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DOI 10.1378/chest.11-2300 2012;141;e691S-e736SChest
Anne-Marie Prabulos and Per Olav VandvikShannon M. Bates, Ian A. Greer, Saskia Middeldorp, David L. Veenstra, Evidence-Based Clinical Practice Guidelinesed: American College of Chest Physicians Therapy and Prevention of Thrombosis, 9thTherapy, and Pregnancy : Antithrombotic VTE, Thrombophilia, Antithrombotic
http://chestjournal.chestpubs.org/content/141/2_suppl/e691S.full.html
services can be found online on the World Wide Web at: The online version of this article, along with updated information and
e691S.DC1.html http://chestjournal.chestpubs.org/content/suppl/2012/02/03/141.2_suppl.Supplemental material related to this article is available at:
ISSN:0012-3692)http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(
written permission of the copyright holder.this article or PDF may be reproduced or distributed without the priorDundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2012by the American College of Chest Physicians, 3300Physicians. It has been published monthly since 1935.
is the official journal of the American College of ChestChest
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
CHEST Supplement
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e691S
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES
Summary of Recommendations
Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommenda-tions sections to indicate recommendations that are newly added or have been changed since the publica-tion of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recom-mendations that remain unchanged are not shaded.
2.2.1. For pregnant patients, we recommend LMWH for the prevention and treatment of VTE, instead of UFH (Grade 1B) .
3.0.1. For women receiving anticoagulation for the treatment of VTE who become pregnant, we recommend LMWH over vitamin K antagonists during the fi rst trimester (Grade 1A) , in the sec-ond and third trimesters (Grade 1B) , and during late pregnancy when delivery is imminent (Grade 1A) .
Background: The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy. Methods: The methods of this guideline follow the Methodology for the Development of Anti-thrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Pre-vention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. Results: We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfi ll the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfraction-ated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B). Conclusions: Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population. CHEST 2012; 141(2)(Suppl):e691S–e736S
Abbreviations: APLA 5 antiphospholipid antibody; aPPT 5 activated partial thromboplastin time; HIT 5 heparin-induced thrombocytopenia; INR 5 international normalized ratio; LMWH 5 low-molecular-weight heparin; NNT 5 number needed to treat; PE 5 pulmonary embolism; RR 5 risk ratio; UFH 5 unfractionated heparin
VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Shannon M . Bates , MDCM ; Ian A. Greer, MD, FCCP ; Saskia Middeldorp , MD , PhD ; David L. Veenstra , PharmD , PhD ; Anne-Marie Prabulos, MD ; and Per Olav Vandvik , MD , PhD
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e692S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
4.0.2. For lactating women using LMWH, dana-paroid, or r-hirudin who wish to breast-feed, we recommend continuing the use of LMWH, danaparoid, or r-hirudin (Grade 1B) .
4.0.3. For breast-feeding women, we suggest alter-native anticoagulants rather than fondaparinux (Grade 2C) .
4.0.4. For breast-feeding women, we recommend alternative anticoagulants rather than oral direct thrombin (eg, dabigatran) and factor Xa inhibi-tors (eg, rivaroxaban, apixaban) (Grade 1C) .
4.0.5. For lactating women using low-dose aspi-rin for vascular indications who wish to breast-feed, we suggest continuing this medication (Grade 2C) .
5.1.1. For women undergoing assisted reproduc-tion, we recommend against the use of routine thrombosis prophylaxis (Grade 1B) .
5.1.2. For women undergoing assisted reproduc-tion who develop severe ovarian hyperstimulation syndrome, we suggest thrombosis prophylaxis (prophylactic LMWH) for 3 months postresolu-tion of clinical ovarian hyperstimulation syndrome rather than no prophylaxis (Grade 2C) .
Remarks : Women who are averse to taking medica-tion for very small benefi t and those who consider self-injecting a considerable burden will be disin-clined to use LMWH for extended thrombosis pro-phylaxis. Given that the absolute benefi t decreases as time from the hyperstimulation event increases, such women will be very disinclined to continue pro-phylaxis throughout the entire resultant pregnancy.
6.2.1. For women undergoing cesarean section without additional thrombosis risk factors, we recommend against the use of thrombosis pro-phylaxis other than early mobilization (Grade 1B) .
6.2.2. For women at increased risk of VTE after cesarean section because of the presence of one major or at least two minor risk factors, we sug-gest pharmacologic thromboprophylaxis (prophy-lactic LMWH) or mechanical prophylaxis (elastic stockings or intermittent pneumatic compres-sion) in those with contraindications to anti-coagulants while in hospital following delivery rather than no prophylaxis (Grade 2B) .
Remarks: The reduced bleeding risk with mechanical prophylaxis should be weighed against the inconve-nience of elastic stockings and intermittent pneu-matic compression.
3.0.2. For women requiring long-term vitamin K antagonists who are attempting pregnancy and are candidates for LMWH substitution, we suggest performing frequent pregnancy tests and substituting LMWH for vitamin K antago-nists when pregnancy is achieved rather than switching to LMWH while attempting pregnancy (Grade 2C) .
Remarks: Women who place little value on avoiding the risks, inconvenience, and costs of LMWH therapy of uncertain duration while awaiting pregnancy and a high value on minimizing the risks of early miscarriage associated with vitamin K antagonist therapy are likely to choose LMWH while attempting pregnancy.
3.0.3. For pregnant women, we suggest limiting the use of fondaparinux and parenteral direct thrombin inhibitors to those with severe allergic reactions to heparin (eg, HIT) who cannot receive danaparoid (Grade 2C) .
3.0.4. For pregnant women, we recommend avoiding the use of oral direct thrombin (eg, dabigatran) and anti-Xa (eg, rivaroxaban, apixa-ban) inhibitors (Grade 1C) .
4.0.1. For lactating women using warfarin, acenocoumarol, or UFH who wish to breast-feed, we recommend continuing the use of war-farin, acenocoumarol, or UFH (Grade 1A) .
Revision accepted August 31, 2011. Affi liations: From the Department of Medicine (Dr Bates), McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada; Faculty of Health and Life Sci-ences (Dr Greer), University of Liverpool, Liverpool, England; Department of Vascular Medicine (Dr Middeldorp), Academic Medical Center, Amsterdam, The Netherlands; Department of Pharmacy (Dr Veenstra), University of Washington, Seattle, WA; Department of Obstetrics and Gynecology (Dr Prabulos), University of Connecticut School of Medicine, Farmington, CT; and Medical Department (Dr Vandvik), Innlandet Hospital Trust and Norwegian Knowledge Centre for the Health Services, Gjøvik, Norway. Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfi zer, Inc; Canyon Pharmaceuticals; and sanofi -aventis US. Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: Shannon M. Bates, MDCM, Department of Medicine, HSC 3W11, 1280 Main St W, Hamilton, ON, L8S 4K1, Canada; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/site/misc/reprints.xhtml ). DOI: 10.1378/chest.11-2300
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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dose LMWH rather than clinical vigilance or routine care (Grade 2C) .
8.2.4. For pregnant women receiving long-term vitamin K antagonists, we suggest adjusted-dose LMWH or 75% of a therapeutic dose of LMWH throughout pregnancy followed by resumption of long-term anticoagulants postpartum, rather than prophylactic-dose LMWH (Grade 2C) .
9.2.1. For pregnant women with no prior his-tory of VTE who are known to be homozygous for factor V Leiden or the prothrombin 20210A mutation and have a positive family history for VTE, we suggest antepartum prophylaxis with prophylactic- or intermediate-dose LMWH and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted at INR 2.0 to 3.0 rather than no prophylaxis (Grade 2B) .
9.2.2. For pregnant women with all other throm-bophilias and no prior VTE who have a positive family history for VTE, we suggest antepartum clinical vigilance and postpartum prophylaxis with prophylactic- or intermediate-dose LMWH or, in women who are not protein C or S defi -cient, vitamin K antagonists targeted at INR 2.0 to 3.0 rather than routine care (Grade 2C) .
9.2.3. For pregnant women with no prior his-tory of VTE who are known to be homozygous for factor V Leiden or the prothrombin 20210A mutation and who do not have a positive family history for VTE, we suggest antepartum clin-ical vigilance and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or vitamin K antagonists tar-geted at INR 2.0 to 3.0 rather than routine care (Grade 2B) .
9.2.4. For pregnant women with all other throm-bophilias and no prior VTE who do not have a positive family history for VTE, we suggest antepar-tum and postpartum clinical vigilance rather than pharmacologic prophylaxis (Grade 2C) .
10.2.1. For women with recurrent early preg-nancy loss (three or more miscarriages before 10 weeks of gestation), we recommend screening for APLAs (Grade 1B) .
10.2.2. For women with a history of pregnancy complications, we suggest not to screen for inher-ited thrombophilia (Grade 2C) .
10.2.3. For women who fulfi ll the laboratory cri-teria for APLA syndrome and meet the clinical
6.2.3. For women undergoing cesarean section who are considered to be at very high risk for VTE and who have multiple additional risk fac-tors for thromboembolism that persist in the puerperium, we suggest that prophylactic LMWH be combined with elastic stockings and/or inter-mittent pneumatic compression over LMWH alone (Grade 2C) .
6.2.4. For selected high-risk patients in whom signifi cant risk factors persist following delivery, we suggest extended prophylaxis (up to 6 weeks after delivery) following discharge from the hos-pital (Grade 2C) .
7.1.1. For pregnant women with acute VTE, we recommend therapy with adjusted-dose sub-cutaneous LMWH over adjusted-dose UFH (Grade 1B) .
7.1.2. For pregnant women with acute VTE, we recommend LMWH over vitamin K antagonist treatment antenatally (Grade 1A) .
7.1.3. For pregnant women with acute VTE, we suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 3 months) in com-parison with shorter durations of treatment (Grade 2C) .
7.1.4. For pregnant women receiving adjusted-dose LMWH therapy and where delivery is planned, we recommend discontinuation of LMWH at least 24 h prior to induction of labor or cesarean section (or expected time of neurax-ial anesthesia) rather than continuing LMWH up until the time of delivery (Grade 1B) .
8.2.1. For all pregnant women with prior VTE, we suggest postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted at INR 2.0 to 3.0 rather than no prophylaxis (Grade 2B) .
8.2.2. For pregnant women at low risk of recur-rent VTE (single episode of VTE associated with a transient risk factor not related to pregnancy or use of estrogen), we suggest clinical vigilance antepartum rather than antepartum prophylaxis (Grade 2C) .
8.2.3. For pregnant women at moderate to high risk of recurrent VTE (single unprovoked VTE, pregnancy- or estrogen-related VTE, or mul-tiple prior unprovoked VTE not receiving long-term anticoagulation), we suggest antepartum prophylaxis with prophylactic- or intermediate-
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e694S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
agulants should be resumed postpartum when ade-quate hemostasis is assured.
12.1.2. In women judged to be at very high risk of thromboembolism in whom concerns exist about the effi cacy and safety of UFH or LMWH as dosed above (eg, older generation prosthe-sis in the mitral position or history of thrombo-embolism), we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH (as above) close to delivery rather than one of the regimens above (Grade 2C) .
Remarks: Women who place a higher value on avoid-ing fetal risk than on avoiding maternal complications (eg, catastrophic valve thrombosis) are likely to choose LMWH or UFH over vitamin K antagonists.
