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correspondence: Low prevalence of coagulation F2 and F5 polymorphisms in mothers and children in a large cohort of patients with neonatal arterial ischemic stroke

2010; Wiley; Volume: 150; Issue: 6 Linguagem: Inglês

10.1111/j.1365-2141.2010.08259.x

1365-2141

Cyrille Renaud, Brigitte Tardy, Émilie Presles, Stéphane Chabrier, Sylvie Nguyen The Tich,

Cardiovascular Issues in Pregnancy

With an annual incidence of 1/2300 to 1/5000 births, perinatal arterial ischemic stroke is the most common form of ischemic stroke in childhood. Moreover, it is the most frequently identified cause of congenital hemiplegia, the most prevalent type of cerebral palsy in term-born children. Yet the causes and mechanisms of this debilitating disorder are still poorly understood. One of the main hypotheses focuses on the role of the placenta. Most of the established risk factors for this disorder are indeed either key determinants or biomarkers of vasculo-placental pathology: thrombophilia, pre-eclampsia, chorio-amnionitis, intra-uterine growth retardation, twin pregnancy, gestational diabetes. Hypercoagulability, whether present in the mother or in the fetus, is furthermore a recognized cause of abnormal vascular development, vessel occlusion and placental infarctions, which may affect the materno-fetal circulation. Such placental injuries have also been described in cases of neonatal stroke. In addition, due to the nature of the fetal circulation, a clot forming in the placenta and subsequently migrating will preferentially embolize to the cerebral vasculature through the foramen ovale. A meta-analysis of published observational studies (in which F2 and F5 polymorphisms were the factors studied in most detail) showed that thrombophilia is a determinant of ischemic stroke in childhood (Kenet et al, 2010). Nevertheless, newborns are underrepresented in comparison with older children in the literature – and consequently in this meta-analysis – and the results obtained in individual studies specifically investigating perinatal stroke are conflicting (Table I). These discrepancies most likely reflect both genetic diversity between the populations and differences between the groups studied. The role of maternal genetic risk factors has received less attention. However, two recent studies, including 60 infants and 51 mothers (Curry et al, 2007) and 47 infants and 22 mothers (Simchen et al, 2009) reported a slightly higher prevalence of thrombophilia in mothers than in children. This study is part of an ongoing project, the AVCnn (accident vasculaire cérébral du nouveau-né) study, designed to generate a large database on the risk factors and outcome of neonatal stroke. This prospective, multicentre cohort study was approved by the Ethics Committee of the Centre Hospitalier Universitaire de Saint-Etienne and parental consent was obtained for all children. Briefly, 100 term newborns with symptomatic arterial ischemic stroke (i.e. neonatal stroke according to the most recent definitions) were consecutively recruited between 2003 and 2006 in 39 centres throughout France. Out of the entire cohort, two babies died during the neonatal period and, to date, four families have been lost to follow-up. The remaining children are regularly followed up according to a pre-defined standardized programme of clinical and laboratory investigations. Thrombophilia was assessed in the mother/child pair at the 12-month follow-up appointment. The tests included DNA analyses for the two most common coagulation factor gene polymorphisms leading to a hypercoagulable state: the F5 R5006Q (factor V Leiden) and the F2 G20210A mutation. According to local practice, some laboratories first evaluated resistance to activated protein C (APC), a coagulation screening test for F5 R5006Q. The data were compared to those determined in cases and controls on other studies addressing perinatal arterial ischemic stroke and including at least 15 children (Hagstrom et al, 1998; Golomb et al, 2001; Mercuri et al, 2001; Kurnik et al 2003; Miller et al, 2006; Curry et al, 2007; Herak et al, 2009; Simchen et al, 2009), and to the meta-analysis (Kenet et al, 2010). Data on F5 R506Q/APC resistance were available for 86 children and 76 mothers, and data on F2 G20210A mutation for 80 children and 67 mothers. In all patients manifesting APC resistance, the presence of F5 R5006Q was confirmed by genomic analysis. The results are summarized in Table I. A slightly higher rate of both gene polymorphisms was found in mothers (3·5%) than in children (2·4%). However, the principal finding was that these rates were similar to those determined