British Society for Haematology guideline for anticoagulant management of pregnant individuals with mechanical heart valves

Abstract

Evidence is limited regarding the prevalence and optimal management of pregnancy in individuals with mechanical heart valves (MHVs). Studies are scarce, often with small numbers of patients included. Mechanical valve thrombosis (MVT) occurs more frequently in pregnancy and there is a high risk of postpartum haemorrhage (PPH). There are a number of options for anticoagulation with differing risks to the pregnant individual and foetus. In the absence of high-quality data, this guideline aims to give recommendations using observational data, evidence from outside of pregnancy and expert opinion to address the key risks at different stages during pregnancy, at delivery and postpartum. Although no single strategy for anticoagulation can be recommended, key risks are identified with recommendations to optimise current management options. Prior to cardiac surgery, all individuals of childbearing age should be counselled about the impact of valve replacement choice on future pregnancy risk by an appropriately trained Cardiologist, recognising individual clinical situations. Discussion should include the risks of re-do surgery and involve a cardiac surgeon. Guidelines recommend consideration of bio-prosthetic valves or, where appropriate, a Ross operation in individuals of childbearing age in view of the high risk of complications during pregnancy in individuals with MHV.1, 2 Assisted conception should not proceed without prior involvement of the specialist team who can recommend on the suitability, preparatory investigations and management of assisted conception. Assisted reproductive techniques (ART) involving ovarian stimulation are an additional risk factor for thrombosis. For invasive procedures associated with bleeding, for example, egg collection in an individual anticoagulated with a VKA should be bridged with twice-daily therapeutic LMWH for the minimum period of time before restarting the VKA. There is insufficient evidence to support admission for UFH.3 The last dose of therapeutic LMWH should be ≥24 h before the scheduled procedure and immediate therapeutic anticoagulation should be avoided post-procedure as per bridging practices used in international studies.4 The bleeding and thrombotic risks of egg collection in individuals anticoagulated for MHV are unknown and likely to be significant. Any individual with an MHV considering ART should have a consultation with the specialist team and their anticoagulation titrated accordingly. All individuals with MHV and confirmed pregnancy should be referred to the specialist team as a matter of urgency (as soon as a pregnancy test is positive) and ideally reviewed by the MDT before 6 weeks of gestation. Individuals should have been informed how to self-refer but any healthcare professional made aware of the pregnancy can refer as a matter of urgency. The first encounter may be with the anticoagulant clinic whose staff should escalate to the specialist team immediately. In very early pregnancy, complex decisions are required regarding optimal anticoagulation regimens and balancing competing risks. If not already completed pre-pregnancy, a written care plan should be agreed and widely circulated with a copy to the individual. Risks associated with pregnancy in this population overall are outlined in Table 2. Pregnancy in individuals with MHV is considered very high risk. Data from the United Kingdom Obstetric Surveillance System (UKOSS)5 showed that maternal mortality was 9% and the risk of severe morbidity was 41%, with 16% of individuals suffering valve thrombosis and 9% having a cerebrovascular accident. Foetal risks are also high, with an increased risk of miscarriage, stillbirth, foetal haemorrhage, and warfarin-induced teratogenicity. Only 16 (28%) pregnant individuals had a good maternal and foetal outcome compared to the Registry of Pregnancy and Cardiac (ROPAC) disease European registry,6 where individuals with a MHV had a 58% chance of experiencing an uncomplicated pregnancy with a live birth. Caring for pregnant individuals with MHV is logistically challenging involving multiple specialist teams including maternal/foetal medicine, cardiology, haematology and anaesthesia. The UKOSS study estimated the incidence of MHV in pregnancy to be 3.7 (95% CI: 2.7–4.7) per 100 000 maternities, so familiarity in management of pregnant patients outside of specialist centres will be limited. In view of the high risks involved and requirement for input by an experienced multidisciplinary specialist team, we support guidance by other specialist societies and recommend that all pregnant individuals with MHV are managed in a tertiary specialist centre with the relevant expertise.1, 2, 7 All anticoagulation regimens are associated with risks for the mother and foetus and management will be planned on an individual basis through