientific journal. Publication will be conform CCMO publication 
policy. [34] 
 
 

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14. STRUCTURED RISK ANALYSIS  
 
Not applicable. 
 
 
 

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