Enoxaparin treatment in women with mechanical heart valves during pregnancy

OBJECTIVE: This prospective audit reports pregnancy outcomes, anticoagulation complications, and anti-Xa levels in women with mechanical heart valves who were treated with therapeutic enoxaparin plus aspirin during pregnancy. STUDY DESIGN: Between 1997 and 1999, 11 women with mechanical heart valves were treated with enoxaparin, 1 mg/kg twice daily, and aspirin, 100 to 150 mg daily during 14 pregnancies. Predose and 4-hour postdose anti-Xa levels were monitored monthly. RESULTS: There were 9 live births, 3 miscarriages, and 2 terminations. In 48 months of enoxaparin treatment, one woman who had a documented valve thrombosis when she presented at 8 weeks' gestation also had a valve thrombosis at 20 weeks' gestation. There were no enoxaparin-related hemorrhagic complications. Mean (SD) anti-Xa levels were 0.46 (0.12) U/mL predose and 0.89 (0.22) U/mL 4 hours postdose. CONCLUSION: Successful pregnancy outcome may be achieved with therapeutic subcutaneous enoxaparin, but its efficacy at preventing valve thrombosis remains uncertain. Further data are required before use of enoxaparin during pregnancy in women with mechanical heart valves can be recommended.     

Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series

Objectives To assess the use of low molecular weight heparin for the treatment of venous thromboembolism in pregnancy.
Design A prospective observational study.
Setting The maternity units in two university teaching hospitals and one district general teaching hospital.
Population Thirty-six consecutive women presenting with objectively diagnosed venous thromboembolism during pregnancy and the immediate puerperium.
Methods Treatment with the low molecular weight heparin enoxaparin, approximately 1 mg/kg sc, twice daily, based on early pregnancy weight.
Main outcome measures Peak anti-Xa activity (three hours post-injection), alterations in treatment, side effects and the use of regional anaesthesia.
Results In 33 women, the initial dose of enoxaparin provided satisfactory peak anti-Xa activity (median 0.8 u/mL, range 0.44–1.0 u/mL) and was continued. Three women required dose reduction since peak anti-Xa activities were above the therapeutic range (1.2, 1.2 and 1.1 u/mL). No woman developed thrombocytopaenia, haemorrhagic complication or further thromboembolic episode. Two women developed allergic skin reactions on enoxaparin and were changed to tinzaparin. Fifteen women had regional anaesthesia for delivery, with a reduced dose of enoxaparin (40 mg once daily), all without complication.
Conclusions Enoxaparin is a safe and effective treatment for venous thromboembolism during pregnancy and confers a major advantage over unfractionated heparin through its simplified regimen of administration.     

Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy

Objective To assess the safety and efficacy of enoxaparin use for thromboprophylaxis or treatment of venous thromboembolism during pregnancy.
Design Retrospective review of casenotes of women who received enoxaparin during pregnancy.
Setting Obstetric Medicine Unit at Glasgow Royal Maternity Hospital.
Sample Data were obtained on 57 pregnancies in 50 women over six years.
Methods Information was obtained from case records in relation to outcome measures, the presence of underlying thrombophilia and indication for anticoagulation.
Main outcome measures Incidences of venous thromboembolism, haemorrhage, thrombocytopenia, peak plasma anti-factor Xa levels and symptomatic osteoporosis.
Results There were no thromboembolic events in the thromboprophylaxis group. There were no incidences of heparin-induced thrombocytopenia. Twenty-two women had spinal or epidural anaesthesia and no complications were encountered. There was one instance of antepartum haemorrhage following attempted amniotomy in a woman with previously unknown vasa praevia. Two women sustained postpartum haemorrhage, both secondary to vaginal lacerations, resulting in blood loss > 1000 mL. Blood loss following caesarean section was not excessive. No instances of vertebral or hip fracture were encountered. The median peak plasma anti-factor Xa level on a dose of 40 mg once daily was 0.235 U/mL; peak plasma anti-factor Xa levels were not affected by gestational age.
Conclusions The use of enoxaparin in pregnancy is associated with a low incidence of complications and a dose of 40 mg once daily throughout pregnancy provides satisfactory anti-factor Xa levels and appears effective in preventing venous thromboembolism.     

Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin.

OBJECTIVES: To determine if a prophylactic dose of dalteparin, 5000 IU daily, and if the adjusted-weight dalteparin therapeutic dose of 100 IU/kg twice daily are appropriate in pregnancy. METHOD: Anti-Xa activity levels were used to assess prophylactic (33 women) and therapeutic (15 women) dalteparin dosage throughout pregnancy. Analysis of variance was used and P-values less than 0.05 were considered statistically significant. RESULTS: In the prophylactic group, anti-Xa activity levels did not vary significantly throughout pregnancy (P=0.15). The initial dalteparin dose was modified on the first anti-Xa activity measurement in eight women, whose weight was statistically different from those remaining on the initial dose (P<0.001). The adjusted-weight therapeutic dalteparin dose induced adequate anti-Xa activity levels. CONCLUSIONS: Dalteparin, 5000 IU daily, is suitable for most pregnant women and does not need to be modified in the third trimester. A therapeutic dalteparin dose adjusted according to pregnancy weight is appropriate.     

Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy

Objective To evaluate the effect and dose of dalteparin given to pregnant women with acute venous thromboembolism.
Design An observational study of pregnant women in Norway.
Setting Delivery and haematological departments in Norway.
Population Twenty women, aged 22–41 years, with acute venous thromboembolism verified by objective means.
Methods Patients were treated with dalteparin from diagnosis until delivery. Treatment was monitored with anti-activated factor Xa (anti-Xa) activity, and the dose was adjusted to achieve target 0.5–1.0 U/mL 2–3 hours post-injection.
Main outcome measure Anti-Xa activity and side effects.
Result None of the patients suffered recurrent venous thromboembolism or major bleeding complications. In 9 of 13 women starting with conventional dose of dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa activity. None of the six women who started with 105–118 iu/kg bd required dose escalation. One woman who started with 133 iu/kg bd required dose reduction. Bioaccumulation of dalteparin was not observed.
Conclusion Our study suggests that dalteparin may be used for the treatment of acute venous thromboembolism in pregnancy. Approximately 10–20% higher doses of dalteparin may be needed as compared with non-pregnant individuals.     

A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation

OBJECTIVE: The purpose of this study was to determine whether standard therapeutic doses of dalteparin maintain peak therapeutic levels of anticoagulation during pregnancy. STUDY DESIGN: This was a prospective trial in which 13 pregnancies that required therapeutic anticoagulation were treated with dalteparin 100 U/kg every 12 hours; peak and trough (predose) low molecular weight heparin (anti-Xa activity) levels were monitored every 2 weeks. Dosage adjustments were made to maintain peak anti-Xa activity between 0.5 and 1.0 IU/ml. Bone density and bone turnover markers were measured. RESULTS: A total of 250 peak and trough low-molecular-weight heparin (LMWH) levels were obtained. Eighty-five percent of pregnancies (11/13) required an upward dosage adjustment. Trough levels were in the therapeutic range only 9% of the time, despite the maintenance of therapeutic peak levels. Bone resorption markers and density were unchanged in singleton pregnancies. CONCLUSION: Dalteparin dosing, based on weight alone, every 12 hours is inadequate to maintain most pregnant women in the therapeutic range throughout pregnancy as measured by anti-Xa activity. Trough levels are rarely in the therapeutic range, despite maintenance of therapeutic peak levels. These notable changes in low molecular weight heparin peak may explain reported failures in pregnancy.     

Prophylactic dosing adjustment in pregnancy based upon measurements of anti-factor Xa levels.

OBJECTIVE: To determine the necessity for monitoring of anti-factor Xa levels in pregnant women taking low molecular weight heparin (LMWH). STUDY DESIGN: A review of a hematological database with chart review was undertaken to identify patients on LMWH. Levels were drawn monthly. They were considered suboptimal if prophylactic and therapeutic doses of LMWH had an anti-Xa value <0.2 U/mL and 0.6 U/mL, respectively. Variables of interest included age, parity, thrombophilias, and antiphospholipid antibody syndrome. RESULTS: Of 30 patients, three required therapeutic-dose LMWH and 27 were on prophylaxis. Sixty-six percent on a therapeutic dose required a dose change, whereas 11% on a prophylactic dose were changed (p = 0.013). None of the variables were predictive of a need for change. One thromboembolic event was noted while on prophylactic-dose LMWH. CONCLUSIONS: No single variable is predictive of a need for dose change. Patients on a therapeutic dose were more likely to need change.     

