Low molecular weight heparin in pregnancy - Wiley Online Library

review

Low molecular weight heparin in pregnancy: current issues Ian Greer1 and Beverley J. Hunt2 1

Division of Developmental Medicine, University of Glasgow, Glasgow Royal Infirmary, Scotland, and 2Departments of Haematology and Rheumatology, Guy’s and St Thomas’ Trust, London, UK

Summary Low molecular weight heparin (LMWH) is now the most commonly used anticoagulant for prophylaxis and treatment of venous thromboembolism in pregnancy and the puerperium in the UK. The reliable pharmacokinetics of LMWHs and their long half-life, resulting in the need for less frequent injections than unfractionated heparin (UFH), makes them attractive for practical use in the 9 months of pregnancy. Widespread use over the last 10 years has shown that LMWHs are safer than UFH in pregnancy. There is, however, poor consensus and wide disparity of views among experts with regard to the appropriate dose for the varying indications, the duration of treatment, and whether and how LMWH should be monitored because of the lack of an evidence base. These areas of uncertainty reflect the fact that clinical practice has grown largely through the publication of small trials, observational studies, personal experience and anecdote. Good clinical trials are urgently required. Keywords: low molecular weight heparin, pregnancy, efficacy, safety. Low molecular weight heparin (LMWH) is now the most commonly used anticoagulant for prophylaxis and treatment of venous thromboembolism (VTE) in pregnancy and the puerperium in the UK (Copplestone et al, 2004). Pregnancy is essentially the only situation in modern therapeutics where heparin is recommended for use over a prolonged period. LMWH is preferred to unfractionated heparin (UFH) as it has a better safety profile (Sanson et al, 1999), is more practical and, at least out with pregnancy, is as effective as UFH for 1 prophylaxis (Leizoroviecz et al, 1992; Nurmohamed et al, 2 1992) and treatment (Leizoroviecz et al, 1994; Lensing et al, 1995; Siragusa et al, 1996; Quinlan et al, 2004). Nonetheless, when LMWH was introduced in the late 1980s, there were concerns about its safety in pregnancy. These concerns were based on the assumption that the maternal side-effects encountered with the prolonged use of UFH, i.e. osteoporosis

Correspondence: Dr Beverley J. Hunt, Department of Haematology, St Thomas’ Hospital, London SE21 7HJ, UK. E-mail: [email protected]

and a recognizable occurrence of heparin-induced thrombocytopenia (HITT), and allergy, would also apply to LMWH (Dahlman, 1993; Barbour et al, 1994; Dahlman et al, 1994; Douketis et al, 1996; Shefras & Farquharson, 1996; Backos et al, 1999a). At that time, UFH was the favoured anticoagulant in pregnancy despite the problems highlighted (Haemostasis & Thrombosis Task Force, 1993). This was because heparin does not cross the placenta and because the only viable alternative was oral anticoagulants, which do cross the placenta and have both teratogenic effects and significant risks of fetal haemorrhage in the second and third trimester. Unfractionated heparin is not a gold standard; however, for the ‘trade-off’ of loss of adverse fetal effects is a 2% risk of symptomatic vertebral fracture because of osteoporosis and, as befits a foreign animal protein, a risk of immunological response including allergy and HITT (Nelson-Piercy, 1997). Moreover UFH has unreliable pharmacokinetics. When administered subcutaneously, UFH produces variable plasma levels depending on the degree of binding to proteins in the plasma and on the endothelium (Glimelius et al, 1978; Young et al, 1992) and thus requires dosage adjustment in each individual after monitoring, usually with the activated partial thromboplastin time (aPTT). This test has limited reliability, particularly in pregnancy where the aPTT response to heparin is often attenuated because of increased levels of factor VIII (FVIII), fibrinogen and heparin-binding proteins (Wheeler et al, 1988; Hyers et al, 1995). Thus, the reliable pharmacokinetics of LMWHs and their long half-life, resulting in the need for less frequent injections (Weitz, 1997), made them attractive for practical use in the 9 months of pregnancy. Widespread use over the last 10 years has shown that LMWHs are safer than UFH in pregnancy, for fewer cases of HITT have been reported with LMWH (Warkentin et al, 1995); indeed no cases of HITT have been described during pregnancy and only five cases of osteoporotic fracture have been reported in the literature to date (Hunt et al, 1997; Byrd et al, 2004). Several observational studies and one randomized trial have shown no significant effect on bone density at least with thromboprophylactic doses (Shefras & Farquharson, 1996; Sanson et al, 1999; Monreal, 2000; Lepercq et al, 2001; Pettila et al, 2002; Schulman & Hellgrne-Wangdahl, 2002). These findings and increasing experience have led European obstetricians and haematologists to become more