discussion between the pregnant individual and the MDT ideally in a pre-pregnancy setting. Table 2 summarises the maternal and foetal benefits and risks of different anticoagulant regimens in pregnant individuals with MHV. Warfarin is the superior anticoagulant in terms of prevention of MVT but is associated with a higher risk to the foetus. The use of LMWH anticoagulation regimens avert the foetal risks observed with VKAs as they do not traverse the placenta, but their use is associated with poorer maternal outcomes. The most commonly used VKA in the UK is warfarin and most of the published data are for this coumarin; however, the same principles apply to other VKAs. Warfarin is an established teratogen. Foetal warfarin syndrome (FWS) comprises of nasal bone hypoplasia and skeletal abnormalities and occurs following warfarin exposure between 6 and 12 weeks of gestation. The risk of FWS varies, but recent studies would suggest that it affects between 6% and 12% of foetuses exposed. Some studies suggest a dose–response relationship with lower levels of FWS at warfarin dosages ≤5 mg/day9, 10, 14; however, the data are far from conclusive.15 Running the INR target below the recommended range to keep the warfarin dose <5 mg is not recommended due to the increased risk of MVT with this approach and the limitations of the studies on which the evidence regarding <5 mg warfarin is based. Warfarin readily crosses the placenta and the foetus is more anticoagulated than the mother, attributed to the immature foetal liver enzymes with low levels of vitamin K-dependent clotting factors and relative absence of foetal vitamin K. Beyond the first trimester of pregnancy, VKA use is associated with foetal, placental and neonatal haemorrhage.16-18 Data on risk are summarised in Table 2. It should be noted that published rates of adverse events are susceptible to reporting bias. When restricted to prospective studies only, Xu et al.10 found similar foetal loss rates for VKA, LMWH/VKA and LMWH regimens (18.44% vs. 18.36% and 16.98%). However, the prospective, observational ROPAC registry6 showed that the use of VKA during pregnancy resulted in fewer live births, with a higher rate of miscarriage (28.6% vs. 9.2% in individuals receiving heparin; p < 0.001) and late foetal death (7.1% vs. 0.7%; p = 0.016). In this study, the reported rate of miscarriage and foetal loss were not significantly different in high- versus low-dose VKA (≤5 mg/day warfarin or ≤2 mg/day acenocoumarol or ≤3 mg/day phenprocoumon). It is currently considered likely that the neurodevelopmental effects of VKA are secondary to bleeding complications such as intracerebral haemorrhage. In a study of 274 school-age children with in utero exposure to coumarins,19 the vast majority showed no clinically significant difference in growth and development compared with controls; however, 18 children (7%) of the coumarin-exposed cohort and 2 children (<1%) in the control cohort had two or more adverse outcome-measures, although the authors acknowledge potential confounding by indication, because the mothers of the exposed children had a medical indication for anticoagulation. Cohort studies indicate that the use of a VKA throughout pregnancy is the best option for preventing MVT in pregnancy, although some international guidelines nuance the advice for the first trimester based on the individual's usual daily warfarin dose.7 The choice of regimen ultimately requires careful counselling and an individual's preference and likely compliance will be a key factor. However, it is reasonable to weight recommendations from the specialist team towards warfarin for pregnant individuals at higher risk of MVT and any can be reviewed during the The European of using the same INR range as outside of pregnancy with INR or 2 weeks with of INR in It is to and high in view of the anticoagulation in the foetus. In the prospective study by et of the MVT in pregnant individuals who were from a VKA to a LMWH in the first trimester with events in trimester and two in the trimester and with postpartum. In a of maternal and foetal complications in individuals from prospective cohort studies with LMWH throughout of valve thrombosis were reported and were attributed to compliance or LMWH in the majority of the The majority of events than postpartum. In a prior by the same of MVT were associated with in the first or trimester and were all associated with anticoagulation and compliance and of postpartum thrombosis were associated with anticoagulation in late pregnancy The UKOSS not give on the of of MVT in all but two of the in the first of from VKA to in the first trimester requires as this a period of very high risk for soon as a pregnancy test is the individual should VKA and twice-daily LMWH The INR not be in the range guidelines on the management of however, evidence that the risk of MVT is and with anticoagulation is a key Although there is no evidence that LMWH with levels in pregnancy