This chapter should be cited as follows:
Malhamé I, Silversides C, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416433
The Continuous Textbook of Women’s Medicine Series – Obstetrics Module
Volume 8
Maternal medical health and disorders in pregnancy
Volume Editor:
Dr Kenneth K Chen, Alpert Medical School of Brown University, USA
Originating Editor: Professor Sandra Lowe
Chapter
Anticoagulation in Pregnant Women with Mechanical Heart Valves
First published: January 2022
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INTRODUCTION
Women with prosthetic heart valves represent an increasing proportion of the obstetric population. As medical and surgical therapies have improved, women with congenital heart disease, including those with prior valve surgeries, are increasingly reaching adulthood.1 All women with prosthetic heart valves are considered at increased risk of fetal, obstetric, and maternal complications during pregnancy. Those with mechanical valves in pregnancy are classified modified WHO class 3 (risk of maternal mortality or cardiac morbidity 30%) while women with bioprosthetic valves are classified as WHO class 2–3 (risk of maternal mortality or cardiac morbidity 18%), with regard to their risk of cardiac events during pregnancy.2 Further, rheumatic heart disease remains prevalent in many countries and some of these women require valve replacements.3 The choice of prosthetic valve is complex and is based on patient age, consideration of future pregnancy, prior interventions, patient-specific characteristics, such as bleeding and thrombosis risks, life expectancy, and patient preference.4 For young women considering pregnancy, bioprosthetic and mechanical valves each have their own advantages and disadvantages. Bioprosthetic valves are generally safe during pregnancy, but have limited durability and require reintervention,4 often within 10–15 years after implantation. In contrast, mechanical heart valves (MHV) are more durable, potentially lasting a lifetime, but can thrombose during pregnancy and require anticoagulation with vitamin K agonists (VKA), which are teratogenic.4 This review discusses the risks of pregnancy for women with prosthetic heart valves with a focus on pregnant women with mechanical valves and anticoagulation options.
Maternal and fetal risks
Women with mechanical valves are at risk for both valve thrombosis and bleeding. In addition to hemodynamic changes, pregnancy is associated with a prothrombotic state secondary to an increased synthesis of prothrombotic factors such as factors VIII, IX, and X, and reduction in antithrombotic factors such as protein S.5 This prothrombotic state may be further worsened by vomiting and dehydration in early pregnancy, or hemorrhage at the time of delivery.5 The prothrombotic state increases the risk of valve thrombosis, which can be fatal. However, pregnant women on anticoagulation are also at increased risk of antepartum, peripartum, and postpartum hemorrhage. In comparison, women with bioprosthetic valves are not at high risk for valve thrombosis nor do they require anticoagulation. In a cohort of 212 women with mechanical valves in the Registry of Pregnancy and Cardiac Disease (ROPAC) study, valve thrombosis occurred in 10 (4.7%) pregnancies and hemorrhagic events occurred in 49 (23.1%) pregnancies.6 In total, only 58% of women with MHV were free from serious adverse events during pregnancy, as compared to 79% of women with bioprosthetic valves, and 78% of women with cardiac disease and no prosthetic valves.6
Anticoagulation options and their relationship to adverse maternal and fetal outcomes
Several anticoagulation strategies may be used in pregnant women with MHV including VKA given throughout pregnancy, low molecular weight heparin (LMWH) given throughout pregnancy, and sequential therapy with LMWH given in the first trimester and VKA given in the second and third trimesters. The risk of valve thrombosis is dependent on the type of anticoagulation used during pregnancy, patient adherence, number of valves, type of valve, and other patient-specific variables.
VKA, including warfarin and acenocoumarin, are associated with a lower rates of valve thrombosis when compared to heparin;7 however, VKA readily cross the placenta and they are associated with an unfavorable fetal and neonatal safety profile. Current data suggest a rate of warfarin embryopathy with first-trimester exposure of around 3.5% pregnancies (95% CI 2.1–4.9%).7 This consists of developmental abnormalities affecting the bones and cartilage, with nasal bone hypoplasia, and skeletal abnormalities being the most consistent features.8,9 Moreover, central nervous system abnormalities have also been reported.9 Administration of VKA in the second and third trimesters is associated with warfarin fetopathy characterized by central nervous system anomalies potentially due to micro-hemorrhages in brain tissue, as well as microcephaly, hydrocephalus, cerebellar and cerebral atrophy, eye and vision abnormalities, and developmental delay.8 Intracranial hemorrhage and fetal bleeding may manifest at any stage of pregnancy.8,9 Miscarriages and stillbirths may also occur.9 While a dose-response relationship between VKA and teratogenicity has been described,10 fetal complications occur even with daily doses ≤5 mg [2.3% (95%CI 0.7–4.0%) with doses ≤5 mg vs. 12.4% (95%CI 3.3–21.6%) with doses >5 mg per day].7,11 The choice of anticoagulant in pregnancy must therefore be carefully considered and individualized.
