1. Use of Antithrombotic Agents
During Pregnancy
Jeffrey S. Ginsberg, MD, FCCP, Chair; Ian Greer, MD; and
Jack Hirsh, MD, FCCP
Abbreviations: APLA ϭantiphospholipid antibody; APTT
ϭactivated partial thromboplastin time; CI ϭ confidence
interval; DVT ϭ deep vein thrombosis; HIT ϭ heparin-
induced thrombocytopenia; INR ϭ international normalized
ratio; IUGR ϭ intrauterine growth restriction; LMWH ϭ
low-molecular-weight heparin; PE ϭ pulmonary embolism; s/c
ϭ subcutaneous; UHF ϭ unfractionated heparin; VTE ϭ
venous thromboembolism
(CHEST 2001; 119:122S–131S)
Fatal pulmonary embolism (PE) remains a common
cause of maternal mortality. Maternal mortality from
PE can be reduced in two ways: (1) by aggressively
investigating symptomatic women when they present with
a clinical suspicion of deep vein thrombosis (DVT) or PE;
and (2) by treatment and/or prophylaxis in women who
have an increased risk for DVT and/or PE. Both ap-
proaches are problematic for several reasons. The first
approach is problematic because nonthrombotic symp-
toms that mimic DVT and PE are common during preg-
nancy, the tests used to diagnose DVT can be altered by
the compressive effects of the gravid uterus on the iliac
veins, and there is a concern about performing procedures
(such as lung scanning) that expose the fetus to radiation.
The second approach is problematic because prophylaxis
or treatment of DVT and PE involves long-term paren-
teral unfractionated heparin (UFH) or low-molecular-
weight heparin (LMWH); both are inconvenient, painful,
expensive, and associated with a risk of bleeding, osteopo-
rosis, and heparin-induced thrombocytopenia (HIT), al-
though these complications are probably less frequent
with LMWH than UFH. Appropriate management of preg-
nant women with prior venous thromboembolism (VTE) is
problematic because, until recently, reliable information on
the true incidence of recurrence in such women was not
available. Furthermore, many women with prior VTE have
an identifiable abnormality associated with thrombophilia,
and the management of such individuals is controversial.
Since our last review, new information has been pub-
lished on the management of pregnant women with
previous VTE, the safety and pharmacokinetics of LMWH
during pregnancy, the mechanisms of osteoporosis caused
by UFH and LMWH, the problems of managing pregnant
women with prosthetic heart valves, and the relation
between thrombophilia and fetal loss, intrauterine growth
restriction (IUGR), and preeclampsia.
In this chapter, we will review the management of
thromboembolic complications during pregnancy with
particular emphasis on important new studies.
Epidemiology of VTE During Pregnancy
The true incidence of VTE associated with pregnancy is
unknown, but there is a strong clinical impression that the
risk is increased compared to the incidence in nonpreg-
nant individuals.1 Available evidence suggests that the risk
of VTE is higher after cesarean section (particularly
emergency cesarean section) than after vaginal delivery.2
There does not appear to be a preponderance of VTE in
any trimester, although there is a striking predisposition
for DVT to occur in the left leg (approximately 90%),3
possibly because during pregnancy there is an exaggera-
tion of the compressive effects on the left iliac vein by the
right iliac artery where they cross.4 A relatively greater
proportion of thrombi during pregnancy are in the iliofem-
oral veins, where they are more likely to embolize.
As in nonpregnant subjects, the clinical diagnosis of DVT
and PE during pregnancy is inaccurate. The nonspecificity is
compounded by the facts that leg swelling and pain (mim-
icking DVT) and chest pain and dyspnea (mimicking PE) are
common during pregnancy and are usually nonthrombotic in
origin. In support of this, the prevalence of DVT in a study5
of consecutive pregnant patients presenting with a clinical
suspicion was Ͻ 10, compared to approximately 25% in
studies of nonpregnant populations,6–9 whereas a recent
study (W.S. Chan; unpublished data) found that only 2 of 50
subjects (4%) with suspected PE had the disease, compared
to about 30% of nonpregnant patients who presented with
suspected PE.10,11
Thrombophilia and Pregnancy
There are two main adverse experiences that are asso-
ciated with thrombophilia and pregnancy. These are (1)
VTE and (2) pregnancy complications associated with
placental infarction, including miscarriage, IUGR, pre-
eclampsia, abruption, and intrauterine death. Friederich
et al12 have shown that asymptomatic women with con-
genital deficiencies of antithrombin, protein C, or protein
S have approximately an eightfold increased risk of VTE
during pregnancy compared to normal control subjects.12
However, in absolute terms, the risk of VTE was relatively
low (7 of 169 pregnancies; 4.1%). Two of these episodes
occurred during the third trimester, and the remaining
five occurred postpartum. In addition, one study13 has
shown that 60% of women who develop VTE during
pregnancy have factor V Leiden. Other thrombophilic
disorders, such as the prothrombin gene mutation,14 hy-
perhomocysteinemia,15 and persistent antiphospholipid
antibodies (APLAs),16 are probably also associated with an
increased risk of VTE during pregnancy and the puerpe-
rium. There is a clinical impression as well as retrospective
data suggesting that antithrombin deficiency imparts a
higher risk of VTE than other thrombophilias. Accord-
ingly, such women should be treated more aggressively
than those with other inherited thrombophilias.17
During pregnancy, the antepartum management of
pregnant women with known thrombophilia and no prior
VTE remains controversial because of our limited knowl-
edge of the natural histories of various thrombophilias and
a lack of trials of VTE prophylaxis; in the study cited
above,12 Ͻ 2% of women with antithrombin, protein C, or
Correspondence to: Jeffrey S. Ginsberg, MD, FCCP, McMaster
University Medical Center, Room 3W12, 1200 Main St. West,
Hamilton, Ontario, L8N 3Z5, Canada
122S Sixth ACCP Consensus Conference on Antithrombotic Therapy

2. protein S deficiency suffered VTE during pregnancy. We
are unaware of prospective data addressing the issue of the
incidence of VTE in a large group of pregnant women with
thrombophilia and no prior VTE.
