European registry of infants born to mothers with antiphospholipid syndrome

Transcript

1 BARI, maggio 2010 XVI Congresso Nazionale della SIN Neonatologia e T. I. N. Ospedale dei Bambini Spedali Civili, Brescia European registry of infants born to mothers with antiphospholipid syndrome Gaetano CHIRICO

2 European registry contributors M Motta, Neonatology and Neonatal Intensive Care, Children s Hospital, Spedali Civili, Brescia, Italy. E Lachassinne, Pediatrics, Assistance Publique - Hôpitaux de Paris, Hôpital Jean-Verdier, Université Paris XIII, Bondy, France. MC Boffa and MH Aurousseau, Laboratoire d Hematologie, Unite Hémostase et Thrombose, Bondy, France. A Tincani, Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy. T Avcin, Pediatrics, University Chidren s Hospital Ljubljana, University Medical Center, Ljubljana, Slovenia. S De Carolis, Obstetrics and Gynecology, Catholic University, Rome, Italy. P Le Toumelin, Public Health and Epidemiology, Hôpital Avicenne, AP- Hôpitaux de Paris, Bobigny, Université Paris XIII, France. A Lojacono, Obstetrics and Gynecology, Spedali Civili and University of Brescia, Brescia, Italy. MP De Carolis, Neonatology, Catholic University, Rome, Italy.

3 International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) (Miyakis et al, Sidney 2006) Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria that follow are met: Clinical criteria 1. Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. 2. Pregnancy morbidity (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or severe preeclampsia defined according to standard definitions, or (ii) recognized features of placental insufficiency, or (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

4 International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) (Miyakis et al, Sidney 2006) Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria that follow are met: Laboratory criteria 1. Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis. 2. Anticardiolipin (acl) antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e. >40 GPL or MPL, or >the 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA. 3. Anti-b2 glycoprotein-i antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA.

5 β2gpi, a plasma protein produced in the liver and in the placenta, is a major Crystal structure of β2gpi antigen for the apl IgG antibodies that recognize epitope Gly40-Arg43 in domain I of β2gpi cause LAC, and their presence correlates strongly with thrombosis de Laat B et al, Blood 2005 b2gpi binds to trophoblast in vitro through its V domain and can be recognised by anti-b2gpi antibodies; the antibody binding downregulates trophoblast hcg synthesis and secretion Di Simone N et al, Ann Rheum Dis 2005

6 Mechanisms of apl antibody-mediated injury Pierangeli S et al, Curr Opin Hematol 2006 Salmon JE et al, Nature Clinical Practice Rheum 2006 FX FVII Platelets TXA2 Platelets Aggregation Tissue Factor Monocyte PMN C3b Inflammation C5a-R C5a C5b b2gpi Upregulation of Tissue Factor FX Tissue Factor FVII FXa Extrinsic coagulation pathway Trophoblast Endothelial Cells

7 Antiphospholipid Syndrome (APS), apl and pregnancy outcome Several clinical trials have concluded that a combination of heparin and low dose of aspirin could significantly improve pregnancy outcome in women with APS by over 70%

8 RELAZIONE TRA TERAPIA ED OUTCOME GRAVIDICO Esperienza Spedali Civili di Brescia ( )

9 Questioni aperte nei nati da madre con APS: Complcanze neonatali? Entità passaggio transplacentare di apl? Tempo di eliminazione degli apl? Rischio di trombosi nei neonati (nei nati da madre con APS sono stati riportati rari casi di trombosi ed ischemia cerebrale associata a presenza di apl)? Evoluzione a lungo termine?

10 Complicanze Neonatali nei nati da madre con APS Diversi studi hanno confermato che le complicanze sono legate alla nascita pretermine Pollard JK et al., Obstet Gynecol 1992 Botet F et al., J Perinat Med 1997 Ruffatti A et al., Clin Exp Rheumatol 1998 Brewster JA et al., J Perinat Med 1999 Tincani A et al., Lupus 2002

11 Esito neonatale in 71 nati da madre con APS e 71 controlli di peso ed età gestazionale simili (Tincani A et al, Lupus 2002). Retinopatia del pretermine Nati da madre con APS Controlli Leucomalacia periventricolare Emorragia cerebrale Malattia polmonare cronica Distress respiratorio Ricovero in TIN

12 Anti-cardiolipina (acl) e anti-b2glicoproteinai in nati da madre con o senza anticorpi antifosfolipidi (Motta M et al, Am J Perinatol 2006) 22 nati da da madre con malattia autoimmune e con anticorpi anti-fosfolipidi: acl e anti b2gpi misurati in ELISA alla nascita ed a 12 mesi 24 nati da da madre con malattia autoimmune e senza anticorpi antifosfolipidi: acl e anti b2gpi a 12 mesi 18 bambini di controllo: acl e anti b2gpi a 12 mesi