maternal there is evidence that of LMWH are associated with a higher risk of MVT in thrombotic events in two pregnant individuals in the study with low In a small study of pregnant with a dose of and of LMWH to a of a in LMWH dose of was In an dose of was required to a of on data from the UKOSS study, the authors suggest of LMWH of for for and for to in a reasonable of It was also noted that most pregnant individuals required dose between and weeks of gestation. Although LMWH in terms of of to due to in and there is currently insufficient data to recommend a for use in pregnant individuals with MHV. LMWH been recommended by some of studies of LMWH a to versus no but not for however, this was by a study levels 12 h a dose of in et anticoagulation with LMWH in individuals with MHV in pregnancy as a of however, this was as found that with levels on a levels were and levels showed some but with In the UKOSS the incidence of maternal complications was similar in individuals with LMWH versus and The of and guidelines recommend target LMWH levels by of at h also that of levels to a may pregnant individuals to therapeutic anticoagulation on The and European for guidelines recommend to LMWH during the first trimester with therapeutic for valve and for and valve In there are data to suggest that therapeutic of LMWH are and that is However, there are insufficient data on versus to that a target of is additional consideration is that it is more and for pregnant individuals to have and levels and the use of more LMWH than is invasive and not in terms of of the most of MVT is with anticoagulation and the and of such a regimen be In the absence of data, we a target of at h to be a reasonable target in the absence of bleeding complications and a for a reasonable with a was by the majority of in an although this not have due to use of LMWH levels be recommended levels should not currently that to LMWH levels with more than twice-daily LMWH regimens should be as a matter of urgency to they superior MVT to pregnant individuals without requires to with and of and impact on dose with for There is no evidence to the of LMWH However, in view of the risks of valve thrombosis in the to we recommend at the target is or there is a below target at any and weeks on studies outside of pregnancy that the of to VKAs in patients with MHV the risk of MVT but at a of a higher risk of mg in to anticoagulation been recommended in individuals with MHV in In the ROPAC no pregnant patients on MVT but more events were however, of patients were so no can be The that is as during pregnancy and can be used in individuals with MHV for other for example, prevention of than for per Although there is an absence of high-quality data on the of in pregnant individuals with in view of the increased risk of valve thrombosis in pregnancy, it is reasonable to mg from early pregnancy there are no or bleeding in pregnant individuals with a higher risk MHV and this should be for the of In pregnant individuals with risk factors for placental who are for at 12 weeks of there is evidence that at a dose than mg may be associated with the in In the absence of evidence of increased bleeding the dose from to mg daily in with therapeutic we that an in the dose of from to mg at can be considered for prevention of in individuals with MHV. management of first trimester miscarriage, that is management for or medical management with in to For anticoagulated pregnant the rates in miscarriage, higher for and increased bleeding with management options in this for of pregnancy, the benefits of management in loss and it the recommended The to which this can be will on the a For medical management will be For miscarriage and of pregnancy, the of anticoagulation should be an risk of bleeding which that risk by the specialist team is required and discussion regarding management of anticoagulation should be should be and the of an or requires a low of in view of the risk in and of potential valve thrombosis include no the from the valve such as increased heart or such as an for example, or as mechanical valve replacement thrombosis may be more with loss of lower such as as may increased heart low or mechanical valve a increased rate and high of for the potential of MVT with is required with and as In where MVT with a team and is MDT including cardiology, cardiac surgery and are recommended and of care to the competing of the pregnant considering MVT and pregnancy and should be is based on clinical of If this is a clinical MDT input from including with in and to management options. for care and care care with a of for but there are no data of Obstetric management will be based on the foetal and in with the maternal weight most from the the weight and not the is as at two of of the of 2. in or of in If by of anticoagulant management should be considered in pregnant individuals with for from LMWH to and to a VKA with mg daily no immediate If the MDT opinion is that cardiac