Women with a history of VTE (with or without throm-
bophilia) are believed to have a higher risk of recurrence
in subsequent pregnancies. Estimates of the rate of recur-
rent venous thrombosis during pregnancy in women with
a history of VTE have varied between zero and 13%.18–21
The higher of these estimates has prompted authorities
(including the American College of Chest Physicians) to
recommend anticoagulant prophylaxis during pregnancy
and the postpartum period in women with a history of
VTE.22 However, the risk is likely to be lower than has
been suggested by some of these studies because objective
testing was used uncommonly to confirm the diagnosis of
recurrent VTE, thereby resulting in a substantial over-
diagnosis of recurrence. Furthermore, the higher esti-
mates of the frequency of recurrence are from retrospec-
tive studies20,21 of nonconsecutive patients, whereas the
lower estimates come from prospective, albeit small stud-
ies (n ϭ 20 and n ϭ 59, respectively).18,19
In order to obtain a reliable estimate of the true incidence
of recurrent VTE in women with prior VTE, Brill-Edwards
and Ginsberg23 recently completed a prospective study of
125 pregnant women with a single previous episode of
objectively diagnosed VTE. Antepartum heparin therapy was
withheld, and anticoagulants (usually warfarin with a target
international normalized ratio [INR] of 2.0 to 3.0 with an
initial short course of UFH or LMWH) were given in the
postpartum period for 4 to 6 weeks. The antepartum recur-
rence rate was 2.4% (95% confidence interval [CI], 0.2 to
6.9%). Ninety-five patients had blood testing to identify
thrombophilia. There were no recurrences in the 44 patients
(0%; 95% CI, 0.0 to 8.0) who did not have thrombophilia and
had a previous episode of thrombosis that was associated with
a temporary risk factor. Patients with abnormal test results
and/or a previous episode of thrombosis that was idiopathic
(unprovoked) had an antepartum recurrence rate of 5.9%
(95% CI, 1.2 to 16%). Based on these results, the absolute
risk of antepartum recurrent VTE in women without throm-
bophilia and whose previous episode of thrombosis was
associated with a temporary risk factor is low and antepartum
heparin prophylaxis is not routinely justified. Further studies
are needed to determine whether prophylaxis is warranted in
patients with thrombophilia by laboratory testing and/or a
previous episode of idiopathic thrombosis.
Repeated screening with noninvasive tests for DVT,
such as compression ultrasound, is not justified for two
reasons in these patients because, even with a sensitivity of
96% and a specificity of 98%, the positive predictive value
of compression ultrasound would be only 10% if we
postulate that the prevalence of recurrent VTE is about
5%. Second, the timing of screening with ultrasound is
problematic. Even if performed as often as weekly, a
woman could still develop clinically important recurrence
2 to 3 days after normal ultrasound findings. Therefore, we
are modifying our previous recommendation that women
at risk for VTE should be screened routinely with regular
noninvasive tests, with the recommendation that they
should be investigated aggressively if symptoms suspicious
of DVT or PE occur.
Thrombophilia and Pregnancy Loss
Maternal thrombophilias are now recognized to be asso-
ciated with pregnancy complications, including fetal loss,
IUGR, preeclampsia, abruption, and intrauterine death.
With regard to miscarriage, several case-control studies
have shown a relationship between factor V Leiden and
second trimester miscarriage. However, in contrast to
APLA syndrome, there are no reliable data at present (and
to our knowledge) to link the congenital thrombophilias
with first trimester loss. Interestingly, hyperhomocysteine-
mia has been associated with early pregnancy loss.24 It has
been postulated that first trimester miscarriage reflects the
failure of implantation while second trimester miscarriage
reflects thrombotic events in the placenta.2
There is also an association between stillbirth and
thrombophilia, particularly with antithrombin deficiency,
but also with combined defects.25,26 The stillbirths may
reflect an increase in the pregnancy complications of
IUGR, preeclampsia, and abruption. The main relation-
ships appears to be with hyperhomocysteinemia, factor V
Leiden, and the prothrombin gene variant.
In view of these data, women with recurrent pregnancy
loss, including at least one second trimester miscarriage,
or a history of intrauterine death or severe or recurrent
preeclampsia or growth restriction, should be screened for
underlying congenital thrombophilias. However, in con-
trast to patients with APLA syndrome with recurrent
miscarriage, where a combination of heparin and low-dose
aspirin have been shown to be effective in reducing
miscarriage rates, we have no data to indicate whether
such antithrombotic therapy is beneficial. Nevertheless,
since many of these women are at risk of VTE, antithrom-
botic therapy should be considered. Although hyperhomo-
cysteinemia has not been associated with DVT in preg-
nancy,27,28 hyperhomocysteinemia and reduced serum
folic acid concentrations are risk factors for recurrent
spontaneous miscarriage; therefore, folic acid supplemen-
tation may be beneficial in such patients.
