New formulations of heparin, termed low-molecular weight heparins, have been demonstrated to be superior to unfractionated heparin in the treatment of many clotting disorders (434–436). LMWH has the advantage of an increased antithrombotic ratio when compared with unfractionated heparin. This results in improved treatment of inappropriate clotting but fewer bleeding side effects. In addition, LMWH has been associated with a decreased incidence of thrombocytopenia and osteoporosis when compared with its unfractionated counterpart. Finally, LMWH has a long half-life and requires less frequent dosing and monitoring, thereby improving patient compliance. LMWH appear to be safe for use in pregnancy, and LMWH has shown promise when combined with low-dose aspirin in the treatment of recurrent pregnancy loss associated with APS (430,435,437). Only a few studies have compared the use of unfractionated heparin and aspirin to LMWH and aspirin in the treatment of women with APS and adverse pregnancy outcomes (433,438). The therapies had similar effects in one study (438). A meta-analysis suggested that unfractionated heparin was superior to LMWH, however, there was significant heterogenicity between studies (433). Efficacy has been suggested for LMWH treatment for patients with recurrent pregnancy loss associated with other thrombophilias, including activated protein C resistance associated with factor V Leiden, mutations in the promoter region of the prothrombin gene, and decreases in protein C and protein S activities (63,439–441). The use of LMWH for this indication appears to have an excellent safety profile for mother and fetus (437,442,443) .
The prophylactic use of daily-low dose aspirin has become common practice within the lay public based on its perceived cardiovascular effects combined with its low incidence of side effects. Its sole use in the treatment of recurrent pregnancy loss has likewise gained momentum, and many patients with histories of recurrent loss will either be self-prescribing this therapy or will inquire about its usefulness. At present, there are no good data supporting its use either in patients with heritable thrombophilias or in the general recurrent pregnancy loss population. Although studies are small, the use of low-dose aspirin alone has not been shown to be effective in the treatment of recurrent pregnancy loss associated with APS (431,444,445). When used in these patients, it should be in combination with unfractionated or LMWH. Large randomized prospective trials examining the empiric use of aspirin alone or in combination with prophylactic doses of heparin have shown no benefit of these therapies in unexplained recurrent pregnancy loss (445). In addition, the use of aspirin in early pregnancy has been called into question with reports of an increased incidence of isolated spontaneous pregnancy loss among women who used this medication (316,317). However, these reports are poorly designed and do not adequately address the level of aspirin exposure (81 mg vs. 325 mg). Although reviews have touted the overall safety of aspirin in pregnancy, outside of use in combination with heparin for patients with recurrent pregnancy loss and APS, this medication should be used only with justification in the well-informed patient during early pregnancy (446).
More directed antithrombotic therapies have also been described for the treatment of recurrent pregnancy loss among patients with thrombophilias. For instance, the use of protein C concentrates has been reported to be associated with favorable pregnancy outcome in a patient with a history of thrombosis, recurrent fetal losses, and protein C deficiency (447).