12.1.3. For pregnant women with prosthetic valves at high risk of thromboembolism, we suggest the addition of low-dose aspirin, 75 to 100 mg/d (Grade 2C) .
This article is devoted to the use of antithrombotic therapy in pregnant women. Anticoagulant ther-
apy is indicated during pregnancy for the prevention and treatment of VTE; for the prevention and treat-ment of systemic embolism in patients with mechan-ical heart valves; and, in combination with aspirin, for the prevention of recurrent pregnancy loss in women with antiphospholipid antibodies (APLAs).
The use of anticoagulation for prevention of preg-nancy complications in women with hereditary throm-bophilia is becoming more frequent. Given the absence of proven-effective therapy in women with unexplained recurrent pregnancy loss, there is also growing pressure to intervene with antithrombotic therapy in affected women with no known underly-ing thrombophilia. The use of anticoagulant therapy during pregnancy is challenging because of the poten-tial for fetal and maternal complications.
1.0 Methods
Table 1 describes both the question defi nition (ie, population, intervention, comparator, and outcomes) and the eligibility cri-teria for studies considered in each section of the recommenda-tions that follow. We consider the desirable and undesirable fetal and maternal consequences of antithrombotic therapy in the following populations: (1) breast-feeding women, (2) women using assisted reproductive technology, (3) women undergoing cesarean section, (4) pregnant women with newly diagnosed VTE, (5) preg-nant women with prior VTE, (6) pregnant women with asymptom-atic thrombophilia, (7) pregnant women with a history of pregnancy complications (including pregnancy loss, preeclampsia, fetal growth restriction, and placental abruption), and (8) pregnant women with mechanical heart valves.
APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic- or intermediate-dose UFH or prophylactic LMWH combined with low-dose aspirin, 75 to 100 mg/d, over no treatment (Grade 1B) .
10.2.4. For women with inherited thrombo-philia and a history of pregnancy complications, we suggest not to use antithrombotic prophy-laxis (Grade 2C) .
11.1.1. For women considered at risk for pre-eclampsia, we recommend low-dose aspirin throughout pregnancy, starting from the second trimester, over no treatment (Grade 1B) .
11.2.1. For women with two or more miscar-riages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B) .
12.1.1. For pregnant women with mechanical heart valves, we recommend one of the following anticoagulant regimens in preference to no anti-coagulation (all Grade 1A) :
(a) Adjusted-dose bid LMWH throughout preg-nancy. We suggest that doses be adjusted to achieve the manufacturer’s peak anti-Xa LMWH 4 h postsubcutaneous-injection or
(b) Adjusted-dose UFH throughout pregnancy administered subcutaneously every 12 h in doses adjusted to keep the mid-interval aPTT at least twice control or attain an anti-Xa heparin level of 0.35 to 0.70 units/mL or
(c) UFH or LMWH (as above) until the 13th week, with substitution by vitamin K antagonists until close to delivery when UFH or LMWH is resumed.
Remarks: For pregnant women with mechanical heart valves, the decision regarding the choice of anticoag-ulant regimen is so value and preference dependent (risk of thrombosis vs risk of fetal abnormalities) that we consider the decision to be completely individ-ualized. Women of childbearing age and pregnant women with mechanical valves, should be counseled about potential maternal and fetal risks associated with various anticoagulant regimens, including con-tinuation of vitamin K antagonists with substitution by LMWH or UFH close to term, substitution of vitamin K antagonists by LMWH or UFH until the 13th week and then close to term, and use of LMWH or UFH throughout pregnancy. Usual long-term antico-
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Tabl
e 1—
[Sec
tion
1.0
] St
ruct
ure
d C
lini
cal
Qu
esti
ons
PIC
O Q
uest
ion
Sect
ion
Info
rmal
Que
stio
nPo
pula
tion
Inte
rven
tion
Com
para
tor
Out
com
eM
etho
dolo
gy
Mat
erna
l com
plic
atio
ns
of a
ntith
rom
botic
th
erap
y (s
ectio
n 2.
0)
• A
dver
se m
ater
nal
ou
tcom
es o
f com
mon
ly
used
ant
ithro
mbo
tic
agen
ts w
hile
pre
gnan
t
• Pr
egna
nt w
omen
• U
nfra
ctio
nate
d he
pari
n•
Low
-mol
ecul
ar-w
eigh
t
hepa
rin
• O
ther
rel
evan
t age
nts a
• N
o an
tithr
ombo
tic
ther
apy
or•
Oth
er a
ntith
rom
botic
th
erap
y
• M
ater
nal b
leed
ing
(tot
al
maj
or)
• M
ater
nal b
leed
ing
(maj
or:
fata
l 1 in
trac
rani
al)
• M
ater
nal b
leed
ing
(maj
or:
nonf
atal
1 n
onin
trac
rani
al)
• M
ater
nal b
leed
ing
(min
or)
• M
ater
nal h
epar
in-in
duce
d th
rom
bocy
tope
nia
• M
ater
nal h
epar
in-a
ssoc
iate
d os
teop
oros
is•
Mat
erna
l ski
n re
actio
n (a
llerg
ic)
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Fet
al c
ompl
icat
ions
of
ant
ithro
mbo
tic
ther
apy
duri
ng
preg
nanc
y (s
ectio
n 3.
0)
• Sa
fety
of a
ntith
rom
botic
ther
apy
duri
ng
preg
nanc
y
• F
etus
es a
nd c
hild
ren
of
wom
en u
sing
an
tithr
ombo
tic
ther
apy
duri
ng
preg
nanc
y
• V
itam
in K
ant
agon
ists
• U
nfra
ctio
nate
d he
pari
n•
Low
-mol
ecul
ar-w
eigh
t
hepa
rin
• O
ther
rel
evan
t age
nts a
• N
o an
tithr
ombo
tic
ther
apy
expo
sure
or
• O
ther
ant
ithro
mbo
tic
agen
t
• F
etal
hem
orrh
age
• Pr
egna
ncy
loss
• C
onge
nita
l mal
form
atio
ns•
Dev
elop
men
tal d
elay
• L
evel
s or
res
ults
of
coag
ulat
ion
test
ing
in
umbi
lical
cor
d bl
ood
• B
irth
wei
ght (
cent
ile);
num
ber
smal
l for
dat
es
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Use
of a
ntith
rom
botic
th
erap
y in
nur
sing
m
othe
rs (s
ectio
n 4.
0)
• Sa
fety
of a
ntith
rom
botic
ther
apy
whi
le
brea
st-f
eedi
ng
• B
reas
t-fe
d in
fant
s
of w
omen
rece
ivin
g an
tithr
ombo
tic
ther
apy
• V
itam
in K
ant
agon
ists
• U
nfra
ctio
nate
d he
pari
n•
Low
-mol
ecul
ar-w
eigh
t
hepa
rin
• O
ther
rel
evan
t age
nts a
• N
o an
tithr
ombo
tic
ther
apy
expo
sure
or
• O
ther
ant
ithro
mbo
tic
agen
t
• In
fant
hem
orrh
age
• L
evel
s or
res
ults
of
coag
ulat
ion
test
ing
in
brea
st m
ilk•
Lev
els
or r
esul
ts o
f co
agul
atio
n te
stin
g in
pl
asm
a of
bre
ast-
fed
infa
nts
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Prev
entio
n of
VT
E w
ith
assi
sted
rep
rodu
ctiv
e te
chno
logy
(s
ectio
n 5.
0)
• R
isk
of V
TE
in w
omen
unde
rgoi
ng a
ssis
ted
repr
oduc
tion
-N
o ad
ditio
nal r
isk
fact
ors
-P
rior
VT
E
-Thr
ombo
phili
a b
• W
omen
usi
ng
as
sist
ed
repr
oduc
tive
tech
nolo
gy to
be
com
e pr
egna
nt
• N
o pr
ophy
laxi
s•
No
inte
rven
tion
• Pr
opor
tion
of p
regn
anci
es
that
are
suc
cess
ful
• D
VT
• Pu
lmon
ary
embo
lism
• M
orta
lity
• M
ajor
ble
edin
g c •
Ble
edin
g du
ring
ooc
yte
retr
ieva
l and
em
bryo
tr
ansf
er
• C
ontr
ol a
rms
of
ra
ndom
ized
co
ntro
lled
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e696S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
PIC
O Q
uest
ion
Sect
ion
Info
rmal
Que
stio
nPo
pula
tion
Inte
rven
tion
Com
para
tor
Out
com
eM
etho
dolo
gy
• C
hoic
e, d
urat
ion,
and
(if a
ppro
pria
te)
rout
e/do
se o
f pr
ophy
laxi
s
• W
omen
usi
ng
as
sist
ed
repr
oduc
tive
tech
nolo
gy to
be
com
e pr
egna
nt
• L
ow-m
olec
ular
-wei
ght
he
pari
n•
Unf
ract
iona
ted
hepa
rin
• G
radu
ated
com
pres
sion
stoc
king
s•
Oth
er r
elev
ant a
gent
s a
• N
o pr
ophy
laxi
s or
• O
ther
inte
rven
tion
• D
VT
• Pu
lmon
ary
embo
lism
• M
orta
lity
• M
ajor
ble
edin
g c •
Ble
edin
g du
ring
ooc
yte
retr
ieva
l and
em
bryo
tran
sfer
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Prev
entio
n of
VT
E
follo
win
g ce
sare
an
sect
ion
(sec
tion
6.0)
• R
isk
of V
TE
follo
win
g
cesa
rean
sec
tion
in
wom
en w
ith
-No
addi
tiona
l ris
k fa
ctor
s
-Pri
or V
TE
-T
hrom
boph
ilia b
-O
ther
com
orbi
d co
nditi
ons
• Pr
egna
nt w
omen
unde
rgoi
ng
cesa
rean
sec
tion
• N
o pr
ophy
laxi
s•
No
inte
rven
tion
• D
VT
• Pu
lmon
ary
embo
lism
• E
mbo
lism
• M
orta
lity
• M
ajor
ble
edin
g d •
Epi
dura
l hem
atom
a
• C
ontr
ol a
rms
of
ra
ndom
ized
co
ntro
lled
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
• C
hoic
e, d
urat
ion,
and
(if a
ppro
pria
te)
rout
e/do
se o
f pr
ophy
laxi
s
• Pr
egna
nt w
omen
unde
rgoi
ng
cesa
rean
sec
tion
• L
ow m
olec
ular
wei
ght
he
pari
n•
Unf
ract
iona
ted
hepa
rin
• G
radu
ated
com
pres
sion
stoc
king
s•
Inte
rmitt
ent p
neum
atic
com
pres
sion
• C
ombi
ned
mec
hani
cal
an
d ph
arm
acol
ogic
pr
ophy
laxi
s•
Oth
er r
elev
ant a
gent
s a
• N
o pr
ophy
laxi
s or
• O
ther
ant
ithro
mbo
tic
stra
tegy