in the most recently published study on a French population with no history of thrombosis (3·84% and 3·07% for F5 R5006Q and F2 G20210A mutation respectively: Mazoyer et al, 2009) and those reported in healthy children in other European and Mediterranean countries (Fig 1). Prevalence of coagulation F5 and F2 polymorphisms in healthy children (first and second number, respectively) in European and Mediterranean countries. Data from studies investigating thrombophilia in children with ischemic stroke that included a control group. Numbers of controls for F5 and F2 are 152/98 respectively for Austria, 112/112 for Croatia, 985/885 for Germany, 230/230 for Israel, 115/113 for Portugal, 294/193 for Turkey and 301/224 for United Kingdom (Herak et al, 2009; Kenet et al, 2010). Our results therefore did not replicate those previously reported. This may be explained by insufficient power, as the confidence intervals were relatively large. Moreover, the lack of a control group precluded statistical confirmation of the results. The AVCnn study is nevertheless the largest to date investigating thrombophilic factors in mother–child pairs. More highly powered data can thus only be obtained from meta-analyses, intrinsically subject to other types of biases and confounding factors than those affecting individual studies (Kenet et al, 2010). Another limitation is that not all subjects underwent the full set of laboratory tests and that mothers were less frequently analysed than children. However, this also applies to other series evaluating mother/child pairs (Curry et al, 2007; Simchen et al, 2009). Moreover, there were no differences in familial and obstetrical history between the patients who were tested and those who were not. The AVCnn cohort study has several strong points. It is a prospective study with a homogeneous population comprising exclusively symptomatic term neonates, whereas other studies (with the exception of that of Kurnik et al, 2003) included both term and preterm children with symptomatic stroke, as well as those without neonatal clinical symptoms (i.e. with presumed perinatal ischemic stroke). As the pathogenesis of perinatal arterial ischemic stroke may differ in infants with neonatal vs. delayed presentation and in term vs. premature babies, this point is of particular interest. Our results may thus indicate that the influence of prothrombotic disorders is less important in the pathogenesis of neonatal stroke than in presumed perinatal stroke. A study specifically focusing on this latter group of children (Golomb et al, 2001) reported, for example, a family history of thrombosis in 48% of the population vs. only 17% in our population. The mechanism of vascular occlusion in these distinct categories of patients with perinatal stroke is likely to differ and these populations should be assessed separately in future studies. The AVCnn study was funded by the Ministère de la santé et des solidarités, the Centre hospitalier universitaire de Saint-Etienne, the Fondation motrice, the Association des paralysés de France (APF) and the Fondation Garches. We declare that we have no conflict of interest. H Testard (Annemasse), J Nzonzila, K Othmani (Aulnay sous bois), M Boutrolle, JP Laboureau (Auxerre), S Lamoureux-Toth, P Masson (Avignon), H Apéré, P Jouvencel, L Lazarro, S Rivera (Bayonne), L Razafimanantsoa (Beauvais), G Thiriez (Besançon), E Lachassine, C Mignot (Bondy), F Audic-Gérard, S Brochard, V Laparra, J Lefranc, S Peudenier (Brest), T Lecine (Cahors), N Meier (Carcassone), S Gay, R Matta (Chalon sur Saône), V Gajdos (Clamart), B Lecomte (Clermont-Ferrand), M Raqbi, L Tahraoui (Creil), C Barnérias, I Layouni, N Yousef (Créteil), N d’Heilly, M Granier (Evry), P Saunier (Fontainebleau), F Cneude (Grenoble), P Landrieu, V Legrez, M Tardieu (le Kremlin-Bicêtre), V Pierrat (Lille), E Agudze, C Laroche (Limoges), D Ville (Lyon), P Garcia-Méric (Marseille), A Roubertie (Montpellier), M Bru, S Nguyen The Tich, J Perrier (Nantes), MC Routon (Orsay), L Delour, S Mallet (Périgueux), Y Aujard, C Farnoux, I Husson, M Rajguru, C Saizou (Robert Debré, Paris), T Blanc, A Charollais, S Marret (Rouen), JM Retbi, P Bolot (Saint-Denis), S Chabrier (Saint-Etienne), M Mokhtari, F Villega (Saint-Vincent de Paul, Paris), E Cheuret, I Glorieux, N Montjaux, S Lebon, JY le Tallec (Toulouse), Y Lakhdari, E Saliba (Tours), C Mignot, ML Moutard (Trousseau, Paris), N Benbrik, D Soupre (Vannes), A Cailho, C Coudy (Versailles), C Ringenbach (Villefranche sur Sâone), N Blanc, MJ Boivin, F Guillot (Villeneuve Saint-Georges) as local clinicians. D Allard, L Hertz-Pannier, B Husson (radiology), MN Varlet (obstetric), B Tardy (haemostasis).