By Ahizechukwu C. Eke, MD, PhD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: In this retrospective cohort study of pregnant women treated with low-molecular-weight heparin (LMWH) alone compared to those switched to unfractionated heparin (UFH) in the peripartum period, the outcomes were similar in both groups.
SOURCE: Enakpene CA, Pontarelli KN, Della Torre M. Comparison of continuation of low-molecular-weight heparin versus switching to unfractionated heparin in the peripartum. Am J Perinatol 2020;37:304-312.
Despite the administration of prophylactic and therapeutic heparin to pregnant women with a current or past history of venous thromboembolism (VTE), VTE remains a major cause of maternal morbidity and mortality.1 Although low molecular-weight-heparin (LMWH) has replaced the use of unfractionated heparin (UFH) during pregnancy to a great extent (because of its lower complication rate, predictable dosing, ease of administration, and greater reduction in thrombus size compared to UFH), a common practice is to switch pregnant women treated with LMWH to UFH approximately three to four weeks prior to the expected date of delivery (around 36 weeks of gestation for a planned term delivery), and continue UFH until after delivery.2 This practice stems from the easy reversibility and short half-life of UFH and the need to balance efficient anticoagulation during pregnancy with the woman’s desire for neuraxial analgesia in the event of spontaneous labor within 12 to 24 hours of administration of LMWH. However, some studies question the practice of switching LMWH to UFH during pregnancy as being inefficient.3 Enakpene and colleagues designed this study to compare the continuation of LMWH to switching to UFH in the peripartum period.3 This study was a retrospective cohort study conducted at the University of Illinois at Chicago Hospital and Health Sciences System (UI Health). Inclusion criteria were pregnant women who received prenatal care, were managed with LMWH, were switched to UFH during pregnancy, and delivered at ≥ 24 weeks of gestation at UI Health between 2005 and 2016.3 Women were excluded if they delivered outside UI Health or if they delivered prior to 24 weeks of gestation. The outcomes of interest were peripartum anesthesia requirements based on the anticoagulant used, and significant peripartum bleeding complications (postpartum hemorrhage > 1,000 mL and severe bleeding complications resulting in hemoperitoneum). Demographics and maternal outcomes were analyzed using standard statistical tests.
From January 2005 to December 2016, 189 pregnant women who received LMWH anticoagulation met the inclusion criteria. Twenty-seven percent (51 women) were switched to UFH at some point during pregnancy, while 73% (138 women) continued LMWH until the time of delivery. The baseline characteristics were similar in both groups. However, women who delivered at < 34 weeks of gestation were five times more likely to be switched to UFH in the peripartum period (P < 0.004), with 82% (42 women) on prophylactic LMWH dosing and 18% (nine women) on therapeutic dosing.3 The type of anticoagulation used (prophylactic vs. therapeutic) did not affect the kind of pain relief option women received (regional vs. general anesthesia). There were no statistically significant differences in peripartum anesthesia requirement and significant peripartum bleeding between women who continued LMWH and those who switched to UFH (82.4% vs. 79.7%, respectively; relative risk [RR], 1.20; 95% confidence interval [CI], 0.52-2.73; P = 0.84).
Composite bleeding complications were threefold higher in women who switched from LMWH to UFH compared to those who continued LMWH, and this was statistically significant (12% vs. 14%, respectively; RR, 2.7; 95% CI, 1.16, 6.40; P = 0.030). Postpartum hemorrhage (bleeding at the time of delivery > 1,000 mL) was similar in the two groups (6% vs. 10%; RR, 0.58; 95% CI, 0.17, 1.94; P = 0.38). In addition, the proportion of women who had re-exploration as the result of bleeding complications and hemoperitoneum after their primary surgery was similar in both groups (2.0% vs. 2.2%, respectively; RR, 0.90; 95% CI, 0.10, 8.48; P = 0.930). Among women who received anticoagulation < 24 hours prior to delivery, there were no statistically significant differences between the two groups after controlling for potential confounders (2.0% vs. 0.7%, respectively; RR, 0.33; 95% CI, 0.07, 1.65; P = 1.000). Similarly, among women who received their last dose of anticoagulant > 24 hours prior to delivery, multivariate analysis demonstrated there was no statistically significant difference between the groups (2.0% vs. 3.0%, respectively; RR, 0.5; 95% CI, 0.13, 2.0; P = 0.33).
