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.     

Is the monitoring of anti-Xa activity necessary in pregnant women undergoing thromboprophylaxis?

Thromboprophylaxis is increasingly advocated in pregnancy for certain clinical conditions. Low molecular weight heparins offer potential benefit over unfractionated heparins with increased bioavailability and a longer half-life, thus allowing for once daily administration. This study aims to determine if monitoring of anti-Xa activity is necessary in pregnant women undergoing thromboprophylaxis. Twenty-five pregnancies were prospectively followed where either tinzaparin or enoxparin was employed for thromboprophylaxis. Once the anti-Xa levels were in the thromboprophylactic range (0.03-0.5 U/ml) no patient required a change of dose. Frequent monitoring of Anti-Xa levels, once in the thromboprophylactic range, may not be required.     

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.     

Prophylactic and therapeutic enoxaparin during pregnancy: indications, outcomes and monitoring

OBJECTIVES: To evaluate the efficacy and safety of prophylactic and therapeutic enoxaparin in pregnancy. STUDY DESIGN: Three-year prospective audit. SETTING: Tertiary level obstetric hospital. POPULATION: Fifty-two women who received subcutaneous enoxaparin, either a prophylactic dose (40 mg daily) in 26 pregnancies or therapeutic dose (1 mg/kg twice daily) in 32 pregnancies. MATERIALS AND METHODS: Pregnant women treated with enoxaparin were prospectively entered into a register. Data were retrieved by case note review. MAIN OUTCOME MEASURES: Pregnancy outcomes, treatment complications and anti-Xa levels. RESULTS: In the prophylactic group there were no fetal losses, thromboembolic events or complications related to enoxaparin. In the therapeutic group there were four first trimester miscarriages, a termination and 27 live births. Therapeutic enoxaparin prevented further thromboembolism without complications. One woman was treated with intermediate dose enoxaparin when she presented at 5 weeks' gestation on warfarin and 7 weeks after a venous thromboembolism. She developed a recurrent pulmonary embolus 3 weeks later and was subsequently treated with therapeutic enoxaparin. In the therapeutic group the enoxaparin dose/kg correlated poorly with anti-Xa levels, and dose adjustments were made. Therapeutic mean (SD) trough and peak anti-Xa levels were 0.33 U/mL (0.14) and 0.86 U/mL (0.24) in the first trimester and 0.48 U/mL (0.19) and 0.84 U/mL (0.23) in the third trimester. CONCLUSIONS: In the present series, prophylactic and therapeutic enoxaparin treatment during pregnancy was effective and safe. Studies are required to determine the optimal duration of treatment with therapeutic enoxaparin following venous thromboembolism in pregnancy and the clinical relevance of anti-Xa monitoring.     

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.     

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.     

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.     

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.     

Venous thromboembolism as a cause of severe maternal morbidity and mortality in the United States

In the U.S., deaths due to pulmonary embolism (PE) account for 9.2% of all pregnancy-related deaths or approximately 1.5 deaths per 100,000 live births. Maternal deaths and maternal morbidity due to PE are more common among women who deliver by cesarean section. In the past decade, the clinical community has increasingly adopted venous thromboembolism (VTE) guidelines and thromboprophylaxis recommendations for pregnant women. Although deep vein thrombosis rates have decreased during this time-period, PE rates have remained relatively unchanged in pregnancy hospitalizations and as a cause of maternal mortality. Changes in the health profile of women who become pregnant, particularly due to maternal age and co-morbidities, needs more attention to better understand the impact of VTE risk during pregnancy and the postpartum period.     

Low-molecular-weight heparins for the prevention and treatment of venous thromboembolism in at-risk pregnant women: a review

Certain pregnant populations are at high risk of developing venous thromboembolism (VTE) during pregnancy. Patients at particularly high risk of VTE are those with a history of VTE, thrombophilia or adverse pregnancy outcomes or with mechanical heart valves. In these high-risk patients, evidence-based guidelines recommend the use of thromboprophylaxis. Low-molecular-weight heparin (LMWH) is a safe and effective thromboprophylaxis option in these patients and has a number of administrative and pharmacokinetic advantages over unfractionated heparin. Furthermore, LMWH has also been shown to be a safe and effective treatment for confirmed deep vein thrombosis in pregnant women.     

