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La patologia uterina morfologica e funzionale, le alterazioni ormonali e cromosomiche sono considerate con certezza come fattori eziologici di aborti ricorrenti spontanei (ARS), recenti studi si orientano verso i fattori immunologici come causa di ARS nel 20% circa dei casi (1). 
Nelle donne con aborti ricorrenti si valutano alcuni parametri immunologici tra cui
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- il livello di anticorpi anticardiolipina (ACA) e antinucleari (ANA). Gli anticorpi anticardiolipina (ACA) e gli anticorpi antinucleari (ANA) svolgono un ruolo importante nella perdita ricorrente della gravidanza, il che è supportato dal VDRL, dal tempo di protrombina (PT) e dal tempo di tromboplastina parziale (PTT) come indicatori indiretti per trovare un difetto nel sistema immunitario di una donna incinta (19). La positività agli ANA e agli ACA tra le donne con aborto spontaneo ricorrente è comune (20). Gli anticorpi antinucleare causano problemi immunitari nel 22% delle donne con gravidanze multiple e nel 50% delle donne sterili che hanno avuto fallimenti di fecondazione in vitro.
- Interleuchina-3 (IL-3): l’IL-3 è un fattore di crescita il cui valore sierico aumenta in gravidanza in correlazione con l’età gestazionale. Svolge un ruolo positivo fondamentale nell’impianto del feto e nella generazione della placenta. Le cellule T, i mastociti e gli eosinofili producono tutti IL-3. In particolare l’attività dell’IL-3 può influenzare l’omeostasi delle citochine Th1 e Th2: l’ARS è associato a Th1, mentre una gravidanza fisiologica è associata a Th2 (21-24).
- Complemento C3 e C4: L’attivazione del complemento aumenta la produzione di mediatori come C3a, C5a e C5b-9 MAC, che promuovono l’attivazione delle piastrine e delle cellule endoteliali, portando a infiammazione, trombosi, necrosi tissutale e, infine, perdita fetale.
- HLA – Tipizzazione – in coppie con abortività ripetuta per consentire una fine interpretazione immunologica del fenomeno abortivo, attraverso la valutazione del grado di condivisione degli aplotipi HLA tra le coppie di partners a rischio.
- Fattori immunologici mucosi nell’interfaccia materno-fetale Si ipotizza che il rigetto immunologico del feto dovuto al riconoscimento degli antigeni paterni da parte del sistema immunitario materno, con conseguente anormalità delle cellule immunitarie e produzione di citochine, sia una delle cause di ARS idiopatico.
- Lupus eritematoso sistemico (LES) – Il Lupus Eritematoso Sistemico (LES) è una patologia infiammatoria sistemica e cronica di origine multifattoriale, prevalentemente autoimmune che comporta manifestazioni estremamente polimorfe, cutaneo-viscerali, che si manifestano a poussées. Nel 90% dei casi è associata la presenza di autoanticorpi antinucleo (ANA) ma molto spesso si osservano anche anticorpi antifosfolipidi (APL), anticorpi anticardiolipina (ACA) e anti-ß2 glicoproteina. Il LES colpisce prevalentemente (90%) le donne soprattutto fra i 15 e i 40 anni di età, in età feconda e ciò fa sospettare un ruolo determinante da attribuire alla presenza degli ormoni sessuali ed in particolare estrogeni. Le manifestazioni cliniche LES si accentuano durante le mestruazioni e le gravidanze.
- Sindrome da anticorpi antifosfolipidi (APS) frequentemente è associata e secondaria al LES ma può esistere anche da sola o essere associata ad altre patologie autoimmuni. Gli anticorpi antifosfolipidi (APL) si legano ai fosfolipidi con una carica negativa e stimolano la coagulazione del sangue, attivano le cellule endoteliali provocando una trombosi delle arterie radiali, mancata irrorazione placentare e conseguente morte del feto. L’APS è la più comune tra le trombofilie acquisite, ha una stretta correlazione causale con i fenomeni trombotici placentari e il conseguente esito avverso della gravidanza attraverso alterazioni del metabolismo di prostaciclina/trombossano. Le alterazioni locali in queste vie a livello dell’interfaccia materno-fetale potrebbero promuovere costrizione vascolare delle arteriole placentari, mancata invasione trofoblastica, adesione piastrinica e infarto placentare. Gli anticorpi antifosfolipidi (IgG e IgM) sono presenti nel 15% delle pazienti ARS e solo nel 2% delle donne con basso rischio abortivo. Allo stesso modo, la positività degli anticorpi antifosfolipidi è stata collegata a riduzioni dei livelli di prodotti antitrombotici placentari, come l’annessina V, tra le donne con ARS. A sostegno di questo concetto, è stato dimostrato che l’aterosclerosi si sviluppa rapidamente nelle arterie spirali delle pazienti positive agli anticorpi antifosfolipidi (5-18).
- Test di Embriotossicità – Analisi di fattori embriotossici materni
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La terapia si avvale dell’utilizzo di eparina, prednisone (Deltacortene® cpr 25 mg: una compressa al dì) e basse dosi di aspirina (100 mg/die) e γ-globuline (Gammagard® flacone ev 5 gr, 10 gr; Privigen® 100 mg/ml flac ev 50 ml) (2-4).
