Professional Documents
Culture Documents
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
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
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
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.
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
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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College of Chest Physicians. The sixth (2000) thrombin inhibitors, inhibit formation of platelet edited the manuscript before submission.