• D
VT
• Pu
lmon
ary
embo
lism
• M
orta
lity
• M
ajor
ble
edin
g: to
tal d
• M
ajor
ble
edin
g d •
Epi
dura
l hem
atom
a
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
• D
ecis
ion
anal
ysis
Trea
tmen
t of p
rove
n ac
ute
VT
E d
urin
g pr
egna
ncy
(sec
tion
7.0)
• C
hoic
e, r
oute
, and
dose
of a
ntith
rom
botic
th
erap
y
• Pr
egna
nt w
omen
with
pro
ven
acut
e V
TE
• V
itam
in K
ant
agon
ists
• U
nfra
ctio
nate
d he
pari
n•
Low
-mol
ecul
ar-w
eigh
t
hepa
rin
• O
ther
rel
evan
t age
nts a
• N
o tr
eatm
ent o
r•
Oth
er a
ntith
rom
botic
th
erap
y or
• T
hera
py in
no
npre
gnan
t po
pula
tion
with
ac
ute
VT
E
• Sy
mpt
omat
ic r
ecur
rent
D
VT
or
pulm
onar
y em
bolis
m•
Fat
al p
ulm
onar
y em
bolis
m•
Maj
or b
leed
ing
• Po
stth
rom
botic
syn
drom
e
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
• D
urat
ion
of a
ntith
rom
botic
ther
apy
• Pr
egna
nt w
omen
with
pro
ven
acut
e V
TE
• T
hrou
ghou
t pre
gnan
cy•
Thr
ough
out p
regn
ancy
and
6 w
k po
stpa
rtum
(a
t lea
st 3
mo)
• T
hrou
ghou
t pre
gnan
cy
an
d 6
wk
post
part
um
(at l
east
6 m
o)•
Thr
ough
out p
regn
ancy
and
inde
fi nite
po
stpa
rtum
• O
ther
dur
atio
n•
Sym
ptom
atic
rec
urre
nt
DV
T o
r pu
lmon
ary
embo
lism
• F
atal
pul
mon
ary
embo
lism
• M
ajor
ble
edin
g
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Tabl
e 1—
Con
tinu
ed
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e697S
PIC
O Q
uest
ion
Sect
ion
Info
rmal
Que
stio
nPo
pula
tion
Inte
rven
tion
Com
para
tor
Out
com
eM
etho
dolo
gy
• R
ole
of v
ena
cava
l fi lt
ers
w
hen
antit
hrom
botic
th
erap
y is
co
ntra
indi
cate
d
• Pr
egna
nt w
omen
with
pro
ven
acut
e V
TE
• Ve
nal c
aval
fi lte
r•
No
vena
cav
al fi
lter
• Sy
mpt
omat
ic r
ecur
rent
D
VT
or
pulm
onar
y em
bolis
m•
Fat
al p
ulm
onar
y em
bolis
m•
Maj
or b
leed
ing
• Po
stth
rom
botic
syn
drom
e
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
• M
anag
emen
t of
an
tithr
ombo
tic th
erap
y ar
ound
del
iver
y
• Pr
egna
nt w
omen
with
pro
ven
acut
e V
TE
• E
lect
ive
deliv
ery e w
ith
di
scon
tinua
tion
of
antit
hrom
botic
th
erap
y 24
to 4
8 h
prio
r to
del
iver
y•
No
elec
tive
deliv
ery,
e
tran
sitio
n to
un
frac
tiona
ted
hepa
rin
• N
o el
ectiv
e de
liver
y, e
tr
ansi
tion
to
prop
hyla
ctic
dos
e of
an
tithr
ombo
tic a
gent
• N
o el
ectiv
e de
liver
y e
with
dis
cont
inua
tion
of a
ntith
rom
botic
th
erap
y as
soo
n as
la
bor
com
men
ces
•Oth
er in
terv
entio
n•
Sym
ptom
atic
rec
urre
nt
DV
T o
r pu
lmon
ary
embo
lism
• M
ajor
ble
edin
g: to
tal d
• E
pidu
ral h
emat
oma
• Po
stth
rom
botic
syn
drom
e
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Prev
entio
n of
rec
urre
nt
VT
E in
pre
gnan
t w
omen
with
pri
or
VT
E (s
ectio
n 8.
0)
• R
isk
of r
ecur
rent
VT
E in
preg
nant
wom
en w
ith:
-A
sing
le u
npro
voke
d ev
ent
-A
sin
gle
even
t tha
t was
asso
ciat
ed w
ith a
tr
ansi
ent r
isk
fact
or
(all,
est
roge
n-re
late
d [O
CP,
pre
gnan
cy])
-M
ultip
le p
rior
eve
nts
-T
hrom
boph
ilia b
• Pr
egna
nt w
omen
with
pri
or V
TE
• N
o pr
ophy
laxi
s•
No
inte
rven
tion
• Sy
mpt
omat
ic D
VT,
pu
lmon
ary
embo
lism
• M
orta
lity
• M
ajor
ble
edin
g: to
tal
• Po
stth
rom
botic
syn
drom
e
• C
ontr
ol a
rms
of
ra
ndom
ized
co
ntro
lled
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
• C
hoic
e an
d (if
app
ropr
iate
)
rout
e an
d do
se o
f an
tithr
ombo
tic
prop
hyla
xis
• Pr
egna
nt w
omen
with
pri
or V
TE
• N
o an
tepa
rtum
prop
hyla
xis,
po
stpa
rtum
onl
y
-All
rele
vant
age
nts
co
nsid
ered
a •
Ant
epar
tum
and
post
part
um p
roph
ylax
is
-All
rele
vant
age
nts
co
nsid
ered
a
• N
o pr
ophy
laxi
s•
Sym
ptom
atic
rec
urre
nt
DV
T o
r pu
lmon
ary
embo
lism
• M
ajor
ble
edin
g: to
tal
• Po
stth
rom
botic
syn
drom
e
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Tabl
e 1—
Con
tinu
ed
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e698S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
PIC
O Q
uest
ion
Sect
ion
Info
rmal
Que
stio
nPo
pula
tion
Inte
rven
tion
Com
para
tor
Out
com
eM
etho
dolo
gy
Prev
entio
n of
pr
egna
ncy-
rela
ted
VT
E in
wom
en
with
thro
mbo
phili
a (s
ectio
n 9.
0)
• R
isk
of p
regn
ancy
-rel
ated
VT
E in
wom
en w
ith
thro
mbo
phili
a b Q16
• Pr
egna
nt w
omen
with
thro
mbo
phili
a b an
d no
pri
or V
TE
• N
o pr
ophy
laxi
s•
No
inte
rven
tion
• Sy
mpt
omat
ic D
VT,
pu
lmon
ary
embo
lism
• M
orta
lity
• M
ajor
ble
edin
g
• C
ontr
ol a
rms
of
ra
ndom
ized
co
ntro
lled
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
• C
hoic
e, d
urat
ion,
and
(if
ap
prop
riat
e) r
oute
/dos
e of
pro
phyl
axis
• Pr
egna
nt w
omen
with
thro
mbo
phili
a b an
d no
pri
or V
TE
• N
o an
tepa
rtum
prop
hyla
xis,
po
stpa
rtum
onl
y
-Low
-mol
ecul
ar-w
eigh
t
hepa
rin
-U
nfra
ctio
nate
d he
pari
n
-Oth
er r
elev
ant a
gent
s a
-Gra
duat
ed c
ompr
essi
on
st
ocki
ngs
-C
ombi
ned
mec
hani
cal
an
d ph
arm
acol
ogic
pr
ophy
laxi
s•
Ant
epar
tum
and
post
part
um
prop
hyla
xis
-S
imila
r ag
ents
as
abov
e
• N
o pr
ophy
laxi
s or
• O
ther
inte
rven
tion
• Sy
mpt
omat
ic D
VT,
pu
lmon
ary
embo
lism
• M
orta
lity
• M
ajor
ble
edin
g
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Prev
entio
n of
pre
gnan
cy
com
plic
atio
ns in
w
omen
with
th
rom
boph
ilia b
(sec
tion
10.0
)
• R
isk
of p
regn
ancy
com
plic
atio
ns in
w
omen
with
th
rom
boph
ilia b
• Pr
egna
nt w
omen
with
thro
mbo
phili
a b an
d a
hist
ory
of p
regn
ancy
co
mpl
icat
ions
-R
ecur
rent
ear
ly
pr
egna
ncy
loss
f
-Lat
e pr
egna
ncy
loss
(sin
gle)
g
-Lat
e pr
egna
ncy
loss
(mul
tiple
) h
-Pre
-ecl
amps
ia
-Int
raut
erin
e gr
owth
rest
rict
ion
-P
lace
ntal
abr
uptio
n
• N
o pr
ophy
laxi
s•
No
inte
rven
tion
• R
ecur
rent
pre
gnan
cy
com
plic
atio
n (a
s de
fi ned
un
der
patie
nt p
opul
atio
n)•
Sym
ptom
atic
DV
T,
pulm
onar
y em
bolis
m•
Mor
talit
y•
Maj
or b
leed
ing
• C
ontr
ol a
rm o
f
rand
omiz
ed
cont
rolle
d tr
ials
• O
bser
vatio
nal s
tudi
es
-Cas
e se
ries
-C
ohor
t stu
dies
-C
ase-
cont
rol s
tudi
es
Tabl
e 1—
Con
tinu
ed
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e699S
PIC
O Q
uest
ion
Sect
ion
Info
rmal
Que
stio
nPo
pula
tion
Inte
rven
tion
Com
para
tor
Out
com
eM
etho
dolo
gy
• C
hoic
e an
d (if
app
ropr
iate
)
rout
e an
d du
ratio
n of
an
tithr
ombo
tic
prop
hyla
xis
• Pr
egna
nt w
omen
with
thro
mbo
phili
a b (a
ntip
hosp
holip
id
antib
odie
s vs
con
geni
tal
thro
mbo
phili
a vs
sp
ecifi
c co
ngen
ital
thro
mbo
phili
a) a
nd a
hi
stor
y of
pre
gnan
cy
com
plic
atio
ns
-Rec
urre
nt e
arly
preg
nanc
y lo
ss f
-L
ate
preg
nanc
y lo
ss
(s
ingl
e) g
-L
ate
preg
nanc
y lo
ss
(m
ultip
le) h
-P
reec
lam
psia
-I
ntra
uter
ine
grow
th
re
stri
ctio
n
-Pla
cent
al a
brup
tion
• A
spir
in•
Unf
ract
iona
ted
he
pari
n ( �
aspi
rin)
• L
ow-m
olec
ular
-wei
ght
hepa
rin
( � as
piri
n)
• N
o pr
ophy
laxi
s or
• O
ther
ant
ithro
mbo
tic
stra
tegy
• R
ecur
rent
pre
gnan
cy
com
plic
atio
n (a
s de
fi ned
un
der
patie
nt p
opul
atio
n)•
Sym
ptom
atic
DV
T,
pulm
onar
y em
bolis
m•
Mor
talit
y•
Maj
or b
leed
ing
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
Prev
entio
n of
rec
urre
nt
pree
clam
psia
or
recu
rren
t pr
egna
ncy
loss
in
wom
en w
ithou
t kn
own
thro
mbo
phili
a b (s
ectio
n 11
.0)
• C
hoic
e an
d (if
app
ropr
iate
)
rout
e an
d du
ratio
n of
an
tithr
ombo
tic
prop
hyla
xis
• Pr
egna
nt w
omen
with
no
know
n th
rom
boph
ilia b a
nd
prio
r pre
ecla
mps
ia•
Preg
nant
wom
en
w
ith n
o kn
own
thro
mbo
phili
a an
d at
leas
t tw
o pr
ior
preg
nanc
y lo
sses
• A
spir
in•
Unf
ract
iona
ted
he
pari
n ( �
aspi
rin)
• L
ow-m
olec
ular
-wei
ght
he
pari
n ( �
aspi
rin)
• N
o pr
ophy
laxi
s•
Rec
urre
nt p
reec
lam
psia
• R
ecur
rent
pre
gnan
cy lo
ss•
Ran
dom
ized
con
trol
led
tr
ials
• O
bser
vatio
nal s
tudi
es
-Cas
e se
ries
-C
ohor
t stu
dies
-C
ase-
cont
rol s
tudi
es
Prev
entio
n of
th
rom
boem
bolis
m in
pr
egna
nt w
omen
with
m
echa
nica
l hea
rt
valv
es (s
ectio
n 12
.0)
• R
isk
of th
rom
boem
bolis
m
in
pre
gnan
t wom
en
with
mec
hani
cal h
eart
va
lves
• Pr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
• N
o an
tithr
ombo
tic
th
erap
y•
No
inte
rven
tion
• M
ater
nal t
hrom
boem
bolis
m•
Maj
or b
leed
ing:
tota
l•
Maj
or b
leed
ing:
mat
erna
l de
ath
• C
onge
nita
l mal
form
atio
ns•
Fet
al/n
eona
tal h
emor
rhag
e•
Preg
nanc
y lo
ss
• C
ontr
ol a
rm o
f
rand
omiz
ed
cont
rolle
d tr
ials
• O
bser
vatio
nal s
tudi
es
-Cas
e se
ries
-C
ohor
t stu
dies
-C
ase-
cont
rol s
tudi
es
Tabl
e 1—
Con
tinu
ed
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e700S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
PIC
O Q
uest
ion
Sect
ion
Info
rmal
Que
stio
nPo
pula
tion
