Skip to main content

Guidance for the treatment and prevention of obstetric-associated venous thromboembolism

Abstract

Venous thromboembolism (VTE), which may manifest as pulmonary embolism (PE) or deep vein thrombosis (DVT), is a serious and potentially fatal condition. Treatment and prevention of obstetric-related VTE is complicated by the need to consider fetal, as well as maternal, wellbeing when making management decisions. Although absolute VTE rates in this population are low, obstetric-associated VTE is an important cause of maternal morbidity and mortality. This manuscript, initiated by the Anticoagulation Forum, provides practical clinical guidance on the prevention and treatment of obstetric-associated VTE based on existing guidelines and consensus expert opinion based on available literature where guidelines are lacking.

Introduction

Venous thromboembolism (VTE), which may manifest as pulmonary embolism (PE) or deep vein thrombosis (DVT), complicates 0.5–2.2 per 1000 deliveries, depending on the population studied [18]. During pregnancy, the risk of VTE is increased five to tenfold compared to non-pregnant women of comparable age [1, 9, 10]. The postpartum period poses a higher risk [1, 7, 10] and during this time frame, the daily risk of VTE is increased 15- to 35-fold compared to age-matched non-pregnant women [1, 9]. The daily risk of pregnancy-associated VTE appears greatest during the first 3–6 weeks postpartum [1, 7]. After that, the risk declines rapidly, although a small residual risk increase may persist for 12 weeks after delivery [7, 10, 11]. Although the absolute VTE rates are low, pregnancy-associated VTE is an important cause of maternal morbidity [1214] and mortality [15, 16].

The treatment and prevention of pregnancy-associated VTE is challenging because of the potential for both fetal and maternal complications, as well as the paucity of relevant high quality research. Although evidence-based guideline recommendations for the use of anticoagulants in this patient population have been published [1725], they are based largely upon observational studies and extrapolated from data in non-pregnant patients. The lack of high quality data specific to pregnancy results in a lack of consistency in their recommendations. This chapter reviews the published evidence base and uses that information, as well as published guidelines, to provide practical guidance for the management and prevention of VTE during pregnancy.

Methods

The goal of this chapter is to provide guidance to providers on how best to individualize care to patients with pregnancy-associated VTE, with specific focus on the questions listed in Table 1. Questions were developed by consensus from the authors. To address these questions, current guidelines from the American College of Obstetricians and Gynecologists (ACOG) [17, 18], the Society of Obstetricians and Gynaecologists of Canada (SOGC) [19], the Royal College of Obstetricians and Gynaecologists (RCOG) [20, 21], clinicians from Australia and New Zealand [22], and American College of Chest Physicians (ACCP) [2325] were reviewed and relevant recommendations were extracted (Tables 2A–2D). The literature was reviewed and data from relevant systematic reviews, randomized trials, and observational studies were incorporated. The authors’ consensus interpretation of these studies, in the context of the realities of VTE care, was distilled into the practical recommendations that are presented in this article.

Table 1 Guidance questions to be considered
Table 2A Guideline summary—anticoagulant choice
Table 2B Guideline summary—management of acute venous thromboembolism
Table 2C Guideline summary—prevention of first and recurrent pregnancy-associated VTE
Table 2D Guideline summary—anticoagulant management around the time of delivery

In making recommendations regarding the need for prophylaxis, the panel used a risk threshold of 3 % and greater for antepartum prophylaxis and 3 % and greater for postpartum prophylaxis. For risk factors for which only case control data are available, a relative risk of at least 30-fold antepartum and 60-fold postpartum are required to reach our thresholds, assuming antepartum and postpartum baseline risks of 0.1 and 0.05 %, respectively [26]. The prophylaxis thresholds above were determined by the majority result of an anonymous vote of the authors. It is important to note that there was inconsistency between the authors in their risk threshold for recommending prophylaxis. For antepartum prophylaxis, three chose 3 % or greater, one 5 % or greater, and one 1 % or greater. For postpartum prophylaxis, four selected a threshold of 3 % or greater and one chose 1 % or greater. The variability in risk thresholds is not surprising given the limitations of the available evidence, as well as the competing benefits and drawbacks of prophylaxis. The panel would emphasize that changes in the antepartum threshold to 5 or 1 % and to the postpartum threshold to 1 % would markedly change the recommendations that follow. When making recommendations, the panel also took into account the estimated risks of major bleeding with prophylactic LMWH (antepartum: 0; 95 % CI 0–0.6 % and postpartum: 0.3 %; 95 % CI 0–1.0 %) [26]; the variability in risk estimates reported in the literature, the 95 % confidence intervals around the risk estimates, and the strengths or weaknesses of relevant study methodology in addition to the above threshold limits.

Guidance

  1. 1.

    What are the risks of anticoagulant use during pregnancy?

During pregnancy, the risks posed to the fetus by anticoagulant therapy, as well as maternal efficacy and safety must be considered. Vitamin K antagonists cross the placenta and have the potential to cause teratogenicity as well as pregnancy loss, fetal bleeding, and neurodevelopmental deficits [2734]. Discontinuation of vitamin K antagonists prior to the 6th week of gestation essentially eliminates the risk of warfarin embryopathy [29, 30, 32]. Pregnant women were excluded from participating in clinical trials evaluating the oral direct thrombin and factor Xa inhibitors (e.g. dabigatran, rivaroxaban, apixaban, edoxaban). These agents are likely to cross the placenta and their human reproductive risks are unknown [3538]. Fondaparinux appears to cross the placenta in small quantities [39]. Reports of the successful use of fondaparinux in pregnant woman have been published [3946] but it is important to recognize that many of these involve second trimester or later exposure.

Unfractionated heparin (UFH), low molecular weight heparin (LMWH) and danaparoid (a heparinoid) do not cross the placenta and are safe for the fetus [4755]. Although UFH can be used during pregnancy for both prevention and treatment of thromboembolism, LMWH has a better safety profile than UFH [56, 57] and the incidence of bleeding and other complications (e.g. heparin induced thrombocytopenia [HIT], and heparin-associated osteoporosis) are lower in pregnant women receiving LMWH than with UFH [5869]. LMWHs are eliminated primarily by renal excretion and may accumulate in patients with significant renal dysfunction. In the non-pregnant population, it has been suggested that therapeutic dose LMWH not be used in patients with significant renal impairment (e.g. a glomerular filtration rate (GFR) of less than 30 mL/min), although it is recognized that accumulation in patients with renal impairment may differ between the various LMWHs [70].

As outlined in Table 2A, there is clear consensus amongst the reviewed guideline documents that, in general, LMWH is the preferred anticoagulant for the management and treatment of VTE in pregnancy [1725].

Guidance Statement

  • Physicians should counsel women receiving long-term therapy with vitamin K antagonists and the oral direct-acting anticoagulants about the fetal risks of these medications before pregnancy occurs.

  • LMWH is the drug of choice for treatment and prevention of VTE in pregnancy, except in patients with HIT, a history of HIT, or significant renal dysfunction. UFH is preferred in patients with significant renal dysfunction.

  • For women taking vitamin K antagonists, two options are available to reduce the risk of warfarin embryopathy. The first is to advise women to perform frequent pregnancy tests and substitute LMWH for warfarin once pregnancy is achieved and before 6 weeks gestation. Alternatively, LMWH or UFH can be substituted for vitamin K antagonists before conception is attempted. Although the latter approach minimizes the risks of early miscarriage associated with vitamin K antagonist therapy, it lengthens the duration of exposure to LMWH or UFH and, therefore, is costly and exposes the patient to a greater burden of treatment associated with the use of injectable heparin therapy. Since warfarin embryopathy is unlikely to result from warfarin exposure before 6 weeks, the first option is usually favored by guidelines. Although the management of women who are receiving long-term therapy with oral direct thrombin and factor Xa inhibitors and attempting to conceive remains controversial, it has been suggested that these women should be converted to a coumarin or LMWH before conception is attempted; failing that, the switch should be made as soon as pregnancy is confirmed.

  • In pregnant women with severe cutaneous allergies to UFH or LMWH or with HIT or a history of HIT, danaparoid or fondaparinux (if danaparoid not available) may be used. Appropriate dosage and management of these anticoagulants around the time of delivery should be discussed with a hematologist or thrombosis specialist.

  1. 2.

    What are the risks of anticoagulation in breastfeeding women?

Neither warfarin, the most commonly used vitamin K antagonist in North America and the United Kingdom nor acenocoumarol, which is commonly used in Europe, is detected in breast milk and neither medication induces an anticoagulant effect in the breast-fed infant when nursing mothers consume the drug [7174]. Phenprocoumon, another vitamin K antagonist with a long half-life, is also widely used outside of North America. This agent is more lipophilic than warfarin and acenocoumarol and so can be excreted into breast milk, although since it is highly protein-bound, the amounts detected are small [75, 76]. Small amounts of LMWH have been detected in the breast milk of women receiving this medication [77]; however, given the very low bioavailability of heparin when ingested orally [78], there is unlikely to be any clinically relevant effect on the nursing infant. All of the guidelines that address the issue of anticoagulant use during breastfeeding agree that warfarin, LMWH, and UFH are safe to use in this setting (see Table 2A) [17, 2022]. Phencoumaron should be reserved for women who are unstable on short-acting acenocoumarol in countries where warfarin is not available [76].

According to the manufacturer’s prescribing information, fondaparinux was excreted in the milk of lactating rats [79]. There are no published data on the excretion of fondaparinux into human milk and the effects on the nursing infant are unknown. The manufacturer recommends that caution be used when administering fondaparinux to breastfeeding women [79]. That said, significant absorption by the nursing infant would be unlikely as orally ingested heparins have low bioavailability [78].

There are no clinical data on the effect of maternally ingested oral direct thrombin and factor Xa inhibitors on breastfed infants. The manufacturers of these agents all recommend against using these medications in breastfeeding women [3537].

Guidance Statement

  • UFH, LMWH, warfarin and acenocoumarol are safe for the breast-fed infant when administered to the nursing mother.

  • The oral direct thrombin and factor Xa inhibitors should not be used while breastfeeding.

  1. 3.

    How is venous thromboembolism during pregnancy treated?