Summary of maternal and fetal/neonatal risks associated with anticoagulation strategies
A large systematic review and meta-analysis, which included 46 studies published between 1969 and 2016, and reported on 2468 pregnancies in 1874 women with MHVs valves, is shown in Table 1.7 Maternal thromboembolic complications (valvular thrombi and extravalvular thromboemboli), maternal mortality, live births, and embryopathy and fetopathy are stratified according to the type of anticoagulation used during pregnancy (Table 1).
1
Maternal and fetal outcomes in patients with mechanical heart valves, stratified by anticoagulation regimens used in contemporary clinical practice.7
| Anticoagulation regimen | Maternal mortality | Thromboembolism | |||||||
| Studies | Events | Estimate (%) | I2 (%) | Studies | Events | Estimate (%) | I2(%) | ||
Vitamin K antagonists | 11 | 7/581 | 0.9 (0.1, 1.6) | 0 | 11 | 22/581 | 2.7 (1.4, 4.0) | 0 | |
Sequential treatment | 20 | 11/530 | 2.0 (0.8, 3.1) | 0 | 20 | 44/530 | 5.8 (3.8, 7.7) | 29 | |
LMWH alone | 10 | 1/132 | 2.9 (0.2, 5.7) | 0 | 9 | 13/127 | 8.7 (3.9, 13.4) | 0 | |
UFH alone | 4 | 2/64 | 3.4 (0, 7.7) | 0 | 3 | 7/52 | 11.2 (2.8, 19.6) | 0 | |
| Anticoagulation regimen | Livebirth rate | Anticoagulant-related FETAL/NEONATAL ADVERSE EVENTS | |||||||
| Studies | Events | Estimate (%) | I2 (%) | Studies | Events | Estimate (%) | I2 (%) | ||
Vitamin K antagonists | 10 | 369/531 | 64.5 (48.8, 80.2) | 95 | 11 | 12/407 | 2.0 (0.3, 3.7)† | 24 | |
Sequential treatment | 18 | 381/475 | 79.9 (74.3, 85.6) | 61 | 19 | 5/431 | 1.4 (0.3, 2.5)* | 0 | |
LMWH alone | 7 | 68/74 | 92.0 (86.1, 98.0) | 0 | 8 | 0/103 | NA | 0 | |
UFH alone | 3 | 33/51 | 69.5 (37.8, 100) | 87 | 4 | 4/44 | 7.6 (0.1, 15.0)* | 0 | |
INR, International Normalized Ratio; LMWH, low molecular weight heparin; NE, not estimable; UFH, unfractionated heparin.
Estimates are presented as proportions per 100 affected pregnancies with 95% confidence intervals.
† Of these 7/407 [0.8% (0.0, 1.7)] represent embryopathy and 5/197 [2.1% (0.1, 4.1)] represent fetopathy.
* All cases represent fetopathy.