Inte
rven
tion
Com
para
tor
Out
com
eM
etho
dolo
gy
• C
hoic
e an
d (if
app
ropr
iate
)
rout
e an
d do
se o
f an
tithr
ombo
tic th
erap
y
• Pr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
• V
itam
in K
ant
agon
ists
thro
ugho
ut p
regn
ancy
• U
nfra
ctio
nate
d he
pari
n
thro
ugho
ut p
regn
ancy
• L
ow-m
olec
ular
-wei
ght
th
roug
hout
pre
gnan
cy•
Vita
min
K a
ntag
onis
ts
su
bstit
uted
with
un
frac
tiona
ted
hepa
rin
duri
ng fi
rst t
rim
este
r (a
t or
befo
re 6
wk)
• V
itam
in K
ant
agon
ists
subs
titut
ed w
ith
low
-mol
ecul
ar-w
eigh
t he
pari
n du
ring
fi rs
t tr
imes
ter
(at o
r be
fore
6 w
k)•
Vita
min
K a
ntag
onis
ts
su
bstit
uted
with
un
frac
tiona
ted
hepa
rin
afte
r 6
wk
• V
itam
in K
ant
agon
ists
subs
titut
ed w
ith lo
w
mol
ecul
ar w
eigh
t he
pari
n af
ter
6 w
k•
Asp
irin
thro
ugho
ut
pr
egna
ncy
• N
o an
tithr
ombo
tic
ther
apy
or•
Oth
er a
ntith
rom
botic
st
rate
gy
• M
ater
nal t
hrom
boem
bolis
m•
Maj
or b
leed
ing
mat
erna
l dea
th•
Con
geni
tal m
alfo
rmat
ions
• F
etal
/neo
nata
l hem
orrh
age
• Pr
egna
ncy
loss
• R
ando
miz
ed c
ontr
olle
d
tria
ls•
Obs
erva
tiona
l stu
dies
-C
ase
seri
es
-Coh
ort s
tudi
es
-Cas
e-co
ntro
l stu
dies
PIC
O 5
pop
ulat
ion,
inte
rven
tion,
com
para
tor,
outc
ome.
a O
ther
rel
evan
t age
nts
incl
uded
in c
ompa
riso
ns w
ere
sele
cted
bas
ed o
n th
eir
rele
vanc
e fo
r a
part
icul
ar q
uest
ion
and
may
incl
ude
any
or a
ll of
the
follo
win
g: u
nfra
ctio
nate
d he
pari
n, lo
w-m
olec
ular
-wei
ght
hepa
rin,
fond
apar
inux
, dan
apar
oid,
dir
ect t
hrom
bin
inhi
bito
r, no
vel o
ral a
ntic
oagu
lant
s (e
g, a
pixa
ban,
dab
igat
ran,
riv
arox
aban
), as
piri
n, a
nd th
rom
boly
sis.
b T
hrom
boph
ilia
is o
ne o
r a c
ombi
natio
n of
the
follo
win
g: c
onge
nita
l, in
clud
ing
antit
hrom
bin
defi c
ienc
y, p
rote
in C
defi
cie
ncy,
pro
tein
S d
efi c
ienc
y, a
ctiv
ated
pro
tein
C re
sist
ance
, fac
tor V
Lei
den,
pro
thro
mbi
n ge
ne m
utat
ion,
per
sist
ently
ele
vate
d fa
ctor
VII
I le
vels
, or
antip
hosp
holip
id a
ntib
odie
s, in
clud
ing
elev
ated
ant
icar
diol
ipin
ant
ibod
y tit
ers,
non
spec
ifi c
inhi
bito
r/lu
pus
antic
oagu
lant
, and
ant
ibod
ies
to
b 2 -
glyc
opro
tein
I.
c For
this
que
stio
n, m
ajor
ble
edin
g w
ould
als
o in
clud
e bl
eedi
ng d
urin
g oo
cyte
har
vest
and
em
bryo
tran
sfer
. d F
or th
is q
uest
ion,
maj
or b
leed
ing
wou
ld a
lso
incl
ude
epid
ural
hem
atom
a.
e Ele
ctiv
e de
liver
y re
fers
to p
lann
ed d
eliv
ery/
sche
dule
d de
liver
y an
d m
ay in
clud
e in
duct
ion
of v
agin
al d
eliv
ery
or c
esar
ean
sect
ion.
f P
refe
rred
as
defi n
ed b
y th
ree
earl
y lo
sses
pri
or to
12
wk;
if n
ot a
ble
to e
xtra
ct b
y th
is d
efi n
ition
, the
n au
thor
s’ de
fi niti
on a
nd c
omm
ent w
ere
used
. g P
refe
rred
as
defi n
ed b
y si
ngle
loss
at 1
2 w
k or
late
r; if
not
abl
e to
ext
ract
by
this
defi
niti
on, t
hen
auth
ors’
defi n
ition
and
com
men
t wer
e us
ed.
h Pre
ferr
ed a
s de
fi ned
by
two
or m
ore
loss
es a
t 12
wk
or la
ter;
if n
ot a
ble
to e
xtra
ct b
y th
is d
efi n
ition
, the
n au
thor
s’ de
fi niti
on a
nd c
omm
ent w
ere
used
.
Tabl
e 1—
Con
tinu
ed
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• Adjusted-dose LMWH: weight-adjusted or full-treatment doses of LMWH given once daily or bid (eg, dalteparin 200 units/kg or tinzaparin 175 units/kg once daily or dalteparin 100 units/kg every 12 h or enoxaparin 1 mg/kg every 12 h)
Postpartum anticoagulation refers to vitamin K antagonists for 6 weeks with a target INR of 2.0 to 3.0, with initial UFH or LMWH overlap until the INR is � 2.0 or prophylactic- or intermediate-dose LMWH for 6 weeks. The term “clinical vigi-lance” refers to patient and physician alertness to the signs and symptoms of VTE and awareness of the need for timely and appropriate objective investigation of women with symptoms sus-picious of DVT or PE. A family history of VTE refers to DVT or PE in a fi rst-degree relative.
1.1 The Implications of Women’s Preferences and Values During Pregnancy
In considering women’s choices regarding risks and benefi ts of antithrombotic therapy in pregnancy, two considerations are of particular importance. First, treatment decisions during preg-nancy and breast-feeding have implications not only for the health and life of the mother but also for the health and life of the fetus or child. Second, many women prefer to see pregnancy as a nor-mal part of a healthy woman’s life course rather than as a medical condition. On the background of these considerations, many fac-tors, including the frequency and type of medication adminis-tration; pain, discomfort, and possible side effects; and the need, frequency, and type of testing associated with a given regimen, will affect women’s choices.
The weight given to harmful effects (eg, maternal bleeding events, congenital malformations) and burden of treatment (eg, self-injecting with LMWH for 9 months) compared with benefi -cial effects (eg, avoiding VTE or pregnancy loss) affects trade-offs between benefi ts and harms of antithrombotic treatment in preg-nancy. A systematic review of patient preferences for antithrom-botic treatment did not identify any studies of pregnant women. 5 The fi ndings of this systematic review, and the value and prefer-ence rating exercise described in Guyatt et al 4 suggest that one VTE should be viewed as more or less equivalent to one major extracranial bleed. Our clinical experience and preliminary results from a cross-sectional interview study (S. M. Bates, MDCM , per-sonal communication, March 27, 2011) to determine the willingness of women with prior VTE who are either pregnant, actively plan-ning a pregnancy, or who may in the future consider pregnancy to receive LMWH prophylaxis during pregnancy for prevention of recurrent VTE suggest that many, but not all women will choose long-term prophylaxis when confronted with the burden of self-injecting with LMWH over several months. Therefore, in general, we only make weak recommendations for long-term prophylaxis with LMWH.
In addition, the burden of long-term prophylaxis or treatment with LMWH or warfarin throughout pregnancy will have an impact on the choice of antithrombotic therapy. Clinical experi-ence suggests that many, but not all women give higher priority to the impact of any treatment on the health of their unborn baby than to effects on themselves, placing a low value on avoiding the pain, cost, and inconvenience of heparin therapy in order to avoid the small risk of even a minor abnormality in their child. Attempts to balance the burden of long-term prophylaxis against the dis-utility associated with VTE or major bleeding events are further complicated by the fact that all pregnant women will experience the disutility of long-term prophylaxis, whereas only a minority will avoid VTE with treatment (because the baseline risk of such events generally is low).
Recommendations in this article, therefore, refl ect our belief that although average women considering antithrombotic therapy
In addition to considering fetal outcomes (eg, pregnancy loss, congenital malformations) and maternal outcomes (eg, mortality, VTE, major maternal hemorrhage), we also consider burden of treatment as an important outcome for pregnant women taking long-term low-molecular-weight heparin (LMWH) or warfarin. When considered relevant, we report deaths (preferably as dis-ease and treatment-specifi c mortality). Maternal thromboem-bolism includes DVT and pulmonary embolism (PE) in sections discussing the treatment and prevention of VTE and systemic embolization and valve thrombosis in sections discussing the management of pregnant women with mechanical heart valves. Major nonfatal maternal hemorrhage is defi ned as a symptomatic bleeding complication noted during pregnancy or within 6 weeks postpartum that involves bleeding into a critical site (intracranial, intraspinal, intraocular resulting in vision changes, retroperitoneal, pericardial, intramuscular with compartment syndrome, or pla-cental abruption), causing a fall in hemoglobin level of � 20 g/L, and bleeding leading to transfusion of two or more units of whole blood or red cells. This defi nition is in part based on the defi nition recommended by the International Society on Thrombosis and Haemostasis. 1 Where major bleeding was not explicitly defi ned in primary research articles, the authors’ defi nition was accepted. Fetal loss refers to loss at any time after confi rmation of a viable intrauterine pregnancy, not including elective termination.