The guideline recommendations for management of acute VTE during pregnancy are summarized in Table 2B. There have been no large studies examining the safety and efficacy of outpatient treatment of VTE diagnosed during pregnancy. Data from the non-pregnant population suggest that outpatient DVT treatment is not associated with an increase in mortality, recurrent VTE, or major bleeding [24]. In non-pregnant patients with acute DVT, outpatient treatment is recommended as long as the patient feels well enough to be treated at home (e.g. does not have severe leg symptoms or comorbidity) and has well-maintained living conditions, strong support from family or friends, telephone access, and the ability to quickly return to hospital if conditions deteriorate [24]. The safety of treating PE at home, even in the non-pregnant population, is uncertain. Prediction rules have been developed for identifying non-pregnant patients with acute PE who might be suitable for outpatient treatment because they are at low risk of serious complications [24, 80].

The results of large trials in non-pregnant patients demonstrating that LMWHs are at least as safe and effective as UFH for the acute treatment of VTE [81, 82] and as vitamin K antagonists for the prevention of recurrent VTE [83, 84], as well as data from subsequent observational studies in pregnant women, support the use of LMWH for treatment of VTE in this patient population [60, 61, 85, 86].

There are no large trials examining the optimal dose of anticoagulants for treatment of acute VTE during pregnancy. Some pharmacokinetic studies suggest that increases in GFR and in patient weight (and, hence, LMWH volume of distribution) that occur during pregnancy may lead to lower LMWH levels and that the dose of LMWH should be adjusted over the course of pregnancy to maintain “therapeutic” anti-Xa LMWH levels [87, 88], or according to changes in weight [89]. However, other researchers have demonstrated that few women require dose-adjustment when therapeutic doses of LMWH are used [9094]. Some recommend a twice-daily LMWH dosing schedule during pregnancy to compensate for increases renal clearance of this medication that occur in the second trimester. In non-pregnant patients, once daily LMWH is as safe and effective as twice daily LMWH when used to treat acute VTE [95]. Observational studies in pregnant women with acute VTE have not demonstrated any increase in the risk of recurrence with a once-daily regimen compared with twice-daily schedules [85, 86] and many clinicians use once-daily therapy to simplify administration and enhance compliance.

There are issues with reliability of anti-Xa LMWH tests [96, 97] and these assays are costly. In the absence of robust data demonstrating that there is an optimal “therapeutic anti-Xa LMWH range” and that dose-adjustments increase the safety or efficacy of LMWH therapy, current guidelines do not mandate routine monitoring of LMWH with anti-Xa levels [2123]. Anti-Xa monitoring may be helpful to ensure appropriate anticoagulant effect in patients with renal impairment and in those at the extremes of body weight [21].

Regimens in which the intensity of LMWH is reduced later during the course of therapy to an intermediate dose regimen [98] or 75 % of a full treatment dose [84] have been used successfully in cancer patients. A recent systematic review that identified four studies in which pregnant women with symptomatic VTE were transitioned from full-dose anticoagulation to intermediate-dose LMWH (less than 75 % of a full treatment dose but greater than prophylactic dose) within 6 weeks of VTE diagnosis, reported a low risk of VTE recurrence (one of 152 patients) during intermediate-dose LMWH therapy; however, the number of patients with PE was small (four) and at least one of the included studies enrolled patients with isolated calf vein thrombosis, which could lead to an overestimation of the positive effect [99]. Some guidelines suggest a dose-reduction strategy for pregnant women at risk of anticoagulant-related bleeding and heparin-induced osteoporosis [23] and in those with isolated calf vein thrombosis [22]. That said, a survey of members of the North American Society of Obstetric Medicine and Thrombosis Canada found that only one-quarter of respondents utilized this strategy in their patients [100].

The risk of HIT in pregnant women treated with LMWH alone is low (less than 0.1 %) [59]; it is higher in pregnant women who have received UFH. Several guidelines suggest that routine platelet count monitoring for detection of HIT is not required in pregnant women treated exclusively with LMWH [21, 25].

Intravenous UFH is preferred when rapid reversal of anticoagulation may be required (i.e. in situations in which urgent delivery or surgery may be necessary) and in patients in whom thrombolysis may be considered (e.g. high risk or massive PE) [24, 80]. UFH should be used in preference to LMWH to treat acute VTE in patients with GFR of less than 30 mL/min [80]. When UFH is preferred, it can be given intravenously or subcutaneously every 12 h in doses adjusted to prolong a mid-interval (6 h post-injection) activated partial thromboplastin time (aPTT) into therapeutic range [101], although it is recognized that aPTT monitoring is less reliable in pregnancy [102].

Concerns about the use of thrombolytic therapy during pregnancy center on its maternal effects (major hemorrhage), as well as those on the placenta (i.e. premature labor, placental abruption, fetal demise), as transplacental passage of tissue plasminogen activator and streptokinase is minimal [103]. There have been several reports of successful thrombolysis in pregnancy with no harm to the fetus; however, the number of cases is small and most cases involved streptokinase [104107]. Therefore, there is agreement amongst available guidelines that the use of thrombolytic therapy in pregnancy is best reserved for limb or life-threatening maternal thromboembolism (e.g. PE with refractory cardiorespiratory compromise) [2123, 80].

There is limited experience with inferior vena caval filters during pregnancy and serious complications, including filter fracture, filter migration, failed retrieval of temporary devices, and inferior vena caval perforation, have been reported [108112]. Current guidelines recommend insertion of temporary inferior vena caval filters in pregnant women with acute VTE and contraindications to anticoagulant therapy [18, 22] or recurrent VTE despite therapeutic anticoagulation [17, 2123]. An alternate strategy involving anticoagulant dose-escalation may also be appropriate for managing the latter situation, based on favorable (but limited) data in cancer patients, in which recurrent VTE despite anticoagulant therapy is treated by increasing the dose of LMWH by approximately 25 % or to therapeutic levels in those receiving lower doses [113, 114].

There are conflicting data concerning the long-term effectiveness of graduated compression stockings to prevent post-thrombotic syndrome. On the basis of two positive open label randomized trials in the non-pregnant population [115, 116], several guidelines have suggested that graduated compression stockings be prescribed to reduce the likelihood of developing post-thrombotic syndrome [19, 22, 23]. However, a recent multicenter placebo-controlled trial that enrolled non-pregnant patients reported that these stockings neither prevented this complication nor reduced the risk of recurrent VTE [117]. In addition, although it is thought that graduated stockings may be useful for acute symptom relief, a subgroup analysis of this study suggests that, at least in the non-pregnant population, this may not be the case [118].

There have been no studies assessing optimal duration of anticoagulant therapy for treatment of pregnancy-related VTE. In non-pregnant patients with VTE, evidence supports a minimum treatment duration of 3 months [24]. Given the increased risk of VTE in pregnant women and following delivery, available guidelines suggest that anticoagulants be continued throughout pregnancy and the postpartum period, and for a minimum of 3 months [19, 2125].

Guidance Statement

  • Outpatient treatment of VTE can be considered in patients who are clinically stable and have good cardiorespiratory reserve, no major risk factors for bleeding and good social support with easy access to medical care. Hospitalization is indicated in patients who are hemodynamically unstable or do not have good social support and those who have extensive VTE, or maternal co-morbidities that limit their tolerance of recurrent VTE or increase their risk of major bleeding.

  • LMWH is the preferred anticoagulant for most pregnant women with acute VTE. UFH should be used instead of LMWH in patients with GFR less than 30 mL/min. Intravenous UFH should be considered in patients who may require thrombolysis, surgery or urgent delivery.

  • If LMWH is used for treatment of acute VTE in pregnancy, the same weight-adjusted dosing regimen as in the nonpregnant population should be utilized (Table  3). Routine monitoring of LMWH dosing with anti-Xa LMWH is likely not required.

    Table 3 Accepted LMWH dosing regimens for treatment of pregnancy-related VTE
  • Thrombolytic therapy should be reserved for pregnant women with PE associated with life-threatening cardiorespiratory compromise or limb-threatening DVT.

  • Insertion of a temporary inferior vena caval filter should be considered in pregnant women with acute VTE and a contraindication to anticoagulant therapy.

  • Anticoagulant therapy for treatment of VTE during pregnancy should be continued throughout pregnancy and for at least 6 weeks postpartum for a minimum duration of 3 months.

  1. 4.

    How is pregnancy-associated VTE prevented?

Decisions regarding the use of prophylactic anticoagulation during pregnancy depend on the balance between the estimated risk of VTE and associated reduction in risk with prophylaxis, along with the burdens associated with anticoagulant therapy. The appropriate use of prophylaxis depends on identifying those at sufficiently high risk of VTE to benefit from this intervention. Risk factors to be considered include prior VTE, familial VTE history, the presence of a known thrombophilia, and clinical factors, including cesarean delivery, prolonged antepartum immobilization, increased body mass index (BMI), as well as significant pregnancy complications and medical comorbidities.

Prophylaxis during pregnancy typically involves long-term subcutaneous injections of LMWH. Although prophylactic LMWH is safe for the fetus [27, 29, 30, 4951] and does not appear to appreciably increase the risk of adverse maternal outcomes [58, 59, 6267]; it is expensive, inconvenient and uncomfortable to administer. Depending on local practice, prophylaxis with LMWH may also necessitate a planned delivery to permit epidural analgesia and women may perceive that it creates an undesirable “medicalization” of their pregnancy.

A Cochrane systematic review of thromboprophylaxis in pregnancy and the early postnatal period that examined 16 randomized trials involving 2592 women concluded that the current available information is insufficient to make firm recommendations for prophylaxis [119]. Current clinical guidelines are based on these small trials, additional observational studies and indirect evidence suggesting that LMWH substantially decreases the risk of VTE in a wide variety of clinical settings. As shown in Table 2C, there is incomplete agreement between the guidelines as to which patients should receive thrombosis prophylaxis and only a few guidelines (SOGC [19] and ACCP for postpartum prophylaxis [23]) explicitly provide information about the risk threshold used to determine whether or not patients should receive prophylaxis.

Given the competing potential drawbacks and benefits of prophylaxis, as well as the limitations of the available evidence, the decision to use or not use LMWH is likely to be value and preference sensitive. In addition to holding different attitudes toward the risk of recurrent thrombosis and about the burdens associated with the use of prophylaxis, women are also likely to place varying importance on minimizing medicalization of their pregnancy. All women, therefore, merit an individualized risk–benefit assessment of their need for prophylaxis and the opportunity to share in a decision making process about this intervention that takes into account their values and preferences.