surgery is required as the or because of medical an experienced MDT team should the optimal foetal If delivery at the of the cardiac this should be with to at the in of cardiac surgery during pregnancy for all that is not a maternal mortality rate of maternal rate of pregnancy loss rate of and neonatal complications in There are in the cardiac procedure that may the risks to the foetus including maternal maternal and a to of the a time to pregnant individuals with due to the to the risk of haemorrhage with the risk of MVT because of a period of anticoagulation. The MDT should a delivery plan that should include the anticoagulation options during options for an the to be and the recommended postpartum anticoagulation regimen following high of pregnant individuals will by but for individuals as it the risk of bleeding, in and is recommended by The UKOSS reported a rate of of which was an procedure and a rate of birth. In between two centres in the UK and the the relative increased incidence of and in centre to with a higher rate of delivery been recommended for individuals on therapeutic LMWH in the of include a observational study of pregnant individuals receiving LMWH for the management of individuals with of had a (95% CI: in the risk of compared with planned of There is an absence of data to the best options for anticoagulation the time of birth. Any data are from For individuals receiving a to therapeutic LMWH or is recommended by weeks 2 weeks before the planned If in on VKA, the INR should be and to maternal haemorrhage risk with a complex at a dose of in to vitamin mg is to of which is at the and requires higher should be considered in view of the foetal bleeding risks. For individuals with the risk of of LMWH during the is a potential risk for It is that this risk is by bridging with It should be that there are no studies the competing risks of bleeding versus valve thrombosis to recommendations on the of delivery in individuals with MHV. It is recommended in individuals receiving therapeutic the last dose should be ≥24 h prior to the planned can be to including and and this should be by the MDT as it may impact for However, there are no data on which to a to therapeutic at h prior to scheduled can be in individuals where may be The to be h prior to which may be to the is the is in early in patients not of LMWH for bridging patients with MHV and familiarity of with is and the risks of and anticoagulation are significant so LMWH may in overall guidelines recommend a time target range for pregnant individuals with however, the therapeutic range for should be by the as the therapeutic target on the In by is as the dose to the in pregnancy may from outside of pregnancy, higher to the same target with a risk of and can be using an appropriately and we recommended this in preference to on the however, we acknowledge that this may not be in a in all is a for and been used in pregnant individuals with on who with haemorrhage. in LMWH is limited and is not recommended risks of include and increased bleeding and thrombosis risk. In pregnant who are at anticoagulated at the time of delivery we recommend a low for use of it can be used as for Evidence is regarding any increased risk of MVT with the use of but a single dose is to be associated with a significant risk considering the very high risk of bleeding which to period of anticoagulation. However, the use of of the two used in the is best If using it is not to however, in view of the high risk of in this of we recommend consideration of for at prior to scheduled delivery with of any associated bleeding There are no high-quality studies the bleeding risk versus the benefits of early therapeutic anticoagulation in individuals with however, there are data on risks in the setting. anticoagulation with been associated with a bleeding without the thrombosis in patients with et that bridging with LMWH to be associated with high bleeding rates multiple In the including patients with mechanical valve replacement all therapeutic LMWH bridging but were to post-procedure to therapeutic LMWH h versus no therapeutic There was no difference in however, patients considered at higher risk of bleeding LMWH significant was found for bridging to Although pregnancy is associated with a and significant risk of valve the risk of thrombosis anticoagulation a period is likely to be however, the risk of bleeding is high in the period and is likely to be using very early postpartum therapeutic anticoagulation. The restarting h delivery there are no bleeding complications and guidance restarting therapeutic LMWH or h birth. The of recommendations on time for anticoagulation postpartum but also recommend therapeutic anticoagulation with LMWH for h a was during and was There is no evidence for recommendations in terms of The UKOSS confirmed the high risk of haemorrhage for pregnant individuals with MHV who are bleeding complications to or in and in of pregnant individuals by