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See also Roeters Van Lennep JE,Meijer E, Klumper FJCM, Middeldorp JM, Bloemenkamp KWM, Middeldorp S. Prophylaxis with low-dose low molecular weight heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9: 473–80; Roeters van Lennep JE, Meijer E, Klumper FJCM, Middeldorp JM, Bloemenkamp KWM, Middeldorp S. Prophylaxis with lowdose low molecular weight heparin during pregnancy and the puerperium: is it effective? Reply to a rebuttal by J. P. Patel, R. K. Patel, J. G. Davies, and R. Arya. This issue, pp 1272–3.
We read with interest the research paper by Roeters Van Lennep et al. , which suggests that venous thromboembolism (VTE) prophylaxis with low-dose low molecular weight heparins (LMWH) in women at moderate to high risk of pregnancy-related VTE leads to considerable treatment failure. At first glance, one could be left with the impression that prophylactic LMWH are ineffective as a prophylactic measure during pregnancy and the puerperium in this population. However, further analysis of their work reveals that, of the 91 women identified as having a moderate to high risk of VTE, 88 received nadroparin at a dose of 2850 IU of anti-factor Xa (FXa) daily (55 during pregnancy and the puerperium, and 34 just during the puerperium). Of the remaining three patients, two received dalteparin (5000 IU of anti-FXa daily) and one patient received enoxaparin (2000 IU of anti-FXa daily). Therefore, their research was more an evaluation of nadroparin at a specific dose of 2850 IU daily than of LMWH per se.
We are not surprised that the authors report a high treatment failure rate with nadroparin at the dose prescribed in their study. The physiological changes of pregnancy leads to an increase in the glomerular filtration rate  and the intravascular volume , with a resultant increase in the clearance and volume of distribution of LMWH during pregnancy . This loss of a predictable pharmacokinetic profile of LMWH during pregnancy means that the optimal regimen in this population is not known, and we agree with the authors on this point. However, there are reputable international guidelines that provide guidance on how this population should be managed [4,5]. The authors themselves refer to the American College of Chest Physicians (ACCP) guidelines for VTE prophylaxis for this population in their paper , and state that these guidelines suggest the use of low-dose LMWH for VTE prophylaxis in women with an intermediate to high risk of pregnancy-related VTE. In the ACCP guidelines, low dose refers to LMWH doses of 5000, 4000 and 4500 IU daily for dalteparin, enoxaparin and tinzaparin, respectively. The authors should have made a clear distinction in their paper between these low doses suggested by the ACCP and the low dose of nadroparin used in their study. The dosing recommendations from the ACCP are echoed by the Royal College of Obstetrics and Gynaecologists (RCOG) guidelines on preventing VTE during pregnancy and the puerperium . Table 1 lists these dosage recommendations, with the RCOG recognizing the role that extremes of body weight plays in LMWH pharmacokinetics .
Table 1. Doses of low molecular weight heparin recommended by the Royal College of Obstetrics and Gynaecologists
|< 50||20 mg daily||2500 units daily||3500 units daily|
|50–90||40 mg daily||5000 units daily||4500 units daily|
|91–130||60 mg daily*||7500 units daily*||7000 units daily*|
|131–170||80 mg daily*||10 000 units daily*||9000 units daily*|
|> 170||0.6 mg kg−1 daily*||75 units kg−1 daily*||75 units kg−1 daily*|
|High prophylactic (intermediate) dose for women weighing 50–90 kg||40 mg 12-hourly||5000 units 12-hourly||4500 units 12-hourly|
|Treatment dose||1 mg kg−1 per 12 h antenatal; 1.5 mg kg−1 per day postnatal||100 units kg−1 per 12 h antenatal; 200 units kg−1 per day postnatal||175 units kg−1 daily (antenatal and postnatal)|
Although we accept that both the ACCP and RCOG dosing recommendations are based on low-level evidence, our experience in the clinical setting using these guidelines as the basis of our practice has been positive, from both an efficacy and a safety point of view. This experience has recently been borne out by the eighth report of the confidential enquiries into maternal deaths in the UK . This report describes a significant fall in deaths as a result of thrombosis and thromboembolism in pregnant and postpartum women, from 41 deaths during the reporting period 2003–2005 to 18 deaths during the period 2006–2008. This is the first time that thrombosis and thromboembolism has not been reported as the leading cause of direct maternal death in the UK. The first RCOG guideline for VTE prophylaxis during pregnancy and the puerperium was published in 2004, and it unlikely to be a coincidence that the significant fall in deaths occurred, after the more widespread use of thromboprophylaxis following the publication of this guideline, illustrating the effectiveness of prophylactic LMWH.