If the decision is made to use antepartum prophylaxis, it should be initiated early in pregnancy as there is evidence of an increased risk of VTE during all three trimesters [120, 121]. Postpartum prophylaxis is less burdensome than antepartum prophylaxis as the duration of prophylaxis is shorter (i.e. 6 weeks) and an oral anticoagulant is available for those uncomfortable with subcutaneous injections (vitamin K antagonists, except for those with protein C or S deficiency who are at risk for developing warfarin-induced skin necrosis) [122124].

The optimal prophylaxis strategy is unknown. Several LMWH dosing regimens have been used for prophylaxis of VTE during pregnancy (Table 4) [59, 62, 118, 125133]. Although all of the studies evaluating these regimens reported low VTE rates, most were cohort studies and, therefore, lacked data from untreated controls. Some investigators have reported failures of prophylactic LMWH; however, it is unclear whether these represent true failures or were due to noncompliance with long-term subcutaneous injections [59, 60, 127, 134, 135]. Different dosing strategies have not been directly compared, although one randomized trial comparing higher doses of LMWH prophylaxis with usual fixed dose prophylaxis is ongoing (Highlow Randomized Controlled Trial: Comparison of Low and Intermediate Dose Low-molecular-weight Heparin to Prevent Recurrent Venous Thromboembolism in Pregnancy; NCT001828697).

Table 4 Suggested LMWH dosing regimens for prophylaxis against pregnancy-related VTE

In hospitalized women, mechanical prophylaxis with elastic stockings and/or intermittent pneumatic compression is an alternative for those with contraindications to anticoagulant prophylaxis [23]; although there is limited evidence that these devices are less effective at prevention of VTE [136].

Duration of anticoagulant prophylaxis after delivery remains controversial. Available guidelines recommend 6 weeks of postpartum prophylaxis in patients with prior VTE and those with some thrombophilias (varies between guidelines) [17, 19, 21, 23]. However, there is minimal evidence to guide duration of prophylaxis in women with other clinical risk factors and recommendations vary. A shorter course of postpartum prophylaxis (until discharge or for one to 2 weeks post discharge) is often suggested for women with transient risk factors [19, 21, 23]. A recent study that used linked primary and secondary care data to assess VTE risk during specific postpartum periods reported that women with pre-eclampsia/eclampsia and acute systemic infection, obesity (body mass index or BMI ≥ 30 kg/m2), and cesarean delivery had elevated VTE risks up to 6 weeks postpartum; while VTE risk was increased only for the first 3 weeks after delivery in those with postpartum hemorrhage or preterm birth [137]. However, the absolute VTE risk during those time frames was low (less than 1 %).

All pregnant women at risk of VTE should be educated about the signs and symptoms of DVT and PE and the need to seek urgent medical attention should they develop. Objective testing is mandatory if symptoms suspicious of DVT or PE occur.

Prevention of recurrent VTE

The most important individual risk factor for pregnancy-associated VTE is a prior history of thrombosis [138]. The absolute risk of recurrent VTE during pregnancy in women not given antepartum prophylaxis remains controversial. In more recent studies, the reported incidence ranged from 2.4 % (95 % CI 0.2–6.9) in a prospective study of 125 pregnant women [139] to approximately 6 % in larger retrospective cohort studies [140, 141]. Differences in study population (later median gestational age at enrollment; inclusion of women with more than one prior episode of VTE in the retrospective studies), as well as failure to independently adjudicate recurrent events in the retrospective studies, may explain the higher risk of recurrence in the latter studies. However, the overall risk of antepartum recurrent VTE in both prospective and retrospective studies was less than 10 % and CI’s around the risk estimates of individual studies are overlapping.

Data regarding prognostic factors for recurrent VTE during pregnancy are inconsistent. Although a subgroup analysis of the prospective cohort study mentioned above found a lower risk of recurrence in women without thrombophilia who had a temporary risk factor (including oral contraceptive therapy or pregnancy) at the time of their prior VTE, than in those with abnormal thrombophilia testing and/or an unprovoked event [138]; in the two subsequent retrospective studies, the presence or absence of a definable thrombophilia did not appear to influence the risk of recurrent pregnancy-associated VTE [140, 141]. Studies in nonpregnant patients have also demonstrated that thrombophilic abnormalities do not play an important role in determining the risk of recurrent VTE, despite being clear risk factors for a first episode of DVT or PE [142]. There was a suggestion in the two retrospective studies that women with a first VTE provoked by oral contraceptives or related to pregnancy might be at higher risk of recurrence in a subsequent pregnancy than those with an unprovoked event or VTE related to a transient non-hormonal risk factor [140, 141]. The latter findings are consistent with those from an observational administrative dataset from California [143].

The above data suggest that pregnant women with a single prior episode of VTE associated with a transient risk factor not related to pregnancy or use of estrogen are likely at lower risk of recurrent antepartum VTE compared to pregnant women with a history of unprovoked, pregnancy or estrogen-related VTE. The ACCP guidelines estimated the risk of recurrent antepartum VTE without prophylaxis to be 2 % in the first group and 8 % in the second group [23]. Current guidelines favor a strategy of antepartum clinical vigilance for those with a single prior episode of VTE associated with a transient risk factor not related to pregnancy or hormone use and antepartum LMWH with a history of unprovoked, pregnancy or estrogen-related VTE [17, 19, 20, 23]. However, as the available data have significant limitations, antepartum clinical vigilance may also acceptable for higher risk patients accepting of the risks of recurrence and for whom the burden of LMWH prophylaxis outweighs potential benefits. Similarly, women with a prior VTE associated with a transient risk factor not related to pregnancy or use of estrogen may benefit from antepartum prophylaxis if they have additional major risk factors for thrombosis. Although supportive data from clinical trials are lacking, postpartum prophylaxis for 6 weeks with prophylactic or intermediate dose LMWH or vitamin K antagonists targeted at INR 2.0–3.0 is generally recommended for all pregnant women with prior VTE not receiving long-term anticoagulants [17, 19, 20, 23].

Prevention of VTE in pregnant women with thrombophilia and no prior VTE

Thrombophilias are laboratory abnormalities associated with an increased risk of thrombosis and can be either inherited or acquired. The majority of studies that have examined the risk of VTE in pregnancy have focused on inherited thrombophilic mutations. Although it has been reported that approximately 50 % of pregnancy-associated VTE are associated with inherited thrombophilia; these abnormalities are very common and collectively are present in at least 15 % of the population [144, 145].

As shown in Table 5, in a systematic review of nine case control studies (n = 2526) that evaluated the association between thrombophilia and pregnancy-associated VTE, the highest risks were associated with homozygosity for factor V Leiden or the prothrombin G20210A variant [146]. Pregnant women with the most common heritable thrombophilias (i.e. heterozygosity for factor V Leiden or the prothrombin G20210A variant) had lower risks. Deficiencies of antithrombin, protein C, and protein S were associated with moderate risk increases. Estimated absolute VTE risks, calculated using the provided odds ratios and a background incidence of VTE during pregnancy of approximately 1/1000 deliveries, suggest a low thrombosis risk (0.5–1.2 % of affected pregnancies) for most of the inherited thrombophilias, except perhaps for homozygous carriers of the factor V Leiden or the prothrombin mutations, where the risk estimate is approximately 4 % (Table 5). However, these findings are limited by the fact that most of the included women would not have had a family history of VTE. A positive family history of VTE increases the risk for VTE two- to four-fold, depending on the number of affected relatives [147, 148] and thrombophilic subjects without a personal or family history of DVT or PE have lower rates of VTE than patients with thrombophilia and a positive family history [149]. Family-based cohort studies not included in the above-mentioned systematic review suggest that the risks of developing a first VTE during pregnancy and the postpartum period are two to four times greater than estimated in thrombophilic women without a positive family history (Table 5) [150161]. However, it should be noted that many of the events occurred during the postpartum period and these risk estimates are very imprecise, particularly for the less common thrombophilias.

Table 5 Risks of pregnancy-related VTE in asymptomatic thrombophilic women

Acquired thrombophilias have been less well studied but repeated antiphospholipid antibody positivity (lupus anticoagulants [non-specific inhibitors], anticardiolipin antibodies, or anti-β2glycoprotein-I antibodies) is associated with an increased risk of VTE [162]. The risk or pregnancy-related VTE in women with antiphospholipid antibodies and no previous history of venous thrombosis is uncertain [163, 164].

There is considerable disagreement between current guidelines about the indication for antepartum thrombosis prophylaxis in pregnant women with deficiencies of antithrombin, protein C, or protein S. The inconsistency in recommendations likely results from the use of different risk thresholds for suggesting prophylaxis, uncertainty in risk estimates in recent studies, as described above, and concerns about VTE risks presented in older studies that suggested that these are high risk thrombophilias [165167]. However, this data is somewhat problematic as these papers have methodologic limitations, including acceptance of non-objectively diagnosed outcome events, failure to clearly specify criteria for the diagnosis of VTE, including recurrent VTE episodes in women who already had had a VTE, and the potential for referral and recall bias, that have the potential to lead to an overestimation of risk.

Prevention of pregnancy-associated VTE in patients with clinical risk factors

Most studies that have assessed clinical and pregnancy-related risk factors for VTE have utilized a case control or cross-sectional design (Table 6) [35, 7, 87, 168170]; although a few recent publications have used large databases to provide population-level absolute and relative risks for VTE [171, 172]. In methodologically stronger studies, most established risk factors have only a modest effect on VTE risk, with few increasing the absolute risk about 1 %. How combinations of independent risk factors might affect overall VTE risk has not been extensively studied and in most cases, it is unclear whether combinations result in additive or multiplicative risks. Further research in this area is required.

Table 6 Clinical risk factors for VTE as determined from case–control or cross-sectional studies

Prevention of pregnancy-associated VTE following cesarean delivery

Several observational studies have assessed the risk of VTE after cesarean delivery. Small prospective studies in which patients underwent screening ultrasounds following cesarean section and were then followed post-discharge for at least 6 weeks reported symptomatic VTE event rates of 0 (95 % CI 0–6.1 %) [173] and 0.5 % (95 % CI 0.1–2.8 %) [174]. The latter is consistent with estimates based on hospital discharge data that antedate the use of thrombosis prophylaxis [1, 175]. Emergency cesarean delivery approximately doubles the risk of VTE [7, 169, 172].

