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FOCUS ON ANTICOAGULATION THERAPIES

Anticoagulation during pregnancy in patients


with a prosthetic heart valve
Jose M. Castellano, Rajeev L. Narayan, Prashant Vaishnava and Valentin Fuster
Abstract | Effective anticoagulation is mandatory for pregnant women with mechanical heart valves. Oral
anticoagulants offer the best maternal protection against thrombosis, but their use might be associated
with an appreciable risk of fetal malformations and pregnancy loss. By contrast, heparin derivatives are
associated with a reduced risk of fetal damage, but an increased risk of valve thrombosis in the mother, even
with appropriate dose adjustment and monitoring of therapeutic efficacy. Given the varying risks of available
anticoagulation strategies, and the paucity of data to inform the optimal approach, no single accepted
treatment option exists for pregnant women with mechanical prosthetic valves. Although low-molecular-weight
heparin is considered more efficacious than unfractionated heparin, treatment failures, even at therapeutic
levels of factor Xa inhibition, have been reported. The risk of warfarin-related embryopathy might be overstated,
particularly at doses ≤5 mg daily. We advocate an individualized anticoagulation strategy that takes into
account the patient’s preferences, calls for the use of vitamin K antagonists throughout pregnancy (substituted
with a heparin derivative only close to term) for those patients at the greatest risk of thromboembolism, and
relies on close multidisciplinary collaboration between the cardiac and obstetric care teams.
Castellano, J. M. et al. Nat. Rev. Cardiol. 9, 415–424 (2012); published online 15 May 2012; doi:10.1038/nrcardio.2012.69

Introduction
In the past 40 years, therapies for children and young oral anticoagulants.7 No data on the efficacy of novel anti-
adults with heart disease have improved dramatically. coagulants (such as dabigatran and rivaroxaban) in patients
These improvements have led to a growing number of with mechanical prosthetic heart valves are available, and
women of childbearing age with valvular heart disease as the safety of these drugs in pregnancy has not been studied.
more patients survive to adulthood.1 The first successful Physicians should consider the hemodynamic, hemo-
term pregnancy in a woman with a prosthetic heart valve static, and metabolic alterations that are characteristic of
was reported in 1966.1 However, the therapeutic manage- pregnancy when choosing anticoagulant strategies for
ment of this population remains challenging; in particular, pregnant women with prosthetic heart valves. During
no clear consensus exists on the optimal prosthetic heart pregnancy, the concentrations of several coagulation
valve (when repair is not feasible) or the most suitable anti- factors, including fibrinogen, increase, whereas stasis,
coagulation strategy for patients who become pregnant. vitamin‑K-dependent activity, protein S activity, and
The association between mechanical valve prosthesis fibrino­lysis decrease, resulting in a hypercoagulable
and adverse pregnancy outcomes has been recognized2 and state and an increased risk of thromboembolism.8 Drug
incorporated into a risk score for adverse cardiac compli- pharmaco­kinetics can also be affected by pregnancy-
cations.3 The presence of a mechanical heart valve confers related physio­logical changes, such as increases in glo-
a high risk of adverse outcomes and necessitates close merular filtration rate (in the second semester) and
monitoring by cardiac and obstetric care teams during plasma volume (which can affect volume of distribution
pregnancy.4 Oral anticoagulation therapy (with warfarin or of drugs). These physio­logical changes have implica-
other vitamin K antagonists) is the most effective strategy tions for the absorption, bioavailability, and clearance of
for preventing thrombo­embolic complications in pregnant anticoagulant medications.9 Zena and Michael A.
women.5 However, the use of oral anticoagulants during Therapeutic decision-making for individual patients Wiener Cardiovascular
pregnancy is associated with increased fetal morbidity should be evidence-based, and physicians should consider Institute, Mount Sinai
School of Medicine,
and mortality. The risk of embryopathy can be reduced the risks and benefits of the various anticoagulation treat- One Gustave L. Levy
by changing to unfractionated or low-molecular-weight ments. In this Review, we discuss the controversies sur- Place, PO Box 1030,
New York,
heparin, either specifically during fetal organogenesis or rounding the choice of prosthetic heart valve in women of NY 10029‑6574, USA
for longer periods during pregnancy.6 However, the risk childbearing age and the advantages and disadvantages (J. M. Castellano,
of potentially life-threatening maternal thromboembolic of various anticoagulation strategies during pregnancy. R. L. Narayan,
P. Vaishnava, V. Fuster).
complications is increased with heparin compared with We suggest a framework for multidisciplinary decision-
making that draws on the best available evidence and Correspondence to:
J. M. Castellano
Competing interests takes into account the need to consider the preferences of jmcastellano.cardio@
The authors declare no competing interests. individual patients. gmail.com

