Fiedler Klaus, Würfel Wolfgang
Kinderwunsch-Centrum München, Munich, Germany.
Eur J Med Res. 2004 Apr 30;9(4):207-14.
Disturbances of the embryo-maternal interaction, i.e. impaired implantation, are seen in only a minor fraction of couples. These malfunctions become evident as recurrent spontaneous abortions (RSA), or repetitive implantation failure (RIF) in cases with IVF or ICSI procedures. The antiphospholipid syndrome (APL) is the only consensus-defined syndrome associated with RSA (anticardiolipin antibodies and/or lupus anticoagulant plus clinical symptoms). Since antiphospholipid antibodies directly interfere with hemostasis (increased coagulation), heparin is an established treatment option in these cases resulting in unequivocal benefits. There is no defined antibody syndrome in RIF even if it may be assumed that it exists. Conclusive evidence for a benefit of heparin (and aspirin) in this situation is lacking as well. However, the majority of investigations including our own experience indicate that anticoagulation may be useful. Besides the extensively studied anticardiolipin antibodies, other - by far less thoroughly investigated - antiphospholid antibodies have been described. So far it is unclear if heparin may exert positive effects in women carrying these antibodies. Autoreactive immune processes may also become apparent by the emergence of further antibodies, such as antinuclear (ANA), thyreoglobulin (TGA) and thyreoperoxidase antibodies (TPO) etc. However, there is no established definition of a syndrome associated with these antibodies, TGA and TPO probably being the most relevant. - Most studies in this area including our own experience indicate that heparin may be a useful. The detection or autoantibodies per se is probably not of pathophysiological relevance if there is no ongoing pathological activation of the immune system. However, an acute autoimmune response associated with irregular antibodies may represent the pathophysiological basis of a reproductive autoimmune failure syndrome. In these cases, immune-equilibrating interventions appear to be more appropriate than heparin therapy. - Coagulation disorders, namely thrombophilia, are a frequent cause of RSA and probably RIF as well, the most relevant being antithrombin deficiency, Factor V Leiden and prothrombin mutations. Deficiencies of protein S, protein C and factor XII and XIII are of minor importance. There is a varying degree of evidence for a benefit of heparin/aspirin in these syndromes. Heparin not only reduces the abortion rate but also lowers the risk for developmental retardation, premature birth and preeclampsia. - The effects of heparin are not restricted to anticoagulation. It is directly or indirectly (e.g. via heparan sulfate proteoglycans or heparin-binding EGF) involved in the adhesion of the blastocyst to the endometrial epithelium and the subsequent invasion. Actually, prolonged heparin treatment (14 days) resulted in an increased pregnancy rate in our patient population. Shorter courses of heparin where not effective.
胚胎与母体相互作用的紊乱，即着床受损，仅在一小部分夫妇中出现。这些功能障碍表现为反复自然流产（RSA），或在体外受精（IVF）或卵胞浆内单精子注射（ICSI）过程中出现反复着床失败（RIF）。抗磷脂综合征（APL）是唯一与RSA相关的已达成共识定义的综合征（抗心磷脂抗体和/或狼疮抗凝物加上临床症状）。由于抗磷脂抗体直接干扰止血（凝血增加），肝素是这些病例中已确立的治疗选择，且已产生明确的益处。在RIF中不存在明确的抗体综合征，尽管可以假定其存在。在这种情况下，也缺乏肝素（和阿司匹林）有益的确凿证据。然而，包括我们自己经验在内的大多数研究表明抗凝可能是有用的。除了广泛研究的抗心磷脂抗体外，还描述了其他（迄今为止研究较少）抗磷脂抗体。到目前为止，尚不清楚肝素对携带这些抗体的女性是否可能产生积极作用。自身反应性免疫过程也可能通过进一步抗体的出现而显现，如抗核抗体（ANA）、甲状腺球蛋白抗体（TGA）和甲状腺过氧化物酶抗体（TPO）等。然而，与这些抗体相关的综合征尚无既定定义，TGA和TPO可能最为相关。——该领域的大多数研究包括我们自己的经验表明肝素可能是有用的。如果免疫系统没有持续的病理激活，自身抗体的检测本身可能没有病理生理学意义。然而，与不规则抗体相关的急性自身免疫反应可能代表生殖自身免疫性失败综合征的病理生理基础。在这些情况下，免疫平衡干预似乎比肝素治疗更合适。——凝血障碍，即易栓症，是RSA的常见原因，可能也是RIF的常见原因，最相关的是抗凝血酶缺乏、因子V莱顿突变和凝血酶原突变。蛋白S、蛋白C以及因子XII和XIII的缺乏重要性较小。在这些综合征中，肝素/阿司匹林有益的证据程度各不相同。肝素不仅降低流产率，还降低发育迟缓、早产和先兆子痫的风险。——肝素的作用不仅限于抗凝。它直接或间接（例如通过硫酸乙酰肝素蛋白聚糖或肝素结合表皮生长因子）参与囊胚与子宫内膜上皮细胞粘附以及随后的侵入过程。实际上，在我们的患者群体中，延长肝素治疗（14天）导致妊娠率增加。较短疗程的肝素治疗无效。