APLAs
APLAs can be detected using clotting assays (lupus
anticoagulant) or immunoassays (anticardiolipin antibod-
ies) and have been reported to occur in systemic lupus
erythematosus with use of certain drugs and in apparently
healthy individuals.29 There is convincing evidence that
the presence of APLAs is associated with an increased risk
of thrombosis16,29 and pregnancy loss.30 Thus, pregnant
women with APLAs should be considered at risk for both
of these complications. In addition, women with recurrent
pregnancy loss should be screened for the presence of
APLA prior to or during the early part of pregnancy. The
management of pregnant women with APLA is problem-
atic because few clinical trials evaluating therapy have
been performed. A relatively large (n ϭ 202), placebo-
controlled, randomized trial31 showed no benefit to using
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3. aspirin and prednisone in pregnant women with prior
pregnancy losses and one or more autoantibodies; 94 of
202 women (46.5%) had APLAs. Two randomized trials
compared aspirin and heparin to aspirin alone and showed
improved fetal survival with heparin and aspirin.32,33 Re-
sults of published case series suggest that LMWH is
efficacious in pregnant women with APLAs and fetal loss.
Currently, we and others are evaluating the efficacy and
safety of LMWHs in randomized trials in women with
APLAs. The available data suggest that aspirin and heparin
therapy is the regimen of choice for the prevention of
pregnancy loss in pregnant women with APLAs and
multiple previous pregnancy losses. It is likely that
LMWHs will also be effective.
Pregnant women with APLAs (particularly “high-titer”
anticardiolipin antibodies and/or lupus anticoagulants), no
pregnancy losses, but previous venous thrombosis should
be considered candidates for UFH or LMWH therapy.
Women with APLAs and neither previous venous throm-
bosis nor pregnancy losses should probably still be consid-
ered to have an increased risk of VTE and should be
treated either with careful clinical surveillance for VTE or
prophylactic UFH or LMWH.
Anticoagulant Therapy During Pregnancy
The anticoagulants currently available for the preven-
tion and treatment of VTE and arterial thromboembolism
include heparin and heparin-like compounds (UFH,
LMWH, and heparinoids), coumarin derivatives, as well as
aspirin. The “direct” thrombin inhibitors, such as hirudin,
cross the placenta and have not yet been evaluated during
pregnancy and therefore will not be further discussed.
LMWHs and Heparinoids
There is accumulating experience with the use of these
agents both in pregnant and nonpregnant patients for the
prevention and treatment of DVT.34–40 Based on the
results of large clinical trials in nonpregnant patients,
LMWH and heparinoids (danaparoid sodium) are at least
as effective and safe as UFH for the treatment of patients
with acute proximal DVT41,42 and for the prevention of
DVT in patients who undergo surgery.43 LMWHs have the
advantage of a longer plasma half-life and a more predict-
able dose response than UFH.44
There is also evidence that LMWH (and heparinoids)
do not cross the placenta,35,46,47 and a recent overview48
concluded that LMWH was safe for the fetus. These
agents have potential advantages over UFH during preg-
nancy because they cause less HIT,49 have the potential
for once-daily administration, and probably result in a
lower risk of heparin-induced osteoporosis.50
Dose Regimens of LMWH
LMWHs are more expensive than UFH, but given the
advantages listed above, the clear-cut evidence of their
efficacy in nonpregnant patients, and the fact that they are
safe for the fetus, they are suitable for routine clinical use
in pregnant patients who require anticoagulant therapy. If
one of these agents is used for acute treatment of VTE, a
weight-adjusted dose regimen (as per the recommenda-
tions of the manufacturer) should be used. As the preg-
nancy progresses (and most women gain weight), the
volume of distribution for LMWH changes. Therefore,
two options are available. The first is to simply change the
dose in proportion to the weight change.51 The second is
to perform weekly anti-factor Xa levels 4 h after the
morning dose and adjust the dose of LMWH to achieve an
anti-Xa level of approximately 0.5 to 1.2 U/mL. For
prophylaxis of VTE, several dose regimens and LMWHs
have been used. Common regimens that have been re-
ported in case series, small cohort studies, and one
randomized trial52 include subcutaneous (s/c) dalteparin,
5,000 U q24h34; enoxaparin, 40 mg q24h39,40; and dose-
adjusted LMWH to achieve a peak anti-Xa level of 0.2 to
0.6 U/mL.34,36 Although all of the studies reported low
recurrence rates, none was a placebo-controlled trial;
therefore, the recurrence rates might have been low
without prophylaxis. LMWH should also be considered in
patients with intractable painful skin reactions to UFH
and in those with osteopenia.
Fetal Complications of Anticoagulants
During Pregnancy
There are two potential fetal complications of maternal
anticoagulant therapy: teratogenicity and bleeding. Nei-
ther UFH53 nor LMWH35,46,47 cross the placenta and
therefore do not have the potential to cause fetal bleeding
or teratogenicity, although bleeding at the uteroplacental
junction is possible. Three studies strongly suggest that
UFH/LMWH therapy is safe for the fetus.48,54,55
In contrast to heparin, coumarin derivatives cross the
placenta and have the potential to cause both bleeding in
the fetus and teratogenicity.56,57 Coumarin derivatives can
cause an embryopathy, which consists of nasal hypoplasia
and/or stippled epiphyses, after in utero exposure to oral
anticoagulants during the first trimester of pregnancy, and
CNS abnormalities, which can occur after exposure to
such drugs during any trimester.56 It is probable that oral
anticoagulants are safe during the first 6 weeks of gesta-
tion, but there is a risk of embryopathy if coumarin
derivatives are taken between 6 weeks and 12 weeks of
gestation.58 In addition, these oral anticoagulants cause an
anticoagulant effect in the fetus which is a concern,
particularly at the time of delivery, when the combination
of the anticoagulant effect and trauma of delivery can lead
to bleeding in the neonate.