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Key points Aortic homografts might be more durable than bio-


prosthetic valves. Improved durability of homograft
■■ The management of pregnant women with prosthetic heart valves is a
valves (n = 72) compared with xenograft implants (n = 73)
clinical challenge
■■ No clear consensus exists on the optimal artificial valve and anticoagulation
has been reported in women aged 12–35 years; 72% of
strategy for these women, owing to the paucity of data that can guide the homograft valves and 18% of the xenografts were
therapeutic decisions still functioning at 10 years (P = 0.0001). In a study of
■■ Cardiac and obstetric care teams need to work collaboratively to help these 1,022 aortic homograft valve replacements, with nearly
patients make personalized decisions that consider the risks and benefits of 30 years of follow-up, freedom from reoperation was
various therapies dependent on the patient’s age. At 15 years after implanta­
■■ Consistent monitoring to maintain effective anticoagulation is crucial, tion, the rate of freedom from reoperation was 85% in
regardless of the chosen treatment strategy
patients aged ≤20 years, compared with 94% among those
■■ Warfarin throughout pregnancy might be appropriate for selected patients,
particularly those at increased risk of thromboembolism and when the risk of
aged >60 years.18 These rates were slightly higher than
adverse fetal outcomes is comparatively low those reported with heterograft valves in all age groups,
■■ Heparin derivatives pose no direct risk to the fetus, but are limited by an although the difference was not statistically signifi-
appreciable risk of maternal thromboembolic complications, even in patients cant.11,12 Aortic homografts might be less prone to struc-
with seemingly therapeutic levels of anticoagulation tural valve deterioration than bioprosthetic valves, but
additional data on the outcome of pregnancy in women
with artificial valves are needed.19–21
Selection of prosthetic valves The Ross procedure22,23 has been advocated as a non-
If feasible, valve repair is always preferable to replace- thrombogenic and potentially durable option for aortic
ment.6 However, when repair is not possible, a choice valve replacement in young women who want to become
must be made between either a mechanical valve or a pregnant.6,14 In this procedure, a patient’s diseased aortic
stented bioprosthesis.10 The selection of prosthetic heart valve is replaced with their own pulmonary valve, and
valves for women of childbearing age who want to become their pulmonary valve replaced with a pulmonary
pregnant relies on an understanding of the advantages and allograft.22 Data on pregnancy in patients after Ross valve
limitations of mechanical prostheses and tissue valves. surgery are scarce.24–26 However, the survival of patients
Long-term anticoagulation therapy is not required in who receive autograft root replacement is comparable to
patients with bioprostheses; therefore, the use of such that of an age-matched and sex-matched British popu-
devices eliminates the need for anticoagulation in preg- lation,27 and a study of 14 pregnancies in women who
nancy. However, tissue valves are associated with a high had undergone pulmonary aortic valve replacement
risk of structural valve deterioration, particularly in reported no maternal deaths or thromboembolic events
young recipients. Data from a retrospective analysis of during pregnancy.25 Unfortunately, the reoperation rate
patients who underwent aortic valve replacement using after the Ross procedure is high; in one study the rate of
porcine valves between 1971 and 1990 showed that freedom from autograft reoperation in such individuals
young age was an independent predictor of structural was reported to be 69 ± 7% at 13 years.28 Furthermore,
valve deterioration.11 Evidence of this deterioration was the reoperation procedures are technically demanding.14
present by the end of the first postoperative decade in up Although mortality associated with the Ross procedure
to 50% of patients who were aged 16–39 years at the time has improved considerably over time,29,30 it remains a
of surgery.11 Other studies have confirmed a high rate of technically difficult operation that should be performed
structural valve deterioration in young patients and at high-volume centers, and data on pregnancy in women
shown that the risk of deterioration is sevenfold greater who have undergone this procedure are lacking.
for mitral valves than for aortic or tricuspid valves.12,13 Unlike bioprostheses, mechanical prosthetic heart
The results of a separate study also suggested that up valves offer the advantage of long-term durability. 14
to 50% of porcine heterografts implanted in women of Increased thrombogenicity, which necessitates the use of
childbearing age might fail within 10 years of implanta- lifelong anticoagulation, is the primary disadvantage
tion. Moreover, reoperative mortality in these patients of mechanical valves, although this problem is less of a
is not trivial and might approach 9%.14–16 In addition, concern with new-generation bileaflet valves, which are
structural valve deterioration—either calcification or inherently less thrombogenic than other designs. The risk
obstruction—might be accelerated by pregnancy. An of adverse maternal, fetal, or neonatal outcomes associ-
analysis of the durability of bioprostheses in women aged ated with mechanical prosthetic valves might depend
<35 years (n = 87) showed structural valve deteriora­tion on the anticoagulation strategy used during pregnancy.
in 14% of the patients (n = 70) who did not become preg- Below, we discuss the advantages and limitations of the
nant, compared with 47% of the patients (n = 17) who available strategies, explain the controversies associated
did become pregnant (P = 0.05).16 However, data from with existing treatment guidelines, and highlight the
other studies have not demonstrated pregnancy to be an need to balance individualized maternal and fetal risks
independent risk factor for structural valve deterioration. to achieve the best patient outcomes.
For example, one study with a relatively short follow-up
period (5 years) showed a comparable rate of structural Oral anticoagulants
valve deterioration in 48 pregnant and 37 nonpregnant Warfarin and coumarin derivatives are the most effec-
recipients of bioprostheses: 27% and 30%, respectively.17 tive oral anticoagulants for reducing thromboembolic