Anti-factor Xa plasma levels in pregnant women receiving low molecular weight heparin thromboprophylaxis

OBJECTIVE: To report the incidence of prophylactic, subprophylactic, and supraprophylactic anti-factor Xa activity in pregnant patients receiving low molecular weight heparin for venous thromboembolism prophylaxis, and to evaluate whether maternal weight, body mass index, age, gestational age, or the low molecular weight heparin dose correlated with anti-factor Xa levels. METHODS: We reviewed 321 anti-factor Xa levels in 77 patients from one Maternal-Fetal Medicine faculty practice. All patients were administered low molecular weight heparin that subsequently was adjusted based upon serial assessment of peak plasma (at 4 hours postinjection) anti-factor Xa levels at less than 36 weeks gestation. Targeted prophylactic range of peak plasma anti-factor Xa level was 0.2-0.4 units/mL. RESULTS: Only 59% of anti-Xa concentrations were in the prophylactic range, whereas 26% were subprophylactic, and 15% were supraprophylactic. Anti-Xa values were not significantly more likely to be prophylactic in early compared with late pregnancy, obese compared with nonobese patients, or in patients receiving a weight-based minimal dose compared with patients receiving less than a weight-based minimal dose. Anti-factor Xa levels did not correlate with maternal age, weight, body mass index, or gestational age, but there was a positive correlation with the percent of the minimal weight-based dose. CONCLUSION: Even with enhanced low molecular weight heparin dosing, 26% of patients have subprophylactic anti-factor Xa levels. Serial anti-factor Xa assessment for dose adjustment should be considered for all pregnant women receiving low molecular weight heparin.     

Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies

Objective To assess the maternal, fetal and neonatal safety of enoxaparin in pregnant women who require antithrombotic therapy.
Design Retrospective analysis of case notes of women who received enoxaparin during pregnancy, irrespective of dose, duration and reason for treatment.
Setting Fifty-five French perinatal centres.
Sample Data from 624 pregnancies in 604 women between 1988 and 1997. The incidence of previous thromboembolism was 29.8%, known thrombophilia 15.2%.
Methods Indication, regimen of enoxaparin and outcome measures were reported for each pregnancy. Information was obtained from case records, validated by research staff and analysed by an independent scientific committee.
Main outcome measures Incidence, seriousness and causality of maternal, fetal and neonatal adverse events, pregnancy outcome, and incidence of venous thromboembolism.
Results Enoxaparin was administered for treatment of an acute episode in 49 cases and for thromboprophylaxis in 574 cases. Serious maternal haemorrhage occurred in 11 cases during pregnancy (1.8%), one being reasonably related to enoxaparin, and in nine cases at delivery (1.4%), all unrelated to enoxaparin. Maternal thrombocytopenia was reported in 10 cases (1.6%), two being serious but unrelated to enoxaparin. Eight pregnancies ended in stillbirth (1.1%). Among the 693 live births, 17 major congenital abnormalities (2.5%) and 10 serious neonatal haemorrhages (1.4%) were reported. None of the fetal or neonatal adverse events was related to enoxaparin. Eight venous thromboembolic events (1.3%) were reported.
Conclusions The incidence of adverse events reported could be explained by the high risk profile of the study population. Overall, this retrospective study suggests enoxaparin is well tolerated during pregnancy.     

Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin

Low molecular weight heparins are used extensively for thromboprophylaxis. The aim of this study was to compare the activity of the low molecular weight heparin, enoxaparin, 20 mg and 40 mg, given once per day with unfractionated heparin, 7500iu given twice per day, in terms of their anti-Xa activity in puerperal women following caesarean section and with an additional risk factor for venous thromboembolism. Seventeen women were randomised to receive one of the three treatments. The anti-Xa activity associated with each treatment was measured prior to treatment and at 2, 4, 6, 12 and 24 hours. The mean anti-Xa values of the groups receiving enoxaparin, 20mg and 40mg, were significantly higher than those of the group receiving unfractionated heparin. There was no difference between the two enoxaparin groups in terms of the anti-Xa activity profiles. This study suggests that the use of enoxaparin is superior to unfractionated heparin in terms of anti-Xa activity.     

