Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: comment

Abstract

We welcome the recent guidelines from the SSC of the ISTH, which provide much-needed guidance on the management of direct oral anticoagulants (DOACs) in women of childbearing potential [1]. We agree with the guidance except for one area, and feel there would be benefit in reconsidering one of the recommendations: 'Should pregnancy be desired, we recommend that the DOAC is switched to an alternative anticoagulant preconceptually, with the main alternative anticoagulant options vitamin K antagonists (VKAs) (to be switched to low molecular weight heparin [LMWH] as soon as possible when pregnant and before 6 weeks of gestation), or LMWH, with cognizance that the latter may result in prolonged subcutaneous injections until pregnancy is achieved.'As the authors succinctly sum up in this guideline, there is uncertainty regarding the teratogenic risk of the DOACs. The Food and Drug Administration assigns dabigatran, edoxaban and rivaroxaban to pregnancy category C, reflecting the potential risks of teratogenicity demonstrated by animal data. Apixaban is assigned to pregnancy category B, as, to date, no teratogenicity has been demonstrated in animals. There is no clear evidence for an increased risk of teratogenicity in humans, although this cannot be ruled out.In contrast, VKAs have a well-established risk of teratogenicity, which is greatest between 6 weeks and 12 weeks of gestation. Skeletal anomalies may develop in the first trimester [2], and exposure in the second and third trimesters can cause fetal hemorrhage with central nervous system abnormalities or death. The rate of these anomalies is difficult to determine, with differing incidence rates being seen between cohorts [2-4]. Switching to LMWH before 6 weeks of gestation dramatically reduces the risk or embryopathy [4,5], although this relies on detecting pregnancy in a timely manner.We recommend reconsideration of the recommendation in this guideline that women who are taking a DOAC (with a theoretical risk of teratogenicity) should move to a VKA (with a known risk of teratogenicity) when they plan for a child. We feel that it would be safer to continue with the DOAC and switch to LMWH at the first sign of pregnancy, before 6 weeks of gestation. We feel that the option (as recommended in the guideline) of switching to LMWH preconceptually can result in potentially long periods on LMWH injections, making this an unpopular option.To date, the DOAC with the lowest risk of teratogenicity is apixaban, and this DOAC could be considered preferentially for women planning to have a child. We feel that this approach will reduce unnecessary exposure of women to a teratogenic agent at this critical time

Contemporary best practice in the management of pulmonary embolism during pregnancy

“…53 The International Society on Thrombosis and Hemostasis (ISTH) recommends against the use of DOACs during pregnancy and also advises on the use of anticoagulants other than DOACs in women trying to become pregnant. 54 Systemic thrombolysis must be considered in pregnant patients with life-threatening hemodynamic instability due to massive PE. A recent literature review summarized 23 case reports on the use of systematic thrombolysis as treatment for massive PE in pregnant patients.…”

Sex matters: Practice 5P's when treating young women with venous thromboembolism

“…The decision to prefer VKA to LMWH is influenced by the uncertain time to conception and the side effects of long‐term use of LMWH. Some clinicians and patients prefer to switch directly from DOAC to LMWH after a positive pregnancy test, although data on safety of DOAC in very early pregnancy are extremely scarce . In those cases, we recommend reporting the DOAC exposure in early pregnancies to the International Society of Thrombosis and Haemostasis registry…”

Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: reply

“…We feel that this constitutes a reasonable and objective approach to acquire the relevant information on DOACs that would, in turn, underpin a revised recommendation in due course, based on emerging evidence. [1]. The authors showed that elevated mean platelet volume (MPV) at admission was associated with poor neurological outcomes and mortality at 30 days.…”

“…Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: reply We thank Desborough et al for their response to the recently published guidance from the SSC of the ISTH on the management of direct oral anticoagulants (DOACs) in women of childbearing potential [1,2]. We have carefully examined their view and seriously considered their proposal regarding the recommendation of this guidance as detailed below.…”

“…Desborough et al . allude to the teratogenicity of VKAs . The most substantive data on this are from a multicenter ( n = 12), observational, prospective study by the European Network of Teratology Information Service, an organization of services that offer counseling on drug risks during pregnancy.…”