Thromboembolic risk in pregnant women with SARS-CoV-2 infection – A systematic review

The infection by SARS-CoV-2 is associated with a thromboembolic complications risk theoretically increased. Pregnancy, isolated, is considered a pro-thrombotic state.This systematic review has the main goal to evaluate the thromboembolic risk in pregnant women with COVID-19 disease, namely for pulmonary embolism (PE) and deep vein thrombosis (DVT). The secondary goal is the evaluation of the need for thromboprophylaxis in these cases.Three databases - PubMed, Scopus and Web of Science – were searched on October 2021, using the following Mesh terms and keywords: “(covid-19 OR SARS-CoV-2 OR Covid) AND (pregnancy) AND (coagulopathy OR blood coagulation disorders OR thrombotic complications OR thromboembolic risk OR venous thromboembolism OR venous thrombosis)”. Information about thrombotic complications in pregnancy and thromboprophylaxis was collected, by two independent reviewers.In total, 12 articles were analyzed, corresponding to 18205 pregnant women with SARS- CoV-2 infection. A total of 85 cases of thromboembolic events were diagnosed (0.46%, 95% CI 0.37–0.58%), of which only 17 reported the use of thromboprophylaxis (20.00%, 95% CI 12.10–30.08%). There were 3 deaths due to thromboembolic complications (3.53%, 95% CI 0.73–9.97%).In conclusion, in pregnant women, the SARS-CoV-2 infection increases the risk of thromboembolic complications. However, the risk is not greater than in the general population. It is recommended thromboprophylaxis with low molecular weight heparin for hospitalized pregnant women, and in groups with moderate to high thromboembolic risk at home self-isolation.     

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.     

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.     

Acute iliac vein thrombosis in pregnancy treated successfully by streptokinase lysis: a case report

BACKGROUND: Postthrombotic syndrome is an important late complication after deep vein thrombosis in pregnancy. Thrombolytic agents are more efficient in preventing this condition but are rarely used in pregnant women. CASE: A 22-year-old woman at 29 weeks of gestation presented with acute iliac vein thrombosis. After application of a heparin bolus, systemic streptokinase lysis was performed. Low-dose heparin therapy was continued for the remainder of the, otherwise unremarkable, pregnancy. Spontaneous delivery of a healthy girl was without complications and thromboprophylaxis with low-molecular heparin was continued. CONCLUSION: Thrombolysis in pregnancy is possible and may help to prevent severe long-term sequelae of thrombosis in young women. Bleeding is a major risk, which must be considered and therapy should only be administered under close observation.     

妊娠合并甲状腺功能低减患者的临床分析

目的 探讨妊娠合并甲状腺功能低减(甲减)患者的围产期发病率、药物治疗剂量及母婴结局.方法 收集我院1995年1月-2006年5月收治的31例妊娠合并甲减患者的临床资料,31例患者均在产科高危门诊定期保健,每1.0～1.5个月监测1次甲状腺功能,并与内分泌科合作调整患者的左旋甲状腺素剂量.对患者的围产期保健、药物治疗量及母婴结局进行回顾性分析.结果 (1)发病率:我院近11年来妊娠合并甲减的发病率为1.27‰(31/24 327)[0.19‰(1/5251)～2.32‰(15/6456)].(2)左旋甲状腺素用量:左旋甲状腺素的平均剂量孕前、孕早期、孕中期、孕晚期、产后分别为(33±35)、(51±36)、(68±42)、(76±42)、(38±34)μg/d,孕早期及产后与孕前比较,差异无统计学意义(P＞0.05);孕中期及孕晚期与孕前比较,左旋甲状腺素应用量明显增加,差异有统计学意义(P＜0.05),整个孕期的左旋甲状腺素平均用量比孕前增加约35%.(3)妊娠结局:31例患者中有5例妊娠期糖代谢异常,发生率为16%(5/31);1例胎儿六指畸形,1例新生儿窒息(Apgar评分1分钟7分,5分钟10分);31例患者中无一例围产儿死亡,无新生儿先天性甲减.结论 妊娠合并甲减发病率逐年升高.孕期需及时增加左旋甲状腺素用量,对改善妊娠合并甲减患者的妊娠结局具有良好的治疗作用.     

Safety and effectiveness of tinzaparin sodium in the management of recurrent pregnancy loss

PURPOSE: To assess the safety and efficacy of tinzaparin sodium for the management of recurrent pregnancy loss. METHODS: The study included 62 women with a history of recurrent pregnancy loss and at least one factor of thrombophilic disorder. Of these, 31 received 50 IU/kg of tinzaparin sodium daily (Group A), and 33 received 100 mg of aspirin daily (Group B). RESULTS: Group A subjects (receiving tinzaparin sodium) had six new abortions, whereas Group B subjects (receiving aspirin) had 11 (significant difference). Cases of intrauterine growth restriction (none in Group A and 2 in Group B), placental abruption (one in Group A and 4 in Group B), and preeclampsia (one in Group A and 3 in Group B) were comparable between the two groups. Finally coagulation disorders (none in Group A and 6 in Group B) were significantly fewer in Group A. CONCLUSION: A 50 IU/kg daily dose of tinzaparin sodium seems to be effective for the management of recurrent abortion and has high standards of safety.     