ª 2004 Blackwell Publishing Ltd, British Journal of Haematology, 128, 593–601

doi:10.1111/j.1365-2141.2004.05304.x

Review relaxed and confident in using LMWH for prolonged periods in pregnancy. Areas of uncertainty with the use of LMWHs in pregnancy do remain, however, reflecting the fact that clinical practice has grown largely through the publication of small trials, observational studies, personal experience and anecdote. There are no large randomized double blind studies of LMWH versus UFH in pregnancy. However, on biological grounds there is no reason to suggest that LMWH would be inferior to UFH. Indeed, the more reliable pharmacokinetics of LMWH would suggest they might be more efficacious. Finding the appropriate dose of LMWH in pregnancy has depended on clinicians performing pilot studies. Data suggest that in pregnancy there is increased turnover of LMWH and thus higher doses are required compared with the nonpregnant patient, both for treatment and thromboprophylaxis (Blomback et al, 1998; Casele et al, 1999; Rodie et al, 2002). Several studies have shown that, to meet a specific target level of anti-Xa, LMWH dose increases are required during pregnancy, reflecting the increasing plasma volume (Hunt et al, 1997). However, at a practical level, at least for prophylaxis, the same dose has been used by some groups throughout pregnancy on the presumption that the modest reduction in LMWH levels in later pregnancy are not associated with a reduction in efficacy (Ellison et al, 2000). There is a broad international agreement that LMWH is the anticoagulant of choice in pregnancy (Ginsberg et al, 2001; Greer, 2002). However, with regard to the appropriate dose for the varying indications, the duration of treatment and whether (and if so how) LMWH should be monitored, there is poor consensus and wide disparity of views among experts because of the lack of an evidence base. The aim of this article is to discuss these issues and set out how progress might be made.

LMWH dosing Anticoagulants are used in pregnancy for the following indications: 1 2 3 4

The treatment of VTE. Thromboprophylaxis (VTE and arterial). Mechanical Heart valves. Prevention of first trimester loss and placental dysfunction in thrombophilic women.

LMWH dosing in the treatment of VTE in pregnancy In the acute management of VTE it seems appropriate that LMWH should be used in standard doses, according to total body weight. It is not clear as to whether the dose should be based on early pregnancy weight or weight at the time of developing the VTE. One of the present authors uses early pregnancy weight. This is on the basis that: first, pregnant women are no longer routinely weighed except at their booking (first) visit; secondly, because LMWH does not cross 594