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complications in women who require anticoagulation proteins that are important in the normal growth and
during pregnancy.31 Their anticoagulant effects result develop­ment of bony structures.46 Osteocalcin carboxy­
from inhibition of the vitamin K epoxide reductase lation is well known to be vitamin K-dependent in
complex. This inhibition causes a reduction in the humans, and circulating osteocalcin is structurally altered
γ‑carboxylation of coagulation factors II, VII, IX, and X,32 by warfarin.47
and, therefore, results in the synthesis of immuno­logically In addition to warfarin-related embryopathy, numer-
detectable, but biologically inactive, forms of these pro- ous neurological sequelae of intrauterine exposure to oral
teins.33 In one study, thrombo­embolism occurred in anticoagulants have been described, including Dandy–
3.9% of 788 women with mechanical prosthetic heart Walker malformation, microcephaly, mental retarda-
valves who were treated with oral anti­coagulants during tion, spasticity, hypotonia, ventral midline dysplasia with
pregnancy.34 Other studies have demonstrated variable corpus callosum agenesis, and dorsal midline dysplasia
rates of thromboembolic complications (Table 1).2,35–37 with optic atrophy.42 Whether these neurological effects
Overall, the published data indicate that one in 25 preg- are a direct result of teratogenicity of the drug or are
nant women with a mechanical prosthetic heart valve second­ary to fetal intracerebral hemorrhage is not clear.
who are treated with oral anti­coagulants will develop An increase in the incidence of spontaneous abortions
valve thrombosis.38 Although the type, position, and and stillbirths related to fetal intracranial hemorrhage has
number of prosthetic heart valves varied among patients also been reported in women who have received warfarin
in these studies, thromboembolic complications were therapy during pregnancy.48–51
seen in both traditionally ‘high-risk’ patients (with first- Although the teratogenic effects of warfarin have
generation prostheses, mitral valve prostheses, history of been well described, the precise nature of the risk in
thromboembolism, atrial fibrillation, or left ventricular an individual fetus exposed to vitamin K antagonists
dysfunction) and ‘low-risk’ patients without these risk during gestation is still largely unknown. The results
factors. Data on the control of anticoagulation to prevent of studies on the overall fetal risks of maternal warfarin
thrombo­embolic complications is limited. Retrospective therapy during pregnancy are varied. In one study, no
studies have reported acceptable international normal- congenital abnormalities were reported in the offspring
ized ratios (INRs) for patients taking oral anticoagulant of 46 women with prosthetic valves who took warfarin
therapy, but data on the amount of time spent within during the first trimester of pregnancy.49 However, data
acceptable INR limits are sparse.31 from other studies have shown impaired fetal outcomes
in women treated with warfarin during their pregnan-
Embryopathy cies, and suggest that a critical period might exist during
Warfarin is the long-term anticoagulant of choice for which warfarin is particularly harmful to the fetus. In a
patients with prosthetic heart valves who are not preg- prospective study of 72 pregnancies in women with arti-
nant. However, the low molecular weight of this drug ficial heart valves, no embryopathy occurred in the 23
allows transplacental passage 39,40 and, consequently, pregnancies in which warfarin was discontinued by the
potential harm to the fetus. For this reason, the FDA sixth week of gestation and restarted only after the twelfth
classes warfarin as a pregnancy category X agent (Table 2). week.52 However, embryopathy did occur in 25% of the
Possible teratogenic effects of warfarin were first sug- 12 pregnancies in which warfarin was continued until
gested in 1965, and initial reports indicated an associ­ after the seventh week of gestation, and in 30% of the
ation with fetal hemorrhage and intrauterine death.41 37 pregnancies detected after the first trimester, in which
In 1966, nasal hypoplasia, optic atrophy, and mental a coumarin derivative was given throughout pregnancy.52
retard­ation were reported in the child of a woman In another study, embryopathy was reported in 12 of 18
who had a mechanical prosthetic heart valve and had infants born to mothers who took warfarin throughout
received warfarin anticoagulation therapy during her pregnancy.53 The most common finding was nasal hypo-
pregnancy.1 In a retrospective study published in 1980, plasia; other major complications occurred only rarely.
chondro­malacia punctata, a warfarin-specific embryo­ A retro­spective analysis of an impressive 30 years of
pathy characterized by nasal and limb hypoplasia and outcome data accrued from 356 pregnant women treated
stippled bone epiphyses, was reported in the children of with warfarin in a Danish population reported only two
women who had received anticoagulation with couma­ malformations (one resulting in stillbirth) consistent with
rin derivatives during pregnancy.42 One-sixth of the warfarin embryopathy (8% of all first-trimester war­farin
418 reported pregnancies resulted in live-born infants exposures).54 These two malformations were seen in the
with central nervous system abnormalities or chondro­ offspring of high-risk patients who were taking high
malacia punctata, and another one-sixth in fetal death. doses of warfarin.
The researchers reported that the critical period for In summary, varying magnitudes of risk have been
intra­uterine exposure to warfarin occurred during reported in studies of the adverse fetal effects of couma-
organogenesis (weeks 6–9 of gestation). 42 However, rin derivatives.55 Pooling of these data suggests that the
subsequent studies have demonstrated that warfarin risk of embryopathy might be <10% when these agents
therapy can still have toxic effects after this period.43–45 are administered in the first trimester, and dramatically
The mechanism has not been fully characterized, but reduced to a level similar to that of an untreated popu-
teratogenicity might result from the drug’s interference lation when oral anticoagulants are substituted with a
with post-translational modification of calcium-binding heparin derivative during weeks 6–12 of gestation.34,42,56,57

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Table 1 | Pregnancy outcomes in women with mechanical prosthetic heart valves


Anticoagulant regimen Maternal thromboembolic Spontaneous abortions/ Stillbirths/
complications/pregnancies (%) pregnancies (%) pregnancies (%)
Oral anticoagulant throughout pregnancy2,34–38 38/959 (3.9) 252/969 (26.0) 8/110 (7.3)
Unfractionated heparin in the first trimester and 27/285 (9.5) 66/285 (23.2) 4/42 (9.5)
oral anticoagulant thereafter34,35,37,90
Low-molecular-weight heparin in the first trimester 1/55 (1.8) 5/55 (9.1) 0/55 (0)
and oral anticoagulant thereafter35,37,38,91
Reprinted from Thromb. Res. 127 (Suppl. 3), McLintock, C. Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option.
S56–S60, Copyright © (2011), with permission from Elsevier.