Maternal Complications of Anticoagulant Therapy
During Pregnancy
In a cohort study,55 the rate of major bleeding in
pregnant patients treated with UFH therapy was 2%,
which is consistent with the reported rates of bleeding
associated with heparin therapy in nonpregnant patients59
and with warfarin therapy60 when used for the treatment
of DVT. In addition, adjusted-dose s/c UFH can cause a
persistent anticoagulant effect at the time of delivery,
which can complicate its use prior to labor.61 In a small
study, an anticoagulant effect persisted for up to 28 h after
the last injection of adjusted-dose s/c heparin, frequently
resulting in deliveries that were complicated by a pro-
124S Sixth ACCP Consensus Conference on Antithrombotic Therapy

4. longed activated partial thromboplastin time (APTT). The
mechanism for this prolonged effect is unclear; however,
one way to avoid an unwanted anticoagulant effect during
delivery in women receiving adjusted-dose s/c UFH ther-
apy is to discontinue the heparin therapy 24 h prior to
elective induction of labor. If spontaneous labor occurs in
women receiving adjusted-dose s/c UFH, careful monitor-
ing of the APTT (or heparin level) is required and, if it is
prolonged near delivery, protamine sulfate may be re-
quired to reduce the risk of bleeding. It is important to
recognize that during pregnancy, the APTT response to
heparin is often attenuated because of increased levels of
factor VIII and fibrinogen.62 This may mislead the clini-
cian into falsely concluding that there is no heparin activity
present because the APTT level can be normal with
significantly elevated heparin levels. Bleeding complica-
tions appear to be very uncommon with LMWH.34–40
Nevertheless, near term, we suggest the same approach to
women receiving “treatment doses” of LMWH as in those
receiving adjusted-dose UFH, namely discontinuing
LMWH therapy 24 h prior to elective induction of labor.
Immune HIT
Approximately 3% of nonpregnant patients receiving
UFH develop immune, IgG-mediated thrombocytopenia,
which is frequently complicated by extension of preexist-
ing VTE or new arterial thrombosi.49 This should be
differentiated from an early, benign, transient thrombocy-
topenia that can occur with initiation of UFH therapy.
Diagnosing immune thrombocytopenia is often difficult
because definitive platelet-activation assays are not widely
available and turnaround times are slow. It should be
suspected when the platelet count falls to Ͻ 100 ϫ 109
/L
or Ͻ 50% of the baseline value 5 to 15 days after
commencing heparin therapy, or sooner with recent hep-
arin exposure.49
In pregnant women who develop HIT and require
ongoing anticoagulant therapy, use of the heparinoid,
danaparoid sodium, is recommended because it is an
effective antithrombotic agent and has much less cross-
reactivity with UFH and, therefore, less potential to
produce recurrent HIT than LMWH.63
Heparin-Induced Osteoporosis
Long-term heparin therapy has been reported to cause
osteoporosis in both laboratory animals and humans.64–71
A number of studies have attempted to quantify the risk of
osteoporosis when heparin is administered for periods of
Ն 1 month. In general, symptomatic vertebral fractures
have been reported to occur in about 2 to 3% of the
patient population, and significant reductions in bone
density have been reported in up to 30% of patients
receiving long-term UFH therapy.64 Dahlman65 studied
184 women receiving long-term prophylactic UFH ther-
apy during pregnancy and reported a 2.2% incidence of
vertebral fracture. In contrast, in a small randomized trial,
Monreal et al66 reported spinal fractures in 6 of 40 patients
(15%) receiving s/c UFH, 10,000 IU bid, for a period of 3
to 6 months. The reason for the higher incidence of
osteoporotic fractures (15% vs 2%) is probably due to the
fact that the patients in the study by Monreal et al66 were
significantly older than those in the study by Dahlman.65
Recently, Shaughnessy and associates67 performed a
series of studies in Sprague Dawley rats and other exper-
imental models that provided new information on the
mechanism of heparin-induced osteoporosis. In one study,
animals treated with UFH at doses ranging from 0.25 to
1.0 anti-Xa U/g for 28 days68 showed a dose-dependent
decrease in cancellous bone volume in the distal third of
the femur. They were also able to show that UFH causes
bone loss by decreasing rates of bone formation while at
the same time increasing rates of bone resorption.
In a second study,69 designed to determine whether the
effects of UFH on bone are reversible, rats were randomized
to once-daily s/c injections of either UFH or saline solution
for 28 days and then followed up for an additional 28 days
without treatment. Heparin caused a 30% loss in cancellous
bone volume over the first 28 days. To explore the mecha-
nism for the prolonged effect of heparin on bone, the
experiment was repeated using 125
I-labeled heparin instead
of unlabeled heparin. 125
I-labeled heparin accumulated in
bone during the course of its administration and was retained
in bone for at least 28 days after stopping heparin treatment.
These findings suggest that heparin-induced osteoporosis is
not rapidly reversible because heparin is sequestered in bone
for extended periods.69
Several lines of evidence now suggest that LMWHs
have a lower risk of osteoporosis than heparin. In the study
by Monreal et al,66 dalteparin, 5,000 IU anti-Xa bid s/c,
was compared with UFH, 10,000 IU bid s/c, in 80 patients
with DVT; both treatments were administered for a period
of 3 to 6 months. Six of the 40 patients (15%) who received
UFH developed spinal fractures compared with only 1 of
40 patients (2.5%) receiving dalteparin. Studies using an
animal model of heparin-induced osteoporosis support the
hypothesis that LMWHs cause less osteoporosis than
UFH. Thus, when rats were treated with once daily s/c
injections of UFH, 1.0 U/g or 0.5 U/g, or the LMWH
tinzaparin, 1.0 U/g or 0.5 U/g, for a period of 32 days, both
treatments decreased cancellous bone volume in a dose-
dependent fashion, but UFH caused significantly more
cancellous bone loss than LMWH.69
Use of Anticoagulants in the Nursing Mother
Heparin and LMWHs are not secreted into breast milk
and can be safely given to nursing mothers.70 There have
been two convincing reports71,72 that warfarin does not
induce an anticoagulant effect in the breast-fed infant
when the drug is given to a nursing mother. Therefore, the
use of warfarin in women who require postpartum antico-
agulant therapy is safe and these women should be
encouraged to breast feed.