COMMENTARY
The duration and type of anticoagulation (prophylactic vs. therapeutic) usually is dictated by the indication for anticoagulation. Therapeutic anticoagulation usually is indicated for current VTE or a history of high-risk thrombophilia. Generally, anticoagulation is commenced during pregnancy and continued until about six weeks postpartum (or longer, depending on risk factors and indication for anticoagulation), since the beneficial effects of anticoagulation in these settings outweigh its potential complications. The initial dosing of UFH is weight-based and typically is administered twice daily through the subcutaneous route. In this study by Enakpene and colleagues, the type of anticoagulation (prophylactic vs. therapeutic) did not affect the kind of anesthesia women received. Although composite bleeding complications were statistically significant between the two groups, postpartum hemorrhage, hemoperitoneum after primary surgery, and the proportion of women who had re-exploration as a result of bleeding complications were not different between both groups. Thus, based on the findings from this study, the authors at UI Health counsel their patients on the risks, benefits, and alternatives of continuing LMWH until delivery vs. switching to UFH, and patients make an informed decision. If patients choose to continue LMWH until delivery, they are counseled to hold their next LMWH dose until they are evaluated by their physician if they suspect they are in labor, have rupture of fetal membranes, and/or have vaginal bleeding.3
Heparin is considered safe during pregnancy since it does not cross the placenta.4 Despite its inability to cross the placenta, monitoring of plasma/serum levels of therapeutic LMWH or UFH is critical, since the physiologic changes during pregnancy can affect LMWH/UFH concentrations. There are differences in how LMWH and UFH are monitored. UFH levels are monitored with activated partial thromboplastin time (aPTT) levels (goal 1.5 to 2.5 during pregnancy), while women on therapeutic LMWH are monitored with anti-Xa levels (with values of 0.6 to 1.2 being the therapeutic range). In addition, women treated with UFH usually require monitoring of platelet counts during the first two to three weeks of therapy because of the small potential for heparin-induced thrombocytopenia (HIT), but the risk of HIT with LMWH is lower. Finally, the advantages of using UFH include the ease of rapid reversal with protamine sulfate, as well as lower cost when compared to LMWH. The potential risks of UFH include unpredictable pharmacodynamics (dose-response), severe bleeding complications, and the risk of HIT, which are all worse with UFH compared to LMWH. Despite these potential risks of UFH, most practitioners continue to switch pregnant women from LMWH to UFH in the third trimester because of the advantage of easy reversal of UFH with protamine sulfate and the short half-life of UFH compared to LMWH in the event of imminent delivery at term.
In conclusion, clinicians can consider continuing to treat pregnant women with both prophylactic and therapeutic doses of LMWH until the time of delivery after appropriate discussions of risks, benefits, and alternatives. However, the American College of Obstetricians and Gynecologists and other professional societies continue to recommend switching from LMWH to UFH, at doses of 10,000 international units of UFH, administered subcutaneously every 12 hours in the third trimester unless the aPTT is elevated, irrespective of indication (prophylactic or therapeutic use).5
REFERENCES
- Greer IA. Venous thromboembolism and anticoagulant therapy in pregnancy. Gen Med 2005;2 (Suppl A):S10-17.
- van Dongen CJ, van den Belt AG, Prins MH, Lensing AW. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 2004:CD001100.
- Enakpene CA, Pontarelli KN, Della Torre M. Comparison of continuation of low-molecular-weight heparin versus switching to unfractionated heparin in the peripartum. Am J Perinatol 2020;37:304-312.
- Ageno W, Crotti S, Turpie AG. The safety of antithrombotic therapy during pregnancy. Expert Opin Drug Saf 2004;3:113-118.
- American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins--Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in pregnancy. Obstet Gynecol 2018;132:e1-e17.