A comprehensive English-language literature search (January 2005-January 2010) was conducted to update our existing literature base. We followed the approach articulated by Grades of Recommen-dations, Assessment, Development, and Evaluation for formula-tion of recommendations. 2-4 In making recommendations, we have placed the burden of proof with those who would claim a benefi t of treatment. Therefore, when there is uncertain benefi t and a prob-ability of important harm associated with ther apy, we generally recommend against intervention.
There is a paucity of high-quality studies addressing risk factors for the outcomes discussed in this article as well as for the risks and benefi ts of antithrombotic therapy during pregnancy. Most recommendations, therefore, are based on low- to moderate-quality evidence and mirror our limited confi dence in relative effect estimates from studies of antithrombotic treatment dur-ing pregnancy. To obtain baseline risk estimates for pregnancy complications, we summarize available observational studies of pregnant women, including case reports and case series of pregnant women in the absence of studies with a cohort design. We then apply the baseline risk estimates to the relative risk esti-mates to establish anticipated absolute benefi ts and harms of intervention. In the absence of direct evidence from random-ized trials of reasonable quality, indirect evidence from random-ized trials in nonpregnant patients is considered applicable to the present patient population (eg, we extrapolate the effect of thromboprophylaxis with LMWH on the incidence of VTE in patients undergoing general surgery to women undergoing cesarean section).
When describing the various regimens of unfractionated hep-arin (UFH) and LMWH, we use the following short forms:
• Adjusted-dose UFH: UFH subcutaneously every 12 h in doses adjusted to target a midinterval activated partial thrombo-plastin time (aPTT) into the therapeutic range
• Prophylactic LMWH: for example, dalteparin 5,000 units subcutaneously every 24 h, tinzaparin 4,500 units subcutane-ously every 24 h, nadroparin 2,850 units subcutaneously every 24 h, or enoxaparin 40 mg subcutaneously every 24 h (although at extremes of body weight, modifi cation of dose may be required)
• Intermediate-dose LMWH: for example, dalteparin 5,000 units subcutaneously every 12 h or enoxaparin 40 mg subcutane-ously every 12 h
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e702S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
prolongation of the aPTT persisted for up to 28 h after the last injection of adjusted-dose subcutaneous heparin. 11 The mechanism for this prolonged effect is unclear. A similar effect has not been noted with IV UFH.
Thrombocytopenia during pregnancy is not uncommon, and pregnancy-specifi c causes 12 should be differentiated from IgG-mediated thrombocyto-penia or HIT, which occurs in � 3% of nonpregnant patients receiving UFH. 13 The diagnosis, prevention, and treatment of HIT are described in Linkins et al 14 in these guidelines. In pregnant women who develop HIT and require ongoing anticoagulant therapy, use of the heparinoid danaparoid sodium is recom-mended because it is an effective antithrombotic agent 15 that does not cross the placenta 16-18 and has low cross-reactivity with UFH 19 ; therefore, it rarely produces HIT (danaparoid was withdrawn from the US market in 2002). Although there are reports of fondaparinux 20,21 being used for this indication in pregnancy, experience with this agent during preg-nancy is too limited to recommend fondaparinux over danaparoid.
Long-term treatment with UFH has been reported to cause osteoporosis in both laboratory animals and humans. 22-30 A number of studies have attempted to quantify the risk of osteoporosis during prolonged treatment ( . 1 month) with UFH. Symptomatic ver-tebral fractures have been reported to occur in � 2% to 3% of the patient population, and signifi cant reductions of bone density have been reported in up to 30%. 22,23 A small study (n 5 40) reported an even higher percentage of fractures (15%) when older nonpregnant patients were treated with bid subcu-taneous injections of 10,000 units UFH for a period of 3 to 6 months. 26
Adverse skin reactions to UFH include bruising, urticarial rashes, erythematous well-circumscribed lesions (because of a delayed type 4 hypersensitivity reaction), skin necrosis (often due to vasculitis), and HIT. The true incidence of skin reactions caused by UFH is unknown. 31
2.2 LMWH Therapy
Despite a paucity of supportive data from con-trolled trials or even large prospective observational studies, LMWH is now commonly used for prophy-laxis and treatment of maternal thromboembolism. This change in practice is based largely on the results of large trials in nonpregnant patients, showing that LMWHs are at least as safe and effective as UFH for the treatment of VTE 32,33 and acute coronary syn-dromes 34 as well as for prophylaxis in high-risk patients. 35
Retrospective analyses and systematic reviews suggest that the incidence of bleeding in pregnant
will also want to avoid medicalizing their pregnancy, they will put an extremely high value on avoiding fetal risk. For women who do not share these values, some of the recommendations in this article may not apply. For most recommendations, optimal decision-making will require that physicians educate patients about their treatment options, including their relative effectiveness, the con-sequences for both mother and baby, the method of administra-tion and monitoring, the likely side effects, and the uncertainty associated with the estimates of all these effects. Once educated, women can participate in the selection of the treatment regimen that best matches their preferences and values.
2.0 Maternal Complications of Anticoagulant Therapy
Maternal complications of anticoagulant therapy are similar to those seen in nonpregnant patients and include bleeding (for all anticoagulants) as well as heparin-induced thrombocytopenia (HIT), heparin-associated osteoporosis, bruising, local allergic reac-tions, and pain at injection sites for heparin-related compounds.
2.1 UFH Therapy
During pregnancy, UFH can be used for both pre-vention and treatment of thromboembolism. Prophy-lactic UFH is typically administered subcutaneously two to three times per day either in fi xed doses or doses adjusted to a target a specifi c anti-Xa UFH level (prophylactic- or intermediate-dose UFH). When used in therapeutic doses, UFH is administered either intravenously by continuous infusion with dose adjustment to achieve a target therapeutic aPTT or subcutaneously by bid injections in doses suffi cient to achieve a therapeutic aPTT 6 h after injection.
During pregnancy, the aPTT response to UFH often is attenuated likely because of increased levels of heparin-binding proteins, factor VIII, and fi brin-ogen. 6 Consequently, the use of an aPTT range that corresponds to therapeutic heparin levels in non-pregnant patients might result in higher dosing (and heparin levels) in pregnant women than in non-pregnant patients. However, it is not clear whether this translates into excessive bleeding because the reported rates of bleeding using the standard aPTT range appear to be low. In a retrospective cohort study of 100 pregnancies in 77 women, 7 the rate of major antepartum bleeding in pregnant women treated with UFH was 1% (95% CI, 0.2%-5.4%), which is consistent with reported rates of bleeding associated with heparin therapy in nonpregnant patients 8 and with warfarin therapy 9,10 when used for the treatment of DVT.
Therapeutic doses of subcutaneous UFH can cause a persistent anticoagulant effect, which can compli-cate its use prior to delivery. In a small cohort study,
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3.0 Fetal Complications of Antithrombotic Therapy During Pregnancy
3.1 Vitamin K Antagonist Exposure In Utero
Vitamin K antagonists cross the placenta and have the potential to cause fetal wastage, bleeding in the fetus, and teratogenicity. 47-58 In a systematic review of the literature published between 1966 and 1997 that examined fetal and maternal outcomes of pregnant women with prosthetic valves, Chan and colleagues 49 provided pooled estimates of risks associated with the following approaches: (1) use of vitamin K antago-nists throughout pregnancy, (2) replacement of vita-min K antagonists with UFH from 6 to 12 weeks, and (3) UFH use throughout pregnancy (Tables S1, S2) (tables that contain an “S” before the number denote supplementary tables not contained in the body of the article and available instead in an online data sup-plement; see the “Acknowledgments” for more infor-mation). The authors found that the use of vitamin K antagonists throughout pregnancy was associated with congenital anomalies in 35 of 549 live births (6.4%; 95% CI, 4.6%-8.9%). A subsequent systematic review covering the years 2000 to 2009 (Tables S1, S2) reported a slightly lower risk estimate (21/559 [3.7%]; 95% CI, 1.9%-4.8%). 50
In both reviews, the most common fetal anomaly was coumarin or warfarin embryopathy consisting of midfacial hypoplasia and stippled epiphyses. Limb hypoplasia has been reported in up to one-third of cases of embryopathy. 51 Embryopathy typically occurs after in utero exposure to vitamin K antagonists during the fi rst trimester of pregnancy. 48 The results of a recently published multicenter European study not included in the systematic reviews, in which the pregnancies of 666 consenting women who contacted one of 12 Teratology Information Services between 1988 and 2004 seeking advice about gestational exposure to vitamin K antagonists were prospectively followed, also suggests that the risk of coumarin embryopathy is not high. 58 Although the frequency of major birth defects after any fi rst trimester exposure to vitamin K antagonists was increased compared with that seen in a control group of 1,094 women counseled during pregnancy about exposures known to be nonteratogenic (4.8% vs 1.4%, respectively; OR, 3.86; 95% CI, 1.86-8.00), there were only two cases of embryopathy among 356 live births (0.6%). Both cases involved exposure to phenprocoumon until at least the end of the fi rst trimester.
The substitution of heparin at or prior to 6 weeks appears to eliminate the risk of embryopathy, raising the possibility that vitamin K antagonists are safe with regard to embryopathy during the fi rst 6 weeks of gestation. In the systematic review by Chan and colleagues, 49 none of the 125 live births (95% CI,
women receiving LMWH is low. 36-38 A systematic review of 64 studies that included 2,777 pregnancies in which LMWH was used reported that the fre-quencies of signifi cant bleeding were 0.43% (95% CI, 0.22%-0.75%) for antepartum hemorrhage, 0.94% (95% CI, 0.61%-1.37%) for postpartum hemorrhage, and 0.61% (95% CI, 0.36%-0.98%) for wound hema-toma, giving an overall frequency of 1.98% (95% CI, 1.50%-2.57%). 38 The risk of HIT appears much lower with LMWH than with UFH. 13,37,38
Evidence suggests that LMWHs carry a lower risk of osteoporosis than UFH. In a study by Monreal and colleagues 26 in which 80 patients (men and women; mean age, 68 years) with DVT were randomized to either subcutaneous dalteparin 5,000 units bid (inter-mediate dose) or subcutaneous UFH 10,000 units bid for a period of 3 to 6 months, the risk of vertebral fractures with UFH (six of 40 [15%] patients; 95% CI, 6%-30%) was higher than with dalteparin (one of 40 [3%] patients; 95% CI, 0%-11%). In another ran-domized trial of 44 pregnant women allocated to prophylactic doses of dalteparin (n 5 21) or UFH (n 5 23), 27 bone density did not differ between women receiving dalteparin and those in a concurrent non-randomized cohort of healthy pregnant women but was signifi cantly lower in those receiving UFH. A prospective observational study in which 55 pregnant women treated with prophylactic LMWH and aspirin and 20 pregnant untreated volunteers reported sim-ilar results. 39 Finally, in an a priori substudy of an ongoing randomized comparison of prophylactic LMWH (subcutaneous dalteparin 5,000 units/d) with placebo for prevention of pregnancy complications, there was no difference between the two groups with respect to mean bone mineral density. 40
Despite these reassuring data, there have been case reports 41-44 of symptomatic osteoporosis occur-ring with LMWH. Osteoporosis may be due to indi-vidual susceptibility, refl ecting the presence of risk factors for osteoporosis, a variable effect of different LMWH preparations or doses on bone density, or a combination of both. Risk factors that make women susceptible to this complication when exposed to LMWH in pregnancy remain to be identifi ed.