Dose-related factors Injectable heparin derivatives


In 1999, researchers described a dose-dependent effect Heparin and its derivative, low-molecular-weight heparin,
of vitamin K antagonist therapy on the risk of fetal com- have immediate onset of action when adminis­tered by
plications in a study of 58 pregnancies in 43 women intravenous injection and are, therefore, the drugs of
with mechanical prosthetic heart valves who received choice when a rapid anticoagulant effect is required.
warfarin during pregnancy.52 Fetal complications were Heparin therapy is usually restricted to the hospital
noted in 15% of 33 pregnancies in which maternal use setting, where its effects can be monitored and the
of warfarin was <5 mg daily, compared with 88% of dosage frequently adjusted. By contrast, low-molecular-
25 pregnancies in which daily maternal use of warfarin weight heparin preparations can be administered sub­
exceeded 5 mg daily.52 A subsequent study expanded this cutaneously without the need for laboratory monitoring;
data set with the inclusion of 13 further pregnancies in therefore, they can be administered both in and out of
11 additional women with mechanical heart valves who the hospital setting.
were treated with warfarin throughout pregnancy.58 In Both heparin and heparin derivatives bind to and
total, 30 fetal complications were noted, including 23 accelerate the activity of antithrombin III. The heparin–
spontaneous abortions, four malformations compatible antithrombin III complex inactivates a number of
with warfarin embryopathy, and five stillbirths. Women coagu­lation enzymes, including thrombin (also known
who took >5 mg of warfarin daily had a higher risk of as factor IIa) and factors Xa, IXa, XIa, and XIIa. Of
fetal adverse events than those taking a lower dose (82% these factors, thrombin and factor Xa are the most sen-
versus 8%, respectively). Both groups of investigators36,58 sitive to inhibition by the heparin–antithrombin III
demonstrated that their results were independent of complex, although the sensitivity of human thrombin is
maternal INR, suggesting a direct dose-dependent effect approximately 10-fold greater than that of factor Xa.62
of vitamin K antagonists on the risk of adverse fetal out- Unlike warfarin, unfractionated and low-molecular-
comes. However, these data originated from a single weight heparin do not cross the placental barrier and
center and were based on overlapping data sets. are not associated with teratogenic effects. However,
Data from a study designed to determine if there was the use of heparin confers an increased risk of maternal
a correlation between warfarin dose and pregnancy thrombo­embolic events. Several studies have suggested
outcome in women with prosthetic heart valves showed that the rate of thromboembolic complications is 12–24%
that warfarin in pregnancy was associated with a low risk among pregnant women receiving heparin derivatives.6
of valve thrombosis or maternal death, and the risk of However, these studies were limited by the inclusion of
fetal abnormalities was not related to warfarin dosage.59 women with early-generation prosthetic valves, which
However, the risk of stillbirth increased significantly are potentially more thrombogenic than devices in
with increasing doses of warfarin.59 Other studies have current use. For this reason, the risks of heparin-based
demon­strated that complications of pregnancy occur anticoagulation therapy need to be given careful con-
even with doses of warfarin <5 mg daily.20,60,61 sideration and weighed against the possibly overstated,
Despite these mixed findings, the suggestion that and apparently dose-dependent, risks of adverse fetal
vitamin K antagonist therapy has a dose-dependent outcomes associated with vitamin K antagonists.
effect on fetal outcomes has implications for the balance Low-molecular-weight heparin offers several advan-
of risks and benefits of continuing warfarin therapy at a tages over unfractionated heparin, including a longer
dose ≤5 mg daily throughout pregnancy. The incidence half-life and more stable and predictable pharmaco­
of fetal complications, even with low-dose warfarin, is kinetics.7 In contrast to unfractionated heparin, low-
still substantial. However, given that mechanical heart molecular-weight heparins have lower antithrombin
valve thrombosis is a serious complication that can activity than anti-factor Xa activity, resulting in a lower
potentially result in maternal morbidity and death, many risk of bleeding at similar levels of anticoagulation.38
mothers might prefer to accept some risk of fetal adverse Moreover, in both pregnant and nonpregnant patients,
events to prevent this devastating outcome. An educated therapeutic doses of low-molecular-weight heparin
discussion must, therefore, ensue between the parents might be more efficacious than therapeutic doses of
and the physician with regard to the anticoagulant unfractionated heparin because of the better pharmaco-
of choice. kinetic profile of the low-molecular-weight drug.60 The

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Table 2 | FDA recommendations for anticoagulant drug use during pregnancy


Drugs FDA category* Crosses Transfer to Adverse effects
placenta breast milk
Acenocoumarol, D‡ Yes Yes (no adverse Embryopathy (mainly in the first trimester), bleeding
warfarin effects reported)
Low-molecular- B§ No No Long-term application is seldom associated with
weight heparin osteoporosis, and is associated with markedly less
thrombocytopenia than unfractionated heparin
Unfractionated B§ No No Osteoporosis and thrombocytopenia are associated with
heparin long-term use
Danaparinoid B§ No No No known adverse effects, but human data are limited
Fondaparinux Not yet categorized Yes No Limited experience
*US Department of Health and Human Services classifications for the use of drugs during pregnancy and breastfeeding range from category A (safest) to
category X (known danger—do not use). ‡Some evidence of risk to human fetuses, but the maternal benefits, such as treatment of life-threatening conditions,
might make the therapy acceptable despite the risk. §Unclear risk. Either animal studies have not demonstrated any fetal risk, but no controlled studies have
been done in pregnant women, or animal studies have shown an adverse effect that was not confirmed in controlled studies in pregnant women. Permission
obtained from Oxford University Press on behalf of the European Society of Cardiology © European Society of Gynecology et al. ESC guidelines on the
management of cardiovascular diseases during pregnancy: The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European
Society of Cardiology (ESC). Eur. Heart J. 32, 3147–3197 (2011).

