Low molecular mass heparin (LMMH) for management of thromboembolic disease in pregnancy

Until now, most pregnant patients who need an anticoagulant treatment receive unfractionated heparin (UFH). However, long-term UFH requires monitoring, causes osteoporosis and can lead to the development of heparin-induced thrombocytopenia. Low molecular mass heparin (LMMH) is effective, safe and associated with fewer side-effects than UFH for the treatment of acute deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) in non-pregnant women. LMMHs do not cross placenta and seem to be safe for the fetus (1). Although there is a growing clinical experience with LMMH used for thromboprophylaxis in pregnancy, good information on appropriate dosage regimes is lacking for treatment of acute DVT. Nineteen women with antenatal deep vein thrombosis objectively confirmed by ultrasound were treated with unfractionated heparin, 500 IU/kg/24 h, iv resulting in prolongation of the APTT, 1.50–2 times (70–100 secs). This treatment was given for one week and thereafter changed to LMMH, Fragmin®(Pharmacia, Sverige AB) using syringes with 10.000 IU twice daily, aming at 125 IU/kg twice daily. Anti-Xa concentration was determined by chromogenic substrate assay, reaching above 0.6 but not higher than 1.3 IU/ml plasma 3 hours post injection. After improvement and disappearance of clinical symptoms and earliest one month after the thromboembolic event, Fragmin® treatment was reduced to 5.000 IU twice daily to give a concentration corresponding to 0.1–0.2 IU anti-Xa units before injection and less than 0.45 IU anti-Xa units per ml plasma three hours post injection. This treatment were continued until delivery. In connection with delivery the dosage was reduced to 2500 IU, sc twice daily. The anticoagulant treatment continued for six months including at least 6 weeks post partum. In four women with the baseline weight of 50, 52, 60 and 63 kg respectively the initial dose 10 000 IU twice daily was decreased to 7.500 IU twice daily since the peek concentration of anti-Xa was 2.25, 2.10, 1.42 and 1.38 IU/ml respectively. In the rest of the women the mean peak anti-Xa value at three hours post injection was 0.89 IU/ml (range 0.62–1.30) and a protective anticoagulant effect maintained 12 h post injection was confirmed by the value 0.38 IU anti-Xa/ml (range 0.22–0.54). During the dosage regime 5000 IU twice daily the 3 h and 12 h value were 0.37 IU anti-Xa/ml (range 0.25–0.45) and 0.19 IU anti-Xa/ml (range 0.11–0.21) respectively. Initial therapy in the management of VTE in the pregnant patient has traditionally consisted of bolus of intravenous UFH (75 IU/kg) followed by a continuous infusion adjusted to maintain a therapeutic activated partial thromboplastin time (APTT). On the basis of a review by Ginsberg intravenous heparin is discontinued and therapy with twice-daily subcutaneous UFH, in doses sufficient to achieve a therapeutic mid-interval APTT, is commenced after 5–10 days and given in full doses until term (2). In non-pregnant patients once-daily administration is recommended for acute treatment of venous thromboembolism (VTE) with LMMH (enoxaparin 1.5 mg/kg bodyweight once daily; dalteparin 200 units/kg, tinzaparin 175 units/kg bodyweight). The pharmacokinetics of LMMH are different in pregnancy than in the same women post partum. The pharmacokinetics also change throughout gestation and are different in early and late pregnancy (3). In view of the alterations in the pharmacokinetics of dalteparin during pregnancy, however, a twice-daily dosage regime in the treatment of VTE in pregnancy is recommended (4). The need for adjusted-dose LMMH was investigated by Nelson-Piercy who showed that anti-Xa levels remained relatively constant throughout pregnancy at a fixed LMMH dose while Hunt et al. found that increasing dose adjustments with each trimester were needed (5,6). In our longitudinal safety study with LMMH during pregnancy 64% of the women maintained the dalteparin dose given at entry throughout the pregnancy. Also according to our data the degree of anticoagulation is dependent on the patients baseline weight more than to the weight gain during pregnancy (7). But as recently shown, the achieved degree of anticoagulation falls throughout pregnancy in accordance with declining anti-Xa levels, also significantly correlated to patient weight (8). Therefore assessment of anti-Xa during LMMH-treatment in pregnancy is recommended until greater experience is available. The duration of therapeutic treatment in the non-pregnant situation is usually 6 months. As Warfarin can’t be used in pregnancy and long-term heparin treatment causes osteoporosis the full treatment period is reduced to 4–5 weeks followed by an increased prophylactic dosage until term. Low-risk mothers are given prophylactic therapy for a further 6 weeks post partum, while patients at high risk should receive extended post partum thromboprophylaxis for at least three months. Patients with recurrent VTE, APLA or antithrombin III deficiency require indefinite treatment because of the high risk of recurrence. If the episode of VTE occurs late in pregnancy, warfarin, which is safe for breast feeding infants, can be substituted following delivery. The pharmacokinetics of LMMH are significantly different during pregnancy than in the same women when non-pregnant. Therefore, at present, it is to recommend a higher daily dosage than in non-pregnant state and a twice-daily dosage regimen in the treatment of VTE in pregnancy. Intravenous UFH is the traditional method of heparin administration in acute VTE in pregnancy and may still be preferred in massive pulmonary embolism (PTE) because of its rapid effect.