Elevated amniotic fluid leptin levels in early second trimester are associated with earlier delivery and lower birthweight in twin pregnancy

OBJECTIVE: To explore the possibility of using early second trimester amniotic fluid leptin levels as a predictor of pregnancy outcome in twin pregnancy. STUDY DESIGN: Amniotic fluid leptin levels from 18 twin-pregnant women in early second trimester were analyzed for their correlation with gestational age at delivery and fetal birthweight. Leptin levels in 16 amniotic fluid samples collected from small for gestational age (SGA) twin pregnancies were compared with those in 20 amniotic fluid samples collected from non-SGA twin pregnancies. RESULTS: A significant correlation was observed between amniotic fluid leptin levels and gestational age at delivery (r = 0.71, p < 0.001) as well as fetal birthweight (r = 0.72, p < 0.001). There was also a significant correlation between gestational age at delivery and fetal birthweight (r = 0.92, p < 0.001). The average gestational age at delivery was 30.4 +/- 1.4 weeks in the SGA group, with a mean birthweight of 1552 +/- 200 g at delivery. For the non-SGA group, the values were 37.3 +/- 0.5 weeks and 2759 +/- 115 g ( p < 0.001), respectively. Amniotic fluid leptin levels were found to be significantly higher ( p < 0.001) for women in the SGA group (11.4 +/- 1.5 ng/mL) than for those in the non-SGA group (5.4 +/- 0.5 ng/mL). CONCLUSION: Higher amniotic fluid leptin levels in early second trimester were associated with both lower gestational age at delivery and lower birthweight. Our results suggest that amniotic fluid leptin levels in early second trimester may be a good marker for the prediction of perinatal complications in twin pregnancy.     

Maternal serum Ca125 and Ca15-3 antigen levels in normal and pathological pregnancy

OBJECTIVE: To evaluate the value of maternal serum CA125 and CA15-3 concentrations for discriminating pathological from normal pregnancies. METHODS: Serum samples from 120 women, in whom pregnancy outcome was pathological, i.e. spontaneous abortion, fetal death, intrauterine growth retardation, chromosomal and structural abnormalities, and (pre)eclampsia, were assessed for CA125 and CA15-3 and compared with levels found in 350 women with a normal pregnancy outcome matched for age and duration of pregnancy. RESULTS: Maternal CA125 serum values were significantly higher in the first and the third trimester of pregnancy (median 23.0 and 21.0 U/ml; p < 0.00001 and p < 0.001, respectively), compared to those in the second trimester (median 14.0 U/ml), but not significantly different from those obtained in pathological pregnancies. Maternal serum CA15-3 values were significantly higher during the third trimester (median 26.0 U/ml) compared to the first and second trimester of pregnancy (median 14.0 and 15.0 U/ml; p < 0.0001); CA15-3 serum levels in normal and pathological pregnancies showed no significant difference. CONCLUSION: Maternal serum levels of CA125 are higher during the first and third trimester of pregnancy. CA15-3 maternal serum levels are higher during the third trimester compared to the first and second trimester. Maternal CA125 and CA15-3 serum levels showed no relation with a pathological outcome of pregnancy.     

Tinzaparin sodium for thrombosis treatment and prevention during pregnancy

OBJECTIVE: This study was undertaken to assess the pharmacodynamic profile, safety, and efficacy of tinzaparin during pregnancy. STUDY DESIGN: Fifty-four pregnant women, 12 for treatment of thrombosis and 42 for thromboprophylaxis, received tinzaparin by once daily injection. Four-hour postdose anti-Xa results were analyzed by use of repeated measures statistical methods. RESULTS: One woman (3.4%) on the 175 anti-Xa U/kg dose and three women (20%) on the 50 anti-Xa U/kg dose required a dose increase during the initial dose titration phase to achieve target anti-Xa activity. No thrombotic events occurred. CONCLUSION: The 175 anti-Xa U/kg dose is appropriate for treatment and for high-risk thromboprophylaxis throughout pregnancy. In pregnant women at moderate risk of thrombosis, a higher tinzaparin dose is required than in the nonpregnant state and 75 anti-Xa U/kg appears to be appropriate. The majority of women do not need a dose increase with advancing gestation.     