evidence shows that low-molecular-weight heparins clearance, which could prolong postdose trough levels and
are associated with a reduced risk of excessive bleeding, subtherapeutic anticoagulation. In a small pilot study of
heparin-induced osteoporosis, and thrombocytopenia 15 pregnant patients receiving subcutaneous, twice-daily,
compared with unfractionated heparin.6,63,64 apparently therapeutic doses of low-molecular-weight
The physiological changes of pregnancy alter the meta­ heparin, 20% and 73% of the 8 h postdose and trough anti-
bolism of low-molecular-weight heparin. In the second factor Xa activity levels, respectively, were subtherapeutic,
trimester, increased extracellular fluid volumes increase despite peak levels being therapeutic.71 Another limitation
the volume of distribution of the drug. The glomeru- of low-molecular-weight heparins is their possible associ­
lar filtration rate also increases. These changes result in ation with an increased (albeit still reasonably low) risk
reduced peak levels of low-molecular-weight heparin of hemorrhage during pregnancy, delivery, and the post-
and an increased rate of drug clearance. Accordingly, the partum period. A systematic review of 64 studies, which
dose of low-molecular-weight heparin that is required included 2,777 pregnancies, showed an overall frequency
to achieve therapeutic levels of anti-factor Xa activity of bleeding of 1.98% (95% CI 1.50–2.57%).72 Heparin
increase during pregnancy, necessitating frequent moni- derivatives, therefore, are advantageous in that they do
toring.63,65,66 Anticoagulation efficacy should, therefore, not have a directly harmful effect on the fetus, but this
be checked at least weekly using an anti-factor Xa assay, benefit comes at the price of a potentially increased risk of
and dosing should be adjusted according to the relevant bleeding events and thromboembolic complications that
guidelines (Table 3).6,56,67 cannot be entirely avoided by maintaining therapeutic
Thromboembolic complications have, however, been peak levels of anti-factor Xa activity.
reported with low-molecular-weight heparin.60,63,68–70 Such
complications are generally attributable to subtherapeutic Novel anticoagulants
doses, patient noncompliance with treatment, or both. For Several novel anticoagulants, including the injec­table
example, in a study of pregnant women with mechanical agents danaparoid, fondaparinux, and lepirudin, can
heart valves, thromboembolism was reported in 14.9% of be used during pregnancy. 73–75 Danaparoid, a low-
47 pregnancies.60 Five of these complications were associ- molecular-weight heparinoid derived from porcine gut
ated with the use of low-molecular-weight heparin, but mucosa, rapidly inhibits thrombin production and might
either noncompliance with therapy or subtherapeutic be efficacious and safe for use in pregnant women with
anticoagulation was identified in each patient.60 However, mechanical valve prostheses. The active components of
the risk of valve thrombosis with low-molecular-weight danaparoid are heparan sulfate and dermatan sulfate.
heparin persists, even when the dose is adjusted to achieve As the drug does not contain heparin or heparin frag-
therapeutic anti-factor Xa activity levels. This problem ments, it is suitable for use in patients with heparin-
adds to the uncertainty surrounding the use of this drug induced thrombocytopenia (HIT) and other forms of
in pregnant women with mechanical valve prostheses. In thrombophilia associated with low-molecular-weight
a study that included 23 women with mechanical heart heparin intolerance (indication-specific danaparoid
valves who were treated with low-molecular-weight dosing schedules are available).76 Danaparoid inter-
heparin and low-dose aspirin during pregnancy, one feres with HIT pathogenesis by decreasing the binding
maternal death (4%) resulting from valve thrombosis of platelet factor 4 to platelets, 77 and has a low rate of
occurred, despite dose adjustment to achieve guideline- crossreactivity with HIT antibodies.78 The favorable
recommended peak anti-factor Xa activity levels.70 safety and efficacy profiles of danaparoid have led to
Thromboembolic complications with low-molecular- worldwide approval for use in patients who cannot tol-
weight heparin might result from increased renal erate low-molecular-weight heparin.77 An analysis of