the placenta fetoplacental weight is not relevant; and thirdly, in their experience, there has been no need to adjust the dose based on early pregnancy weight, and according to manufacturer’s instructions, to obtain satisfactory anti-Xa levels (for enoxaparin and dalteparin). This seems rational unless a woman has had excessive weight gain in pregnancy or is at extremes of body mass index (BMI). There was initial concern that, outside of pregnancy, morbidly-obese patients receiving treatment doses of LMWH may become over anticoagulated, as the bulk of their weight is accounted for by adipose tissue, which receives a comparatively small blood supply. It might be expected that such obese patients should be dosed according to their ideal body weight (dose capping) (Sanderink et al, 2002). However, the literature does not support this view (Yee & Duffull, 2000; Hainer et al, 2002). Majority of the trials have used LMWH prescribed by weight in patients weighing up to 190 kg with no evidence of increased bleeding (Wilson et al, 2001; Hainer et al, 2002; Smith & Canton, 2003; Spinler et al, 2003). Indeed there is evidence that larger LMWH doses should be considered in some cases, e.g. with enoxaparin using 1 mg/kg b.i.d instead of 1Æ5 mg/kg/d (Merli et al, 2001). Some reviews recommend the use of higher prophylactic doses (which are fixed doses, not prescribed according to weight) in obese patients (Scholten et al, 2002). There is no reason why this should not apply in pregnancy, particularly in view of the physiological changes in the coagulation and fibrinolytic systems that occur. Because of the increased clearance rate of LMWH in pregnancy, twice daily dosing regimes are generally recommended (Casele et al, 1999). It has been suggested that, for enoxaparin, these doses provide appropriate anti-Xa levels (Rodie et al, 2002). The next decision to consider is how long to continue full treatment doses of LMWH. In general terms, a patient should continue anticoagulant treatment until the risk of treatment outweighs the risk of recurrent VTE. Out with pregnancy, the main risk of treatment is bleeding while on warfarin, where 1% of patients per year with a target international normalized ratio (INR) of 2–3 have a bleed, 25% of which are fatal. But this does not apply to LMWH. So what are the concerns with regard to LMWH? First, if therapeutic doses are used for a prolonged period, the mother may be exposed to an increased risk of bleeding and possibly osteoporosis; secondly, if inadequate doses are used, she may be at risk of recurrent VTE. In the absence of randomized trials, these issues have to be addressed by extrapolation from studies of non-pregnant cases and by expert opinion. It is recognized that switching from therapeutic to prophylactic doses of UFH is associated with a recurrent VTE rate of over 40% in the non-pregnant (Hull et al, 1982). But this is not true of LMWH. The CLOT (Randomized Comparison of LowMolecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent VTE in Patients with Cancer) study (CLOT investigators, 2003), a large multicentre study, compared the use of LMWH versus warfarin in cancer patients. Cancer patients, like pregnant women, have a high risk of


Review recurrence compared with other patients with VTE, yet the study showed that dalteparin, given initially at full therapeutic doses and then reduced to 150 IU/kg, was significantly more effective than warfarin with a target INR of 2Æ5 in preventing recurrent VTE and also had a lower bleeding risk. In addition, Marchetti et al (2001) have produced a meta analysis of studies comparing the use of thromboprophylactic doses of LMWH versus warfarin in pooled data from six published trials, in which patients received full-dose LMWH for 5 d after VTE and continued therapy for at least 3 months with either oral anticoagulants or LMWH (dalteparin, enoxaparin, nadroparin and Kabi 2165 heparin fragment) at prophylactic doses, and found little difference in recurrence rates between the two treatments. Moreover, the bleeding risk may be greater with therapeutic compared with intermediate or prophylactic doses at least out with pregnancy (Leizoroviecz et al, 1992) and while there are extensive data showing a lack of association between prophylactic doses of LMWH and osteoporosis, there are few data on therapeutic doses. Absence of evidence on osteoporosis is not an evidence of absence of effect. The use of LMWH in pregnancy in the UK is disparate for there is no consensus (Copplestone et al, 2004). In women with VTE during pregnancy many experts continue on full treatment dose for the rest of pregnancy, others will switch to an intermediate dose after a set period. The former view is based on the fact that LMWH appears safe and that gestational VTE is usually associated with the presence of persistent risk factors for recurrence. For example, in non-pregnant patients the presence of a persistent risk factor gives a relative risk of >2Æ0, a FVIII level of >200 IU/ml carries a relative risk of 6Æ0 and heritable thrombophilia, a relative risk of 1Æ4–4Æ0 (Kearon, 2003). Pregnancy is itself a risk factor for VTE, FVIII levels are generally above 200 IU/ml in normal pregnancy and at least 50% of VTEs in pregnancy are associated with a heritable thrombophilia; therefore these patients will usually have multiple, continuing risk factors for recurrent VTE. In contrast, the latter view is based on concerns that therapeutic doses of LMWH may not be free of risk of osteoporosis and that studies such as the CLOT trial are reassuring with regard to efficacy of an intermediate dose in a high-risk population. Until more evidence is available, it would appear that both strategies are reasonable. The clinician should therefore be guided by the balance between the perceived risk of recurrence versus the perceived risk of side-effects in a particular patient with regard to the duration of full therapeutic dosing. We would, however, suggest continuing on a treatment dose of LMWH for a minimum of 1 month before switching to an intermediate dose of LMWH and also taking into account the risk factors such as the underlying thrombophilia, immobility, obesity and operative intervention that are present in the particular patient. In future, a trial of the use of intermediate dose LMWH versus full dose LMWH in women with VTE after a fixed dose of LMWH would be welcomed. The appropriate end points would be recurrence and also the rate of resolution of VTE