In the Cochrane systematic review mentioned above, four (840 women) of the nine included trials that examined prophylaxis following cesarean delivery compared heparin (UFH or LMWH) with placebo [119]. There was no evidence that using any form of heparin following delivery reduced the risk of maternal VTE (risk ratio [RR] vs no heparin for symptomatic events of 1.30; 95 % CI 0.39–4.27) and the authors concluded there was insufficient evidence on which to base recommendations.

Guidance Statement

Note: Given the uncertainty around optimal prophylactic strategies, all women should be provided with the opportunity to participate in shared decision making regarding this intervention, including a discussion of VTE risks, potential benefits (reduction in VTE risk) and drawbacks (risks of bleeding and localized skin reactions; cost; potential limitation of analgesic options at the time of delivery; anxiety associated with injections) of prophylaxis along with their values and preferences. Physicians and patients (and, perhaps, societies) with a lower threshold for recurrent VTE may choose a more aggressive anticoagulant strategy than recommended, whereas withholding prophylaxis may be appropriate in those who are willing to accept a higher risk of recurrence in order to forgo the drawbacks associated with prophylaxis.

General Comments

  • All pregnant women at risk of VTE should be educated about the signs and symptoms of DVT and PE and the need to seek urgent medical attention should they develop. Objective testing is mandatory if symptoms suspicious of DVT or PE occur.

  • All women should undergo an individualized risk assessment for VTE prior to pregnancy, once pregnancy is achieved and throughout pregnancy as new clinical situations arise.

  • When considering the use of thrombosis prophylaxis during pregnancy and/or the postpartum period, the absolute risk of VTE, the risk reduction with prophylaxis, drawbacks of prophylaxis, and the woman’s values and preferences should all be taken into account. Given the limitations of the available data, clinical vigilance rather than prophylaxis may also be acceptable for patients accepting the VTE risks quoted above and for whom the burden of LMWH prophylaxis outweighs potential benefits.

  • If the decision is made to use antepartum prophylaxis, it should be initiated early in pregnancy.

  • Six weeks of postpartum prophylaxis is recommended in patients with prior VTE and those with some thrombophilias. A shorter course of postpartum prophylaxis (until discharge or for 1–2 weeks post discharge) is suggested for women with transient risk factors.

Prevention of recurrent VTE

  • Pregnant women with prior VTE who are not receiving long-term anticoagulation should receive 6 weeks of postpartum prophylaxis.

  • Antepartum prophylaxis should be considered in pregnant women with prior unprovoked VTE or pregnancy- or estrogen-related VTE not receiving long-term anticoagulation.

Prevention of VTE in women with thrombophilia and no prior VTE

  • Asymptomatic women who are homozygous for the factor V Leiden mutation or prothrombin gene mutation and who have a family history of VTE should receive antepartum and postpartum prophylaxis.

  • Consideration should be given to providing postpartum prophylaxis in asymptomatic women who are heterozygous for the factor V Leiden mutation or prothrombin gene mutation or who have protein C or protein S deficiency and who have a family history of VTE.

  • Given the variability in the VTE risk estimates for asymptomatic women with antithrombin deficiency and a family history of VTE, either a strategy of antepartum and postpartum prophylaxis or postpartum prophylaxis alone is reasonable.

  • Asymptomatic women who are homozygous for the factor V Leiden mutation or prothrombin gene mutation and who have no family history of VTE should receive postpartum prophylaxis.

  • Asymptomatic women with all other thrombophilias who do not have a family history of VTE do not require prophylaxis, in the absence of other risk factors. However, given the variability in the VTE risk estimates for asymptomatic women with antithrombin deficiency and no family history of VTE, consideration could also be given to utilizing postpartum prophylaxis in these patients.

Prevention of VTE in women with clinical risk factors

  • Antepartum prophylaxis should be provided to immobilized (strict bedrest) women with a pre-pregnancy BMI of at least 25 kg/m 2 and to those with a prior history of VTE regardless of their BMI. Consideration should be given to providing prophylaxis during antepartum immobilization (as defined above) to women with a lower body mass index who have other significant comorbidities (e.g. systemic lupus erythematosus, sickle cell disease, heart disease) associated with an increased risk of VTE or a thrombophilia.

  • Consideration should be given to providing postpartum prophylaxis while in hospital to women with a history of antepartum immobilization (as defined above) for at least 7 days and to those who are immobilized postpartum who have a known thrombophilia or significant medical comorbidity

Prevention of VTE in after cesarean delivery

  • Prophylaxis should be provided after cesarean delivery to women with the following risk factors:

    • One or more of prior VTE, a history of antepartum immobilization (strict bedrest for at least 1 week), significant postpartum infection, postpartum hemorrhage of at least 1000 mL requiring re-operation, pre-eclampsia with growth restriction, significant medical co-morbidities (systemic lupus erythematosis, heart disease, or sickle cell disease) or a known thrombophilia.

    • Two or more of (or one or more in the setting of emergency cesarean delivery) of postpartum hemorrhage of at least 1000 mL that does not require re-operation, BMI >30 kg/m 2 , fetal growth restriction, pre-eclampsia, multiple pregnancy and tobacco use during pregnancy (at least 10 cigarettes per day)

  1. 5.

    How is peripartum anticoagulation managed?

The delivery options in women using anticoagulants are best considered by a multidisciplinary team in order to minimize the risks of maternal hemorrhage, epidural hematoma, and VTE around the time of delivery. In a systematic review of 2777 pregnancies in which LMWH was utilized in either therapeutic or prophylactic doses, postpartum hemorrhage of greater than 500 mL occurred in 26 pregnancies (0.94 %; 95 % CI 0.61–1.37 %) and wound hematoma in 17 pregnancies (0.61 %, 95 % CI 0.36–0.98 %) [59]. A more recent systematic review of 18 studies that focused solely on pregnant women (n = 981) receiving treatment for acute VTE during pregnancy reported an incidence of major bleeding during the first 24 h after delivery of 1.90 % (95 % CI 0.80–3.60 %) [60]. Although epidural hematomas in obstetrical patients receiving epidural analgesia/anesthesia are rare, with an estimated incidence of less than 1 in 150,000 [176]; the potential complications are devastating and include permanent neurologic dysfunction.

Depending on local practice, delivery options include spontaneous labor and delivery, induction of labor, and planned cesarean delivery. Induction of labor may help to avoid an unwanted anticoagulant effect during delivery (especially with neuroaxial anesthesia) in women receiving LMWH. Current guideline recommendations for management of anticoagulant therapy around the time of delivery are outlined in Table 2D. Anesthesia and obstetrical guidelines agree that 24 h should pass between the last dose of therapeutic LMWH and insertion of a neuroaxial catheter [17, 1923, 177]. For prophylactic LMWH, catheter insertion should occur no sooner than 10–12 h after the last LMWH dose [17, 1923, 177].

At some centers, women are converted from therapeutic adjusted-dose LMWH to subcutaneous twice daily therapeutic dose UFH in the last month of pregnancy. However, therapeutic doses of subcutaneous UFH may cause a persistent anticoagulant effect. One study reported that six of 11 women receiving subcutaneous UFH during pregnancy had an elevated aPTT at delivery despite discontinuing their injections at the onset of labour to 12 h prior to elective induction [178].

Patients should be instructed to withhold their injections if they believe that they have entered labor spontaneously. In centers with laboratory support that allows for rapid assessment of heparin levels, testing can be considered to guide anesthetic and surgical management; otherwise time since last injection should be used. If anticoagulation precludes regional techniques, alternative analgesic options include intravenous analgesia or general anesthesia for cesarean delivery [2022].

The potential increased risk of wound hematoma after cesarean delivery in patients receiving anticoagulant therapy has led to the suggestion that wound drains and closure techniques that allow easy hematoma drainage be considered in this population [179]. If bleeding occurs that is considered secondary to LMWH rather than an obstetric cause, protamine sulfate may provide partial neutralization [180].

Women diagnosed with proximal DVT or PE within two to 4 weeks of delivery are at very high risk for recurrent VTE with prolonged anticoagulant cessation [181, 182]. A strategy involving planned delivery with transition to intravenous UFH will minimize time off therapeutic anticoagulation [22, 23]. Discontinuation of intravenous UFH four to 6 h prior to the expected time of delivery or epidural insertion with a repeat activated partial thromboplastin time drawn after 4 h to confirm normalization will ensure that there is no residual anticoagulant effect. For the highest risk patients (e.g. VTE within 2 weeks), consideration can be given to insertion of a temporary inferior vena caval filter that can be removed postpartum.

Anticoagulants should be recommenced post-delivery as soon as adequate hemostasis is assured. Guidelines generally recommend resumption of prophylactic LMWH four to 12 h following delivery [17, 19]; and not sooner than 4 h after epidural catheter removal (with a longer delay for bloody or traumatic neuroaxial procedures) [177]. There are no definitive recommendations for resumption of full-dose LMWH following epidural catheter removal; however, it appears safe to do so 24 h of catheter removal (again, with a delay if placement was bloody or traumatic) [19, 22]. The timing of resumption of postpartum vitamin K antagonists for patients who choose this option remains controversial; some guidelines recommend a delay of at least 5 days [21, 22], although this recommendation appears based on the results of a single centre retrospective audit [183]. Once an INR of at least 2.0 is achieved, bridging LMWH can be discontinued.

Guidance Statement

  • All pregnant women receiving anticoagulants should have an individualized delivery plan that addresses obstetrical, anesthetic and thrombotic concerns.

  • All pregnant women should be advised to discontinue anticoagulant therapy upon the onset of spontaneous labor.

  • If there is a planned delivery, therapeutic LMWH should be discontinued at least 24 h prior to the expected time of epidural analgesia or delivery. Prophylactic LMWH should be stopped at least 10–12 h prior to epidural analgesia.

