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Clinical Trial Details — Status: Enrolling by invitation

Administrative data

NCT number NCT04529382
Other study ID # P19.069
Secondary ID
Status Enrolling by invitation
Phase
First received
Last updated
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
Health authority
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.

Study Design


Related Conditions & MeSH terms


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, 

References & Publications (28)

Bayley, N., Bayley scales of infant and toddler development-Third edition. 2006: San Antonio, TX: Pearson Education, Inc.

Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy. 2001;20(1):IX-XIV. Review. — View Citation

Bussel JB, Berkowitz RL, Lynch L, Lesser ML, Paidas MJ, Huang CL, McFarland JG. Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition of low-dose steroid to intravenous gamma-globulin. Am J Obstet Gynecol. 1996 May;174(5):1414-23. — View Citation

Dreyfus M, Kaplan C, Verdy E, Schlegel N, Durand-Zaleski I, Tchernia G. Frequency of immune thrombocytopenia in newborns: a prospective study. Immune Thrombocytopenia Working Group. Blood. 1997 Jun 15;89(12):4402-6. — View Citation

Driessen, G.J., Richtlijn diagnostiek naar onderliggende aandoeningen bij kinderen met recidiverende luchtweginfecties. 2016.

Emons JA, Flokstra BM, de Jong C, van der Molen T, Brand HK, Arends NJ, Amaral R, Fonseca JA, Gerth van Wijk R. Use of the Control of Allergic Rhinitis and Asthma Test (CARATkids) in children and adolescents: Validation in Dutch. Pediatr Allergy Immunol. 2017 Mar;28(2):185-190. doi: 10.1111/pai.12678. Epub 2016 Dec 23. — View Citation

Fonseca JA, Nogueira-Silva L, Morais-Almeida M, Azevedo L, Sa-Sousa A, Branco-Ferreira M, Fernandes L, Bousquet J. Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma. Allergy. 2010 Aug;65(8):1042-8. doi: 10.1111/j.1398-9995.2009.02310.x. Epub 2010 Feb 1. — View Citation

Foundation, J.M. 10 Warning signs of primary immunodeficiency. 2016 [cited 2019 31-05].

Gilijns P, V.L., Het CITO leerlingvolgsysteem: Met het oog op de praktijk [The CITO pupil monitoring system: focus on practice]. Pedagogische Studiën 1992. 86:291-6.

Janssen J, V.N., Engelen R, et al., Wetenschappelijke verantwoording van de toetsen LOVS rekenen-wiskunde voor groep 3 tot en met 8. [Scientific justification of the mathematics test for grade 1 until grade 6]. 2010, Cito: Arnhem.

Mols A, K.F., Wetenschappelijke verantwoording van de toetsen Spelling nietwerkwoorden voor groep 7 en 8. [Scientific justification of the spelling test for grade 5 and 6]. . 2010, Cito: Arnhem.

Radder CM, de Haan MJ, Brand A, Stoelhorst GM, Veen S, Kanhai HH. Follow up of children after antenatal treatment for alloimmune thrombocytopenia. Early Hum Dev. 2004 Oct;80(1):65-76. — View Citation

Tiller H, Kamphuis MM, Flodmark O, Papadogiannakis N, David AL, Sainio S, Koskinen S, Javela K, Wikman AT, Kekomaki R, Kanhai HH, Oepkes D, Husebekk A, Westgren M. Fetal intracranial haemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry. BMJ Open. 2013 Mar 22;3(3). pii: e002490. doi: 10.1136/bmjopen-2012-002490. — View Citation

Touwen BC, Hempel MS, Westra LC. The development of crawling between 18 months and four years. Dev Med Child Neurol. 1992 May;34(5):410-6. — View Citation

UNESCO, Institute for Statistics. International standard classification of education: ISCED 2011. 2012, UNESCO Institute for Statistics, : Montreal.

van Gils JM, Stutterheim J, van Duijn TJ, Zwaginga JJ, Porcelijn L, de Haas M, Hordijk PL. HPA-1a alloantibodies reduce endothelial cell spreading and monolayer integrity. Mol Immunol. 2009 Jan;46(3):406-15. doi: 10.1016/j.molimm.2008.10.015. Epub 2008 Nov 26. — View Citation

Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 2001 Aug;39(8):800-12. — View Citation

Verhulst, F.C., J. van der Ende, and H.M. Koot,, Child Behavior Checklist (CBCL)/4-18 manual. 1996: Rotterdam: Afdeling Kinder- en Jeugdpsychiatrie, Sophia Kinderziekenhuis/Academisch Ziekenhuis Rotterdam/ Erasmus Universiteit Rotterdam.

Volpe JJ. Intraventricular hemorrhage and brain injury in the premature infant. Diagnosis, prognosis, and prevention. Clin Perinatol. 1989 Jun;16(2):387-411. Review. — View Citation

Ward MJ, Pauliny J, Lipper EG, Bussel JB. Long-term effects of fetal and neonatal alloimmune thrombocytopenia and its antenatal treatment on the medical and developmental outcomes of affected children. Am J Perinatol. 2006 Nov;23(8):487-92. Epub 2006 Nov 8. — View Citation

Wechsler, D., Wechsler Intelligence Scale for Children (5th ed.). 2014a, San Antonio, TX: NCS Pearson

Wechsler, D., Wechsler Preschool and Primary Scale of Intelligence - Third Edition (WPPSI-III-NL). 2002: TX, The Psychological Corporation.

Weekers A, G.I., Kleintjes F, et al., Wetenschappelijke verantwoording papieren toetsen Begrijpend lezen voor groep 7 en 8. [Scientific justification of the reading comprehension test for grade 5 and 6]. 2011, Cito: Arnhem.

Williamson LM, Hackett G, Rennie J, Palmer CR, Maciver C, Hadfield R, Hughes D, Jobson S, Ouwehand WH. The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as determined by antenatal screening. Blood. 1998 Oct 1;92(7):2280-7. — View Citation

Winkelhorst D, Kamphuis MM, Steggerda SJ, Rijken M, Oepkes D, Lopriore E, van Klink JMM. Perinatal Outcome and Long-Term Neurodevelopment after Intracranial Haemorrhage due to Fetal and Neonatal Alloimmune Thrombocytopenia. Fetal Diagn Ther. 2019;45(3):184-191. doi: 10.1159/000488280. Epub 2018 May 4. — View Citation

Winkelhorst D, Murphy MF, Greinacher A, Shehata N, Bakchoul T, Massey E, Baker J, Lieberman L, Tanael S, Hume H, Arnold DM, Baidya S, Bertrand G, Bussel J, Kjaer M, Kaplan C, Kjeldsen-Kragh J, Oepkes D, Ryan G. Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review. Blood. 2017 Mar 16;129(11):1538-1547. doi: 10.1182/blood-2016-10-739656. Epub 2017 Jan 27. Review. — View Citation

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017 Aug;10(8):729-737. doi: 10.1080/17474086.2017.1346471. Epub 2017 Jun 29. Review. — View Citation

Yougbaré I, Lang S, Yang H, Chen P, Zhao X, Tai WS, Zdravic D, Vadasz B, Li C, Piran S, Marshall A, Zhu G, Tiller H, Killie MK, Boyd S, Leong-Poi H, Wen XY, Skogen B, Adamson SL, Freedman J, Ni H. Maternal anti-platelet ß3 integrins impair angiogenesis and cause intracranial hemorrhage. J Clin Invest. 2015 Apr;125(4):1545-56. doi: 10.1172/JCI77820. Epub 2015 Mar 16. — View Citation

* Note: There are 28 references in allClick 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.
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