In 2022, results from two long-awaited clinical trials shed light on two key concerns in obstetrical hematology: what dose of heparin to use in pregnant patients for thromboprophylaxis, and whether heparin increases live birth rate in patients with recurrent pregnancy loss and thrombophilia.
LMWH: Which dose should be used for prophylaxis in pregnancy?
Deep vein thrombosis and pulmonary embolism are the leading causes of peripartum maternal mortality.1 In patients with a prior history of venous thromboembolism (VTE) who are not on long-term anticoagulant therapy, the 2018 ASH clinical practice guidelines recommend that all such women receive postpartum anticoagulant prophylaxis. While in the antepartum setting, it is recommended that women with high-risk features (prior unprovoked or hormonal-related VTE) receive anticoagulant prophylaxis.2 The optimal prophylactic dose of heparin remains unclear, however, and is still a contentious issue given the risks of bleeding around pregnancy.
In the Highlow trial,3 pregnant women with a prior history of unprovoked or provoked (by hormonal or minor risk factors), who were less than 14 weeks gestational age, were randomized to intermediate-dose versus low-dose low-molecular-weight heparin (LMWH) for the duration of their pregnancy and until six weeks postpartum. The intermediate-dose LMWH was adjusted by weight, while the low-dose group received a fixed dose. The primary efficacy outcome was symptomatic, objectively confirmed VTE during pregnancy until six weeks postpartum, and the primary safety outcome was ISTH major bleeding. Among the patients enrolled, prior VTE events had occurred due to prior hormonal therapy (58 percent), during pregnancy or postpartum (26-30 percent), unprovoked (13-16 percent), or other reasons.
The investigators found that intermediate-dose LMWH did not reduce the risk of VTE compared with fixed low-dose prophylaxis. The primary efficacy outcome occurred in 2 percent (intermediate-dose) versus 3 percent (low-dose; RR, 0.69; 95% CI, 0.32-1.47), and there was no difference in major bleeding in the on-treatment analysis (4% vs. 4%). In the postpartum period (when the daily VTE risk is highest),4 there were numerically fewer pulmonary embolism events (1 [<1%] vs. 7 [1%]) and fewer superficial vein thrombosis (0 vs. 11 [2%]) in the intermediate-dose group. However, these differences were not statistically significant.
This is an impactful study as higher doses of LMWH may complicate peripartum anticoagulant management by requiring a longer interruption interval before neuraxial anesthesia. Higher doses may also have increased potential for bruising or peripartum bleeding complications (although not borne out in this study). The study also provides prospective data on the absolute risk of VTE in pregnancy for patients receiving anticoagulant prophylaxis. In summary, the authors are to be congratulated for establishing fixed low-dose LMWH as the standard prophylaxis regimen for pregnant women with prior VTE. The possibility of higher efficacy in the postpartum setting for intermediate-dose LMWH is hypothesis-generating and merits further evaluation.
Does LMWH improve live birth rate in pregnant patients with recurrent pregnancy loss and hereditary thrombophilia?
The evidence on whether there is an association between inherited thrombophilia and pregnancy loss is conflicting.5 Meanwhile, the association between pregnancy loss and antiphospholipid syndrome, an acquired thrombophilia, is well established.6 Heparin in combination with aspirin have been shown to increase live birth rate in patients with antiphospholipid syndrome and recurrent pregnancy loss.7 However, the efficacy of heparin for recurrent pregnancy loss in patients with inherited thrombophilia remains unknown. The ALIFE study did not demonstrate a benefit to heparin in patients with recurrent pregnancy loss, but that study only included a minority of patients with inherited thrombophilia.8
In the ALIFE2 study, the investigators examined the question of whether LMWH therapy improved live birth rate in patients with inherited thrombophilia who previously had two or more pregnancy losses.9 Patients with confirmed inherited thrombophilia (factor V Leiden, prothrombin gene mutation, antithrombin, protein C or protein S deficiency) who were actively trying to conceive or who were less than seven weeks pregnant, were eligible. They were randomized to receive prophylactic-dose LMWH or standard pregnancy surveillance upon confirmation of pregnancy, and LMWH was continued from randomization until end of pregnancy.
At the time of this writing, the trial has been published as a Late-Breaking Abstract at the 2022 ASH Annual Meeting and has not yet been presented. The study randomized 326 women to the two treatment arms; the most common thrombophilia types were factor V Leiden (56%), prothrombin gene mutation (25%), and protein S deficiency (14%). Live birth rates were 116 (71.6%) of 162 in the LMWH group, and 112 (70.9%) of 158 in the standard surveillance group (no statistical difference). Bleeding rates have not been reported yet, though adverse event rates were similar in both groups. Secondary outcomes, including obstetrical complications (HELLP syndrome, pre-eclampsia, intrauterine growth restriction) have not yet been reported.
These are impactful results that should change practice. Use of anticoagulant prophylaxis in women with recurrent pregnancy loss and inherited thrombophilia is widespread, despite the lack of evidence. The trial now establishes that LMWH in patients with inherited thrombophilia does not improve live birth rate, confirming that it should not be used. The trial strengthens the notion that routine testing for inherited thrombophilia in patients with recurrent pregnancy loss should not be done, since the results will not impact management. The results are aligned with the TIPPS study, which showed no improvement in VTE or pregnancy outcomes in patients with inherited thrombophilia and VTE risk factors or prior placenta-mediated pregnancy complications.9
These two landmark studies will clarify key issues in the field of obstetrical hematology. They suggest that standard low-dose prophylaxis should be used in patients who require thromboprophylaxis in pregnancy for prior VTE, but that thromboprophylaxis is not indicated for increasing live birth rate in thrombophilic patients with prior recurrent pregnancy loss. The authors are to be congratulated for completing these studies in an important patient population, where the evidence base is often slim.
Dr. Tseng indicated no relevant conflicts of interest.