using modern imaging techniques such as magnetic resonance direct thrombus imaging (Kelly et al, 2003).

Thromboprophylaxis The overall incidence of fatal pulmonary thromboembolism in the UK has fallen substantially from the early 1950s; however, the greatest reduction in the number of deaths has been those following vaginal delivery (Drife & Lewis, 2001). Nonetheless. in recent years there has been no further reduction in fatalities after vaginal delivery and the number of deaths during the antenatal and intrapartum period have changed little from the early 1950s despite major advances in identification of risk, thromboprophylaxis and diagnostic and therapeutic intervention over this same period (Department of Health, Welsh Office, Scottish Home and Health Department and Department of Health and Social Services Northern Ireland, 2000). The total number of deaths following caesarean section had also changed little from the 1950s until the guidelines on thromboprophylaxis were published (Royal College of Obstetricians and Gynaecologists, 1995). After the introduction of these guidelines, the number of deaths fell dramatically. This highlights the usefulness of appropriate thromboprophylaxis following caesarean section and, perhaps more importantly, emphasizes the need for better prophylaxis in the antenatal period and after vaginal delivery. The majority of deaths after vaginal delivery were in women who were obese and >35 years of age. The new RCOG guidelines (Royal College of Obstetricians and Gynaecologists, 2004) attempt to address this issue through risk assessment with LMWH prescribed, where the threshold for intervention is reached. As noted above, studies of anti-Xa levels suggest that increased doses of LMWH are required during pregnancy if the aim is to maintain a particular anti-Xa activity at a constant level. However, there is no evidence in pregnancy to support aiming for a certain level of anti-Xa activity to prevent VTE. What is really required is a clinical study where the incidence of VTE is assessed in a trial comparing the same dose of LMWH through pregnancy versus an increasing dose where anti-Xa levels are measured. It seems unlikely that this study will ever be performed because of the need for a very large study population. There is no consensus in the UK about thromboprophylactic dosing. Some experts are of the view that 40 mg of enoxaparin is sufficient in most women but accept that the anti-Xa level may fall towards term. Some use the knowledge of fall in anti-Xa levels to use a fixed intermediate dose during pregnancy. Others monitor anti-Xa activity monthly. But the concern about those monitoring is whether the target anti-Xa levels used are appropriate and whether trough or peak levels should be measured. In terms of bleeding risk and ultimately the reduction in risk of recurrent VTE, no such trial has been performed in pregnancy. A further area where there is lack of agreement is in women on long-term warfarin therapy outside of pregnancy because of recurrent or previous VTE or antiphospholipid syndrome.


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Review Should these women be switched to full treatment doses of LMWH during pregnancy or could they be managed on an intermediate or even thromboprophylactic dose? Outside of pregnancy, evidence from the CLOT study (CLOT investigators, 2003) and Marchetti et al (2001) would support prophylactic or intermediate dose LMWH. The St Thomas’ group (Hunt et al, 1997, 2003) suggests that intermediate dose LMWH is effective in the prevention of VTE in high-risk women, most of them on long-term warfarin for antiphospholipid syndrome. It is a surprising paradox that this group of women, who were given therapeutic doses of warfarin outside of pregnancy, can be effectively managed on an intermediate dose of LMWH during pregnancy, when the prothrombotic tendency is increased. This emphasizes the fact that these anticoagulants function in different ways and that an equivalent anticoagulant effect, in terms of traditional coagulation tests, is not required for equivalent efficacy.