  • For planned deliveries, intravenously administered unfractionated heparin should be stopped at 4–6 h prior to the expected time of epidural analgesia or delivery and the aPTT checked to ensure normalization. For therapeutic doses of unfractionated heparin administered subcutaneously, the last dose should be given no sooner than 12 h and preferably closer to 24 h prior to expected time of epidural analgesia or delivery and the aPTT checked to ensure normalization. Guidelines differ in their requirement for a delay prior to epidural analgesia in patients receiving prophylactic dose unfractionated heparin up to 10,000 units daily; when possible prophylactic unfractionated heparin should be discontinued 8–10 h prior to planned procedures.

  • Prophylactic LMWH may be started/restarted 6–12 h after delivery (no sooner than 4 h after epidural catheter removal), as long as hemostasis is assured and there has not been a bloody or traumatic epidural. For prophylactic unfractionated heparin, the recommended time interval from epidural catheter removal is one to 8 h.

  • Therapeutic LMWH may be started/restarted 24 h after delivery (no sooner than 24 h after epidural catheter removal), as long as hemostasis is assured and there has not been a bloody or traumatic epidural. Attainment of therapeutic levels of intravenous unfractionated heparin should be delayed for the same amount of time.

Conclusion

Women are at increased risk of VTE during pregnancy and the postpartum period. Treatment and prevention of VTE in this patient population is complicated by the need to consider fetal, as well as maternal, wellbeing when making management decisions. Although our knowledge of risk factors for pregnancy-related VTE and the safe and effective use of anticoagulants used to prevent and treat VTE in this population continues to increase, there are still important gaps and high quality research in this area should be a priority. In the interim, all women should be provided with the opportunity to participate in shared decision making regarding their management. To make the best decisions, absolute risks and potential benefits of interventions, guideline recommendations, and patient values and preferences should all be taken into account. Table 7 summarizes these guidance statements.

Table 7 Summary of guidance statements

References

  1. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ 3rd (2005) Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 143:697–706

    PubMed  Article  Google Scholar 

  2. Gherman RB, Goodwin TM, Leung B et al (1999) Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 94:730–734

    PubMed  CAS  Article  Google Scholar 

  3. Lindqvist P, Dahlback B, Marsal K (1999) Thrombotic risk during pregnancy: a population study. Obstet Gynecol 94:595–599

    PubMed  CAS  Article  Google Scholar 

  4. Simpson EL, Lawrenson RA, Nightingale AL, Farmer RD (2001) Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. Br J Obstet Gynecol 108:56–60

    CAS  Google Scholar 

  5. James A, Jamison MG, Brancazio LR, Myers ER (2006) Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 194:1311–1315

    PubMed  Article  Google Scholar 

  6. Andersen BS, Steffensen FH, Sorensen HT et al (1998) The cumulative incidence of venous thromboembolism during pregnancy and puerperium: an 11 year Danish population- based study of 63,300 pregnancies. Acta Obstet Gynecol Scand 77:170–173

    PubMed  CAS  Article  Google Scholar 

  7. Jacobsen AF, Skjeldestad FE, Sandset PM (2008) Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study. Am J Obstet Gynecol 198:233.e1-7

    PubMed  Article  Google Scholar 

  8. McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA, Carty MJ, Greer IA (1997) Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 78:1183–1188

    PubMed  CAS  Google Scholar 

  9. Anderson FA Jr, Wheeler HB, Goldberg RJ et al (1991) A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester Study. Arch Intern Med 151:933–938

    PubMed  Article  Google Scholar 

  10. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ (2008) Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 6:632–637

    PubMed  CAS  Article  Google Scholar 

  11. Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS (2014) Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 370:1307–1315

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  12. McColl MD, Ellison J, Greer IA, Tait RC, Walker ID (2000) Prevalence of the post thrombotic syndrome in young women with previous venous thromboembolism. Br J Haematol 108:272–274

    PubMed  CAS  Article  Google Scholar 

  13. Rosfors S, Noren A, Hjertberg R, Persson L, Lillthors K, Torngren S (2001) A 16-year haemodynamic follow-up of women with pregnancy-related medically treated iliofemoral deep venous thormbosis. Eur J Vasc Enodovasc Surg 22:448–455

    CAS  Article  Google Scholar 

  14. Wik HS, Jacobsen AF, Sandvik L, Sandset PM (2012) Prevalence and predictors for post-thrombotic syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based, cross-sectional, case-control study. J Thromb Haemost 10:840–847

    PubMed  CAS  Article  Google Scholar 

  15. Chang J, Elam-Evans LD, Berg CJ et al (2003) Pregnancy-related mortality surveillance: United States, 1991–1999. MMWR Surveill Summ 52:1–88

    PubMed  Google Scholar 

  16. Centre for Maternal Child Enquiries (CMACE) (2011) Saving Mothers’ Lives: Reviewing Maternal Deaths to Make Motherhood Safer: 2006–2008. The eighth report on confidential enquiries into maternal deaths in the United Kingdom. BJOG 118(Suppl 1):1–203

    Google Scholar 

  17. James A, Committee on Practice Bulletins—Obstetrics (2011) Practice Bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol 118(3):718–729

    PubMed  Article  Google Scholar 

  18. Branch DW, Holmgren C, Goldberg JD, Committee on Practice Bulletins-Obstetrics (2012) Practice Bulletin no 132: antiphospholipid antibody syndrome. Obstet Gynecol 120(6):1514–1521

    Article  CAS  Google Scholar 

  19. Chan WS, Rey E, Kent NE; VTE in Pregnancy Guideline Working Group, Chan WS, Kent NE, Rey E, Corbett T, David M, Douglas MJ, Gibson PS, Magee L, Rodger M, Smith RE (2014) Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can 36(6):527–53

  20. Royal College of Obstetricians and Gynaecologists (2015) Green-top Guideline No. 37a. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg37a/. Accessed 10 June 2015

  21. Royal College of Obstetricians and Gynaecologists (2015) Green-top Guideline No. 37b. Thromboembolic disease in pregnancy and the puerperium: acute management. https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg37b/. Accessed 10 June 2015

  22. Mclintock C, Brighton T, Chunilal S, Dekker G, McDonnell N, McRae S, Muller P, Tran H, Walters BNJ, Young L (2012) Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period. ANZJOG 52:14–22

    PubMed  Google Scholar 

  23. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO, American College of Chest Physicians (2012) VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e691S–e736S

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Kearon C, Akl EA, Comerota A, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR, American College of Chest Physicians (2012) Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e419S–e3494S

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Linkins L-A, Dans AL, Mores LK, Bona R, Davidson BL, Schulman S, Crowther M, American College of Chest Physicians (2012) Treatment and prevention of heparin-induced thrombocytopenia; Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):e495S–e530S

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  26. Rodger M (2014) Pregnancy and venous thromboembolism: ‘TIPPS’ for risk stratification. Hematology 2014:387–392

    PubMed  Article  Google Scholar 

  27. Ginsberg JS, Hirsh J, Turner CD et al (1989) Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 61:197–203

    PubMed  CAS  Google Scholar 

  28. Hall JAG, Paul RM, Wilson KM (1980) Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122–140

    PubMed  CAS  Article  Google Scholar 

  29. Chan WS, Anand S, Ginsberg JS (2000) Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 160:191–196

    PubMed  CAS  Article  Google Scholar 

  30. Hassouna A, Allam H (2010) Anticoagulation of pregnant women with mechanical heart valve prosthesis: a systematic review of the literature (2000–2009). J Coagul Disorders 2:81–88

    Google Scholar 

  31. Pauli RM, Haun J (1993) Intrauterine effects of coumarin derivatives. Dev Brain Dysfunct 6:229–247

    Google Scholar 

  32. Schaefer C, Hannemann D, Meister R et al (2006) Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study. Thromb Haemost 95:949–957

    PubMed  CAS  Google Scholar 

  33. Hirsh J, Cade JF, O’Sullivan EF (1970) Clinical experience with anticoagulant therapy during pregnancy. Br Med J 1:270–273

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  34. van Driel D, Wesseling J, Sauer PJJ et al (2001) In utero exposure to coumarins and cognition at 8 to 14 years old. Pediatr 107:123–129

    Article  Google Scholar 

  35. Boehringer Ingelheim. Prescribing information: Pradaxa. Date of text revision: 09/2014. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf

  36. Janssen Pharmaceuticals. Prescribing information: Xarelto. Date of text revision: 09/2014. http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf

  37. Bristol-Myers Squibb. Prescribing information: Eliquis. Date of text revision: 08/2014. http://packageinserts.bms.com/pi/pi_eliquis.pdf

  38. Tang A-W, Greer I (2013) A systematic review on the use of the new anticoagulants in pregnancy. Obstet Med 6:64–71

    Article  Google Scholar 

  39. Dempfle CE (2004) Minor transplacental passage of fondaparinux in vivo. N Engl J Med 350:1914–1915 (Letter)

    PubMed  CAS  Article  Google Scholar 

  40. Harenberg J (2007) Treatment of a woman with lupus and thromboembolism and cutaneous intolerance of heparins using fondaparinux during pregnancy. Thromb Res 119:385–388

    PubMed  CAS  Article  Google Scholar 

  41. Mazzolai L, Hohfeld P, Spertini F et al (2006) Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 108:1569–1570

    PubMed  CAS  Article  Google Scholar 

  42. Wijesiriwardana A, Lees DA, Lush C (2006) Fondaparinux as anticoagulant in a pregnant woman with heparin allergy. Blood Coagul Fibrinolysis 17:147–149

    PubMed  CAS  Article  Google Scholar 

  43. Gerhardt A, Zotz RB, Stockschlaeder M, Eberhard R, Scharf E (2007) Fondaparinx is an effective alternative anticoagulant in pregnant women with high risk for thromboembolism and intolerance to low molecular weight heparin and heparinoids. Thromb Haemost 97:496–497

    PubMed  CAS  Google Scholar 

  44. Winger EE, Reed JL (2009) A retrospective analysis of fondaparinux versus enoxaparin treatment in women with infertility or pregnancy loss. Am J Reprod Immunol 2:253–260

    Article  CAS  Google Scholar 

  45. Knol HM, Schultinge L, Erwich JJHM, Meijer K (2010) Fondaparinux as an alternative anticoagulant therapy during pregnancy. J Thromb Haemost 8:1876–1879

    PubMed  CAS  Article  Google Scholar 

  46. Elsaigh E, Thachil J, Nash MJ, Tower C, Hay CR, Bullough S, Byrd L (2014) The use of fondaparinux in pregnancy. Br J Haematol. doi:10.1111/bjh.13147. [Epub ahead of print]

