The evidence informing the doses of medications prescribed during pregnancy is often poor, as is the case for venous thromboembolsim (VTE). Many uncertainties remain on how best to manage women using a low molecular weight heparin (LMWH) for antenatal VTE; especially whether it should be prescribed once or twice a day. The physiological changes during pregnancy are known to alter the pharmacokinetics of LMWH: the glomerular filtration rate (GFR) is reported to increase by up to 50% by 15 weeks gestation as does plasma volume over the course of pregnancy. These changes directly impact on both the clearance and volume of distribution of LMWH which has led many to believe that because the GFR increases, so must LMWH clearance thereby requiring a higher dose or more frequent dosing.
The current guideline from the Royal College of Obstetricians and Gynaecologists (RCOG) on the management of antenatal VTE suggests a twice daily dose of enoxaparin or dalteparin, whereas the American College of Chest Physicians (ACCP) states that a once or twice daily dose could be used, acknowledging the uncertainty that exists around the optimal LMWH dosing regimen for this indication. The evidence for increasing the total dose and/or dosing frequency during pregnancy is based on small historical observational studies. Researchers in the UK developed a population pharmacokinetic (PK) model to better understand the specific PK changes of LMWH during pregnancy and, through PK simulation, determined the optimal dosing strategy to use during pregnancy for the treatment of antenatal VTE.
The study recruited 123 pregnant women, aged >18 years, prescribed enoxaparin for all antenatal indications, one-third of whom were of African-Caribbean origin, one-fifth were obese class I or above and two-thirds were prescribed antenatal enoxaparin for VTE prophylaxis. They had blood drawn for up to 3 anti-Xa activities at each clinic visit; trough, 1 hour and 3 hours post enoxaparin injection.
This study found that as pregnancy progresses, although 3 hour anti-Xa activity decreases, trough anti-Xa activity increases- this can be explained by an increase in apparent volume of distribution, and should be expected given the physiological changes known to occur during pregnancy. Although clearance increases during pregnancy, so too does the volume of distribution; and the elimination half-life, is a function of both these parameters. The researchers conclude that the increase in volume of distribution during pregnancy leads to a prolongation of enoxaparin half-life, so that once daily dosing is adequate for this group of patients. They suggest that current national and international guidelines should be re-considered in light of these findings.
The researchers acknowledge that some clinicians may feel apprehensive about employing a once daily LMWH regimen during the first few weeks, particularly in those women with extensive thrombosis or who have an event early on during pregnancy. In such situations, an initial twice daily strategy, followed by once LMWH might be justifiable. They add that monitoring 3 hour/peak anti-Xa activity is not appropriate in the antenatal setting, as the result will reflect both the changes in clearance and volume of distribution seen, rendering any interpretation, and subsequent dose change, difficult. They accept that most women do not require routine anti-Xa monitoring, but if it is deemed necessary then monitoring the trough concentration would appear more informative. They note that the current ACCP guidelines suggest maintaining a 4 hour peak anti-Xa activity between 1-1.2 IU/mL. However they believe that trough activity monitoring would be more informative because increasing the dose of LMWH to maintain 4 hour peak anti-Xa activity with the progression of pregnancy, may result in over anticoagulation and the patient experiencing a bleed.
The researchers note limitations of their model, such as being based on the assumption that women inject the enoxaparin at the same time each day and that adherence was complete (i.e. 100%) but believe it is robust enough to support use of once daily LMWH for the management of antenatal VTE.