Thromboprophylaxis for women with prosthetic heart valves Pregnant women with prosthetic heart valves pose problems because of the lack of data on the efficacy or appropriate doses of LMWH and UFH in preventing thrombotic complications and the risk of teratogenesis, neurodevelopmental problems and maternal and fetal bleeding with warfarin. A systematic review of the literature examining fetal and maternal outcomes of pregnant women with prosthetic heart valves has been performed (Chan et al, 2000) consisting of prospective and retrospective cohort studies. This studied the three most commonly reported anticoagulant regimes namely: use of warfarin throughout pregnancy; replacement of warfarin with UFH from 6 to 12 weeks’ gestation; and UFH use throughout pregnancy. In the warfarin regimes, UFH was used at term in order to avoid delivery of an anticoagulated fetus. The use of warfarin throughout pregnancy was associated with warfarin embryopathy in 6Æ4% of live births, but this was eliminated if heparin was substituted at, or prior to, 6 weeks gestation. The use of warfarin throughout pregnancy was also associated with the lowest risk of thromboembolic problems (3Æ9%) compared with pregnancies where the warfarin was replaced by heparin. Using UFH only between 6 and 12 weeks’ gestation was associated with an increased risk of valve thrombosis (9Æ2%), while using UFH throughout pregnancy was associated with a 25% rate of valve thrombosis with adjusted doses and 60% with low-dose UFH. However, modern bi-leaflet valves have much less thrombotic potential than earlier mechanical valves, such as the Starr–Edwards valve, that were present in many of the published studies, making it difficult to extrapolate the thrombotic risk to women with these newer less thrombogenic valves. Adverse pregnancy outcome in terms of spontaneous loss, stillbirths and neonatal deaths was similar in the three groups. Thus, on the basis of these available data, warfarin appears more effective than UFH for thromboembolic prophylaxis of women with mechanical heart valves in pregnancy, 596

but is associated with significant fetal problems, which have been shown to relate to warfarin dosage by others (Vitale et al, 1999). In addition, the data of risk on thrombosis with adjusted dose UFH are limited. Clearly the use of low-dose UFH is inadequate. There are now reports of LMWH in pregnant women with prosthetic heart valves and this option is attractive in terms of maternal side-effects and ease of use. However, there are now a number of reports of valve thrombosis and stroke with LMWH in and out of pregnancy (Idir et al, 1999; Berndt et al, 2000; Lev-Ran et al, 2000; Oles et al, 2001; Roberts et al, 2001; Mahesh et al, 2002). Indeed no LMWH is licensed for use with prosthetic valves outside of pregnancy and their use in pregnant women with prosthetic valves has been discouraged. Ginsberg et al (2003) and also Topol (2003), on behalf of the members of the Anticoagulation in Prosthetic Valves and Pregnancy Consensus Report, challenged the scientific rationale for this. They both pointed out that the other options are far from ideal gold standards. Better comparative data on LMWH at an appropriate dose versus UFH or warfarin would be valuable in determining the optimal approach. Until better data are available, all three approaches seem reasonable and the patient’s views and her thrombotic risk factors such as a metal valve, atrial fibrillation and left ventricular dysfunction should be taken into account when determining the risks that she would wish to accept with regard to the balance of maternal and fetal problems. We agree with Ginsberg et al (2003) that the field of management of pregnant women with mechanical heart valves requires a consensus among experts to systematically gather the best available evidence, identify unresolved issues and generate studies designed to answer these questions.

Prevention of first trimester loss in thrombophilic women First trimester loss is a feature of antiphospholipid syndrome (Wilson et al, 1999) and the latter is thought to be responsible for up to 20% of recurrent miscarriage. It is hypothesized that the antiphospholipid antibody interferes with trophoblast invasion and in vitro the use of heparin has been shown to ameliorate this effect (Chamley et al, 1998; Di Simone et al, 1999). Clinical studies have produced conflicting results as to whether aspirin, alone or in combination with an empirical fixed thromboprophylactic dose of initially UFH and now LMWH in women with antiphospholipid antibodies and a history of previous pregnancy loss (but not previous thrombosis), improves fetal outcome (Kutteh, 1996; Rai et al, 1997; Backos et al, 1999b; Pattison et al, 2000; Empson et al, 2002; 3 Farquharson et al, 2002, overview in Derksen et al, 2004). There have been no studies however, assessing the effect of increasing the dose of LMWH on pregnancy outcome in these women. At the time of going to press, an elegant article by Girardi et al (2004) strongly suggested that the mechanism by which heparins reduce fetal loss in mice is not through their anticoagulant effects but through inhibition of complement