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Table 3 | Guidelines for anticoagulation therapy in pregnant women with mechanical heart valves
Recommendation ACC/AHA6 ACCP67 ESC56
Oral anticoagulants Can be used throughout Can be used throughout pregnancy in If the warfarin dose is ≤5 mg
pregnancy, with substitution by high-risk* patients, with substitution daily, oral anticoagulants
dose-adjusted UFH or LMWH by LMWH or UFH close to term (time throughout pregnancy is the
during weeks 6–12 of gestation frame not specified but normally 48 h safest regimen (associated with
if preferred by the patient before delivery) <3% embryopathy)
Heparin derivatives Monitored UFH or LMWH might Dose-adjusted and monitored LMWH LMWH or UFH during
be options throughout gestation or UFH throughout pregnancy or weeks 6–12 of gestation should
or during weeks 6–12 of during weeks 6–12 of gestation is be considered if high-dose
gestation. LMWH dose should acceptable. In low-risk patients, warfarin is required to maintain
be adjusted to give an LMWH should be given twice daily therapeutic anticoagulation.
anti-factor Xa activity and the dose adjusted to achieve the LMWH dose should be adjusted
0.7–1.2 U/ml 4–6 h after manufacturer’s peak inhibition of to give an anti-factor Xa activity
administration factor Xa 4 h after subcutaneous of 0.8–1.2 U/ml 4–6 h after
injection administration
Aspirin Low-dose aspirin in addition to Low-dose aspirin in addition to Aspirin in addition to
anticoagulation during the anticoagulation in high-risk* patients anticoagulation is not
second and third trimesters recommended
Anticoagulation target INR 3 for all patients with INR 2–3 for patients with bileaflet No INR target recommendation
mechanical prosthetic heart aortic valves without high-risk
valves features*
*First-generation prostheses, mitral valve prostheses, history of thromboembolism, atrial fibrillation, or left ventricular dysfunction. Abbreviations:
ACCP, American College of Chest Physicians; ESC, European Society of Cardiology; INR, international normalized ratio; LMWH, low-molecular-weight heparin;
UFH, unfractionated heparin.

91 case reports of danaparoid use in pregnant women given these limited data, the use of fondaparinux during
with heparin intolerance showed that this treatment was the first trimester of pregnancy should be avoided.
safe when initiated at any time during pregnancy.75 The In contrast to fondaparinux, the direct thrombin inhib-
rates of live births, spontaneous miscarriages, and pre- itors, argatroban, bivalirudin, and lepirudin exert their
eclampsia in pregnant women treated with danaparoid75 anticoagulant effects independently of antithrombin.
compared favorably with those reported for pregnant These three drugs do not generate or interact with HIT
women with HIT or low-molecular-weight heparin antibodies.85 They all have a very short half-life (approxi-
intolerance who were treated with other antithrombotic mately 25 min in patients with normal renal function),
regimens,64,79,80 although the rate of premature birth was and so must be administered by continuous intravenous
increased from approximately 7%81 in the general popu- infusion. Antidotes are not available, but are unlikely to
lation to 14.8%.75 in women treated with danaparoid. be required. The aPTT is generally used to monitor the
The reasons for this increase are not clear. These obser- anticoagulation efficacy of argatroban and lepirudin,
vations indicate that danaparoid might be an effective whereas activated clotting time, partial thromboplastin
and safe alternative antithrombotic agent in pregnan- time, or INR can be used to monitor the therapeutic effect
cies complicated by HIT or intolerance or resistance to of bivalirudin. No data on the safety and efficacy of these
low-molecular-weight heparin. three drugs in pregnant women are available, but the low
The binding of fondaparinux, a direct inhibitor of molecular weight of argatroban makes trans­placental
factor Xa, causes antithrombin to undergo an irreversible passage likely. However, the intravenous method of
conformational change that increases its ability to inacti- administering the drugs makes them impractical for
vate factor Xa.82 The drug has no effect on thrombin and long term use during pregnancy.
does not affect the activated partial thromboplastin time Dabigatran is a competitive, direct thrombin inhibitor;
(aPTT); its half-life is 17 h and no antidote is available. its active moieties inhibit both free and clot-bound throm-
Fondaparinux is commonly used as an anticoagulant bin, as well as thrombin-induced platelet aggregation. The
in nonpregnant patients who develop heparin intoler- results of animal studies suggest that dabigatran might
ance. However, data on its use in pregnancy are limited not be safe for use during human pregnancy,86 although
to animal models and a few case reports.83 No adverse the full risks are currently unknown. The FDA has clas-
outcomes in pregnancy have been reported, although sified dabigatran as a pregnancy category C medication,
transplacental passage of the drug can occur, resulting in meaning that it might not be safe for pregnant women.87
a small, but measurable, reduction in levels of factor Xa Given the scarcity of data on the safety of direct throm-
activity in cord blood.73 Isolated case reports suggest that bin inhibitors during pregnancy, current guidelines
fondaparinux might be an effective and safe anticoagu- do not recommend the use of these agents in pregnant
lant for use in pregnant women with HIT.84 This drug has women.6,56,67 In our opinion, the use of direct thrombin
also been used as an alternative anticoagulant in preg- inhibitors in pregnant women should be limited to the
nant women who developed hypersensitivity skin reac- extremely low number of patients with severe heparin
tions to heparin and was not associated with bleeding or allergies (including patients with HIT) who develop an
other complications in the mother or child.73 However, intolerance to danaparoid.

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FOCUS ON ANTICOAGULATION THERAPIES