Safety of Aspirin During Pregnancy
Potential complications of aspirin during pregnancy
include birth defects and bleeding in the neonate and in
the mother. The results of a meta-analysis73 and a large
(Ͼ 9,000 patients) randomized trial74 reported that low-
dose (60 to 150 mg/d) aspirin therapy administered during
the second and third trimesters of pregnancy in women at
CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT 125S

5. risk for pregnancy-induced hypertension or intrauterine
growth retardation was safe for the mother and fetus
because no increase in maternal or neonatal adverse
effects occurred in individuals treated with aspirin. Thus,
based on current evidence, low-dose aspirin (Ͻ 150 mg/d)
during the second and third trimesters appears to be safe,
but the safety of higher doses of aspirin and/or aspirin
ingestion during the first trimester remains uncertain.
Efficacy of Anticoagulants for the Prevention and
Treatment of VTE During Pregnancy
There is a paucity of data about the efficacy of antico-
agulants for the prevention and treatment of VTE during
pregnancy. Accordingly, the recommendations about their
use during pregnancy are based largely on extrapolations
from data from nonpregnant patients, from case reports,
and from case series of pregnant patients. Based on the
safety data, a heparin-related compound (LMWH or
UFH) is the drug of choice for the prevention and
treatment of VTE during pregnancy. There are now many
well-designed randomized trials and meta-analyses com-
paring IV UFH and s/c LMWH for the treatment of acute
DVT and PE.41,42 They show that LMWH is at least as safe
and effective as UFH. There are also studies in nonpreg-
nant patients showing that long-term LMWH (and UFH)
are as effective and safe as warfarin for the prevention of
recurrent VTE.50,59 In view of the totality of the data, we
endorse the use of LMWH for initial and long-term
treatment of acute VTE. Two alternative approaches are
reasonable: IV UFH followed by at least 3 months of s/c
heparin, in doses adjusted to prolong a mid-interval APTT
into the therapeutic range (adjusted-dose s/c heparin); or
adjusted-dose s/c heparin can be used both for initial and
long-term treatment.
Prophylaxis of VTE in Pregnant Women
With Thrombophilia
When evaluating women who are deemed to have an
increased risk of VTE, several issues must be addressed.
The first is to critically evaluate the evidence that the
women indeed have VTE and/or thrombophilia. Once this
is done, based on laboratory and clinical data, women can
be categorized as follows: (1) single episode of VTE
associated with a transient risk factor; (2) single idiopathic
episode of VTE and not receiving long-term anticoagula-
tion therapy; (3) single episode of VTE and thrombophilia
(confirmed laboratory abnormality) and not receiving
long-term anticoagulation therapy; (4) no prior VTE and
thrombophilia (confirmed laboratory abnormality); or (5)
multiple (two or more) episodes of VTE and/or women
receiving long-term anticoagulation therapy (eg, single
episode of VTE, either idiopathic or associated with
thrombophilia).
These are broad categories, and the risk assessment for
each patient should be individualized. For example, a
woman with a single episode of VTE in association with a
transient risk factor might be treated more aggressively if
she required bed rest or was morbidly obese.
Based on the currently available studies, there are two
general approaches to pregnant patients with previous
VTE: (1) active prophylaxis with UFH or LMWH; and (2)
clinical surveillance. Several cohort studies and one ran-
domized trial have reported low recurrence rates with the
use of prophylactic once-daily LMWH treatment.34–40,52
Given the added convenience of LMWH and decreased
HIT and osteoporosis, it is becoming the preferred choice.
Alternatively, UFH, 5,000 U s/c q12h, is effective and safe
for the prevention of VTE in high-risk nonpregnant
patients,75 and its use has been recommended in pregnant
patients. However, there is a concern that a dose of
heparin, 5,000 U s/c q12h, may be insufficient in high-risk
situations because it does not reliably produce detectable
heparin levels. There are also published data65 that more
intense heparin therapy, in doses that produce plasma
heparin levels (measured as anti-factor Xa activity) of 0.1
to 0.2 U/mL, is associated with low recurrence rates in
pregnant women with previous VTE. Until comparative
studies are performed, it is impossible to make definitive
recommendations about which regimen to use for prophy-
laxis (if active prophylaxis rather than clinical surveillance
is chosen).
Management of Pregnant Women With Prosthetic
Heart Valves
Pregnant women with prosthetic heart valves pose
problems because of the lack of reliable data on the
efficacy and safety of antithrombotic therapy during preg-
nancy. A retrospective survey by Sbarouni and Oakley76 of
outcomes in pregnant women with mechanical heart
valves concluded (1) that warfarin was safe and not
associated with embryopathy, and (2) that heparin was
associated with more thromboembolic and bleeding com-
plications than warfarin.