Inherited thrombophilias and anticoagulation in pregnancy

Thromboprophylaxis, primary or secondary, should be considered in selected pregnant women with inherited thrombophilias; such women may be divided into high-, medium- and low-risk categories on the basis of the specific thrombophilic defect and any personal or family history of venous thromboembolism (VTE). Women at high risk of VTE should receive treatment doses of low-molecular-weight heparin (LMWH) throughout pregnancy and should remain on anticoagulation for 6 weeks postpartum, or, where appropriate, long-term. Women at moderate risk should be treated with prophylactic fixed-dose LMWH throughout pregnancy and for 6 weeks postpartum. Women at low risk should receive prophylactic fixed-dose LMWH for 6 weeks postpartum, and low-dose aspirin LDA should be considered during pregnancy. LWMH offers important advantages over unfractionated heparin (UFH); heparin-induced thrombocytopaenia (HIT) and osteopaenia are rarely seen. For treatment doses of LMWH, dosage adjustment based on anti-Xa levels is usually required as pregnancy progresses. Warfarin should be avoided throughout pregnancy. LMWH, UFH and warfarin are safe for breast-feeding mothers.     

Heparin levels to guide thromboembolism prophylaxis during pregnancy

OBJECTIVE: Our purpose was to determine the dose of heparin required in pregnant women to achieve the same heparin levels as standard doses of 5000 units given subcutaneously every 12 hours in the nonpregnant population.STUDY DESIGN: Fourteen pregnant women placed on heparin prophylaxis for a history of thromboembolism had blood drawn for 64 anti-Xa level determinations in the second and third trimesters. Heparin doses were adjusted in an attempt to achieve a midinterval or peak level of 0.05 to 0.25 U/ml, which corresponds to the range seen in nonpregnant patients given standard doses of 5000 units subcutaneously every 12 hours.RESULTS: A standard heparin dose of 5000 units given subcutaneously every 12 hours was inadequate to achieve the desired range in this pregnant population. In five of nine second-trimester pregnancies 7500 units given subcutaneously every 12 hours was inadequate to attain this range. In six of 13 third-trimester pregnancies, > 10,000 units subcutaneously every 12 hours was needed.CONCLUSIONS: Heparin requirements may increase and are highly variable in patients during pregnancy. Until appropriate clinical outcomes trials can determine optimal dosing, measuring anti-Xa activity may be useful to guide therapy.     

Maternal CA 125 serum level in intrauterine pregnancy and abortion in the first trimester

OBJECTIVE: Maternal CA 125 levels are supposed to rise in pregnancies complicated by vaginal bleedings in dependence to the extent of decidual disruption which is directly related to the outcome of pregnancy. MATERIAL AND METHODS: The prognostic value of maternal CA 125 serum measurement was investigated in 239 women with a first trimester intact pregnancy, imminent, incomplete, complete or missed abortion. RESULTS: 43.9% of the CA 125 serum levels were without normal range (> 20 U/ml). Mean CA 125 serum levels were higher in patients with incomplete (52.4 +/- 67.4 U/ml), complete (34.3 +/- 46.1 U/ml), and imminent abortion (33.0 +/- 45.8 U/ml) as compared with normal pregnancies (28.9 +/- 28.8 U/ml) and missed abortion (23.5 +/- 21.5 U/ml). CA 125 levels in first trimester pregnancies tended to be higher in patients with vaginal bleedings than in patients without bleeding (40.5 U/ml +/- 55.0 vs. 28.9 U/ml +/- 28.8; p = 0.65). CONCLUSIONS: For clinical use CA 125 serum measurement is not relevant. First trimester CA 125 measurement can not serve as an accurate predictor of pregnancy outcome due to the wide overlap of ranges.     