Adverse skin reactions similar to those seen with UFH can also occur with LMWH, although the fre-quency appears reduced in patients receiving the latter. The reported incidence ranges from 1.8% to 29%. 38,45 Most LMWH-induced skin lesions are benign; however, HIT should be excluded. 46
Recommendation
2.2.1. For pregnant patients, we recommend LMWH for the prevention and treatment of VTE, instead of UFH (Grade 1B) .
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vitamin K antagonist therapy before pregnancy occurs. If pregnancy is still desired, the following two options can reduce the risk of warfarin embryopathy:
1. Performance of frequent pregnancy tests and substitution of adjusted-dose LMWH or UFH for warfarin when pregnancy is achieved or
2. Replacement of vitamin K antagonists with LMWH or UFH before conception is attempted
Both approaches have limitations. The fi rst assumes that vitamin K antagonists are safe during the fi rst 4 to 6 weeks of gestation. Although the second approach minimizes the risks of early miscarriage associated with vitamin K antagonist therapy, it lengthens the dura-tion of exposure to heparin and, therefore, is costly and exposes the patient to a greater burden of treatment associated with the use of parenteral anticoagulants.
3.2 UFH Exposure In Utero
UFH does not cross the placenta 63 and, therefore, does not have the potential to cause fetal bleeding or teratogenicity; although bleeding at the uteroplacental junction is possible. Several studies provide high-quality evidence that UFH therapy is safe for the fetus. 7,47,64
3.3 LMWH Exposure In Utero
As determined by measurement of anti-Xa activity in fetal blood, LMWH also does not cross the pla-centa. 65,66 There is no evidence that LMWH causes teratogenicity or increases the risk of fetal bleeding. 36
3.4 Danaparoid Exposure In Utero
Animal experiments and human case reports sug-gest negligible transport of danaparoid across the placenta 16-18,67 Thus, there is no demonstrable fetal toxicity with maternal danaparoid use. However, the quality of evidence available to support that claim is low. (Note: Danaparoid was withdrawn from the US market in 2002.)
3.5 Pentasaccharide Exposure In Utero
Although no placental passage of fondaparinux was demonstrated in a human cotyledon (small lobe on the uterine or maternal surface of the placenta) model, 68 anti-Xa activity (at approximately one-tenth the concentration of maternal plasma) was found in the umbilical cord plasma of fi ve newborns of mothers treated with fondaparinux. 69 Although there have been a small number of reports of the successful use of this agent in pregnant woman, 70-76 most of these involve second trimester or later exposure. Thus, the quality of evidence regarding supporting use of fondaparinux in pregnancy is very low. Potential del-eterious effects on the fetus cannot be excluded.
0%-3.0%) in which vitamin K antagonists were replaced with UFH at or before 6 weeks gestation or UFH used throughout pregnancy was associated with congenital fetal anomalies. In the European multicenter Teratology Information Services study, there were no cases of embryopathy among 235 live births when vitamin K antagonists were discontinued before week 8 after the fi rst day of the last menstrual period. 58
Vitamin K antagonists have also been associated with CNS abnormalities after exposure during any trimester. 48 Two patterns of CNS damage have been described: dorsal midline dysplasia (agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy) and ventral-midline dys-plasia leading to optic atrophy. 48 These complications are uncommon. 48,49
Although one cohort study reported that the use of coumarins during the second and third trimester was not associated with major risks for abnormalities in growth and long-term development of offspring, the authors noted an increased risk of minor neuro-developmental problems (OR, 1.7; 95% CI, 1.0-3.0) in children exposed to coumarins in the second and third trimester of pregnancy compared with age-matched nonexposed children (14% vs 8%, respec-tively). 59 However, these minor neurodevelopmental problems are likely of minor importance because there were no differences in mean IQ or performance on tests for reading, spelling, and arithmetic between exposed and nonexposed children. 60
Vitamin K antagonists have been linked to an increased risk of pregnancy loss 49,50,58,61 and can cause fetal hemorrhagic complications likely because the fetal liver is immature and fetal levels of vitamin K-dependent coagulation factors are low. Fetal coag-ulopathy is of particular concern at the time of delivery when the combination of the anticoagulant effect and trauma of delivery can lead to bleeding in the neonate. The risk of delivering an anticoagulated infant can be reduced by substituting UFH or LMWH for vitamin K antagonists approximately 3 weeks prior to planned delivery 61 and discontinuing these medi-cations shortly before delivery. Others have advocated the use of planned cesarean section at 38 weeks with only a brief (2 to 3 day) interruption of anticoagulant therapy. 62 This approach resulted in good neonatal and maternal outcomes in a study of 30 babies. Cesarean section is not without risk and is not recommended for other conditions associated with an increased risk of neonatal intracranial hemorrhage at the time of delivery (eg, immune thrombocytopenia purpura).
3.1.1 Thromboprophylaxis in Women Using Vitamin K Antagonists and Planning Pregnancy: Physicians should counsel women receiving vitamin K antagonist ther-apy and contemplating pregnancy about the risks of
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3.9 Thrombolysis During Pregnancy
Although investigations with 131 I-labeled streptoki-nase or tissue plasminogen activator showed minimal transplacental passage, 91 concerns remain about the use of thrombolytic therapy during pregnancy due to maternal and placental effects. Although there have been reports of successful thrombolysis in pregnancy (most involving streptokinase), 91-94 the number of cases is small. Given this and limitations of available data regarding the safety of this intervention in preg-nancy, the use of thrombolytic therapy is best reserved for life-threatening maternal thromboembolism. 95
Recommendations
3.0.1. For women receiving anticoagulation for the treatment of VTE who become pregnant, we recommend that LMWH over vitamin K antagonists during the fi rst trimester (Grade 1A) , in the second and third trimesters (Grade 1B) , and during late pregnancy when delivery is imminent (Grade 1A) .
3.0.2. For women requiring long-term vitamin K antagonists who are attempting pregnancy and are candidates for LMWH substitution, we suggest performing frequent pregnancy tests and substituting LMWH for vitamin K antago-nists when pregnancy is achieved rather than switching to LMWH while attempting pregnancy (Grade 2C) .
Remarks: Women who place little value on avoid-ing the risks, inconvenience, and costs of LMWH therapy of uncertain duration while awaiting pregnancy and a high value on minimizing the risks of early miscarriage associated with vitamin K antagonist ther-apy will probably choose LMWH while attempting pregnancy.
3.0.3. For pregnant women, we suggest limiting the use of fondaparinux and parenteral direct thrombin inhibitors to those with severe allergic reactions to heparin (including HIT) who cannot receive danaparoid (Grade 2C) .
3.0.4. For pregnant women, we recommend avoiding the use of oral direct thrombin (eg, dabigatran) and anti-Xa (eg, rivaroxaban, apixa-ban) inhibitors (Grade 1C) .
4.0 Use of Anticoagulants in Breast-feeding Women
In order for a drug to pose a risk to the breast-fed infant, not only must it be transferred and excreted into breast milk but also it must be absorbed from
3.6 Parenteral Direct Thrombin Inhibitor Exposure In Utero
Investigations have documented placental transfer of r-hirudin in rabbits and rats. 77,78 Although small numbers of case reports have documented successful outcomes with r-hirudin use in pregnancy, 77,79,80 there are insuffi cient data to evaluate its safety. Three case reports have been published describing the use of argatroban late in pregnancy. 81-83 There are no pub-lished reports on the use of bivalirudin.
3.7 New Oral Direct Thrombin and Anti-Xa Inhibitor Exposure In Utero
Pregnant women were excluded from participating in clinical trials evaluating these new agents. There are no published reports describing the use of new oral direct thrombin inhibitors (eg, dabigatran) or anti-Xa inhibitors (rivaroxaban, apixaban) in preg-nancy. The Summaries of Product Characteristics for dabigatran and rivaroxaban describe animal repro-ductive toxicity. 84,85 The human reproductive risks of these medications are unknown.
3.8 Aspirin Exposure In Utero
Aspirin crosses the placenta, and animal studies have shown that aspirin may increase the risk of con-genital anomalies. Several systematic reviews have examined the safety of aspirin use during pregnancy (Tables S1-S3). 86-88 A meta-analysis of 31 randomized studies comparing antiplatelet agents with either pla-cebo or no antiplatelet agents in 32,217 pregnant women at risk for developing preeclampsia 86 reported that aspirin therapy was not associated with an increase in the risk of pregnancy loss, neonatal hem-orrhage, or growth restriction. However, in a meta-analysis of eight studies that evaluated the risk of congenital anomalies with aspirin exposure during the fi rst trimester, aspirin use was associated with a twofold increase in the risk for gastroschisis (OR, 2.37; 95% CI, 1.44-3.88). 87 The validity of this risk estimate is questionable because of a signifi cant risk of bias in the contributing studies.
One population-based study did note an increased risk of miscarriage with aspirin use that was greatest when aspirin was taken around the time of concep-tion 89 ; however, the number of aspirin users was small, aspirin doses were unknown, and users may have had conditions associated with an increased risk of preg-nancy loss. 90 A meta-analysis of seven randomized trials in which women started aspirin later in preg-nancy (Tables S1, S3) failed to establish or refute an increase in risk of miscarriage with aspirin compared with placebo (risk ratio [RR], 0.92; 95% CI, 0.71-1.19 for fi rst or second trimester exposure; RR, 1.3; 95% CI, 0.63-2.69 for fi rst trimester exposure only). 88
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on the excretion of fondaparinux into human milk, and the effects on the nursing infant are unknown. As a negatively charged oligosaccharide, only minor amounts of fondaparinux are expected to pass the intestinal epithelial barrier after oral administration, and signifi cant absorption by the nursing infant is unlikely. 105 However, the manufacturer recommends that caution be used when administering fondaparinux to breast-feeding women.
4.5 Use of Parenteral Direct Thrombin Inhibitors in Breast-feeding Women
In a single-case report, no r-hirudin was detected in the breast milk of a nursing mother with a thera-peutic plasma hirudin level. 106 Enteral absorption of r-hirudin appears to be low. 78 Therefore, it is unlikely that exposed infants would experience a signifi cant anticoagulant effect, even if small amounts of r-hirudin appear in breast milk.