References:
- Y.J. Meir, L. Fischer Tamaro, N. Di Giusto, G. D’Ottavio e G. P.Mandruzzato: Aborto ripetuto immunologico (Atti SIGO, Congresso Napoli 2000; Fratelli Ferraro Editore, SRL; pagg 165-174).
- Franklin RD, Kutteh WH. “Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population”. Hum Reprod. 2002 Nov;17(11):2981-5.
- Backos M, Rai R, Baxter N, Chilcott IT, Cohen H, Regan L.: “Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin”.Br J Obstet Gynaecol. 1999 Feb;106(2):102-7.
- Sher G, Matzner W, Feinman M, Maassarani G, Zouves C, Chong P, Ching W.: “The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization”. Am J Reprod Immunol. 1998 Aug;40(2):74-82.
- Out, HJ, et al., Uno studio multicentrico prospettico e controllato sui rischi ostetrici delle donne in gravidanza con anticorpi antifosfolipidi. Am J Obstet Gynecol, 1992. 167 (1): p. 26-32
- Kutteh, WH, et al., Associazione di anticorpi anticardiolipina e perdita di gravidanza nelle donne con lupus eritematoso sistemico. Fertil Steril, 1993. 60 (3): p. 449-55.
- Hanly, JG, et al., Lupus gravidanza. Uno studio prospettico dei cambiamenti placentari. Arthritis Rheum, 1988. 31 (3): p. 358-66.
- Lockshin, MD, et al., Antibody to cardiolipin predice l’insufficienza placentare in pazienti gravide con lupus eritematoso sistemico. New England Journal of Medicine, 1985. 313: p. 152-156.
- Harris, EN, et al., Thrombocytopenia in SLE e relative malattie autoimmuni: associazione con l’anticorpo anticardiolipina. Br J Haematol, 1985. 59 (2): p. 227-30.
- Cariou, R., et al., Inibizione dell’attivazione della proteina C da parte delle cellule endoteliali in presenza di lupus anticoagulante. N Engl J Med, 1986. 314 (18): p. 1193-4.
- Freyssinet, JM, et al., Un anticoagulante del lupus IgM che neutralizza l’effetto potenziante del fosfolipide sull’attività della trombomodulina endoteliale purificata – un meccanismo per la trombosi. Thromb Haemost, 1986. 55 (3): p. 309-13.
- Gris, J., et al., Sindromi antifosfolipidiche e antiproteiche in donne non trombotiche e non autoimmuni con perdita fetale precoce primaria ricorrente inspiegabile. Studio di ostetricia ed ematologia di Nimes – NOHA. Thromb Haemost, 2000. 84 (2): p. 228-36.
- Rand, JH, et al., Riduzione dell’annessina-V (proteina anticoagulante placentare-I) sui villi placentari di donne con anticorpi antifosfolipidi e aborto spontaneo ricorrente. Am J Obstet Gynecol, 1994. 171 (6): p. 1566-72.
- Rand, JH, et al., Perdita di gravidanza nella sindrome da anticorpi antifosfolipidi – un possibile meccanismo trombogenico. N Engl J Med, 1997. 337 (3): p. 154-60.
- Cervera R, Balasch J: autoimmunità e perdite di gravidanze ricorrenti. Clin Rev Allergy Immunol, 2010. 39 (3): p. 148-152
- .Lyden, TW, AK Ng e NS Rote, Modulazione dell’espressione dell’epitopo della fosfatidilserina da parte delle cellule BeWo durante il trattamento con forskolina. Placenta, 1993. 14 (2): p. 177-86
- Bulla, R., et al., Inibizione dell’adesione del trofoblasto alle cellule endoteliali da parte dei sieri di donne con aborti spontanei ricorrenti. Am J Reprod Immunol, 1999. 42 (2): p. 116-23.
- Ernest JM, Marshburn PB, Kutteh WH: Obstetric antiphospholipid syndrome: an update on pathophysiology and management. Semin Reprod Med, 2011. 29 (6): p. 522-539.
- AL-Jabery R, SH I. College of Science. University of Basrah; 2006. Rilevamento di anticorpi antifosfolipidi e anticardiolipina in donne affette da aborto ricorrente e isolamento dell’antigene cardiolipina dal cuore di manzo.
- AL-Husaynee AJ. Valutazione degli anticorpi anticardiolipina e antifosfatidilserina nelle donne con aborto ricorrente. Ann. Coll. Med. Mosul. 2008;34(1):54–57.
- Metcalf D. Citochine ematopoietiche. Sangue. 2008;111(2):485–491. doi: 10.1182/blood-2007-03-079681.
- López C, Zamorano P, Teuber S, Salas M, et al. L’interleuchina-3 previene la morte cellulare indotta dallo stress ossidativo nelle cellule HEK293. J Cell Biochem. 2017;118(6):1330–1340.
- Holtan SG, Chen Y, Kaimal R, Creedon DJ, et al. Modellazione della crescita dell’ambiente citochinico materno durante la gravidanza normale: la chemiochina derivata dai macrofagi diminuisce con l’aumento dell’infiammazione/controregolazione. J. Immunol. Res. 2015;2015:952571.
- Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 e paradigma delle cellule T regolatrici in gravidanza. Am J Reprod Immunol. 2010;63(6):601–610.
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