Vitamin K antagonists throughout pregnancy
VKAs given throughout pregnancy are associated with the lowest incidence maternal morbidity and mortality, but the highest frequency of fetal/neonatal morbidity and mortality. Thromboembolic events occurred in 2.7% and maternal deaths occurred in 0.9% of women.7 However, the live birth rate was 64.5% and anticoagulation-related fetal/neonatal adverse events occurred in 2%.7 When stratified by warfarin dose, the live birth rates were 83% and 43.9%, 95% for warfarin doses ≤5 mg and >5 mg, respectively.7 Moreover, the fetal adverse events rates were 2.3% and 12.4% for warfarin doses ≤5 and >5 mg, respectively.7 However, fetal adverse events were not described as being related to anticoagulation or not, and did not systematically include warfarin fetopathy.7
While there may be a dose-response relationship between VKA, with a high incidence of fetal and neonatal complications in those on >5 mg daily doses of warfarin, smaller doses of warfarin are also associated with adverse fetal/neonatal events, and the live birth rate remains low overall among the group of women treated with VKA throughout pregnancy. Given pharmacokinetic changes in pregnancy, the dose of VKA should be carefully adjusted with close monitoring of international standardized ratio (INR) throughout pregnancy. INR targets depend on prosthesis thrombogenicity and patient-specific risks.12
Low molecular weight heparin throughout pregnancy
LMWH given throughout pregnancy is associated with higher maternal morbidity and mortality than VKA (8.7% vs. 2.7% thromboembolic events and 2.9% vs. 0.9% maternal deaths).7 However, the live birth rate was 92%, and anticoagulation-related fetal/neonatal adverse events occurred in none of the 103 infants.7 For women with MHVs treated with LMWH, the dose should be weight-based and always given twice daily at a minimum.13 In addition, current guidelines suggest close monitoring of anti-Xa serially in order to ensure therapeutic levels of LMWH.12,14
Sequential therapy with low molecular weight heparin and vitamin K antagonists
Sequential therapy is associated with a 2% incidence of maternal mortality and 5.8% incidence of thromboembolic complications.7 The live birth rate of 79.9%, and anticoagulation-related fetal/neonatal adverse events of 1.4% is higher than with LMWH, but lower than with VKA.7
Anticoagulation recommendations during pregnancy
Pregnant women with mechanical heart valves should be managed within a multidisciplinary team comprising specialists in cardiology, hematology, neonatology, anesthesia, as well as maternal-fetal medicine and obstetric medicine, where available. American and European clinical guidelines recommend that women consider continuing VKA through pregnancy if they are on a lower dose (5 mg warfarin-equivalent) of VKA.12,14 Women on higher doses of VKA, may consider sequential treatment with transition off VKA during the first trimester.12,14 However, some women may wish to avoid VKA altogether and elect to continue LMWH throughout pregnancy. Measurement of anti-Xa is recommended for monitoring and dose-adjustment of LMWH for MHV in pregnancy.12,14,15 However, whether anti-Xa level monitoring improves clinical outcomes among women with MHVs is not well known, as adverse outcomes have been described among in women within the recommended therapeutic target peak range of 1.0–1.2 IU/ml.16
There is currently limited evidence to support or refute the simultaneous use of antiplatelet agents in this population. In the ROPAC study, none of the 13 patients with aspirin in addition to anticoagulation had thromboembolic events whereas 2.5% of patients without aspirin developed mitral valve thrombosis.6 In a Cochrane review on anticoagulation of adults with MHVs (outside of pregnancy), antiplatelet agents given in addition to anticoagulation decreased the risk of embolic complications and death among patients with MHV, although the risk of bleeding events was slightly increased.17 Low-dose aspirin should be considered for women at increased risk of pre-eclampsia,18 even with concomitant anticoagulation. The decision to initiate aspirin must be balanced against the risk of hemorrhagic events. Further guidance on the addition of aspirin as part of the antithrombotic regimen is currently needed.
While LMWH is a reasonable option in high-resource settings and is increasingly being used,19 its administration in low- and middle-income countries is challenging for a number of reasons, including women presenting late in pregnancy for antenatal care, challenges with monitoring of anticoagulant activity, and cessation of anticoagulation due to high costs.20
In addition, in low- and middle-income countries where obstetric complications such as pre-eclampsia, preterm birth, and fetal growth restriction are high,21 consideration could be given to universal administration of low-dose aspirin (75–162 mg/day) to women with MHVs, since its use has been shown to reduce the incidence of these obstetric complications,18,21,22,23,24 and may also reduce thromboembolic complications.
While determining the optimal anticoagulation regimen, risk factors associated with higher thromboembolic risks should be considered. These include valve type, valve position (higher in mitral or tricuspid than in aortic valves), valve function, previous thromboembolism, atrial fibrillation, and left ventricular systolic dysfunction.12 Prosthesis-related thrombogenicity is highest in women with ball-and-cage valves compared to single tilting disk or bileaflets valves (Table 2).12 While guidelines are helpful, clinicians involved in decision-making must have a thorough understanding of the pros and cons of available anticoagulation modalities, and should consider an individual’s risk of thrombosis and bleeding as well as and costs, adherence and patient values.25 A summary of the main guidelines for the anticoagulation of women with MHVs in pregnancy is provided in Table 3.
