The challenge of anticoagulation during pregnancy in patients with mechanical heart valves

Introduction

Managing anticoagulation in individuals with mechanical heart valves in pregnancy has remained challenging due to a high rate of maternal and fetal complications. This can happen irrespective of the anticoagulation used.

Maternal and fetal risks of anticoagulation

Whereas Vitamin K antagonists (VKA) exhibit a better safety profile respect of maternal thromboembolic events and mortality, the fetal risks are high. This includes embryopathy in the first trimester, fetopathy in the second and third trimesters, and increased rates of miscarriages and stillbirth. Heparins do not cross the placenta and therefore do not affect the fetus but around 1 out of 10  pregnant patients will experience valve thrombosis, other thromboembolic events and even death.(1) Therefore three different anticoagulation regimen were described in the first ESC guidelines for the management of cardiovascular diseases during pregnancy in 2018: VKA throughout pregnancy, low molecular weight heparin (LMWH)  throughout pregnancy or sequential treatment with unfractionated heparin or LMWH in the first and VKA in the second and third trimester. An important determinant of maternal and fetal risks was the VKA dose needed to achieve adequate INR levels – with higher fetal complication rates associated with higher doses of VKA. (2) 

Insights from the ROPAC III registry

The aim of the ROPAC III registry was to further study maternal and fetal pregnancy outcomes in patients with prosthetic heart valves and to assess the impact of the type and dose of anticoagulation. The hope was that a plan for anticoagulation monitoring might be associated with a reduced maternal thromboembolic and bleeding complications. (3) Four-hundred and eleven pregnancies in patients with mechanical heart valves were enrolled between January 2018 and April 2023. 332 pregnancies were from low- and middle-income countries (LMIC) and 79 from high-income countries (HIC).

Overall, the chance of an uncomplicated pregnancy with a successful live birth was only 54% in women with a mechanical valve prosthesis and this was not different from the earlier ROPAC II from 2015.(4) Most patients from LMIC were treated with VKA throughout pregnancy (33%) or had sequential treatment with UFH in the third trimester (41%) compared to HIC where a regimen including LMWH was chosen in 84 % of pregnancies - 32% received LMWH throughout pregnancy. This was attributed to differences in access to medical resources and particular easier availability of anti Xa testing in HIC with the hope to be able to control risks with adequate monitoring. Nevertheless, a significantly higher risk for any thromboembolic event was found in pregnancies with a regimen involving LMWH: 16% in those on LMWH throughout and 12% with sequential therapy.

Additionally hemorrhagic complications, predominantly in the postpartum period, were higher in patients receiving any regimen including LMWH (31% and 34%). In comparison, thromboembolism occurred in 3.4% and hemorrhagic events in 14% of pregnancies who received VKA. Of note, 74% of pregnant patients who received LMWH at some point had a plan for anti-factor Xa monitoring although frequency of testing and targets of peak anti-factor Xa levels varied between centers. A trend was observed towards a lower risk of thromboembolic events in patients who had a plan for anti Xa testing compared to those who had not (10% and 21%) but, possibly due to low numbers, this was not statistically significant (p=0,06).  Neither the frequency of testing, nor the target of the peak anti Xa level, nor the number of anti Xa measurements within the target levels led to a lower rate of thromboembolic events. 

Monitoring and outcomes

A plan for INR monitoring not only did not impact the risk for thromboembolic events but increased the risk for hemorrhagic complications. A not significant difference but trend towards a higher fetal death rate was observed in pregnancies, where VKA was used throughout pregnancy compared to those who received only LMWH (23% vs 11%, p= 0.055). Early miscarriage was observed more frequently on higher Warfarin equivalent doses (≥6mg/d) while late miscarriage and stillbirth mostly occurred on doses between 4.0-4.9mg/s. Average mean daily Warfarin equivalent dose used was 4.7 ± 1,6 mg in pregnancies on VKA. As a predictor for valve thrombosis a mechanical prosthesis in mitral position (OR 3.3; 95% CI 1.9–8.0) was identified.  

Updated ESC guideline recommendations (2025)

In the new ESC guidelines for the management of cardiovascular disease and pregnancy 2025 VKA in the second and third trimester have remained a IIA recommendation, whereas dose adjusted LMWH, administered twice daily, may be considered in cases when the risk of valve thrombosis is low and only if regular anti-factor Xa testing is available (IIB). Switching to LMWH in the first trimester until gestational week 12 is an alternative in patients on higher doses of VKA. (5) The guidelines stress the importance of specialized pregnancy care for these patients from a multidisciplinary pregnancy heart team and pre-pregnancy counselling. Pregnancy risks and treatment options should be discussed with patients and their families and patient’s preferences integrated into decision making. The patient’s perspective might differ to their physician’s though, with the focus on having a successful live birth and a healthy baby, neglecting their own risk. In a recent methodological review of systematic reviews the rate of fetal loss was 35,5% and of congenital anomalies 2% on VKA therapy compared to 8,0 % and 0,0% on LMWH and 20,1% and 1,4%, when sequential therapy was chosen.(6) 

Patient perspectives and shared decision-making

Therefore discussing pregnancy risks should start as early as a patient undergoes valve surgery and alternative valve options (biological prostheses, Ross operation) should be considered when available. (5) Otherwise efforts must continue to improve safety of anticoagulation during pregnancy in patients with MHV and further studies focusing on details of the type of heparin used, specified protocols for dosing and monitoring and adding Aspirin are needed.