bleeding complications h in this observational The for this be established from observational data but the use of anticoagulation due to valve thrombosis may be a factor. recommend and management of and in this cohort as their can to in therapeutic anticoagulation. MDT approach with low for and to bleeding is recommended and any in should be in view of the of anticoagulation postpartum. Table summarises observational cohort data on the risk of and in pregnant individuals with Although there is no of bleeding, any the risk of bleeding to be complications associated with delivery in pregnant individuals with MHV may in a in thrombosis risk as have to be bleeding, including to for with the risk of and recommend a more of anticoagulation including a in the of anticoagulation to and risks. recommend or of LMWH for the first h following The risk of MVT the of pregnancy and postpartum period than to However, the risk of haemorrhage is in the period of time also recommend that individuals with MHV should VKAs from to 7 following with LMWH therapeutic INR a higher bleeding risk with of VKAs. data on pregnancy of individuals with MHV should ideally have a of with should be reviewed by an before weeks (as delivery rates are in a a discussion on the options of the and the of For that can be considered include a of and and such as or using or The of regimens in this cohort is that they are not on of anticoagulation. are commonly a with MHV on therapeutic anticoagulation with LMWH in The regimens include the or a superior compared to using an have the of the to in of an birth. the to anticoagulation at time before they can be time to before anticoagulation can be The have published guidelines on time for in patients For individuals receiving an INR is receiving therapeutic a between the last dose of LMWH and is If a dose of LMWH been to the therapeutic anticoagulation for the recommended time for of is 12 For patients receiving a minimum of h should without ideally confirmed with a and before a is The guidance and the recommended time for a dose of LMWH following an for h and of 12 The MDT to the risks and benefits of of any anticoagulant an is in very and the same with the If a dose of LMWH is with an in the should be 12 h the last dose of LMWH following delivery in with techniques be considered in patients in The time to be to for patients having a a When recommended have not been a is The reported rates in patients with MHV having a from to or a can be considered in a pregnant having a be using and a of may be following the of pregnancy, an increased bleeding risk been in individuals on therapeutic anticoagulation for and or may be is often following a for a is commonly to and in this or the absence of heart or or the absence of or of pregnancy, disease or are the that can be used in this If in and on VKA 2 a should be considered to foetal complications from and invasive foetal should be However, in very an delivery may be to the foetus than a should not be with the team is required and a should be on the INR the range should be managed with vitamin by than the neonatal dose and or should be can be on LMWH or VKAs. The maternal during the postpartum and the cardiac between and h following this a time heart may there is with MHV a plan for care and including plan for as required there is about valve or cardiac The of should be in the period the to anticoagulation. for INR should be in with a plan for for clinical discussion about or events and future pregnancy All postpartum individuals with a plan for agreed with the individual and the should include consideration of the risks of future pregnancy, for compliance and risk from In some of an or may be at the time of delivery or on the The of and guidance for the for individuals with cardiac UK for There is no advice on choice in individuals with MHV but it in individuals with complex and heart disease and the guidance also that the of a MHV the risk of to be in the postpartum of the will the any evidence that would the of the recommendations made in this or it The will be reviewed by the relevant and the will be to for any evidence that may have been The will be and from the current guidelines it If recommendations are an will be published on the guidelines the advice and in this guidance is to be and at the time of to the the the any for the of this All authors to and the the All authors to and the of the and at the time of this guideline were as and The the during the of this All authors have made a of to the and which may be on from and and and of for and support to from and and of for guideline was to the at The of and was used to levels of evidence and to the of The can be found at In the the a and the a that is was using the terms in of the was by the for Guidelines and Guidelines and by the and of the It also been to the following for UK Obstetric Obstetric and the UK do not or the The is not for the or of any by the Any than should be to the for the