2
Inherent prosthesis thrombogenicity. Modified from to the European Society of Cardiology Guidelines for the management of cardiovascular diseases during pregnancy.12
Low | Carbomedics, Medtronic Hall, ATS, or Medtronic Open-Pivot, St Jude Medical, On-X, or Sorin Bicarbon. |
Medium | Bileaflet valves with insufficient data. |
High | Lillehei–Kaster, Omniscience, Starr–Edwards (ball-cage), Björk– Shiley and other tilting-disc valves; any mechanical valve in the pulmonary position. |
3
Current International Guidelines for the antithrombotic management of women with mechanical heart valves in pregnancy.32,33
First trimester | Second and third trimesters | Aspirin use | Monitoring with anti-Xa levels | |
European Society of Cardiology 201812 | Warfarin dose <5 mg/day Consider continuation of VKA Warfarin dose >5 mg/day Should consider discontinuation of VKA between weeks 6 and 12 and replacement with adjusted-dose IV UFH (aPTT>2 × control) or adjusted-dose LMWH twice daily | Warfarin dose <5 mg/day Recommended continuation of VKA Warfarin dose >5 mg/day Should consider VKA to be continued May consider LMWH with anti-Xa level monitoring and dose adjustment | “Addition of low-dose aspirin or heparins has no proven advantage in preventing valve thrombosis but is associated with significantly more maternal bleeding-complications, including fatal events” | LMWH is not recommended when weekly anti-Xa level monitoring and dose-adjustment is not available |
American Heart Association 202033 | Warfarin dose ≤5 mg/day Reasonable to continue warfarin after discussion with the patient of risks and benefits or Dose-adjusted LMWH ≥2 times daily may be considered Warfarin dose >5 mg/day Dose-adjusted LMWH ≥2 times daily is reasonable or Dose-adjusted continuous infusion UFH if dose-adjusted LMWH is unavailable is reasonable (aPTT ≥2 × control) | Warfarin dose ≤5 mg/day Warfarin after discussion with the patient of risks and benefits is reasonable Warfarin dose >5 mg/day Warfarin to goal INR is reasonable or Dose-adjusted LMWH ≥2 times daily may be considered | Low-dose aspirin (75–100 mg once per day) in addition to anticoagulation may be considered, if needed for other indications | LMWH should not be administered unless anti-Xa levels are monitored 4–6 h after administration and dose is adjusted according to level Target anti-Xa level 0.8–1.2 U/ml |
American College of Chest Physicians 201215 | Recommend all the following anticoagulant regiments in preference to no anticoagulation Dose-adjusted LMWH twice daily throughout pregnancy or Dose-adjusted UFH s/c twice daily throughout pregnancy (mid-interval aPTT ≥2 × control or anti-Xa heparin level 0.35–0.70 IU/mL) or UFH or LMWH (as above) until 13th week then with substitution by VKA until close to delivery when UFH or LMWH is resumed In women judged to be at very high risk of TEC in whom concerns exist about the efficacy and safety of UFH or LMWH as dosed above, suggest VKA throughout pregnancy | For women at high risk of TECs, suggest low-dose aspirin (75–100 mg daily) | Suggest that doses be adjusted to achieve the manufacturer’s peak anti-Xa level 4 h post s/c injection | |
aPTT, activated partial thromboplastin time; INR, International normalized ratio; LMWH, low-molecular-weight heparin; s/c, subcutaneous; TEC, thromboembolic complications; UFH, unfractionated heparin; VKA, vitamin K antagonists.
Peripartum management of anticoagulation
Delivery of pregnant women with mechanical heart valves should occur at a center with cardiology, hematology, neonatology, anesthesia, and maternal-fetal medicine expertise. The timing of birth should be planned to allow appropriate cessation of anticoagulation to minimize the risk of bleeding and thrombosis. Heparins can be continued until the time of a planned vaginal or cesarean delivery, and vaginal birth may be an option for women still on heparins early in spontaneous labor. Intravenous UFH infusion must be ceased 4–6 h prior to neuraxial analgesia whilst subcutaneous therapeutic dose LMWH must be stopped for 24 h prior to neuraxial analgesia.26 Patients treated with VKA require specific peripartum care plans. The fetal liver is unable to clear VKA that cross the placental barrier into the fetal circulation resulting in a prolonged anticoagulant effect on the fetus, lasting over 2 weeks.27,28 As such, if a vaginal birth is planned, VKA are discontinued at approximately 36–37 weeks’ gestation, and heparins are commenced with appropriate monitoring. Intramuscular vitamin K is routinely given to infants within the first hours after birth to prevent vitamin K deficiency-associated bleeding, and no specific modification in dose is required for women taking VKA.29
A cesarean delivery is recommended for patients that present in labor while on VKA or within a few days of discontinuing VKA. While some centers continue to administer VKA until the time of childbirth, and perform planned cesarean deliveries on all patients,30 vaginal births are associated with smaller peripartum fluid shifts and fewer obstetric and anesthetic adverse events, and are preferred in the absence of strong clinical indication for a cesarean delivery. Where possible, neuraxial analgesia, (with appropriate planned cessation of anticoagulation) is preferred over general anesthesia, which continues to be associated with more maternal anesthesia-related adverse events, including pulmonary, cardiac, and neurologic complications.26,31
Postpartum, therapeutic anticoagulation can be resumed as soon as 4–6 h after delivery providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. Subsequently, VKA, which are compatible with breastfeeding, may be resumed. They should be commenced and either LMWH or UFH continued until an appropriate INR target is achieved. A suggested plan for the management of anticoagulation in the peripartum period is presented in Table 4.
