Citation
Akker, E. van den. (2008, June 19). Fetal thrombocytopenia : preventive strategies.
Retrieved from https://hdl.handle.net/1887/12967
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License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/12967
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Chapter 1
General introduction and
outline of thesis
GENERAL INTRODUCTION
Intracranial haemorrhage (ICH) among term neonates is associated with neo- natal death or lifelong disability1-3. Between all the proposed etiological mecha- nisms, including impairments in coagulation, hypoxic-ischemic injury and birth related trauma, thrombocytopenia seems to be the most important predictor of ICH among term neonates and is also associated with the most severe forms of haemorrhage4,5.
Normal platelet counts in term neonates are in the same range as those of healthy older children and adults (150-450 x 109/L)6. Thrombocytopenia is defined as a platelet count < 150 x 109/L, although many otherwise healthy newborns may have counts between 100 and 150 x 109/L6,7. For severe thrombocytopenia, with a risk for bleeding problems, a cut-off level of 50 x 109/L is commonly used4,8,9.
The incidence of thrombocytopenia (< 150 x 109/L) in all newborns is 1-410-14. However, due to absence of clinical signs, it is often not noted. This means that in the Dutch population every year an estimated 2000-8000 thrombocytopenic neonates are born.
In general, the etiology of thrombocytopenia can be classified into disorders associated with increased destruction, including consumption, or decreased pro- duction of platelets. In the table, the causes of fetal and early neonatal (<72 h old) thrombocytopenia are summarised. Fetal and neonatal alloimmune thrombocy- topenia (FNAIT) is the most common cause of thrombocytopenia, especially in otherwise healthy term newborns.
Most patients at risk for a fetal platelet disorder are identified only after a baby is born with a low platelet count. It is vital to identify the cause of the thrombo- cytopenia as quickly as possible, primarily to be able to start the correct treatment without delay. In addition establishing the cause of any neonatal thrombocytope- nia is essential to institute proper management in the next pregnancy.
The Department of Obstetrics at the Leiden University Medical Centre is the national referral centre for the management of severe alloimmune pregnancy dis- orders. In 1965 the first intrauterine blood transfusion was performed in Leiden for Rhesus D alloimmunisation.
After the publication of Daffos et al. in 1984, fetal blood sampling with intra- uterine platelet transfusion became, at least for several years, the standard treat- ment in FNAIT15. Consequently since then FNAIT cases were, in addition to the severe red cell alloimmunisation cases, also referred to the LUMC. Because of this centralisation with a single centre for a referral base of 16 million people, the
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Leiden centre is one of the largest referral centres for patients with FNAIT in the world. This provides us with the opportunity, and the obligation, to contribute to scientific research to advance our understanding of this rare disease.
The studies described in this thesis were designed to further improve the out- come of pregnancies complicated by fetal thrombocytopenia.
Table: Causes of fetal and early neonatal (<72 h old) thrombocytopenia
FNAIT
Congenital infections (CMV, Syphilis, PARVO, Toxoplasmosis, Rubella, HIV) Maternal autoimmune diseases (ITP, SLE)
Severe fetal haemolytic disease by red cell alloimmunisation Placental insufficiency (pre-eclampsia, IUGR, diabetes) Asphyxia
Perinatal infections (GBS, E. coli, Listeria) Disseminated intravascular coagulation (DIC) Thrombosis (renal vein, aortic)
Congenital syndromes (TAR, Kasabach-Meritt, Amegakaryocytosis, trisomies, triploidy) Metabolic disorders
Hepatomegaly / splenomegaly
OUTLINE OF THIS THESIS
The aim of the studies described in this thesis was to contribute to improve the outcome of pregnancies complicated by fetal thrombocytopenia, caused by allo- immune thrombocytopenia, red cell alloimmunisation (Rhesus D and Kell) and Parvovirus B19 infection.
In Chapter 2, an extensive review of the literature is given on fetal and neonatal alloimmune thrombocytopenia (FNAIT), which is the most common cause of thrombocytopenia in term neonates.
In Chapter 3, we describe the outcome of pregnancies with FNAIT treated in our centre, in relation to the invasiveness of the management protocol.
In Chapter 4, we report our less invasive treatment strategy in FNAIT in cases at
high risk for intracranial haemorrhage (ICH). After balancing the risk for seri- ous complications from cordocentesis for fetal blood sampling on one hand and ICH on the other, we designed a protocol to further reduce invasive procedures in these patients.
In Chapter 5, we report our experience with the safety of vaginal delivery in FNAIT pregnancies without ICH in a previous child.
In Chapter 6, the results from the NOICH study are reported. In this randomised trial the hypothesis was tested that intravenous immunoglobulin (IVIG) in a low dose of 0.5 g/kg/wk was at least as effective as the standard dose of 1.0 g/kg/wk in preventing ICH and severe fetal thrombocytopenia in pregnancies at risk for FNAIT.
The calculated sample size was 2 arms of 106 patients. After almost three years of recruitment, a total of only 23 pregnancies had been randomised, which led to the decision by the steering committee to prematurely end the recruitment.
In Chapter 7 we evaluated the clinical significance of fetal thrombocytopenia in RhesusD alloimmunised pregnancies.
In Chapter 8 we report that in contrast to hydropic fetuses with Rhesus D haemo- lytic disease, we found that fetuses with severe anaemia due to Kell alloimmunisa- tion are generally not at risk for substantial thrombocytopenia.
In Chapter 9 we evaluated the significance of thrombocytopenia in hydropic anaemic fetuses with congenital Parvovirus B19 infection.
In Chapter 10, a discussion of the overall results is presented. In a flowchart, the Leiden management protocol of FNAIT is given. Finally, future perspectives and proposals for future research are given.
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