  47. Flessa HC, Kapstrom AB, Glueck HI et al (1965) Placental transport of heparin. Am J Obstet Gynecol 93:570–573

    PubMed  CAS  Google Scholar 

  48. Clark NP, Delate T, Witt DM, Parker S, McDuffie R (2009) A descriptive evaluation of unfractionated heparin use during pregnancy. J Thromb Thrombolysis 27:267–273

    PubMed  CAS  Article  Google Scholar 

  49. Ginsberg JS, Kowalchuk G, Hirsh J et al (1989) Heparin therapy during pregnancy: risks to the fetus and mother. Arch Intern Med 149:2233–2236

    PubMed  CAS  Article  Google Scholar 

  50. Forestier F, Daffos F, Capella-Pavlovsky M (1984) Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound. Thromb Res 34:557–560

    PubMed  CAS  Article  Google Scholar 

  51. Forestier F, Daffos F, Rainaut M, Toulemonde F (1987) Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thromb Haemost 57:234

    PubMed  CAS  Google Scholar 

  52. Peeters LLH, Hobbelen PMJ, Verkeste CM et al (1986) Placental transfer of Org 10172, a low-molecular-weight heparinoid in the awake late-pregnant guinea pig. Thromb Res 44:277–283

    PubMed  CAS  Article  Google Scholar 

  53. Henny CP, ten Cate H, ten Cate JW et al (1986) Thrombosis prophylaxis in an AT III deficient pregnant woman: application of a low molecular-weight heparinoid. Thromb Haemost 55:301 (letter)

    PubMed  CAS  Google Scholar 

  54. Greinacher A, Eckhrdt T, Mussmann J, Mueller-Eckhardt C (1993) Pregnancy-complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (Org 10172). Thromb Res 71:123–126

    PubMed  CAS  Article  Google Scholar 

  55. Lindhoff-Last E, Kreutzenbeck H-J, Magnani HN (2005) Treatment of 51 pregnancies with danaparoid because of heparin intolerance. Thromb Haemost 93:63–69

    PubMed  CAS  Google Scholar 

  56. Warkentin TE, Levine MN, Hirsh J et al (1994) Heparin induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. N Engl J Med 332:1330–1335

    Article  Google Scholar 

  57. Weitz JI (1997) Low-molecular-weight heparin. N Engl J Med 337:688–698

    PubMed  CAS  Article  Google Scholar 

  58. Sanson BJ, Lensing AWA, Prins MH et al (1999) Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 81:668–672

    PubMed  CAS  Google Scholar 

  59. Greer IA, Nelson Piercy C (2005) Low molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 106:401–407

    PubMed  CAS  Article  Google Scholar 

  60. Romualdi E, Dentali F, Rancan E, Squizzato A, Steidl L, Middeldorp S, Ageno W (2013) Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. J Thromb Haemost 11:270–281

    PubMed  CAS  Article  Google Scholar 

  61. Lepercq J, Conard J, Borel-Derlon A et al (2001) Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. Br J Obstet Gynaecol 08:1134–1140

    Google Scholar 

  62. Pettila V, Leinonen P, Markkola A et al (2002) Postpartum bone mineral density in women treated with thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost 87:182–186

    PubMed  CAS  Google Scholar 

  63. Carlin AJ, Farquharson RG, Quenby SM et al (2004) Prospective observational study of bone mineral density during pregnancy: low molecular-weight heparin versus control. Hum Reprod 19:1211–1214

    PubMed  CAS  Article  Google Scholar 

  64. Rodger MA, Kahn SR, Cranney A, Hodsman A, Kovacs MJ, for the TIPPS Investigators et al (2007) Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial. J Thromb Haemost 5:1600–1606

    PubMed  CAS  Article  Google Scholar 

  65. Lefkou E, Khamashta M, Hampson G, Hunt BJ (2010) Low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity? Lupus 19:3–12

    PubMed  CAS  Article  Google Scholar 

  66. Byrd LM, Schiach CR, Hay CRM, Johnston TA (2008) Osteopenic fractures in pregnancy: Is low molecular weight heparin (LMWH) implicated? J Obst and Gynaecol 28:539–542

    CAS  Article  Google Scholar 

  67. Le Templier G, Rodger MA (2008) Heparin-induced osteoporosis and pregnancy. Curr Opin Pulm Med 14:403–407

    PubMed  Article  CAS  Google Scholar 

  68. Bank I, Libourel EJ, Middeldorp S, van der Meer J, Buller HR (2003) High rate of skin complications due to low molecular weight heparin in pregnant women. J Thromb Haemost 1:859–861

    PubMed  CAS  Article  Google Scholar 

  69. Wutschert R, Piletta P, Bounameuaux H (1999) Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf 20:515–525

    PubMed  CAS  Article  Google Scholar 

  70. Lim W, Dentali F, Eikelboom JW, Crowther MA (2006) Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 144(9):673–684

    PubMed  CAS  Article  Google Scholar 

  71. Orme ML, Lewis PJ, de Swiet M et al (1977) May mothers given warfarin breast-feed their infants? Br Med J 1:1564–1565

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  72. McKenna R, Cole ER, Vasan V (1983) Is warfarin sodium contraindicated in the lactating mother? J Pediatr 103:325–327

    PubMed  CAS  Article  Google Scholar 

  73. Houwert-de Jong M, Gerards LJ, Tetteroo-Tempelman CAM, de Wolff FA (1981) May mothers taking acenocoumarol breast feed their infants? Eur J Clin Pharmacol 21:61–64

    PubMed  CAS  Article  Google Scholar 

  74. Fondavilla CG, Meschengieser S, Blanco A, Penalva L, Lazzari MA (1989) Effect of acenocoumarine on the breast-fed infant. Thromb Res 56:29–36

    Article  Google Scholar 

  75. Olthof E, de Vries TW (1993) Breast feeding and oral anticoagulants. Tijdschr Kindergeneeskd 61:175–177

    PubMed  CAS  Google Scholar 

  76. von Kries R, Nocker D, Schmitz-Kummer E, de Vries JX (1993) Transfer of phenprocoumon in breast milk. Is oral anticoagulation with phenprocoumon a contraindication for breastfeeding? Monatsschr Kinderheilkd 141:505–507

    Google Scholar 

  77. Richter C, Sitzmann J, Lang P et al (2001) Excretion of low-molecular-weight heparin in human milk. Br J Clin Pharmacol 52:708–710

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  78. GlaxoSmithKline. Prescribing Information: Arixtra. Date of test revision: 09/2013. https://www.gsksource.com/gskprm/htdocs/documents/ARIXTRA-PI-PIL.PDF

  79. Vetter A, Perera G, Leithner K, Klima G, Bernkop-Schnurch A (2010) Development and in vivo bioavailability study of an oral fondaparinux delivery system. Eur J Pharm Sci 41:489–497

    PubMed  CAS  Article  Google Scholar 

  80. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M, Authors/Task Force Members (2014) ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)—Endorsed by the European Respiratory Society (ERS). Eur Heart J 35:3033–3073. doi:10.1093/eurheartj/ehu283 Epub 2014 Aug 29

    PubMed  Article  Google Scholar 

  81. Gould MK, Dembitzer AD, Doyle RL et al (1999) Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 130:800–809

    PubMed  CAS  Article  Google Scholar 

  82. Quinlan DJ, McMillan A, Eikelboom JW (2004) Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized controlled trials. Ann Intern Med 140:175–183

    PubMed  CAS  Article  Google Scholar 

  83. van der Heijden JF, Hutten BA, Buller HR, et al (2000) Vitamin K antagonists or low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev 2000; CD002001

  84. Lee AYY, Levine MN, Baker RI et al (2003) Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146–153

    PubMed  CAS  Article  Google Scholar 

  85. Voke J, Keidan J, Pavord S, Spencer HN, Hunt BJ, on behalf of the British Society of Haematology Obstetric Haematology Group (2007) The management of antenatal venous thromboembolism in the UK and Ireland: a prospective multicentre observational study. Br J Haematol 139:545–558

    PubMed  CAS  Article  Google Scholar 

  86. Knight M, on behalf of UKOSS (2008) Antenatal pulmonary embolism: risk factors, management and outcomes. BJOG 115:453–461

    PubMed  CAS  Article  Google Scholar 

  87. Barbour LA, Oja JL, Schultz LK (2004) A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 191:1024–1029

    PubMed  CAS  Article  Google Scholar 

  88. Jacobsen AF, Qvisgstad E, Sandset PM (2002) Low molecular weight heparin (dalteparin) for treatment of venous thromboembolism in pregnancy. Br J Obstet Gynaecol 110:139–144

    Article  Google Scholar 

  89. Crowther MA, Spitzer K, Julian J et al (2000) Pharmacokinetic profile of a low-molecular weight heparin (Reviparin) in pregnant patients: a prospective cohort study. Thromb Res 98:133–138

    PubMed  CAS  Article  Google Scholar 

  90. Rodie VA, Thomson AJ, Stewart FM et al (2002) Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: case series. Br J Obstet Gynaecol 109:1020–1024

    CAS  Article  Google Scholar 

  91. Rey E, Rivard GE (2000) Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin. Int J Gynecol Obstet 71:19–24

    CAS  Article  Google Scholar 

  92. Smith MP, Norris LA, Steer PJ, Savidge GF, Bonnar J (2004) Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 190:495–501

    PubMed  CAS  Article  Google Scholar 

  93. Patel JP, Green B, Patel RK, Marsh MS, Davies JG, Arya R (2013) Population pharmacokinetics of enoxaparin during the antenatal period. Circulation 128:1462–1569

    PubMed  CAS  Article  Google Scholar 

  94. Nelson-Piercy C, Powrie R, Borg JY, Rodger M, Talbot DJ, Stinson J et al (2011) Tinzaparin use in pregnancy: an international retrospective safety of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol 159:293–299

    PubMed  CAS  Article  Google Scholar 

  95. Bhutia S, Wong PF (2013) Once versus twice daily low molecular weight heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev 7:CD003074. doi:10.1002/14651858.CD003074.pub3

  96. Kovacs MJ, Keeney M, MacKinnon K, Boyle E (1999) Three different chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin. Clin Lab Haematol 21:55–60