13 Anticardiolipin and anti-b2 glycoprotein I antibodies in infants born to mothers with antiphospholipid antibody-positive % autoimmune disease: a follow-up study Motta M et al, Am J Perinatol 2006 Placental transfer of auto-abs

14 Meccanismi che limitano il passaggio transplacentare degli apl Circolazione materna Eparina apl b2gpi Circolazione fetale Sinciziotrofoblasto

15 Anticardiolipin and anti-b2 glycoprotein I antibodies in infants born to mothers with antiphospholipid antibody-positive % autoimmune disease: a follow-up study Motta M et al, Am J Perinatol 2006 apl at birth and at 12 months

16 Anticardiolipin and anti-b2 glycoprotein I antibodies in infants born to mothers with antiphospholipid antibody-positive % autoimmune disease: a follow-up study Motta M et al, Am J Perinatol 2006 a-b2gpi at 12 months in three infant groups

17 Anticorpi apl nel neonato Il passaggio transplacentare di apl è ridotto Si può ipotizzare che la placenta, che esprime la b 2 GPI, e la terapia eparinica riducano il passaggio La valutazione di acl sembra il marker più sensibile della scomparsa degli apl materni La positività degli anti b 2 GPI a 12 mesi può essere legata a fattori aspecifici (infezione, sensibilizzazion ad antigeni alimentari) Nessun caso di trombosi

18 Questioni aperte nei nati da madre con APS: Entità passaggio transplacentare di apl? Tempo di eliminazione degli apl? Rischio di trombosi nei neonati (nei nati da madre con APS sono stati riportati rari casi di trombosi ed ischemia cerebrale associata a presenza di apl)? Evoluzione a lungo termine?

19 European registry of infants born to mothers with antiphospholipid syndrome, : preliminary results. Inclusions: 138 mothers / 141 babies (3 twin) 108 Primary APS: - 91 obstetrical syndromes Mothers with history of intra-uterine deaths (n=42) recurrent fetal losses (n=25), severe intra-uterine growth retardation (n=5) neonatal death (n=1), preeclampsia and abruptio placentae (n=3) obstetrical syndrome with thromboses (n=8) intra-uterine deaths and thromboses (n = 3) - 17 thromboses

20 European registry of infants born to mothers with antiphospholipid syndrome: preliminary results. Inclusions: 138 mothers / 141 babies (3 twin) 30 Secondary APS: 18 systemic lupus: 13 thromboses, 3 RFL, 2 IUD 12 auto-immune diseases (5 connective diseases, 3 thyroiditis, 1 mulptiple sclerosis, 1 Basedow, 1 diabetes) 4 thrombosis, 1 IUD, 2 RFL, 3 thrombosis with IUD

21 IMMUNOLOGICAL RESULTS IN APS MOTHERS apl present in the mothers during pregnancy Lupus anticoagulant: 39% Anticardiolipin ab.: 80% Antib2-GPI antibodies: 48% Anti-prothrombin IgG: 19%

22 Clinical data, newborns: gestational age 118 full term neonates 23 premature babies: 16.3% 1 at 27 weeks of gestation 3 at 32 weeks 3 at 33 weeks 3 at 34 weeks 2 at 35 weeks 11.3% 11 at 36 weeks Weeks of gestation

23 Clinical data, newborns: birth weight % < Birth weight <1500 SGA

24 IMMUNOLOGICAL RESULTS IN 127 NEONATES 43 / 127 apl positive neonates (33.8%) %c LAC acl a-b2gpi anti-ii (14 infants with 2 or 3 different acl)

25 Follow up: Clinical Evaluation (1) No severe medical events, thrombosis or auto-immune disease during the follow-up except 17 hospitalizations in 8 babies (neonatal period excluded): 4 for asthma, 6 for upper or lower respiratory tract infections, 3 for gastro-enteritis, 1 for cranial traumatism, 1 for non confirmed phacomatosis 1 surgery for angioma removal 1 for cyanosis 9 cases of eczema and/or asthma and/or allergy reported, 1 cow s-milk allergy, 2 case of IgA deficit

26 Follow up: Clinical Evaluation (2) All infants have normal growth except: 1 macrocephalia at 10 months, 2 microcephalia at 9 months, 3 cases of failure to thrive 1 case of excess weight (Body mass index > 97 p) 2 height > 97 p 1 case of excess height and weight > 97 p Babies followed for 3 months to 5 years (mean 20 months) All of them were evaluated with WIPPS-III 5 abnormal behaviours with 2 autism spectrum disorders (1 acl positive)

27 CONCLUSIONS No severe medical events, thrombosis or auto-immune disease during follow-up. 5 cases of abnormal behaviour (1 transient), with 2 cases of ASD/141 (3.5%) Autism or pervasive developmental disorders: 1.6% children in general population? References: Brain-specific autoantibodies in the plasma of subjects with ASD (Cabanlit 2007) Serum anti-myelin-associated glycoprotein antibodies in autistic children (Mostafa 2008) Autoimmunity in autism (Enstrom 2009)