In order to examine the validity of these conclusions
and explore optimum antithrombotic regimens, Chan and
colleagues77 performed a systematic review of the litera-
ture examining fetal and maternal outcomes of pregnant
women with prosthetic heart valves. Since no randomized
trials were identified, the overview consisted of prospec-
tive and retrospective cohort studies. Pooled estimates of
maternal and fetal risks associated with the following three
commonly used approaches were determined: (1) oral
anticoagulants throughout pregnancy (in widespread use
in Europe); (2) replacing oral anticoagulants with UFH
from 6 to 12 weeks; and (3) UFH use throughout preg-
nancy. In both warfarin-containing regimens, heparin was
usually used close to term in order to avoid delivery of an
anticoagulated fetus. Outcomes included pregnancy loss
and fetopathic effects (including warfarin embryopathy),
as well as maternal bleeding, thromboembolic complica-
tions, and death.
The use of oral anticoagulants throughout pregnancy
was associated with warfarin embryopathy in 6.4% of live
births (Table 1). The substitution of heparin at or prior to
6 weeks eliminated this risk. Overall, the rates of fetal
wastage (spontaneous loss, stillbirths, and neonatal deaths)
were similar in the three groups. The overall pooled
maternal mortality rate was 2.9% (Table 2). Major bleed-
ing occurred in 2.5% of all pregnancies, mostly at the time
126S Sixth ACCP Consensus Conference on Antithrombotic Therapy

6. of delivery (Table 3). The regimen associated with the
lowest risk of valve thrombosis/systemic embolism (3.9%)
was the use of oral anticoagulants throughout; using UFH
only between 6 weeks and 12 weeks gestation was associ-
ated with an increased risk of valve thrombosis (9.2%;
Table 2).
This analysis suggests that oral anticoagulants are more
efficacious than UFH for thromboembolic prophylaxis of
women with mechanical heart valves in pregnancy; how-
ever, coumarins increase the risk of embryopathy. Substi-
tuting oral anticoagulants with heparin between 6 weeks
and 12 weeks reduces the risk of fetopathic effects, but
possibly subjects the woman to an increased risk of
thromboembolic complications. The use of low-dose UFH
is inadequate; the use of adjusted-dose UFH warrants
aggressive monitoring and appropriate dose adjustment.
The need for a large prospective study to determine the
best regimen for pregnant women with mechanical valves
is clear.
Although the reported high rates of thromboembolism
with UFH might be explained by inadequate dosing
and/or the use of an inappropriate target therapeutic
range, this overview does raise the concern that patients
with mechanical heart valves are resistant to moderate
doses of UFH and draws attention to the need to use
adequate heparin doses in these patients. Insufficient
heparin dosing is associated with treatment failure, em-
phasizing the need for adequate initial heparinization and
stringent monitoring.77 Contemporary APTT reagents are
more sensitive to the anticoagulant effect of heparin;
therefore, a minimum target APTT ratio of 1.5 times the
control is likely to be inadequate. A target APTT ratio of at
least twice the control should be attained.78 Finally,
reports of LMWH use in pregnant women with prosthetic
heart valves are starting to appear.79 They might ultimately
have a definitive role for this indication.
To summarize, there are still insufficient grounds to
make definitive recommendations about optimal anti-
thrombotic therapy in pregnant patients with mechanical
heart valves because properly designed studies have not
been performed. Substantial concern remains about the
fetal safety of warfarin, the efficacy of s/c heparin in
preventing thromboembolic complications, and the risks
of maternal bleeding with various regimens. We believe
Table 1—Frequency of Fetal Complications Reported With Various Anticoagulation Regimens*
Anticoagulation Regimen Spontaneous Abortions Congenital Fetal Anomalies Fetal Wastage
OA throughout with/without heparin at term 196/792 (24.8%) 35/549 (6.4%) 266/792 (33.6%)
Heparin in first trimester, then OA throughout
with/without heparin near term
Heparin use at/before 6 wk 19/129 (14.7) 0/108 (0.0) 21/129 (16.3)
Heparin use after 6 wk 19/56 (33.9) 4/36 (11.1) 20/56 (35.7)
Heparin use at unknown time in first trimester 19/45 (42.2) 2/30 (6.7) 20/45 (44.4)
Total 57/230 (24.8) 6/174 (3.5) 61/230 (26.5)
Heparin used throughout
Adjusted-dose heparin 4/16 (25.0) 0/12 (0.0) 7/16 (43.8)
Low-dose heparin throughout 1/5 (20.0) 0/5 (0.0) 2/5 (40.0)
Total 5/21 (23.8) 0/17 (0.0) 9/21 (42.9)
No anticoagulation
Nothing 2/35 (5.7) 2/33 (6.1) 7/35 (20.0)
Antiplatelet agent 8/67 (11.9) 1/59 (1.7) 13/67 (19.4)
Total 10/102 (9.8) 3/92 (3.4%) 20/102 (19.6)
*Data are presented as No./patients (%); OA ϭ oral anticoagulants.
Table 2—Frequency of Maternal Complications Reported With Various Anticoagulation Regimens*
Anticoagulation Regimen TEC
Death (All
Causes) *Comments
OA throughout, with/without
heparin near term
31/788 (3.9) 10/561 (1.8) Eight cases of TEC occurred with heparin
(six receiving IV or adjusted dose; two on low-dose)
Heparin use in first trimester,
then OA throughout with/out
heparin near term
21/229 (9.2) 7/167 (4.2) All 21 cases of TEC occurred with heparin
(10 receiving IV or adjusted dose; 10 on low-dose;
dose unknown in 1 case)
Heparin throughout
Adjusted-dose heparin 4/16 (25.0) 1/15 (6.7)
Low-dose heparin 3/5 (60.0) 2/5 (40.0)
Total 7/21 (33.3) 3/20 (15.0)
No anticoagulation
Nothing 6/38 (15.8) 2/37 (5.4)
Antiplatelet agent 20/69 (29.0) 3/69 (4.4)
Total 26/107 (24.3) 5/106 (4.7)
*Data are presented as No./patients (%); TEC ϭ thromboembolic complications; see Table 1 for other abbreviation.
CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT 127S

7. that warfarin should be avoided between 6 weeks and 12
weeks of gestation (to avoid embryopathy) and close to
term (to avoid delivery of an anticoagulated fetus), but is
probably safe at other times. We believe it is reasonable to
use LMWH or UFH either during these periods only,
combined with warfarin with a target INR of 3.0 (range,
2.5 to 3.5; range, 2.0 to 3.0 in patients with a bileaflet
aortic valve provided they do not have atrial fibrillation or
left ventricular dysfunction) at other times, or to use UFH
or LMWH throughout pregnancy. In addition, European
experts have recommended warfarin therapy throughout
pregnancy in view of the reports of bad outcomes with
heparin and the impression that the risk of embryopathy
with coumarin derivatives has been overstated.76 Although
this latter approach is reasonable, it is fraught with
medicolegal concerns, because the package insert states
that warfarin is contraindicated during pregnancy. Before
this approach is used, it is crucial to explain the risks
carefully to women. If used, s/c UFH therapy should be
initiated in high doses (17,500 to 20,000 U q12h) and
adjusted to prolong a 6-h postinjection APTT into the
therapeutic range; strong efforts should be made to ensure
an adequate anticoagulant effect, since inadequate doses
of heparin are ineffective. LMWH is probably a reason-
able substitute for UFH because it seems to reduce the
risk of bleeding and osteoporosis and does not cross the
placenta, but further information is required about dosing
for this indication. In addition, for some high-risk patients,
aspirin, 80 mg daily, can be considered in an attempt to
reduce the risk of thrombosis, recognizing that it increases
the risk of bleeding.80
Summary and Conclusions
Anticoagulant therapy is indicated during pregnancy for
the prevention and treatment of VTE; for the prevention
and treatment of systemic embolism in patients with
mechanical heart valves; and, often in combination with
aspirin, for the prevention of pregnancy loss in women
with APLAs or thrombophilia and previous pregnancy
losses. Several questions concerning anticoagulant therapy
remain unanswered. It appears that LMWH will largely
replace UFH. Oral anticoagulants are fetopathic, but the
true risks of the warfarin embryopathy and CNS abnor-
malities remain unknown. There is considerable evidence
that warfarin embryopathy occurs only when oral antico-
agulants are administered between the sixth week and the
12th week of gestation and that oral anticoagulants may
not be fetopathic when administered in the first 6 weeks of
gestation. Oral anticoagulant therapy should be avoided in
the weeks before delivery because of the risk of serious
perinatal bleeding caused by the trauma of delivery to the
anticoagulated fetus. The safety of aspirin during the first
trimester of pregnancy is still a subject of debate. There is
a concern about the efficacy of UFH in the prevention of
arterial embolism in pregnant women with mechanical
heart valves. Finally, the optimum management of preg-
nant women with thrombophilia (and prior pregnancy loss
and/or prior VTE) is unknown, but trials of anticoagulant
therapy are ongoing.
Because it is safe for the fetus, LMWH (or UFH) is the
anticoagulant of choice during pregnancy for situations in
which its efficacy is established. There is some doubt that
heparin is effective for the prevention of systemic embo-
lism in patients with mechanical heart valves. Low doses of
heparin or poorly controlled heparin therapy are not
effective in preventing systemic embolism in patients with
mechanical heart valves.
Recommendations
When describing the various regimens of UFH
and LMWH, we will use the following terminology:
1. mini-dose UFH (UFH, 5,000 U s/c q12h);
2. moderate-dose UFH (UFH s/c every 12 h in doses
adjusted to target an anti-Xa level of 0.1 to 0.3 U/mL);
3. adjusted-dose UFH (UFH s/c every 12 h in
doses adjusted to target a mid-interval APTT into the
therapeutic range);
4. prophylactic LMWH (either dalteparin, 5,000 U
s/c q24h, or enoxaparin, 40 mg s/c q24h, or any
once-daily LMWH adjusted to target a peak anti-Xa
level of 0.2 to 0.6 u/mL);
5. adjusted-dose LMWH (weight-adjusted, full-
treatment doses of LMWH; for example, dalteparin,
200 U/kg q24h, or enoxaparin, 1 mg/kg q12h);
6. postpartum anticoagulants (warfarin for 4 to 6
weeks with a target INR of 2.0 to 3.0, with initial
UFH or LMWH overlap until the INR is Ն 2.0.
In addition, the term surveillance refers to clinical
vigilance and aggressive investigation of women with
symptoms suspicious of DVT or PE.
Management of Pregnant Patients at Increased
Risk for VTE
(1) For single episode of prior VTE associated with
a transient risk factor (and no additional current risk
factors, such as morbid obesity or strict bed rest),
surveillance and postpartum anticoagulants. This is a
grade 1C recommendation.
(2) For single episode of idiopathic VTE in pa-
tients not receiving long-term anticoagulation ther-
apy, surveillance or mini-dose UFH or moderate-
dose UFH or prophylactic LMWH, plus postpartum
anticoagulants. This is a grade 1C recommendation.
(3) For single episode of VTE and thrombophilia
(confirmed laboratory abnormality) in patients not
receiving long-term anticoagulation therapy, surveil-
Table 3—Pooled Frequency of Bleeding Complications
Reported From All Studies
Major Bleeding No. of Women Comments
Occurring at
delivery 25
11 women were receiving IV
or adjusted-dose heparin;
14 were receiving
warfarin, 6 were unknown
Occurring outside
of delivery 6
Total 31
Percent of all
pregnancies 2.5
128S Sixth ACCP Consensus Conference on Antithrombotic Therapy

8. lance or mini-dose UFH or moderate-dose UFH or
prophylactic LMWH, plus postpartum anticoagu-
lants. The indication for active prophylaxis is stronger
in antithrombin-deficient women than the other
thrombophilias. This is a grade 1C recommendation.
