We appreciate the interest and comments from Patel et al. about our paper ‘Prophylaxis with low-dose low molecular weight heparin during pregnancy and postpartum: is it effective?’ .
In our study, thromboprophylaxis consisted of nadroparin at a dose of 2850 units of anti-activated factor Xa (FXa) subcutaneously once daily in 81 (96.7%) of the 91 women. In our opinion, it is the strength of the study that women were treated with a homogeneous regimen of low molecular weight heparin (LMWH). We take the point that our results are an evaluation of this regimen, but disagree that this regimen is not representative of prophylactic (low-dose) LMWH. The literal text of the guidelines of the American College of Chest Physicians is ‘Prophylactic LMWH: e.g. dalteraprin 5000 U subcutaneously q24h, tinzaparin 4500 U subcutaneously q24h, or enoxaparin 40 mg subcutaneously q24h’ . The appropriate prophylactic dose for nadroparin is not mentioned, as nadroparin is not licensed in the USA. The same is true for the recommendations of the Royal College of Obstetricians and Gynaecologists, which the authors show in their Table 1 .
In the Netherlands, we have extensive experience with the use of nadroparin for thrombosis prophylaxis in various indications. According to the pharmacologic instructions, the appropriate prophylactic dosage of nadroparin is 2850 units of anti-FXa without recommendations for weight adjustment . The Dutch guidelines for prevention, diagnosis and treatment of venous thrombosis define the prophylactic dose of nadroparin as 2850 units of anti-FXa for patients <70 kg, and 3800 units of anti-FXa units for patients >70 kg . According to these guidelines, a dose of 2850 units of anti-FXa daily is also prescribed to patients undergoing orthopedic surgery (as is used as example by the authors). In our study population, three of the seven women who experienced a pregnancy-related venous thromboembolism (VTE) had a weight ≥80 kg, and we agree that, in retrospect, these women might have benefited from a higher dose of nadroparin of 3800 units of anti-FXa.
With respect to the two antepartum events, we agree that the women should have been started on LMWH prophylaxis as soon as they had a positive pregnancy test. However, we aimed to describe the real world, in which some women start LMWH prophylaxis later, for a variety of reasons. In retrospect, we can conclude that these VTEs might have been prevented if thromboprophylaxis had been started earlier, and that low-dose LMWH was not sufficient for these women, which was the message of our paper. Similar arguments apply to the discussion about the postpartum events. Regarding the two events that we observed shortly after LMWH prophylaxis had been discintinued, Patal et al. state that the pregnancy-induced hemostatic changes have normalized within 6 weeks postpartum. Although the risk of VTE is highest in the first 6 weeks postpartum (relative risk [RR] 84.0, 95% confidence interval [CI] 31.7–222.7) the risk remains increased between 7 weeks and 3 months postpartum (RR 8.9, 95% CI 1.8–48.1), and only normalizes after 3 months (RR 0.3, 95% CI 0.1–1.3) .
Finally, we do agree that nadroparin at a dose of 2850 units of anti-FXa might not be sufficient as thromboprophylaxis in pregnant women at high risk for VTE, and that this may not be the case for other low doses of LMWH. The optimal dose and duration of LMWH as thromboprophylaxis for women with an increased risk of pregnancy-related VTE are as yet unknown, and this clearly underlines the need for a randomized trial between doses and, potentially, duration.