Review activation. Neither fondaparinux nor hirudin inhibited complement or prevented pregnancy loss, suggesting that anticoagulant therapy alone is an insufficient protection against antiphospholipid syndrome-associated miscarriage. Recent data also suggest an association between other heritable and acquired thrombophilias such as Factor V Leiden, prothrombin G20210A (Rey et al, 2003) and circulating pro-coagulant microparticles (Laude et al, 2001; Carp et al, 2004) and recurrent pregnancy loss. These data suggest that a procoagulant phenotype, regardless of the specific thrombophilia, is a risk factor for first trimester loss, so raising the question as to whether antithrombotic therapy should be used more widely in women with recurrent miscarriage and adverse pregnancy outcomes. It is therefore critical to assess, in a randomized trial, the role of antithrombotic therapy in this situation.

Prevention of placental dysfunction in thrombophilic women There is now compelling evidence that heritable and acquired thrombophilias are associated with a proportion of cases of placental dysfunction in the second and third trimester, which manifest as intrauterine death, stillbirth, intrauterine growth restriction, pre-eclampsia and placental abruption (Preston 4 et al, 1996; Gris et al, 1999; Kupferminc et al, 1999; Brenner, 2004; Vossen et al, 2004), although caution must be used, for the relationship may be small in that only a minority of women with thrombophilia have placental dysfunction and indeed only a minority of placental dysfunction relates to thrombophilia. Placental histopathological studies in antiphospholipid syndrome suggest that the aetiology relates to thrombosis placental infarction (Out et al, 1991). Anecdotally, antithrombotic therapy has been shown to be of benefit in improving fetal outcome in women with antiphospholipid syndrome and previous second and third trimester placental dysfunction, although there has never been a randomized double blind trial of this group (summarized in Derksen et al, 2004). Until recently, it has not been clear whether antithrombotic therapy is useful in women with previous placental dysfunction and inherited thrombophilia. Many physicians have been treating such women with antithrombotic therapy on the basis of logic and anecdotal evidence. The prospective follow-up study by the European prospective cohort on thrombophilia confirmed a slightly increased risk of fetal loss in women with thrombophilia (Preston et al, 1996). Prophylactic antithrombotic therapy in 83 women varied widely in type, dose and duration precluding solid conclusions on the effect of thromboprophylaxis on fetal loss. An important and timely study by Gris et al (2004) showed that, in 160 women with a heritable thrombophilia and one previous fetal loss (defined as after the10th week of pregnancy, i.e. second or third trimester), enoxaparin (40 mg) produced a significantly higher live birth rate than 100 mg aspirin alone.