(4) For no prior VTE and thrombophilia (confirmed
laboratory abnormality), surveillance or mini-dose UFH
or prophylactic LMWH, plus postpartum anticoagu-
lants. The indication for active prophylaxis is stronger in
antithrombin-deficient women than the other thrombo-
philias. This is a grade 1C recommendation.
(5) For multiple (more than two) episodes of VTE,
and/or women receiving long-term anticoagulation
therapy (eg, single episode of VTE, either idiopathic
or associated with thrombophilia), adjusted-dose UFH or
either prophylactic or adjusted-dose LMWH, followed by
resumption of long-term anticoagulation therapy postpar-
tum. This is a grade 1C recommendation.
Treatment of VTE of Pregnancy
We recommend either adjusted-dose LMWH
throughout pregnancy, or IV UFH (bolus followed by
a continuous infusion to maintain the APTT in the
therapeutic range) for at least 5 days, followed by
adjusted-dose UFH for the remainder of the preg-
nancy. To avoid an unwanted anticoagulant effect
during delivery in women receiving adjusted-dose
LMWH or UFH therapy, we recommend discontinu-
ing the heparin therapy 24 h prior to elective induc-
tion of labor. If the woman is deemed to have a very
high risk of recurrent VTE (eg, proximal DVT within
2 weeks), therapeutic IV UFH therapy can be initi-
ated and discontinued 4 to 6 h prior to the expected
time of delivery. Postpartum anticoagulation therapy
should be administered for at least 6 weeks. This is a
grade 1C recommendation.
Unexpected Pregnancy or Planned Pregnancy
in Patients Who Are Receiving Long-term
Anticoagulation Therapy
If possible, such women should be counseled
about the risks before pregnancy occurs. If preg-
nancy is still desired, two options can be considered:
(1) Perform frequent pregnancy tests and substi-
tute adjusted-dose UFH or LMWH for warfarin
when pregnancy is achieved; or
(2) Replace warfarin with UFH or LMWH before
conception is attempted. Both approaches have lim-
itations; the first approach assumes that warfarin is
safe during the first 4 to 6 weeks of gestation; the
second approach increases the duration of exposure
to heparin and, therefore, to a higher risk of osteo-
porosis. We favor the first approach because it is
convenient and appears to be safe. These are grade
1C recommendations.
Prophylaxis in Patients With Mechanical
Heart Valves
One of three approaches is recommended:
(1) Aggressive adjusted-dose UFH therapy through-
out pregnancy (ie, administered s/c every 12 h in doses
adjusted to keep the mid-interval APTT at least twice
the control, or an anti-Xa heparin level of 0.35 to 0.70
U/mL). This is a grade 2C recommendation;
(2) Adjusted-dose LMWH therapy throughout
pregnancy in doses adjusted according to weight or
to keep a 4-h postinjection anti-Xa heparin level at
approximately 1.0 U/mL. This is a grade 2C rec-
ommendation; or
(3) UFH or LMWH (as above) therapy until the 13th
week, a change to warfarin until the middle of the third
trimester, and then restart UFH or LMWH therapy until
delivery. This is a grade 2C recommendation.
Long-term anticoagulation therapy should be re-
sumed postpartum with all regimens.
Management of Pregnant Women at Increased
Risk for Pregnancy Loss
(1) Women with recurrent pregnancy loss (three or
more miscarriages) should be screened for APLAs. If
the losses include one or more second-trimester
losses, screening for congenital thrombophilia should
be performed. Women with prior severe or recurrent
preeclampsia, IUGR, abruption, or otherwise unex-
plained intrauterine death should be screened for
congenital thrombophilia and APLAs.
(2) Pregnant patients with APLAs and a history of
multiple (two or more) early pregnancy losses or one or
more late pregnancy losses or preeclampsia, IUGR, or
abruption should be treated with antepartum aspirin
plus mini-dose or moderate-dose UFH or prophylactic
LMWH. This is a grade 1B recommendation.
(3) Women found to be homozygous for thermo-
labile variant (C677T) of methylenetetrahydrofolate
reductase should be treated with folic acid supple-
ments prior to conception or, if already pregnant, as
soon as possible. This is a grade 2C recommendation.
(4) Women with a thrombophilic deficit and (A)
recurrent miscarriages, (B) a second-trimester or
later loss, or (C) preeclampsia, IUGR, or abruption
should be considered for low-dose aspirin therapy
plus either mini-dose heparin or prophylactic
LMWH therapy. We also administer postpartum
anticoagulants to these women. These are grade 2C
recommendations.
(5) Patients with APLAs and a history of venous
thrombosis are usually receiving long-term oral antico-
agulation therapy because of the high risk of recur-
rence. During pregnancy, we recommend adjusted-
dose LMWH or UFH therapy throughout pregnancy
and resumption of long-term oral anticoagulation ther-
apy postpartum. This is a grade 2C recommendation.
(6) Patients with APLAs and no prior VTE or
pregnancy loss should be considered to have an
increased risk for the development of venous throm-
bosis and, perhaps, pregnancy loss. We recommend
one of four approaches: surveillance, mini-dose hep-
arin, prophylactic LMWH, or low-dose aspirin, 80 to
325 mg qd. This is a grade 2C recommendation.
CHEST / 119 / 1 / JANUARY, 2001 SUPPLEMENT 129S

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