Nadroparin, although licensed, has never been launched by the manufacturer in the UK. We therefore have limited personal experience of its use in a clinical setting, but we have no reason to believe that it would be ineffective for this indication, when used at the right dose, and others have reported success with its use during pregnancy . Our understanding is that, outside of pregnancy, for example for VTE prophylaxis during surgery, patients at moderate risk would be prescribed a dose of 2850 units daily. For patients at high risk (e.g. patients undergoing orthopedic surgery), the suggested doses are adjusted according to body weight, with the usual doses being 38 units kg−1 preoperatively and for 3 days after the procedure, after which the dose is increased to 57 units kg−1 daily. It seems to us that a more reasonable dose of nadroparin to prescribe in the moderate-risk to high-risk pregnant and postpartum population would be 57 units kg−1 daily. For a woman weighing 70 kg at booking, this would result in a dose approaching 4000 units of anti-FXa activity daily, a dose that is more comparable with the LMWH doses suggested in the ACCP and RCOG guidelines.
On further inspection of the pregnancy-related VTE events in this study, when only the first pregnancy was considered in the 91 women from the authors’ database, five pregnancy-related VTE events were recorded (one antepartum and four postpartum). When all pregnancies were considered for the 91 women in the study, seven pregnancy-related events were recorded (two antepartum and five postpartum). This illustrates the higher risk of VTE during the postpartum period than during the antenatal period . We note that, of the two patients suffering an event antepartum, one patient was heterozygous for the prothrombin 20210A gene and had a history of a left pelvic vein thrombosis during the postpartum period in a previous pregnancy. She then suffered a further probable event in her left leg at 28 weeks of gestation during the index pregnancy, despite being started on thromboprophylaxis at 22 weeks of gestation. VTE events are almost equally distributed throughout pregnancy , and the patient should have been started on prophylaxis sooner. This fact is illustrated by the second antepartum case in this research study, where the patient who had experienced two previous episodes of left leg DVT and who was a heterozygous carrier of FV Leiden (FVL) was started on nadroparin thromboprophylaxis at 9 weeks of gestation, and subsequently developed an event at 11 weeks of gestation. If the nadroparin dose had been higher and the prophylaxis commenced in a timely manner, could these events have been prevented?
We also note, from the supplementary information that the authors of the study provide, that two of the five events that occurred during the postpartum period were experienced by women with previous histories of VTE who were homozygous for FVL. A previous systematic review suggests that women who are homozygous for FVL are at much higher risk for pregnancy-related VTE , with the reported absolute risks being between 9% and 16% . Given the fact that these two patients had symptomatic homozygous FVL, a higher dose of nadroparin during pregnancy and the postpartum period should definitely have been considered, and may have prevented their events.
Finally, we disagree with the author’s assertion that, in a high-risk group, 6 weeks of postpartum thromboprophylaxis might be too short. Of the five events in their study, two occurred after 6 weeks postpartum; one was in one of the aforementioned cases with homozygous FVL, occurring 53 days postpartum, and, arguably, this patient should have been on long-term anticoagulation. The second was in a patient who had a history of left leg deep vein thrombosis during pregnancy and developed a recurrence in that left leg at 65 days postpartum. We feel, on this basis, that there is insufficient evidence to alter the current practice of giving 6 weeks of prophylaxis in this population, by which time the hematological changes of pregnancy and the puerperium have, in the main, normalized [11,12].
In light of this, we feel that the authors should revise the headline conclusion of their study from ‘although current guidelines support the use of low-dose LMWH during pregnancy and postpartum to prevent VTE in pregnant women, this dose might not be sufficient’ to nadroparin at a dose of 2850 units is ineffective as VTE prophylaxis in women identified as moderate to high risk during pregnancy and the puerperium, and a higher dose should be considered.