Drawing First Blood
Dr . Murphy : There are a several areas where we need more research . One question is whether we de-escalate anticoagulant dosing for women with pregnancy-associated VTE after an initial treatment period – particularly for women who are at a high risk of anticoagulant-related bleeding . A systematic review of four studies asking precisely this question found that it appeared to be safe , but there are concerns about the generalizability of the findings . 7 I don ’ t think this is routinely done in clinical practice .
Anticoagulant dosing for a woman with a prior history of VTE is another controversial area . While the decision hinges , in part , on whether the prior clot was pregnancy- or estrogen-related , most guidelines agree that either prophylactic or intermediate dose LMWH or UFH should be used . A randomized trial comparing two doses of LMWH for the prevention of recurrent VTE is underway in pregnant women comparing these two doses of LMWH for the prevention of recurrent VTE . 8
Dr . Connors : Unfortunately , there are almost no data on anticoagulation in this setting because it is extremely difficult to conduct a randomized , controlled trial of any question related to pregnancy . For instance , more than a decade ago , a Canadian research team was planning a trial comparing prophylactic enoxaparin with or without aspirin , but they had to close early because of low enrollment . Another trial in Israel compared two doses of enoxaparin , rather than a placebo-controlled trial because the investigators knew it would be nearly impossible to get women to sign up to possibly receive a placebo . 6 Of course , no pharmaceutical manufacturer wants to sponsor such a high-risk trial , where the outcomes could include fetal and maternal death .
“ There are almost no data on anticoagulation in this setting because it is extremely difficult to conduct a randomized , controlled trial of any question related to pregnancy .”
— JEAN MARIE CONNORS , MD
Dr . Murphy : We need more data to help guide treatment decisions in so many aspects of pregnancy-related VTE , yet I worry that the challenges of enrolling pregnant women in clinical trials means data will remain limited . As mentioned before , our evidence-based guideline recommendations are derived from observational studies or extrapolation of data from non-pregnant patients ; we are in dire need of more high-quality research in this area .
The lack of solid clinical trials data available to guide treatment in this population also strongly speaks to the need for multidisciplinary care throughout a patient ’ s pregnancy . As hematologists , we need to align ourselves and communicate closely with our obstetrics team and anesthesiologists to ensure our pregnant patients have a cohesive plan to minimize their risks for thrombosis and bleeding throughout pregnancy and the postpartum period .
Dr . Connors : I completely agree . If a patient who requires daily anticoagulation intends to get pregnant , we need to work with a multitude of providers , including the obstetrician , the cardiologist ( if a patient has a mechanical heart valve ), and eventually the anesthesiologist who will be involved in delivery , to plan for limited exposure of the baby to the drug , safe use of neuraxial anesthesia , and decreased bleeding during delivery .
Dr . Murphy : Managing anticoagulation for pregnant patients means navigating the challenges during pregnancy , then another set of challenges during delivery , when we have to shift gears and think about the risk-benefit ratio a bit differently than in the antepartum period . Dr . Connors , how do you adjust anticoagulation as delivery nears ?
Dr . Connors : We try to switch patients on enoxaparin for VTE that developed during pregnancy to subcutaneous UFH 250 IU / kg twice-daily . Sometimes it feels like we “ cave ” to the obstetricians and the anesthesiologists because they are unfamiliar with the pharmacokinetics of UFH , and they don ’ t often see patients who require anticoagulation . In many cases , we could probably continue LMWH , but the shorter half-life of UFH and ability to monitor pharmacologic activity with partial thromboplastin time ( PTT ) makes obstetricians and anesthesiologists more comfortable . Only 2 percent of the total pregnant population has a VTE , so it ’ s not something they handle every day .
For example , I had one patient on full-dose , subcutaneous UFH in preparation for delivery whose obstetrician suddenly wanted to induce delivery after observing some suboptimal fetal stress tests , but the patient had already taken her morning dose of UFH and her PTT was around 120 – which freaked everyone out ! As hematologists , we know that this is what happens with twice-daily , full-dose UFH : There are peaks and valleys in the PTT , rather than a continuous level as seen with intravenous UFH , aiming for a PTT of 80 . Eventually , the obstetrics team just waited for the enoxaparin ’ s effects to wear off before performing the cesarean section , and the mother and baby were healthy .
