Towards Routine HPA-screening In Pregnancy to Prevent FNAIT (HIP)

Towards Routine HPA-screening in Pregnancy to Prevent FNAIT: Assessing Disease Burden and Optimising Risk Group Selection

Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is the most common cause of severe thrombocytopenia in otherwise healthy born neonates. FNAIT results in a risk of bleeding the most severe complication being intracranial haemorraghes (ICH). Bleedings can be prevented by effective antental treatment. In the absence of screening programs this treatment is too late to prevent the first affected child. The investigators aim to identify the pregnancies at risk and describe the incidence and natural course of this disease. In this way fetuses at risk can be identified in the future and timely antenatal treatment can be initiated.

Study Overview

• Status: Completed
• Conditions: Fetal and Neonatal Alloimmune Thrombocytopenia
• Intervention / Treatment: Other: Clinical data collection.

Detailed Description

Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is the most common cause of severe thrombocytopenia in neonates. It is an immunological process, in which Human Platelet Antigen (HPA) alloantibodies produced by the mother can cross the placenta and target fetal platelets. The most frequent alloantigen to elicit platelet-reactive antibody responses is HPA-1a. The resulting low platelet count in the fetus or neonate correlates with an increased risk of bleeding complications and severe adverse outcome, defined as perinatal death or intracranial haemorrhage (ICH). This can lead to life-long handicaps, cerebral palsy, cortical blindness and mental retardation. One in 50 pregnancies is at risk for FNAIT, since 2,1% of the Caucasian population is HPA-1a negative. Alloantibodies are calculated to be present in 1:400 pregnancies, leading to FNAIT-related severe adverse outcome in at least 1:1300 fetuses or neonates, and this is likely an underestimation. There is a highly effective antenatal treatment available for preventing these severe adverse outcomes, consisting of weekly injection of intravenous immunoglobulins (IvIG). Unfortunately, in the current practice, this treatment can only be applied in subsequent pregnancies with known alloimmunization, after a symptomatic sibling leading to diagnosis of the disease. In potential future antenatal screening for HPA-alloantibodies, all pregnancies at risk can be identified in time, to start antenatal treatment and reduce severe adverse outcomes. However, before such a program can be realised, detailed information about incidence and natural course of the disease is needed. Furthermore, laboratory tests to identify fetuses at high risk to prevent overtreatment are needed, since approximately 10-30% of the HPA alloimmunized cases result in severe thrombocytopenia and clinically relevant disease.

Objectives:

1. The main objective of this study is to assess the incidence and severity of FNAIT and bleeding complications (including ICH) among neonates.
2. To develop a screening platform, including diagnostic assay(s) to identify fetuses at high risk for bleeding complications due to FNAIT.

Study design: Prospective observational cohort

Study population: Pregnant women

Main study parameters/endpoints: The main study parameters are HPA-1a alloantibodies, clinically relevant FNAIT. Secondary parameters include: neonatal outcome (bleeding signs other than ICH, treatment for thrombocytopenia, morbidity).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: These pregnant women participate in the national antenatal screening programme for Prevention and Screening of Infectious diseases and Erythrocyte Immunisation (PSIE) and have a routine blood sampling at 27th week of gestation. This blood sample will be used this to perform all necessary tests, so no additional (medical) procedures will be performed. Additionally, after delivery clinical data concerning the pregnancy, delivery and the health of the child in the first postnatal period are collected by questioning the obstetric health care provider.

• Study Type: Observational
• Enrollment (Actual): 3660

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Stichting Bloedbank Sanquin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pregnant women.

Description

Inclusion Criteria:

• All pregnant women, of whom routine blood samples are taken at 27 weeks gestational age (GA).

Exclusion Criteria:

• There are no predefined exclusion criteria, since we are aiming to determine the incidence in the complete pregnant population in the Netherlands.

