Effectivity of heparin in assisted reproduction.

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.