Guidelines for anticoagulation therapy guidelines, which were updated in 2012, suggest that
During pregnancy several approaches are acceptable, as no consensus
Current guidelines for anticoagulation therapy in preg- strategy exists for anticoagulation in pregnant women
nant women with mechanical prosthetic heart valves with prosthetic valves. The ACCP guidelines state
are based on an inadequate amount of prospective data. that the choice of anticoagulant regimen for pregnant
However, they do offer guidance that might inform women with mechanical heart valves should be com-
decisions about therapy for individual patients, even pletely indivi­dualized, as the decision is dependent on
in the absence of sufficient evidence to make definitive the personal values and preferences of the patient, who
recom­mendations.6,56,72 In both European and American must balance the risk of thrombosis versus the risk of
guidelines, continuous anticoagulation therapy is recom­ fetal abnormalities. Oral anticoagulants can be used
mended throughout pregnancy in patients with prosthetic throughout pregnancy, and should be substituted with
heart valves, with frequent monitoring to ensure that anti- low-molecular-weight or unfractionated heparin only
coagulation reaches therapeutic levels (Table 3). These when the patient is close to term (normally 48 h before
guidelines also share a consensus on the need for dialogue delivery). Dose-adjusted and therapeutically monitored
between the patient, her partner, and the multidisciplinary low-molecular-weight or unfractionated heparin, either
care team, to transmit information on the advantages throughout pregnancy or only during weeks 6–12, are
and disadvantages of varying anticoagulation regi- acceptable alternatives (Table 3).67 The ACCP also advo-
mens so that everyone involved in the decision-making cates consideration of the individual patient’s risk factors
process is well informed. for thromboembolism. In particularly high-risk patients,
The poor maternal outcomes with unfractionated such as those with a first-generation mitral valve prosthe-
heparin and the generally scarce data on the use of sis, a history of thromboembolism, or atrial fibrillation,
low-molecular-weight heparin in this setting led the the ACCP guidelines suggest that oral anticoagulants
authors of the European Society of Cardiology (ESC) should be used until close to delivery (normally inter-
guidelines to suggest that warfarin therapy should be preted as 48 h before delivery), when they should be
continued throughout pregnancy, particularly if thera- replaced with unfractionated or low-molecular-weight
peutic levels of anticoagulation can be maintained at heparin (Table 3).67 By suggesting the use of oral anti-
low doses.56 However, as noted above, this recommen- coagulants throughout pregnancy in appropriately
dation was made on the basis of the favorable findings selected patients at an increased risk of thromboembolic
reported by only one institution.58 The ESC guidelines events, the ACCP guidelines draw attention to the fact
state that patients who are taking warfarin ≤5 mg daily, that avoiding maternal complications also indirectly
phenprocoumon <3 mg daily, or acenocoumarol <2 mg decreases the risk of some adverse fetal outcomes, such
daily should first be informed that continuing the oral as fetal death (Table 3).
anticoagulant throughout their pregnancy is the safest Although all three sets of guidelines demonstrate a
treatment regimen, and that the risk of embryopathy clear consensus on the need for frequent laboratory
is <3% with this course of action (Table 3).56 Only after monitoring to maintain therapeutic anticoagulation,
sharing this information should a switch to unfraction- subtle differences are evident in the intensity of anti-
ated or low-molecular-weight heparin during week 6–12 coagulation that is considered necessary. These differ-
of pregnancy, when the teratogenic potential of warfarin ences have arisen partly because the proposed target
seems to be greatest, be considered. The authors of the levels are not based on data. The ACC/AHA guidelines
ESC guidelines concede the need to consider discontin- assign a class I recom­mendation to a target INR of 3.0
uation of oral anticoagulant therapy during week 6–12 for all patients with mechanical prosthetic heart valves,
if high doses are necessary to maintain therapeutic whereas the ACCP guidelines advise a lower thera-
anti­coagulation levels (Table 3).56 peutic target (INR 2.0–3.0) for patients with bileaflet
In American guidelines, jointly released by the aortic valves who do not have high-risk features, such
ACC and AHA,6 warfarin therapy throughout preg- as atrial fibrillation or left ventricular dysfunction
nancy is not endorsed as strongly as in the ESC guide- (Table 3).6,72 The ESC guidelines advise that anti-factor Xa
lines. A Class I recommendation is assigned to the use activity levels should be maintained at 0.8–1.2 U/ml
of continuous intravenous unfractionated heparin, dose- among patients electing to use low-­molecular-weight
adjusted subcutaneous unfractionated heparin, or heparin, and that anticoagulation activity should be
dose-adjusted subcutaneous low-molecular-weight measured 4–6 h after administration.56 The ACC/AHA
heparin during weeks 6–12 of gestation in patients who guidelines advocate a slightly lower thera­peutic range of
wish to discontinue warfarin during this period (Table 3).6 anti-factor Xa activity levels (0.7–1.2 U/ml).6 The three
After a full discussion with the patient, continuous intra­ guidelines share a general consensus that the aPTT
venous or dose-adjusted unfractionated heparin, or dose- value should be at least twice that of the normal range in
adjusted low-molecular-weight heparin might be used patients receiving unfractionated heparin.
in lieu of warfarin throughout pregnancy (also a Class I Another area of divergent opinion concerns the use
recommendation; Table 3).6 of low-dose aspirin in addition to anticoagulants during
The recommendations of the American College of pregnancy. The ESC guidelines do not recommend
Chest Physicians (ACCP)67 might offer a middle ground the addition of aspirin, as insufficient data are avail-
between those of ACC/AHA, and the ESC. The ACCP able to prove its efficacy and safety in pregnant women