4.6 Use of New Oral Direct Thrombin and Factor Xa Inhibitors in Breast-feeding Women
Breast-feeding women were excluded from trials evaluating new oral direct thrombin and anti-Xa inhibitors, and there are no clinical data on the effect of these agents on breast-fed infants. The Summary of Product Characteristics for rivaroxaban notes that animal data indicate that this agent is secreted into breast milk. 85 The manufacturers of dabigatran and rivaroxaban both recommend against using these medications in breast-feeding women. 84,85
4.7 Use of Aspirin in Breast-feeding Women
Although aspirin is a polar, acidic drug that is poorly lipid soluble and highly bound to plasma proteins, maternal aspirin ingestion is associated with excre-tion of salicylates into breast milk. 107 There are, there-fore, potential risks of platelet dysfunction and GI bleeding in nursing infants of mothers using high doses of this drug. 107,108 Metabolic acidosis has been reported in breast-fed infants of mothers taking several grams of aspirin per day. 109,110 Theoretically, nursing infants of mothers taking aspirin could be at risk for developing Reye syndrome. 107 The use of low-dose aspirin ( , 100 mg/d) late in pregnancy was not associated with signifi cant effects on neonatal platelet function. 111,112 In a prospective study of 15 breast-feeding mothers taking aspirin therapy, no negative effects were noted (Tables S4, S5). 113
Recommendations
4.0.1. For lactating women using warfarin, aceno-coumarol, or UFH who wish to breast-feed, we recommend continuing the use of warfa-rin, acenocoumarol, or UFH (Grade 1A) .
the infant’s gut. Drugs that are poorly absorbed are unlikely to affect the neonate. Lipid-soluble drugs with a low molecular weight that are not highly protein bound are more likely to be transferred into breast milk. 96
4.1 Use of Vitamin K Antagonists in Breast-feeding Women
Despite a lack of data suggesting any harmful effect to breast-feeding infants, many obstetricians remain reluctant to prescribe warfarin to lactating women. This might refl ect concerns that less polar, more lipophilic vitamin K antagonists rarely used in North America (eg, phenindione, anisindione, and phenprocoumon) might be excreted into breast milk. 97 Warfarin, the oral anticoagulant prescribed for most patients in North America, is polar, nonlipophilic, and highly protein bound. There have been two convincing reports demonstrating that warfarin is not detected in breast milk and does not induce an anti-coagulant effect in the breast-fed infant when nurs-ing mothers consume the drug. 98,99 Acenocoumarol, which is commonly used in Europe, has similar prop-erties (Tables S4, S5). 100,101 Therefore, the use of warfarin and acenocoumarol in women who require postpartum anticoagulant therapy is safe.
4.2 Use of UFH and LMWH in Breast-feeding Women
Because of its high molecular weight and strong negative charge, UFH does not pass into breast milk and can be safely given to nursing mothers. 102 In a case series of 15 women receiving 2,500 International Units of LMWH after cesarean section, there was evidence of excretion of small amounts of LMWH into the breast milk in 11 patients (Tables S4, S5). 103 However, given the very low bioavailability of oral heparin, there is unlikely to be any clinically relevant effect on the nursing infant.
4.3 Use of Danaparoid in Breast-feeding Women
Very little is known about the passage of dana-paroid into breast milk. A small number of case reports have reported no or very low anti-Xa activity in the breast milk of danaparoid-treated women. 77 Because danaparoid is not absorbed by the GI tract after oral intake, it is unlikely that any anticoagulant effect would appear in breast-fed infants.
4.4 Use of Fondaparinux in Breast-feeding Women
According to the manufacturer’s prescribing infor-mation, fondaparinux was found to be excreted in the milk of lactating rats. 104 There are no published data
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5.1 Prevention of VTE in Patients Undergoing Assisted Reproductive Technology
The bleeding risk most relevant to this popula-tion is intraabdominal and vaginal bleeding. The esti-mates of normal blood loss during uncomplicated oocyte retrieval vary, ranging from approximately 230 mL in one prospective cohort of 220 women 123 to 13 mL (range, 0-98 mL) in a study of 83 women. 124 Although patient-important vaginal bleeding appears to occur in up to 2% to 3% of patients, signifi cant intraabdominal bleeding is much less common ( � 0.5% procedures) (Table S7). 120,125-132 Whether these risks are increased with antithrombotic prophy-laxis is uncertain.
All studies that address the impact of prophylaxis in in vitro fertilization have important limitations, and the number of patients who have received anticoagu-lants is too small to draw any conclusions about safety and effi cacy (Table S8). 133-135 Therefore, we used indi-rect evidence from a meta-analysis of thrombopro-phylaxis in patients undergoing hip arthroplasty 136 to estimate the relative effects LMWH prophylaxis in assisted reproductive technology. Table 2 and Table S9 summarize the quality of evidence and anticipated absolute effects of thrombosis prophylaxis in women with and without ovarian hyperstimulation syndrome. We rate the quality of evidence as low due to indi-rectness of the population and intervention and due to considerable imprecision in risk estimates for major bleeding events and VTE. In women with severe ovarian hyperstimulation syndrome, thromboprophy-laxis may result in 26 fewer VTE per 1,000 women treated (number needed to treat [NNT] of 39 [given an estimated baseline risk of VTE of 4%]), with no increased risk of signifi cant bleeding. However, in women without ovarian hyperstimulation syndrome in whom the baseline risk of VTE is estimated to be � 0.2%, the use of LMWH prophylaxis is of very limited value (NNT, 781).
Data regarding the risk of VTE in women with thrombophilia or prior VTE who undergo assisted reproduction are lacking. Given the low baseline risk of VTE associated with assisted reproduction, if the magnitude of relative risk increases is similar to that reported with pregnancy-related VTE (sections 8 and 9), women with low-risk thrombophilias or prior VTE associated with major transient risk factors will receive only very small benefi t from prophylaxis.
Dosage and duration of thromboprophylaxis after assisted reproductive therapy has not been well studied. If LMWH is used in women who develop ovarian hyperstimulation, extension of prophylaxis for 4 to 8 weeks postresolution of hyperstimulation 114 or throughout any resultant pregnancy and into the postpartum period 115 has been suggested given that
4.0.2. For lactating women using LMWH, dana-paroid, or r-hirudin who wish to breast-feed, we recommend continuing the use of LMWH, danaparoid, or r-hirudin (Grade 1B) .
4.0.3. For breast-feeding women, we suggest alternative anticoagulants rather than fonda-parinux (Grade 2C) .
4.0.4. For breast-feeding women, we recom-mend alternative anticoagulants rather than oral direct thrombin and factor Xa inhibitors (Grade 1C) .
4.0.5. For lactating women using low-dose aspi-rin for vascular indications who wish to breast-feed, we suggest continuing this medication (Grade 2C) .
5.0 VTE in Patients Using Assisted Reproductive Technology
Assisted reproductive technology, which refers to all treatments or procedures involving in vitro han-dling of human oocytes and sperm or embryos for the purpose of achieving pregnancy, 114,115 may be associated with VTE. Data regarding the frequency of VTE, however, comprise predominantly of case reports, case series, and relatively small cohort studies (Table S6). 116-121 In two large retrospective series of patients undergoing in vitro fertilization, thrombosis complicated 0.1% (95% CI, 0%-0.3%) 116 and 0.3% (95% CI, 0%-0.8%) 117 of cycles. A hospital-based case-control study demonstrated a fourfold increase in antenatal VTE with assisted reproductive technology for singleton pregnancies and a sixfold incidence in twin pregnancies but no statistically signifi cant association with postpartum VTE. 121 Thus, although in vitro fertilization appears to be a risk factor for antepartum thromboembolism, the overall absolute incidence of symptomatic thrombosis appears to be low.
The risk of thrombosis may be higher in women with ovarian hyperstimulation syndrome, with an incidence of thrombosis of up to 4.1% (95% CI, 1.1%-13.7%) in severe cases. 116 In a review of thrombosis associated with assisted reproductive technology, Chan and col-leagues 122 identifi ed 61 reports of venous thrombosis (49 cases involving the veins of the neck and arm) and 35 arterial events. Ovarian hyperstimulation syndrome was reported in 90% of arterial cases and 78% of venous events. In 98% of cases, thrombosis occurred after ovulation induction. Venous events were delayed compared with those involving the arterial circulation (42.4 days after embryo transfer and 10.7 days post-transfer, respectively). 122
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Table 2— [Section 5.1.1, 5.1.2] Summary of Findings: Prophylactic-Dose LMWH vs No Thromboprophylaxis for Women Who Undergo Assisted Reproductive Therapy
Outcomes
Participants (Studies), Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI) a
Anticipated Absolute Effects During Pregnancy
Risk Without Prophylaxis
Risk Difference With LMWH (95% CI)
Symptomatic VTE, DVT, and pulmonary embolism
1,953 (6 RCTs), 27-35 d
postoperative
Low due to indirectness b and
imprecision a
RR 0.36 (0.20-0.67)
Without severe ovarian hyperstimulation syndrome2 VTE per 1,000 c 1 fewer VTE per 1,000 (from
2 fewer to 0 fewer)With severe ovarian hyperstimulation syndrome
40 VTE per 1,000 c 26 fewer per 1,000 (from 32 fewer to 13 fewer)
Major bleed 5,456 (7 RCTs), 3 wks-9 mo
Low due to indirectness b and
imprecision a
RR 0.43 (0.11-1.65)
30 bleeding events per 1,000 c
No signifi cant difference 17 fewer bleeding events per 1,000 (from
27 fewer to 20 more)
GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation; LMWH 5 low-molecular-weight heparin; RCT 5 randomized controlled trial; RR 5 risk ratio. a Rated down for imprecision due to imprecise control group risk estimates for bleeding events and for VTE in the subset of women with ovarian hyperstimulation ( Tables S6-S8 ). b The population did not include pregnant women. Different doses of LMWH were used, treatment was initiated variably before or after surgery with a duration of � 7 d (in hospital). Outcomes were variably reported; meta-analysis also provides other outcomes such as mortality, asymptomatic DVT, and specifi c bleed outcomes (wound hematoma, transfusion). Follow-up varied between trials from 3 wk to 9 mo. c Control group risk for VTE and major bleed come from observational studies of women undergoing assisted reproductive technology, with many studies following women until delivery ( Tables S6-S8 ).
tional studies have assessed the risk of VTE after cesarean section, with absolute risk estimates rang-ing from , 1 in 1,000 up to 18 of 1,000 cesarean deliveries. 121,139-148 However, studies based on hospital records and disease coding may result in an underes-timation of the true incidence of symptomatic VTE. 149 A Norwegian study of 59 low-risk women undergoing elective cesarean section who underwent screening for DVT using triplex ultrasonography (compression ultrasonography, color Doppler echocardiography, and spectral Doppler echocardiography) 2 to 5 days after delivery and followed up for 6 weeks reported that none had symptomatic or asymptomatic VTE (95% CI, 0%-6.1%). 144 A small prospective study in which patients after cesarean section underwent screening ultrasounds at hospital discharge and 2 weeks postpartum and were followed for 3 months reported a symptomatic event rate of fi ve of 1,000 (95% CI, 0.1%-2.8%). 147 This is consistent with estimates based on hospital discharge data antedating the use of thromboprophylaxis. 138,140
Observational studies provide evidence concerning risk factors for VTE in pregnant women (Tables S10, S11) 121,146,148,150-152 ; these are likely to be relevant in women undergoing cesarean section. In assessing risk in this setting, the number of risk factors, the magnitude of risk associated with these factors, and their impact when occurring together are all rele-vant. Table 3 provides an overview of major and minor risk factors we suggest clinicians use to identify women at increased risk of VTE after cesarean sec-tion. The presence of one major or at least two minor risk factors will indicate whether patients qualify for
most reported events have developed days to weeks (range, 2 days-11 weeks) after resolution of ovarian hyperstimulation. 115 However, given the lack of a clear association between assisted reproductive technology and postpartum events, 117,121 continuing anticoagulant prophylaxis after delivery is less likely to be of benefi t.
