Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience

Abstract

Brief Report IntroductionProvision of safe and effective anticoagulation for pregnant women with mechanical heart valves is a challenging management problem. All current anticoagulation regimens are associated with maternal thromboembolism (TE) and/or bleeding. Vitamin K antagonist (VKA) therapy throughout pregnancy results in the lowest observed risk of TE (3.9%). However, VKA use is associated with fetal anomaly rates of 6.4%, fetal death of 12% and neurodevelopmental problems.1,2 The rate of TE with unfractionated heparin (UFH) is high at 25% if used throughout pregnancy and 9% if used for the first trimester. 1 Therapeutic dose LMWH is an attractive alternative to VKAs and UFH. However, in the HIP-CAT study which compared enoxaparin with sequential UFH and warfarin in pregnant women with mechanical valves, 2/7 women receiving therapeutic dose enoxaparin 1 mg/kg 12 hourly developed fatal valve thrombosis. 3 The incidence of TE using LMWH in this setting is not known because of the limited data available, but James et al. found an overall TE rate of 22% and a maternal mortality of 4%. 4 In another review, Oran et al. found an overall incidence of valve thrombosis of 8.64% (8/81) and the overall TE rate 12.35% (10/81).5 However, 9 of these 10 patients received a fixed dose of LMWH, and in 2 of these a low fixed dose was used. Among 51 pregnancies where antiXa levels were monitored, only one patient was reported to have had TE. The American College of Chest Physicians (ACCP) advises that there are insufficient data for definitive recommendations on how best to anticoagulate women with mechanical valves in pregnancy, in view of concerns for fetal well-being with warfarin therapy and the possible poorer efficacy of subcutaneous UFH and LMWH in preventing maternal TE. 6 Recommendations have included adjusted dose LMWH throughout pregnancy to keep a 4 h post-dose anti-Xa level of 1.0-1.2 IU/mL although updated ACCP guidelines recommend adjusted dose LMWH to achieve the manufacturer's peak anti-Xa level 4 h post subcutaneous injection (approximately 1.0 IU/mL) with consideration of LDA in women with prosthetic heart valves at particularly high risk of thrombosis. 7Against this background, we conducted a prospective audit of our experience with the use of our dose-adjusted regimen of high intensity LMWH in pregnant women with mechanical heart valves, and documented TE and bleeding complications, pregnancy outcome, as well as anti-Xa levels throughout their pregnancies. Design and MethodsAll pregnancies in women with mechanical heart valves between 2001 and 2007 who received LMWH were included. The use of standard dose low molecular weight heparin (LMWH) to anticoagulate women with mechanical valves in pregnancy is associated with morbidity and mortality. We conducted a prospective audit of the use of adjusted dose high intensity LMWH in 12 pregnancies in 11 women with prosthetic heart valves. LMWH ± low-dose aspirin was started at therapeutic-dose with monitoring of anti-Xa levels to achieve a target level of 1.0-1.2 ...

VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy

“…Among 51 pregnancies in which anti-Xa LMWH levels were monitored and doses adjusted according to the result, only one patient was reported to have experienced a thromboembolic complication. Two subsequent case series 334,335 and one cohort study without internal control 336 that evaluated LMWH given every 12 h and adjusted to maintain therapeutic peak anti-Xa LMWH levels reported risks of maternal valve thrombosis or systemic thromboembolism ranging between 4.3% and 16.7%.…”

“…49,50,[332][333][334][335][336] Most published studies suggest that risks of malformation are also low ( , 2%) if UFH or LMWH are substituted for vitamin K antagonists during the fi rst trimester (preferably before the 6th week of gestation). 49,50,[332][333][334][335][336] The number of pregnancy losses appears higher in those patients who receive either vitamin K antagonists or a heparin throughout pregnancy than in those in whom UFH or LMWH are substituted for vitamin K antagonists in the fi rst trimester and at term. 49,50,[332][333][334][335][336][337][338][339][340] Adjusted-dose bid LMWH throughout pregnancy, with doses adjusted to achieve the manufacturer's peak anti-Xa LMWH 4 h postsubcutaneous injection (Grade 1A).…”

“…49,50,[332][333][334][335][336][337][338][339][340] In a systematic review of observational studies between 1966 and 1997 that reported on outcomes with various anticoagulant regimens in pregnant women with mechanical prosthetic valves, the regimen associated with the lowest risk of valve thrombosis/systemic embolism was the use of vitamin K antagonists throughout pregnancy (3.9%). 49 The use of UFH in the fi rst trimester and near term was associated with a higher risk of valve thrombosis (9.2%).…”

Clinical outcomes of pregnant women with mechanical heart valves

“…Basude ve ark., [23] 15 hastada 32 gebeliği retrospektif olarak incelemiş, dört hastaya DMAH, 22 hastaya varfarin ve altı hastaya kombinasyon tedavisi uygulayarak takip etmişler ve DMAH uygulanan tüm hastalar ile kombinasyon tedavisi uygulanan hastaların yarısında, kapak trombozu, maternal ölüm ve postpartum hemorajiyi içeren ciddi aksi maternal olaylar geliştiğini bildirmişlerdir. Yakın anti-Xa takibi ile iyi sonuçlar bildiren çalışmalar [24] var olmasına rağmen, DMAH'lerin bu hastalarda güvenilirliğiyle ilgili daha fazla bilimsel kanıta ihtiyaç vardır.…”

662: Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis

“…Except for the one fatal antepartum case where peak anti-Xa level was 1U/ml (authors' reference range 1-1.2U/ml), 17 and one postpartum case where anti-Xa levels were not reported, 18 all other cases of TECs were associated with non-compliance and/or subtherapeutic LMWH doses. [17][18][19][20][21][22] These data are limited, however, to 10 studies (132 pregnancies) resulting in wide confidence intervals around the estimates. Moreover, LMWH is more expensive, potentially requires close monitoring and there is a precaution in the label regarding its use in pregnancy for MHVs.…”