Monitoring LMWH in pregnancy This remains the most contentious area, sparking much debate 5,6 (Bounameaux & De Moerloose, 2004; Harenberg, 2004), with many haematologists providing weekly or monthly level adjustment to maintain anti-Xa activity within a certain band for women on treatment and thromboprophylactic doses of LMWH. Several studies have demonstrated that anti-Xa levels are not a good predictor of bleeding and antithrombotic efficacy in thromboprophylaxis (Leizoroviecz et al, 1993; Alhenc-Gelas et al, 1994). However, the clinical study that is required to assess the rate of recurrence of VTE in these monitored levels versus non-monitored levels has not been performed. Indeed, there is no consensus on the best way to monitor these women – should trough or peak levels be measured? Peak levels provide a guide to bleeding risk, thus it seems illogical to measure such levels in patients receiving thromboprophylactic doses. Trough levels assess continued anticoagulant effect and seem more logical, if levels are to be measured at all. But why measure levels at all? Certainly with warfarin and UFH, where each individuals’ pharmacokinetics is different and varies from day-to-day, it is a necessity. But LMWHs have reliable pharmacokinetics and studies now exist showing how, with increasing plasma volume and haemostatic changes in pregnancy, the need for LMWH can be predicted. So is there a need to monitor? There is, perhaps, in women at extremes of BMI, as discussed earlier. The other issue about monitoring regards accuracy. A recent study from the UK national external quality assessment scheme (NEQAS) has shown that Haematology Laboratories throughout the UK have a poor ability to provide accurate levels of anti-Xa activity. A UK NEQAS survey 135 sent two plasma samples containing LMWH to the laboratories in the UK measuring anti-Xa activity (UK NEQAS for Blood Coagulation, personal communication). A low-value anti-Xa activity was measured in 83 laboratories, producing a median value of 0Æ48 with a chromogenic assay and 0Æ39 with a clotting assay. However, the range of values received was from 0Æ22 to 0Æ90. Similarly, another sample produced a median value of 0Æ76, but the range was enormous with values between 0Æ08 and 1Æ70, and a coefficient of variance of 30%. So, even if anti-Xa levels are being monitored, are the values from the laboratories providing meaningful values? 7 Baxter Diagnostics (Irvine, CA, USA) introduced pointof-care anti-Xa assays for cardiac doses of enoxaparin. Such near-patient assessment would be helpful for thromboprophylactic anti-Xa levels in the clinic, especially in women at the extremes of BMI. All these concerns led the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis to conclude that ‘…whilst anti-Xa assays may provide some clues to LMWH pharmacokinetics in individual subjects, such as the obese, the underweight, pregnant women and infants, only limited information on antithrombotic effect


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Review and bleeding risk can be deduced from this measurement. If anti-Xa assay is employed for monitoring in these clinical situations the limitations of the information generated must be borne in mind’ (Greaves, 2002). Ultimately however, a trial of monitored versus fixed-dose LMWH is required in women requiring LMWH in pregnancy.

Conclusions The indications for the use of LMWH include the management and prevention of VTE in pregnancy and they are now becoming established in the prevention of pregnancy morbidity associated with heritable and acquired thrombophilia. However, the practical use of LMWHs, notably dosage and whether to monitor, remains contentious and requires further clinical studies to develop a satisfactory evidence base. The key areas that require clinical trials at present include: 1 Comparisons of fixed-dose regimes against monitored dosage in venous thromboprophylaxis and treatment. 2 Assessment of the efficacy of high dose versus intermediatedose LMWH in the prevention of pregnancy morbidity associated with thrombophilias. Whether these trials will occur will depend on the collaboration of large numbers of haematologists and obstetricians is not clear. The difficulties of starting such studies should not be underestimated, for LMWH are unlicensed in the areas of study, the numbers recruited need to be large and the costs of running the studies will be enormous. The future prospects for LMWH in pregnancy in the long term are dependent ultimately on transplacental passage of the new anticoagulants that have arrived or are on the threshold of being introduced. It seems unlikely that there will be a major shift over to a new anticoagulant in view of the experience built up with LMWH, unless an oral agent is found that does not cross the placenta. Fondaparinux, a synthetic pentasaccharide, has been shown to be at least as, if not more, efficacious as LMWH in thromboprophylaxis after orthopaedic surgery (Turpie, 2004). Moreover, its mechanisms of action preclude it from causing HITT; and because it is synthetic, concerns about using bovine or porcine proteins are quelled. In an ex vivo model with the use of dually perfused human cotyledons, Lagrange et al (2002) did not see transplacental passage. Dempfle (2004) studied fondaparinux efficacy in umbilical cord blood from five infants whose mothers had received 2Æ5 mg of fondaparinux daily. The concentration of activity was approximately one-tenth the concentration of normal plasma, suggesting it may be reasonably safe in the second and third trimester. It may be an attractive option in women with previous HITT or heparin allergy. The first of a new class of oral anticoagulant, ximelagatran, a direct thrombin inhibitor, has been widely studied and is available, initially for orthopaedic thromboprophylaxis in 8 mainland Europe (Hirsh et al, 2004). If it is not teratogenic 598

and does not cross the placenta (no data were available at the time of writing), then it would prove to be an exciting and attractive option to LMWH.

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