[ WILSONBEKWAAM EXCLUSIE]

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pregnant women, HPA-1a positive; RhD or Rhc negative women, identified through prenatal screening for red cell alloimmunization, that are typed as HPA-1a positive.	Other: Clinical data collection.; The following clinical data will be collected; maternal baseline characteristics, delivery related data, neonatal outcome, neonatal bleeding signs.
Pregnant women, HPA-1a negative with HPA-1a alloantibodies; RhD or Rhc negative women, identified through prenatal screening for red cell alloimmunization, that are typed as HPA-1a negative and have formed anti-HPA-1a alloantibodies.	Other: Clinical data collection.; The following clinical data will be collected; maternal baseline characteristics, delivery related data, neonatal outcome, neonatal bleeding signs.
Pregnant women, HPA-1a negative without HPA-1a alloantibodies; RhD or Rhc negative women, identified through prenatal screening for red cell alloimmunization, that are typed as HPA-1a negative and did not have formed anti-HPA-1a alloantibodies.	Other: Clinical data collection.; The following clinical data will be collected; maternal baseline characteristics, delivery related data, neonatal outcome, neonatal bleeding signs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical relevant FNAIT	Incidence of HPA-1a mediated FNAIT. defined as severe or mild FNAIT Severe: Intracranial haemorrhage or Internal organ haemorrhage Mild: petechiae, hematoma, purpura or mucosal bleeding.Thrombocytopenia for platelet transfusion, IVIg or clinical observation.	Within 7 days after birth.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neonatal thrombocytopenia	Thrombocytopenia: platelet count <150 x10^9/L Moderate thrombocytopenia: platelet count <100 x10^9/L Severe thrombocytopenia: platelet count <50 x10^9/L Extremely severe thrombocytopenia: platelet count <20 x10^9/L	Within 7 days after birth.
Neonatal infection	CRP >10 and positive blood culture, for which antibiotics are administerd	Within 7 days after birth.
Chromosomal abnormality	Chromosomal abnormalities as measured by DNA assessment (karyotyping, array, WGS/WES)	Within 7 days after birth.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal age	Maternal age in years	Measured at 27 weeks gestational age of current pregnancy.
Number of participatnts with idiopathic thrombocytopenic purpura	Idiopathic thrombocytopenic purpura defined as thrombocytopenia in presence of autoantibodies.	At inclusion
Spontaneous miscarriage in obstetric history	Number of previous spontaneous miscarriage before 12 weeks' gestation	At inclusion
Intrauterine fetal demise in obstetric history	Number of previous IUFD after 12 weeks' gestation	At inclusion
Number of participants with hypertensive disorder	Pre-eclamspsia or pregnancy induced hypertension	3 months after delivery
Prematurity	Gestational age at delivery below 37 weeks (premature) Or below 34 weeks gestation (very premature)	through study completion, until delivery, an average of 6 months
Apgar Score at 5 minutes after birth	Measured as Apgar Score below 7 at 5 minutes after birth	5 minutes after birth
Small for gestational age	Birth weight (in grams) below the 10th percentile for the corresponding estational age at delivery	through study completion, until delivery, an average of 6 months

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Sanquin Research & Blood Bank Divisions; Landsteiner Foundation for Blood Transfusion
• Investigators: Study Director: Dick Oepkes, Prof MD PhD, Department of Obstetrics, Leiden University Medical Centre, Leiden; Study Director: Masja de Haas, Prof MD PhD, Department of Immunohematology Diagnostics, Sanquin Diagnostics, Amsterdam; Study Director: Ellen vd Schoot, Prof MD PhD, Department of Experimental Immunohematology, Sanquin Reseach, Amsterdam

Publications and helpful links

General Publications

• Winkelhorst D, de Vos TW, Kamphuis MM, Porcelijn L, Lopriore E, Oepkes D, van der Schoot CE, de Haas M. HIP (HPA-screening in pregnancy) study: protocol of a nationwide, prospective and observational study to assess incidence and natural history of fetal/neonatal alloimmune thrombocytopenia and identifying pregnancies at risk. BMJ Open. 2020 Jul 20;10(7):e034071. doi: 10.1136/bmjopen-2019-034071.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): April 1, 2020
• Study Completion (Actual): April 1, 2020

Study Registration Dates

• First Submitted: July 16, 2019
• First Submitted That Met QC Criteria: August 22, 2019
• First Posted (Actual): August 26, 2019

Study Record Updates

• Last Update Posted (Actual): September 2, 2020
• Last Update Submitted That Met QC Criteria: September 1, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Infant, Newborn, Diseases; Blood Platelet Disorders; Thrombocytopenia; Thrombocytopenia, Neonatal Alloimmune
• Other Study ID Numbers: P16.002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No information will be given about individual participant data to the participating pregnant women, nor the obstetric caregiver will be informed about the serological HPA-1a typing results. Also, we decided to perform the antibody detection test after birth. Thus no additional information can be known that would otherwise change the management of the current pregnancy, according to the Dutch Guidelines.

Study Data/Documents

1. Information website
   Information comments: Information for participating caregivers, participants or other interested parties.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No