    PubMed  CAS  Article  Google Scholar 

  97. Kitchen S, Iampietro R, Woolley AM, Preston FE (1999) Anti Xa monitoring during treatment with low molecular weight heparin or danaparoid: inter-assay variability. Thromb Haemost 82:1289–1293

    PubMed  CAS  Google Scholar 

  98. Monreal M, Lafoz E, Olive A et al (1994) Comparison of subcutaneous unfractionated heparin with low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 71:7–11

    PubMed  CAS  Google Scholar 

  99. Gandara E, Carrier M, Rodger MA (2014) Intermediate doses of low-molecular weight-heparin for the long-term treatment of pregnancy thromboembolism. A systematic review. Thromb Haemost 111:559–561

    PubMed  CAS  Article  Google Scholar 

  100. Gandara E, Carrier M, Rodger MA (2014) Management of pregnancy-associated venous thromboembolism. Thrombosis J 12:12

    Article  CAS  Google Scholar 

  101. Hull RD, Delmore TJ, Carter CJ et al (1982) Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thromboembolism. N Engl J Med 306:189–194

    PubMed  CAS  Article  Google Scholar 

  102. Chunilal SD, Young E, Johnston MA et al (2000) The aPTT response of pregnant plasma to unfractionated heparin. Thromb Haemost 87:92–97

    Google Scholar 

  103. Pfeifer GW (1970) Distribution studies and placental transfer of 131 I streptokinase. Australas Ann Med 19(Suppl 1):17–18

    PubMed  Google Scholar 

  104. Leonhardt G, Gaul C, Nietsch HH, Buerke M, Schleussner E (2006) Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 21:271–276

    PubMed  Article  Google Scholar 

  105. Ahearn GS, Hadjilaiadis D, Govert JA, Tapson VF (2002) Massive pulmonary embolism during pregnancy treated with recombinant tissue plasminogen activator. A case report and review of treatment options. Arch Intern Med 162:1221–1226

    PubMed  Article  Google Scholar 

  106. Doreen te Raa G, Ribbert LSM, Snijder RJ, Biesma DH (2009) Treatment options in massive pulmonary embolism during pregnancy: a case report and review of the literature. Thromb Res 124:1–5

    PubMed  Article  CAS  Google Scholar 

  107. Holden EL, Ranu H, Sheth Abhijat (2011) Thrombolysis for massive pulmonary embolism in pregnancy—a report of three cases and follow-up over a two year period (Letter to the Editors-in-Chief). Thromb Res 127:58–59

    PubMed  CAS  Article  Google Scholar 

  108. Gupta S, Ettles DF, Robinson GJ, Lindow SW (2008) Inferior vena cava filter use in pregnancy: preliminary experience. BJOG 115(6):785–788

    PubMed  CAS  Article  Google Scholar 

  109. Cheung MC, Asch MR, Gandhi S, Kingdom JCP (2005) Temporary inferior vena caval filter use in pregnancy. J Thromb Haemost 3:1076–1079

    Article  Google Scholar 

  110. Ganguli S, Tham JC, Komlos F, Rabkin DJ (2006) Fracture and migration of a suprarenal inferior vena cava filter in a pregnant patient. J Vasc Interv Radiol 17:1707–1711

    PubMed  Article  Google Scholar 

  111. Milford W, Chadha Y, Lust K (2009) Use of a retrievable inferior vena cava filter in term pregnancy: case report and review of the literature. Aust NZ J Obstet Gynaecol 49:331–333

    Article  Google Scholar 

  112. McConville RM, Kennedy PT, Collins AJ, Ellis PK (1998) Failed retrieval of an inferior vena cava filter during pregnancy because of filter tilt: report of two cases. Cardiovasc Intervent Radiol 32:174–177

    Article  Google Scholar 

  113. Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY (2009) Dose-escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 7:760–765

    PubMed  CAS  Article  Google Scholar 

  114. Iladdadene R, Le Gal G, Delluc A, Carrier M (2014) Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis. Thromb Res 134:93–95

    Article  CAS  Google Scholar 

  115. Brandjes DPM, Buller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, ten Cate JW (1997) Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 349:759–762

    PubMed  CAS  Article  Google Scholar 

  116. Prandoni P, Lensing AWA, Prins MH, Fulla M, Marchiori A, Bernardi E, Tormene D, Mosena L, Pagnan A, Girolami A (2004) Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 141:249–256

    PubMed  Article  Google Scholar 

  117. Kahn SR, Shapiro S, Wells PS, Rodger MA, Kovacs MJ, Anderson DR, Tagalakis V, Houweling AH, Ducruet T, Holcroft C, Johri M, Solymoss S, Miron MJ, Yeo E, Smith R, Schulman S, Kassis J, Kearon C, Chagnon I, Wong T, Demers C, Hanmiah R, Kaatz S, Selby R, Rathbun S, Desmarais S, Opatrny L, Ortel TL, Ginsberg JS; SOX trial investigators (2014) Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 383(9920):880–888. doi:10.1016/S0140-6736(13)61902-9. Epub 2013 Dec 6

  118. Kahn SR, Shapiro S, Ducruet T, Wells PS et al (2014) Graduated compression stockings to treat acute leg pain associated with proximal DVT: a randomised controlled trial. Thromb Haemost 112(6):1137–1141

    PubMed  CAS  Article  Google Scholar 

  119. Bain E, Wilson A, Tooher R, Gates S, Davies L-J, Middleton P (2014) Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD001689

  120. Ray JG, Chan WS (1999) Deep vein thrombosis during pregnancy the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 54:265–271

    PubMed  CAS  Article  Google Scholar 

  121. Blanco-Molina A, Trujillo-Santos J, Criado J, Lopez L, Lecumberri R, Gutierrez R, Monreal M, Investigators RIETE (2007) Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry. Thromb Haemost 97:186–190

    PubMed  CAS  Google Scholar 

  122. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingemann HG (1983) Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 49:251

    PubMed  CAS  Google Scholar 

  123. Locht H, Lindstrom FD (1993) Severe skin necrosis following warfarin therapy in a patient with protein C deficiency. J Intern Med 233:287–289

    PubMed  CAS  Article  Google Scholar 

  124. Berkompas DC (1991) Coumadin skin necrosis in a patient with a free protein S deficiency: case report and literature review. Indiana Med 84:788–791

    PubMed  CAS  Google Scholar 

  125. Gates S, Brocklehurst P, Ayers S, Bowler U (2004) Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin. Am J Obstet Gynecol 191:1296–1303

    PubMed  CAS  Article  Google Scholar 

  126. Pettila V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E (1999) Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res 96:275–282

    PubMed  CAS  Article  Google Scholar 

  127. Rozanski C, Lazo-Langner A, Kovacs M (2009) Prevention of venous thromboembolism (VTE) associated with pregnancy in women with a past history of VTE. Blood Supplement abstract # 3132 ASH

  128. Blomback M, Bremme K, Hellgren M, Siegbahn A, Lindberg H (1998) Thromboprophylaxis with low molecular mass heparin, ‘Fragmin’ (dalteparin), during pregnancy—a longitudinal safety study. Blood Coagul Fibrinolysis 9:1–9

    PubMed  CAS  Article  Google Scholar 

  129. Brennand JE, Walker ID, Greer IA (1999) Anti-activated factor X profiles in pregnant women receiving antenatal thromboprophylaxis with enoxaparin. Acta Haematol 101:53–55

    PubMed  CAS  Article  Google Scholar 

  130. Dargaud Y, Rugeri L, Vergnes MC, Arnuti B, Miranda P, Negrier C, Bestion A, Desmurs-Clavel H, Ninet J, Gaucherand P, Rudigoz RC, Berland M, Champion F, Trzeciak MC (2009) A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study. Br J Haematol 145:825–835

    PubMed  Article  Google Scholar 

  131. Folkeringa N, Brouwer JL, Korteweg FJ, Veeger NJ, Erwich JJ, van der Meer J (2007) High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects. Br J Haematol 138:110–116

    PubMed  Article  Google Scholar 

  132. Dulitzky M, Pauzner H, Langevitz P, Pras M, Many A, Schiff E (1996) Low-molecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies. Obstet Gynecol 87:380–383

    Article  Google Scholar 

  133. Casele HL, Laifer SA, Woelkers DA, Venkataramanan R (1999) Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 181(5 Pt 1):1113–1137

    PubMed  CAS  Article  Google Scholar 

  134. Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S (2011) Prophylaxis with low dose low molecular weight heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 9:473–480

    PubMed  CAS  Article  Google Scholar 

  135. Galambosi Paivi J, Ulander V-M, Kaaja RJ (2014) The incidence and risk factors of recurrent venous thromboembolism. Thromb Res 134:240–245

    PubMed  CAS  Article  Google Scholar 

  136. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, Samama CM, American College of Chest Physicians (2012) Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2):e227s–e277s

    PubMed  PubMed Central  CAS  Google Scholar 

  137. Sultan AA, Grainge MJ, West J, Fleming KM, Nelson-Piercy C, Tata LJ (2014) Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England. Blood 124:28872–28880

    Google Scholar 

  138. Pabinger I, Grafenhofer H, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K et al (2002) Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood 100:1060–1062

    PubMed  CAS  Article  Google Scholar 

  139. Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J, Burrows R, Kearon C et al (2000) Safety of withholding heparin in pregnant women with a history of venous thromboembolism. N Eng J Med 343:1439–1444

    CAS  Article  Google Scholar 

  140. Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C et al (2005) Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 3:949–954

    PubMed  CAS  Article  Google Scholar 

  141. De Stefano V, Martinelli I, Rossi E, Battaglioli T, Za T, Mannuccio MP et al (2006) The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 135:386–391

    PubMed  Article  Google Scholar 

  142. Middeldorp S (2011) Is thrombophilia testing useful? Hematology (Am Hem Soc Hematol Educ Program) 2011:150–155

    Article  Google Scholar 

  143. White RH, Chan WS, Zhou H, Ginsberg JS (2008) Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost 100:246–252

    PubMed  CAS  Google Scholar 

  144. Greer IA (1999) Thrombosis in pregnancy: maternal and fetal issues. Lancet 10(353):1258–1265

    Article  Google Scholar 

  145. Middeldorp S, van Hylckama Vlieg A (2008) Does thrombophilia testing help in the clinical management of patients? Br J Haematol 143:321–335