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REVIEWS

Woman with prosthetic heart valve


heparin should be replaced by intravenous unfraction-
ated heparin at least 12–24 h before the planned deliv-
ery. If unfractionated heparin is used, the drug should
Usual care of patients Very early diagnosis of pregnancy is critical be continued until 4–6 h prior to the planned delivery
with prosthetic heart Advise patient of the need for immediate
valve blood hCG testing if a menstrual period is and can be restarted 4–6 h after delivery if no bleeding
missed and there is a possibility of pregnancy complications occur.31
The American Society of Regional Anesthesia has
Patient should be published recommendations regarding the feasibility
cared for by both Pregnant
a perinatologist of regional anesthesia in patients receiving anticoagu-
and a cardiologist
lation therapy.88 In patients receiving twice-daily low-
molecular-weight heparin, regional anesthesia is contra-
OAC ≤5 mg OAC >5 mg indicated if the most recent dose was administered in
the previous 24 h. Intravenous heparin can be initiated
Week 6–12: If informed consent
1 h after neuraxial anesthesia, with catheter removal
switch to is obtained, continue 2–4 h after the last heparin dose. Subcutaneous unfrac-
LMWH or UFH OAC >5 mg
tionated heparin, administered twice daily at a total daily
dose of <10,000 U, is not a contraindication to neuraxial
anesthesia. However, neuraxial anesthesia has not been
Week 36: switch to LMWH or UFH established to be safe in patients receiving unfractionated
heparin at daily doses >10,000 U or more frequently than
Individualized delivery twice daily.88 Unfractionated heparin should be stopped
■ Time of delivery
Delivery
in these individuals when labor is established or 4 h
■ Method of induction
■ Analgesia/regional anaesthesia
before neuraxial catheter placement.31

Figure 1 | Proposed algorithm for anticoagulation therapy during pregnancy in Conclusions


women with prosthetic heart valves. These patients should be advised of the need Despite advances in the treatment of children and young
for immediate testing if there is a possibility that they could be pregnant. During adults with heart disease, the management of women of
pregnancy they should be cared for by both a perinatologist and a cardiologist. childbearing age remains challenging, and an optimal
Treatment with ≤5 mg of warfarin can be continued throughout pregnancy until choice of prosthetic heart valve for these patients is not
week 36. However, if a dose of oral anticoagulant >5 mg is required, the patient can
available. Tissue valves eliminate the need for long-term
either switch to low-molecular-weight or unfractionated heparin during weeks 6–12
of gestation or, if informed consent is obtained, they can continue oral anticoagulant
anticoagulation therapy, but are prone to structural valve
therapy throughout pregnancy. Regardless of the dose of the oral anticoagulant, deterioration, which is an age-dependent process that
patients should switch to low-molecular-weight or unfractionated heparin from might be accelerated by pregnancy. Although mechanical
week 36 of gestation onwards. Delivery strategies for women with prosthetic heart heart valves are limited by their thrombogenicity, new-
valves, including the time of planned delivery, method of labor induction, and choice generation bileaflet mechanical valves might be a reason-
of analgesia or regional anesthesia should be tailored to individual patients. able and durable choice in young women who are likely
Abbreviations: hCG, human chorionic gonadotropin; LMWH, low-molecular-weight to be adherent to long-term anticoagulation therapy.
heparin; OAC, oral anticoagulant; UFH, unfractionated heparin.
Transcatheter aortic valve replacement (TAVR) avoids
both the potential for structural valve deterioration
(Table 3).56 By contrast, the ACC/AHA guidelines assign and the need for anticoagulation associated with valve
a class IIa recommendation to the use of low-dose replacement, so could be another feasible alternative for
aspirin in the second and third trimesters of pregnancy women of childbearing age. This novel procedure, which
(Table 3).6 The ACCP once again offers a middle ground involves the percutaneous implantation of an aortic pros-
by recommending the use of low-dose aspirin in preg- thesis, is currently indicated only in selected, very sick
nant women with prosthetic valves who are at high risk patients who have an extremely high risk of surgical
of thromboembolism (Table 3).72 valve replacement. However, as the technique, experi­
ence, and prostheses improve, the indications might
Peripartum broaden to younger, not so sick individuals, possibly
Similarly to deciding upon an anticoagulation strategy eventually including women of childbearing age. TAVR
for pregnant women with valve prostheses, decision- is the only novel procedure that has shown significant
making regarding anticoagulation options around the positive results compared with standard surgical valve
time of delivery should take into account the mode of replacement in clinical trials.89
delivery, the patient’s preferences, and the risks and bene­ Anticoagulant therapy is mandatory for pregnant
fits associated with variations in the timing of delivery, patients with mechanical heart valves. However, no
method of induction, and the use of anesthesia. The anticoagulation strategy is without risk and treatment
general consensus between physicians is that, if vaginal decisions need to take into account the preferences
delivery is planned, oral anticoagulant therapy should be and capabilities of individual patients, including their
discontinued at week 36 of gestation and replaced with compliance with therapy, willingness to self-inject low-
appropriately monitored therapeutic doses of a heparin molecular-weight heparin 2–3 times daily, and their
derivative. 6,56,72 Furthermore, low-molecular-weight ability to monitor anticoagulation efficacy using the

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© 2012 Macmillan Publishers Limited. All rights reserved
FOCUS ON ANTICOAGULATION THERAPIES

anti-factor Xa assay. Other patient-specific features and obstetric care teams need to work collaboratively to
that modify the risk of thromboembolic events, such help patients make informed and personalized decisions
as the anatomical position of the prosthesis, must also that balance the risks and benefits of various therapies.
be considered.
Oral anticoagulant therapy throughout pregnancy Review criteria
could be the safest and most effective regimen, par- A search for original articles was performed in PubMed.
ticularly at doses of warfarin ≤5 mg daily (Figure 1). The search terms used were “prosthetic heart valves”,
However, the use of heparin derivatives is limited by an “pregnancy”, “anticoagulation”, and “anticoagulation
increased risk of thromboembolic complications, even embryopathy”, alone and in combination. All papers
at seemingly therapeutic levels of anticoagulation. As a identified were full-text papers published in English. We
also searched the reference lists of identified articles for
paucity of data is available to guide decisions relating to
further relevant papers.
the choice of anticoagulation strategy, cardiac, surgical,

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