Inherited thrombophilia: treatment during pregnancy

OBJECTIVE: Inherited thrombophilia is associated with thromboembolic events and/or poor obstetric outcome. We evaluated the pregnancy outcome in women with inherited thrombophilia treated with low-molecular-weight heparin (LMWH). METHODS: 38 thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome were treated during their 39 consecutive pregnancies with LMWH from pregnancy verification until 4-6 weeks in puerperium. A fixed dose of enoxaparin 4,000 IU/day (except 1 case who required nadroparin 0.3 ml/day) was administered in most cases, adopting a higher dose (6,000 IU/day to 6,000 IU twice a day) in those with previous thromboembolic events. RESULTS: In the treated women, all had a good obstetric outcome, whereas in the previous untreated pregnancies (n = 78), the rate of fetal loss (early and late) was 76.9%, only 12 live infants survived (66.6%). Moreover, birth weight resulted significantly higher in live infants born to treated pregnancies in comparison to that of previous untreated pregnancies (p = 0.009). No maternal thrombosis or major bleeding complications were recorded. CONCLUSIONS: The treatment with LMWH improved pregnancy outcome resulting effective and safe in thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome.     

Treatment of deep venous thrombosis in pregnant women

The recommended dosage of tinzaparin in the treatment of thromboembolism during pregnancy is 175 IU/kg/day, as for non-pregnant subjects. In clinical practice, we have experienced a need for a higher dosage, especially in the initial phase of the treatment of deep vein thrombosis, based on four-hour post-dose measurements of anti-Xa activity. Twenty-two pregnant patients with a confirmed deep venous thrombosis were treated with tinzaparin either in a once- or twice-daily regimen. Four-hour post-dosage plasma anti-Xa activity was measured in 357 sequential blood samples during treatment. An higher dosage than recommended, was required to maintain anti-Xa activity in the target range. We suggest that the starting dosage should be 250 IU/kg/day in a twice-daily regimen, and that the dose in the initial phase be adjusted by daily monitoring of anti-Xa.     

Serum concentration of CA-125 during the first trimester of normal and abnormal pregnancies

A prospective study was initiated to closely examine maternal serum concentrations of CA-125 during the early first trimester of normal and abnormal pregnancies. Sequential serum specimens were obtained from 43 women with a normal intrauterine pregnancy, 20 with a surgically confirmed ectopic gestation and 10 whose pregnancies ended in spontaneous abortion. In normal pregnancies the CA-125 levels increased significantly from the first week after the missed menses (39.9 +/- 8.2 U/mL [mean +/- SEM]) to the second week (48.3 +/- 6.9 U/mL) (P less than .05) and from the second to the third week (62.5 +/- 9.8) (P less than .05). After the third week after the missed menses the mean CA-125 serum concentrations plateaued, but levels observed during the fourth (59.6 +/- 8.8 U/mL) and fifth (48.8 +/- 7.2 U/mL) weeks were still significantly greater than at week 1. In addition, the mean CA-125 concentrations were significantly higher in normal pregnancies than in ectopic gestations during the second, third and fourth weeks after the missed menses. Although there was a tendency for the CA-125 levels to be lower in women who had a spontaneous abortion when compared to normals, these differences were not statistically significant. Serum levels of CA-125 may prove useful in monitoring early pregnancy.     

Management of pregnancy with congenital antithrombin III deficiency: two case reports and a review of the literature.

Women with antithrombin (AT) III deficiency are prone to pregnancy-associated venous thromboembolism. We report 2 cases with genetically confirmed ATIII deficiency, one with a mutation in exon 3A and the other with an exon 4 deletion, in whom the pregnancies were successfully managed with prophylactic therapies for thrombosis. A 35-year-old pregnant woman was treated with intravenous infusions of ATIII concentrate alone, and the other 22-year-old pregnant woman was mainly treated with subcutaneous injections of heparin and oral low-dose aspirin therapy. Both pregnancies resulted in vaginal deliveries of healthy neonates. The literature concerning prophylactic therapies for thrombosis in ATIII deficiency-complicated pregnancy is reviewed, and the clinical problems, including the adverse effects of the therapies, are discussed.