Risk of venous thrombo-embolic events in pregnant patients with cancer

Objective: Venous thromboembolism (VTE) is one of the leading causes of pregnancy-associated death in the Western world. Cancer is a known risk factor for thrombosis outside of pregnancy. The objective of this study is to evaluate the effect of cancer on the risk of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) in pregnancy.

Methods: We conducted a retrospective population-based cohort study using the Health Care Cost and Utilization Project database from 2003 to 2011. Risk of developing DVT, PE and VTE among pregnant patients with the 10 most prevalent malignancies was measured using unconditional logistic regression analysis.

Results: A total of 2826 women were identified with underlying malignancies, among our study cohort of 7?917?453 women. Risk of VTE was increased among pregnant patients with cervical cancer (OR 8.64, 95% CI (2.15–34.79)), ovarian cancer (OR 10.35, 95% CI (1.44–74.19)), Hodgkin’s disease (OR 7.87, 95% CI (2.94–21.05)) and myeloid leukemia (OR 20.75, 95% CI (6.61–65.12)). There was no increased risk of VTE among women with brain cancer, thyroid cancer, melanoma and lymphoid leukemia.

Conclusion: Many cancers may increase risk of VTE in pregnancy. Appropriate thromboprophylaxis should be considered in some of these women, particularly those with hematological malignancies and gynecologic cancers.     

A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy

OBJECTIVE: To assess the maternal response to low molecular weight heparin during pregnancy, by estimation of plasma anti-Xa activity, at three specified gestation points and in the nonpregnant state. METHODS: A longitudinal, prospective, observational study was set in a tertiary referral recurrent miscarriage clinic. Twenty-four women, attending consecutively, were invited to participate and gave informed consent. Each woman had a history of recurring pregnancy loss and positive preconception screening for antiphospholipid syndrome. After confirmation of a viable pregnancy all subjects began taking 5000 IU of dalteparin once daily subcutaneously. Serial measurement of plasma anti-Xa activity after administration of dalteparin was performed at three standard gestation points (12, 24, and 36 weeks) and in the nonpregnant state (6 weeks postpartum). RESULTS: Peak anti-Xa levels occurred at 4 hours postbolus in pregnancy, as compared with 2 hours in the nonpregnant state. The mean anti-Xa levels at 12, 24, and 36 weeks' gestation were significantly reduced, at 2 hours postinjection, as compared with the nonpregnant state (P <.001, P <.01, P <.001, respectively). The lowest dose-response curve was at 36 weeks' gestation. A repeated-measures analysis of variance found a significant difference (P <.05) between the 36-week group and the postterm group but not between any of the other groups. CONCLUSION: During pregnancy, differences in the pharmacokinetics of low molecular weight heparin were observed, with an overall reduction in anti-Xa activity. On the basis of this study it is questionable to extrapolate dosing and lack of dose monitoring, in pregnant women, using data derived from a nonpregnant population.     

PREVENTION AND TREATMENT OF VENOUS THROMBOEMBOLISM (VTE) IN OBSTETRICS

OBJECTIVE: to identify risk factors for venous thromboembolism (VTE) in the peripartum period and to provide guidelines for risk assessment and thromboprophylactic measures for VTE in pregnant women. Guidelines for diagnostic testing and for acute and long term treatment of VTE are also provided.OPTIONS: specific subgroups of pregnant women are defined and appropriate prophylactic measures are outlined. OUTCOMES: venous thromboembolism remains a major cause of morbidity and mortality in pregnancy and the postpartum period. Identification of risk and adequate prophylaxis can decrease the incidence of VTE.EVIDENCE: evidence was gathered using Medline (National Library of Medicine) to identify relevant studies and from bibliographies of articles thus identified.RECOMMENDATIONS: although evidence is lacking to date from Grade I studies (properly controlled randomized studies) in pregnant patients, there is good evidence to support the role of prophylaxis in reducing the incidence of VTE in patients identified to be at risk in the non-pregnant population (II B). Based on risk assessment more patients should be considered for thromboprophylaxis, including women with a past history of a VTE and a known thrombophilia on long-term anticoagulation, women with a past history of a VTE, women with a known thrombophilia who have never experienced a VTE and potentially considered in women at the time of Caesarean section (II B; III C). The occurrence of VTE is effectively reduced by the use of low dose unfractionated heparin. Experience with low molecular weight heparin and pregnancy is building, but is limited at present. Unfractionated heparin remains the standard for the treatment of VTE in pregnancy at the present time. Following initial heparinization for the treatment of VTE, patients should be continued on anticoagulation throughout pregnancy and for six to 12 weeks postpartum or a total of three months of anticoagulation (II A).