4
Recommendations for peripartum management of anticoagulation.9
Method of maternal anticoagulation | Planned delivery | Emergency delivery | Postpartum recommencement | |
Reducing risk of maternal bleeding | Reducing risk of fetal bleeding | |||
VKA | Stop VKA and transition to either LMWH or UFH at least 2 weeks prior to delivery | Prothrombin complex concentrate prior to cesarean section + vitamin K (1–2 mg). | Cesarean delivery is recommended as high risk of fetal intracranial hemorrhage during vaginal delivery. Prothrombin complex concentrate and vitamin K titrated to INR levels if required for neonate. | Restart UFH 4–6 h postpartum provided there are no bleeding concerns [*500 IU/h for 6 h (no bolus) increase to 1000 IU/h for further 6 h then to target aPTT as previous]. Timing of the re-introduction of VKA differs by center – some centers transition to VKA prior to discharge from hospital and some others continue LMWH/UFH for 5–7 days with a more gradual transition to VKA to avoid maternal bleeding. |
LMWH | Last dose 36 h prior to planned delivery; switch to UFH infusion; [*bolus 5000 IU then 1250 IU/h to target aPTT 2–3 times baseline. Local protocols may differ Stop UFH when in active labor or 4–6 h prior to placement of neuraxial catheter for regional anesthesia. | Consider protamine (note – will only partially reverse the anticoagulant effect of LMWH). | No fetal concerns from maternal anticoagulation. | Restart UFH 4–6 h postpartum provided there are no bleeding concerns [*500 IU/h for 6 h (no bolus) increase to 1000 IU/h for further 6 h then to target aPTT as previous]. Timing of the re-introduction of VKA differs by center – some centers transition to VKA prior to discharge from hospital and some others continue LMWH/UFH for 5–7 days with a more gradual transition to VKA to avoid maternal bleeding. |
VKA, vitamin K antagonists; LMWH, low molecular weight heparin; UFH, unfractionated heparin; aPTT. activated partial thromboplastin time.
*suggested regimen only – local protocols may differ.
CONCLUSION
Women with mechanical valves are at high risk for both thromboembolic and bleeding events. Risks vary according to the type of anticoagulation used during pregnancy, and each strategy is associated with trade-offs. Physicians must be familiar with potential risks and benefits of each strategy and locally available resources, in order to inform patient-centered discussions. Anticoagulation must be monitored thoroughly during pregnancy, and delivery must be carefully planned by an interdisciplinary team.
PRACTICE RECOMMENDATIONS
- Women with mechanical valves (MHVs) are at risk for both valve thrombosis and bleeding.
- Several anticoagulation strategies may be considered including vitamin K antagonists (VKAs) given throughout pregnancy, low molecular weight heparin (LMWH) given throughout pregnancy, and sequential therapy with LMWH given in the first trimester and VKA given in the second and third trimesters.
- VKA are associated with a lower rates of valve thrombosis when compared to heparins. However, VKA readily cross the placenta and are associated with an unfavorable fetal and neonatal safety profile. Although these adverse events are higher in those taking warfarin doses >5 mg/day, they may also be encountered in those taking lower doses.
- LMWH throughout pregnancy is an expensive anticoagulation strategy and requires intensive monitoring, which may be challenging in low- and middle-income countries, where VKA throughout pregnancy and sequential treatment may still be preferred.
- Risk factors associated with higher thromboembolic risks as well as patient values and preferences should be considered when determining the optimal anticoagulation regimen.
- Delivery of pregnant women with mechanical heart valves should be carefully planned and occur at a center with multidisciplinary expertise.
- In most instances, a vaginal birth is feasible and recommended, with appropriate management of anticoagulation in the peripartum period. A cesarean delivery is reserved for obstetric indications and patients that present in labor while on VKA or within a few days of discontinuing VKA.
- Physicians must be familiar with the trade-offs of each anticoagulation strategy and locally available resources, in order to inform patient-centered discussions
CONFLICTS OF INTEREST
The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.
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