Peri-delivery management is tough . I used to try to convince the obstetrics team to stick with enoxaparin the whole way through pregnancy and up to delivery , especially for prophylactic dose and for planned induction or cesarean section . Because the obstetrician or anesthesiologist are so much more comfortable with prophylactic dose UFH , which at our institution is 10,000 IU twice-daily , it is hard to insist on sticking with LMWH .
Dr . Murphy : This reiterates what I mentioned earlier – good communication with patients and the health-care team is absolutely key ! I ask all my pregnant patients at their first visit about their birth plan , including whether they want an epidural . Obviously , plans change in the moment , but I start these conversations early so we have ample time to discuss the risks and benefits of every option .
Women should be advised to stop their LMWH when contractions begin . For a planned delivery , most guidelines recommend stopping enoxaparin within 24 hours , and this is especially important if an epidural is desired . Like you , Dr . Connors , I try to continue with LMWH as opposed to switching to UFH , although I have certainly done this as well based on shared decisions with other providers .
Dr . Connors : That ’ s a great point . At our institution , we started a program in which patients on anticoagulation , no matter what the dose , go for an anesthesia consult prior to delivery , since the biggest concern with neuraxial anesthesia is the risk of epidural hematoma in an anticoagulated patient . Then , when a patient arrives in the middle of the night , everyone is more comfortable because there is an anesthesia plan recorded in the patient ’ s chart – in addition to the obstetrician ’ s and hematologist ’ s recommendations .
Dr . Murphy : That ’ s fantastic . We recently started an obstetric hematology clinic in which we follow every pregnant woman who has a VTE during pregnancy . We also have wonderful working relationships with our obstetric and anesthesia teams and hold multidisciplinary conferences where we discuss mutual patients and prepare for what ’ s going to happen during delivery . These conversations can mitigate much of the confusion and make everyone – the patient and her providers – more comfortable . ●
REFERENCES
1 . Bates SM , Middeldorp S , Rodger M , et al . Guidance for the treatment and prevention of obstetric-associated venous thromboembolism . J Thromb Thrombolysis . 2016 ; 41:92-8 .
2 . Gherman RB , Goodwin TM , Leung B , et al . Incidence , clinical characteristics , and timing of objectively diagnosed venous thromboembolism during pregnancy . Obstet Gynecol . 1999 ; 94:730-4 .
3 . Alshawabkeh L , Economy KE , Valente AM . Anticoagulation during pregnancy : evolving strategies with a focus on mechanical valves . J Am Coll Cardiol . 2016 ; 68:1804-13 .
4 . Royal College of Obstetricians & Gynaecologists . Reducing the risk of venous thromboembolism during pregnancy and the puerperium : Green-top guideline No . 37a , April 2015 . Accessed November 4 , 2017 , from https :// www . rcog . org . uk / globalassets / documents / guidelines / gtg-37a . pdf .
5 . Dempfle CE . Minor transplacental passage of fondaparinux in vivo . N Engl J Med . 2004 ; 350:1914-5 .
6 . Brenner B , Hoffman R , Carp H , et al . Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss : the LIVE-ENOX study . J Thromb Haemo . 2005 ; 3:227-9 .
7 . Gandara E , Carrier M , Rodger MA . Intermediate doses of low molecular weight heparin for the long term treatment of pregnancy thromboembolism . A systematic review . Thromb Haemost . 2014 . 111:559-61 .
8 . ClinicalTrials . gov . Comparison of low and intermediate dose low-molecularweight heparin to prevent recurrent venous thromboembolism in pregnancy ( NCT01828697 ). Accessed November 9 , 2017 , from https :// clinicaltrials . gov / ct2 / show / NCT01828697 .
108 ASH Clinical News December 2017