    PubMed  Article  Google Scholar 

  146. Robertson L, Wu O, Langhorne P et al (2005) for The Thrombosis Risk and Economic Assessment of Thrombophilia Screening (Treats) Study: thrombophilia in pregnancy: a systematic review. Br J Haematol 132:71–196

    Google Scholar 

  147. Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ (2008) The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 169:610–615

    Article  Google Scholar 

  148. Zoller B, Ohlsson H, Sundquist J, Sundquist K (2013) Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nation-wide family study in Sweden. Thromb Haemost 109:361–362

    Article  CAS  Google Scholar 

  149. Lensen RP, Bertina RM, de Ronde H, Vandenbroucke JP, Rosendaal FR (2000) Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost 83:817–821

    PubMed  CAS  Google Scholar 

  150. Friederich PW, Sanson BJ, Simioni P, Zanardi S, Huisman MV, Kindt I et al (1996) Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann Int Med 125:955–960

    PubMed  CAS  Article  Google Scholar 

  151. Mahmoodi BK, Brouwer J-LP, Ten Kate MK, Lijfering WM, Veeger NJGM, Mulder AB, Kluin-Nelemans HC, van der Meer J (2010) A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C and antithrombin. J Thromb Haemost 8:1193–1200

    PubMed  CAS  Article  Google Scholar 

  152. Middeldorp S, Libourel EJ, Hamulyak K, van der Meer J, Buller HR (2001) The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden. Br J Haematol 113:553–555

    PubMed  CAS  Article  Google Scholar 

  153. Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano V, Mannucci PM (2001) Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 86:800–803

    PubMed  CAS  Google Scholar 

  154. Tormene D, Simioni P, Prandoni P, Luni S, Zerbinati P, Sartor D et al (2001) Factor V Leiden mutation and the risk of venous thromboembolism in pregnant women. Haematologica 86:1305–1309

    PubMed  CAS  Google Scholar 

  155. Middeldorp S, Henkens CMA, Koopman MMW, van Pampus ECM, van der Meer J, Hamulyak K et al (1998) The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Int Med 128:15–20

    PubMed  CAS  Article  Google Scholar 

  156. Simioni P, Sanson BJ, Prandoni P, Tormene D, Friederich PW, Girolami B et al (1999) The incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 81:198–202

    PubMed  CAS  Google Scholar 

  157. Middeldorp S, Meinardi JR, Koopman MMW, van Pampus ECM, Hamulyak K, van der Meer J et al (2001) A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Int Med 135:322–327

    PubMed  CAS  Article  Google Scholar 

  158. Simioni P, Tormene DF, Prandoni PF, Zerbinati PF, Gavasso S, Cefalo P et al (2002) Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study. Blood 99:1938–1942

    PubMed  CAS  Article  Google Scholar 

  159. Couturaud F, Leroyer C, Mottier D (2008) Risk factors and clinical presentation of venous thromboembolism according to the age of relatives of patients with factor V Leiden. Thromb Haemost 99:793–794

    PubMed  CAS  Google Scholar 

  160. Bank I, Libourel EJ, Middeldorp S, van Pampus ECM, Koopman MMW, Hamulyak K et al (2004) Prothrombin 20210A mutation: a mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study. Arch Int Med 164:1932–1937

    CAS  Article  Google Scholar 

  161. Coppens M, van der Poel MH, Bank I, Hamulyak K, van der Meer J, Veeger NJ et al (2006) A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation. Blood 108:2604–2607

    PubMed  CAS  Article  Google Scholar 

  162. Galli M, Barbui T (2005) Antiphospholipid syndrome: clinical and diagnostic utility of laboratory tests. Semin Thromb Hemost 31:17–24

    PubMed  Article  Google Scholar 

  163. Bergrem A, Jacobsen EM, Skjeldestad FE, Jacobsen AF, Skogstad M, Sandset PM (2010) The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis—a population-based case-control study. Thromb Res 125:e222–e227

    PubMed  CAS  Article  Google Scholar 

  164. Quenby S, Farquharson RG, Dawood F, Hughes AM, Topping J (2005) Recurrent miscarriage and long-term thrombosis risk: a case-control study. Hum Reprod 20:1729–1732

    PubMed  CAS  Article  Google Scholar 

  165. Conard J, Horellou MH, van Dreden P, Lecompte T, Samama M (1990) Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost 63:319–320

    PubMed  CAS  Google Scholar 

  166. De Stefano V, Leone G, Mastrangelo S, Tripodi A, Rodeghiero F, Castaman G, Barbui T, Finazzi G, Bizzi B, Mannucci PM (1994) Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, and protein S. Thromb Haemost 71:799–800

    PubMed  Google Scholar 

  167. Vincente V, Rodriguez C, Soto I, Fernandez M, Moraleda JM (1994) Risk of thrombosis during pregnancy and post-partum in hereditary thrombophilia. Am J Hematol 46:151–152

    Article  Google Scholar 

  168. Henriksson P, Westerlund E, Wallén H, Brandt L, Hovatta O, Ekbom A (2013) Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. BMJ:346:e8632. doi:10.1136/bmj.e8632

  169. Jacobsen AF, Skjeldestad FE, Sandset PM (2008) Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J Thromb Haemost 6:905–912

    PubMed  CAS  Article  Google Scholar 

  170. Kevane B, Donnelly J, D’Alton M, Cooley S, Roger JSP, Ni Ainle F (2014) Risk factors for pregnancy-associated venous thromboembolism: a review. J Perinat Med 42:417–425

    PubMed  Google Scholar 

  171. Sultan AA, Tata LJ, West J, Fiaschi L, Fleming KM, Nelson-Piercy C, Grainge M (2013) Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood 121:3953–3961

    PubMed  Article  CAS  Google Scholar 

  172. Kane EV, Calderwood C, Dobbie R, Morris C, Roman E, Greer IA (2013) A population-based study of venous thrombosis in Scotland 1980–2005. Eur J Obstet Gynecol Reprod Biol 169:223–229

    PubMed  Article  Google Scholar 

  173. Jacobsen AF, Drolsum A, Ne Klow, Dahl GF, Qvigstad E, Sandset PM (2004) Deep vein thrombosis after elective cesarean section. Thromb Res 113:283–288

    PubMed  CAS  Article  Google Scholar 

  174. Sia WW, Powrie RO, Cooper AB, Larson L, Phipps M, Spencer P, Sauve N, Rosene-Montella K (2009) The incidence of deep vein thrombosis in women undergoing cesarean delivery. Thromb Res 123:550–550

    PubMed  CAS  Article  Google Scholar 

  175. Macklon SN, Greer IA (1994) Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scott Med J 41:83–86

    Google Scholar 

  176. Ruppen W, Derry S, McQuay H, Moore RA (2006) Incidence of epidural hematoma, infection, and neurologic injury in obstetric patients with epidural analgesia/anesthesia. Anesthesiology 105(2):394–399

    PubMed  Article  Google Scholar 

  177. Narouze S, Benzon H, Provenzano DA et al (2015) Interventional Spine and Pain Procedures in Patients on Antiplatelet and Anticoagulant Medications: Guidelines From the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain. Reg Anesth Pain Med 40:182–212

    PubMed  CAS  Article  Google Scholar 

  178. Anderson DR, Ginsberg JS, Burrow R, Brill-Edwards P (1991) Subcutaneous heparin therapy during pregnancy: a need for concern at the time of delivery. Thromb Haemost 65:248–250

    PubMed  CAS  Google Scholar 

  179. Greer IA (2012) Thrombosis in pregnancy: updates in diagnosis and management. Hematol Am Soc Hematol Educ Program 2012:203–207

    Google Scholar 

  180. Massonnet-Castel S, Pelissier E, Bara L et al (1986) Partial reversal of low molecular-weight heparin (PK 101699) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation. Haemostasis 16:139–146

    PubMed  CAS  Google Scholar 

  181. Investigators Columbus (1997) Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 337:657–662

    Article  Google Scholar 

  182. Kearon C, Hirsh J (1997) Management of anticoagulation before and after elective surgery. N Engl J Med 336:1506–1511

    PubMed  CAS  Article  Google Scholar 

  183. McLintock C, McCowan LM, North RA (2009) Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. BJOG 116:1585–1592

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgments

We wish to acknowledge the support provided by Myelin and Associates with the preparation of this manuscript for submission. The work contained in this manuscript was partially funded by support from the following companies: Boehringer Ingelheim, Daiichi Sankyo and Janssen Pharmaceuticals. This guidance document is endorsed by the Anticoagulation Forum’s Board of Directors: Mark Crowther, MD, MSc, FRCPC, Jack E. Ansell, MD, Allison Burnett, PharmD, Nathan Clark, PharmD, Adam Cuker, MD, David Garcia, MD, Scott Kaatz, DO, MSc, FACP, Renato D. Lopes, MD, PhD, Tracy Minichiello, MD, Edith Nutescu, PharmD, FCCP, Lynn Oertel, MS, ANP, CACP, Eva Kline-Rogers, MS, RN, NP,Terri Schnurr, RN, CCRC, Michael Streiff, MD, Diane Wirth, ANP, CACP, BCPS, CACP, Daniel Witt, Pharm D, Ann Wittkowsky, PharmD, CACP, FASHP, FCCP.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shannon M. Bates.

Ethics declarations

Disclosures

SBates: salary support through the Eli Lilly Canada/May Cohen Chair in Women’s Health. S Middeldorp: reports grant support from Sanquin, grant support and fees paid to her institution from Aspen, GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, and fees paid to her institution from Bayer, Boehringer Ingelheim, and Daiichi Sankyo. Recipient of a VIDI innovation research grant from the Netherlands Organization for Scientific Research. M Rodger: Recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and a Chair in Venous Thrombosis and Thrombophilia from the Department of Medicine and Faculty of Medicine, University of Ottawa. A James: nothing to disclose. I Greer: received honoraria from Sanofi and LEO Pharma in the last 5 years.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bates, S.M., Middeldorp, S., Rodger, M. et al. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. J Thromb Thrombolysis 41, 92–128 (2016). https://doi.org/10.1007/s11239-015-1309-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-015-1309-0

Keywords

  • Pregnancy
  • Obstetric
  • Venous thromboembolism
  • Pulmonary embolism
  • Deep vein thrombosis
  • Prophylaxis
  • Anticoagulants