Recommendations
5.1.1. For women undergoing assisted reproduc-tion, we recommend against the use of routine thrombosis prophylaxis (Grade 1B) .
5.1.2. For women undergoing assisted reproduc-tion who develop severe ovarian hyperstimulation syndrome, we suggest thrombosis prophylaxis (prophylactic LMWH) for 3 months postresolu-tion of clinical ovarian hyperstimulation syn-drome rather than no prophylaxis (Grade 2C) .
Remarks: Women who are averse to taking medica-tion for very small benefi t and those who consider self-injecting a considerable burden will be disin-clined to use LMWH for extended thrombosis pro-phylaxis. Given that the absolute benefi t decreases as time from the hyperstimulation event increases, such women will be very disinclined to continue prophy-laxis throughout the entire resultant pregnancy.
6.0 VTE Following Cesarean Section
6.1 Risk of VTE Following Cesarean Section
The puerperium is the time of maximal daily risk of pregnancy-associated VTE. 137,138 Several observa-
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of study participants and outcome events provide insuffi cient evidence on which to make prophylaxis recommendations. A decision analysis model sug-gested that the benefi ts of LMWH prophylaxis exceed risks after cesarean section 141 but that this benefi t was small in women with no risk factors and the low-quality evidence makes the assumptions that under-lie the model questionable.
We use indirect evidence from patients under-going general surgery 156 to generate anticipated abso-lute effects of LMWH on VTE and major bleeding events in pregnant women undergoing cesarean sec-tion. Table 4 and Table S12 show the quality of evidence and main fi ndings from a meta-analysis of three trials comparing LMWH vs placebo in 4,890 patients undergoing general surgery. 162 We have rated down the quality of evidence because of indirectness. Extra-polating from general surgery patients ( Table 4 , Table S12), the balance of desirable and undesir-able consequences would suggest prophylaxis for women with an absolute VTE risk of � 30 of 1,000. With a baseline risk of fi ve of 1,000 VTE after cesar-ean delivery, the presence or absence of risk fac-tors will determine the absolute benefi t of thrombosis prophylaxis. We categorize women into low risk (fi ve of 1,000) and high risk (30 of 1,000); clinicians can use Table 3 to determine to which group their patient belongs.
Mechanical prophylaxis with elastic stockings or intermittent pneumatic compression are alternatives to pharmacologic prophylaxis in pregnant women at high risk of VTE and may be used with LMWH in women at particularly high risk of VTE. We consider evidence from a variety of populations undergoing general surgery to be applicable to pregnant women undergoing cesarean section and, therefore, refer the reader to Gould et al 156 in these guidelines for a detailed review of the evidence supporting the use of mechanical thromboprophylaxis with elastic stock-ings or intermittent pneumatic compression. In short, when compared with pharmacologic prophylaxis, mechanical prophylaxis is associated with less major bleeding (RR, 0.51; 95% CI, 0.40-0.64 for high-quality evidence) but a higher risk of VTE (RR, 1.8; 95% CI, 1.2-2.8 for low-quality evidence). Applying the base-line risk estimates for VTE and major bleeding events provided in Table 4 to 1,000 pregnant women at high risk of VTE after cesarean section, it follows that selecting mechanical prophylaxis over pharmacologic prophylaxis would result in 24 more VTE and seven fewer bleeding events. Although elastic stockings have been associated with skin breakdown when used poststroke (RR, 4.0; 95% CI, 2.4-6.9), this compli-cation is much less likely to occur in young women. Elastic stockings and intermittent pneumatic compres-sion may be inconvenient and cumbersome to use.
our weak recommendation for thrombosis prophylaxis (section 6.2). Extrapolating from high-risk popula-tions, 154-156 the combination of LMWH prophylaxis with mechanical methods may be of benefi t when multiple major risk factors for VTE are present. Fur-ther, when major risk factors continue in the puer-perium, consideration should be given to extending prophylaxis for the 6 weeks during which pregnancy-associated prothrombotic changes may persist. 137
6.2 Thromboprophylaxis Following Cesarean Section
A recent systematic review 157 identifi ed four stud ies (830 women) comparing prophylaxis with LMWH 158,159 or UFH 160,161 with placebo. There was no statistically signifi cant difference between groups with respect to symptomatic VTE for LMWH vs pla-cebo (two of 105 and zero of 105, respectively; RR, 2.97; 95% CI, 0.31-28.03) and UFH vs placebo (three of 297 and four of 333, respectively; RR, 0.85; 95% CI, 0.19-3.76). 157 However, the small number
Table 3— [Section 6.2.1-6.2.4] Risk Factors for VTE Resulting in a Baseline Risk of Postpartum VTE of . 3%
Major risk factors (OR . 6): presence of at least one risk factor suggests a risk of postpartum VTE . 3%
Immobility (strict bed rest for � 1 week in the antepartum period) Postpartum hemorrhage � 1,000 ml with surgery Previous VTE Preeclampsia with fetal growth restriction Thrombophilia Antithrombin defi ciency a Factor V Leiden (homozygous or heterozygous) Prothrombin G20210A (homozygous or heterozygous) Medical conditions Systemic lupus erythematosus Heart disease Sickle cell disease Blood transfusion Postpartum infectionMinor risk factors (OR . 6 when combined): presence of at least
two risk factors or one risk factor in the setting of emergency cesarean section suggests a risk of postpartum VTE of . 3%
BMI . 30 kg/m 2 Multiple pregnancy Postpartum hemorrhage . 1 L Smoking . 10 cigarettes/d Fetal growth restriction (gestational age 1 sex-adjusted birth
weight , 25th percentile) Thrombophilia Protein C defi ciency Protein S defi ciency Preeclampsia
Data from Jacobsen et al, 121 Jacobsen et al, 144 Lindqvist et al, 146 Simpson et al, 148 Knight, 150 Robertson et al, 151 and James et al. 152 a Although the OR in a systematic review was 4.69, CIs were wide and numbers small. Further, other retrospective studies have calculated ORs of 282 (95% CI, 31-2,532) for type 1 antithrombin defi ciency and 28 (95% CI, 5.5-142) for type 2 defi ciency. 153 Thus, antithrombin defi ciency has been left as a major risk factor.
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Table 4— [ Section 6.2.1-6.2.4] Summary of Findings: LMWH vs No Thromboprophylaxis for Prevention of VTE in Women Undergoing Cesarean Section
OutcomesParticipants (Studies),
Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI) a
Anticipated Absolute Effects Over 6 wk Postpartum
Risk Without Prophylaxis
Risk Difference With LMWH (95% CI)
Symptomatic VTE, DVT, and pulmonary embolism
4,890 (3 RCTs), 3 wk-9 mo
Moderate due to indirectness b
RR 0.29 (0.11-0.73)
Low risk (see Table 13 )5 VTE per 1,000 a 3 fewer VTE per 1,000 (from 4
fewer to 1 fewer)High risk (see Table 13 )
40 VTE per 1,000 a 21 fewer per 1,000 (from 27 fewer to 9 fewer)
Major bleed c 5,456 (7 RCTs), 3 wk-9 mo
Moderate due to indirectness c
RR 2.03 (1.37-3.01)
20 bleeding events per 1,000 d
20 more bleeding events per 1,000 (from 8 more to 40 more)
See Table 2 legend for expansion of abbreviations. a Control group risk estimates come from studies providing risk factors for VTE after cesarean section (Tables S10 and S11). b Rated down for indirect study population (general surgery patients). We did not rate down for risk of bias, although only fi ve of eight RCTs of LMWH vs placebo/no treatment reported mortality. c Rated down for indirectness due to variable bleeding defi nitions in trials: bleeding leading to death, transfusion, reoperation, or discontinuation of therapy. Measured at end of therapy. d Control group risk estimate comes from a decision analysis by Blondon et al. 141
Remarks: The reduced bleeding risk with mechanical prophylaxis should be weighed against the inconve-nience of elastic stockings and intermittent pneu-maric compression.
6.2.3. For women undergoing cesarean section who are considered to be at very high risk for VTE and who have multiple additional risk factors for thromboembolism that persist in the puerperium, we suggest that prophylactic LMWH be combined with elastic stockings and/or intermittent pneumatic compression over LMWH alone (Grade 2C) .
6.2.4. For selected high-risk patients in whom signifi cant risk factors persist following delivery, we suggest extended prophylaxis (up to 6 weeks after delivery) following discharge from the hospital (Grade 2C) .
7.0 Treatment of Proven Acute VTE During Pregnancy
PE remains a leading cause of maternal mortality in the western world, 168,169 and VTE in pregnancy is an important cause of maternal morbidity. 168,170,171 Results from studies in which either all or most patients underwent accurate diagnostic testing for VTE report that the incidence of VTE ranges from 0.6 to 1.7 episodes per 1,000 deliveries. 138,139,146,148,152,172 A meta-analysis showed that two-thirds of DVT occur antepartum, with these events distributed through-out all three trimesters. 173 In contrast, 43% to 60%
The optimal duration of prophylaxis after cesarean section is not established. If we extrapolate from gen-eral surgery, 156,163-166 treatment until discharge from the hospital, with extended prophylaxis for those with signifi cant ongoing risk factors, may be appropriate. We express a preference for LMWH over UFH because of its favorable safety profi le (see section 4.0).
There are no relevant cost-effectiveness data in this setting using UFH or LMWH; however, in one study modeling the cost-effectiveness of intermittent pneumatic compression, this intervention was con-sidered cost-effective when the incidence of post-cesarean section DVT was at least 6.8 of 1,000 167 (Tables S13, S14). However, these devices are not readily available at all sites, and patients and nurses often fi nd them to be inconvenient and cumbersome to use.
Recommendations
6.2.1. For women undergoing cesarean section without additional thrombosis risk factors, we recommend against the use of thrombosis pro-phylaxis other than early mobilization (Grade 1B) .
6.2.2. For women at increased risk of VTE after cesarean section because of the presence of one major or at least two minor risk factors ( Table 3 ), we suggest pharmacologic thrombo-prophylaxis (prophylactic LMWH), or mechan-ical prophylaxis (elastic stockings or intermittent pneumatic compression) in those with contrain-dications to anticoagulants while in the hospital following delivery rather than no prophylaxis (Grade 2B) .
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of major bleeding events. 175-178 Table 5 and Table S15 summarize the quality of evidence and main fi ndings from a systematic review of nonpregnant patients deemed applicable to the present population of preg-nant women with acute VTE. Given these results, we consider the burden of self-injecting with LMWH for several months and possibility of skin reactions of lesser importance.
If LMWH is used for treatment of acute VTE in pregnancy, a weight-adjusted dosing regimen should be used. LMWH requirements may alter as preg-nancy progresses because the volume of distribution of LMWH changes and glomerular fi ltration rate increases in the second trimester. The latter has led some to recommend a bid LMWH dosing schedule. However, many clinicians use a once-daily regimen to simplify administration and enhance compliance. Observational studies have not demonstrated any increase in the risk of recurrence with the once-daily regimen over the bid regimen. 150,174
The need for dose adjustments over the course of pregnancy remains controversial. Some suggest that dose should be increased in proportion to the change in weight. 181 On the basis of small studies showing the need for dose-escalation to maintain therapeutic anti-Xa LMWH levels, 182,183 some advocate the per-formance of periodic (eg, every 1-3 months) antifac-tor Xa LMWH levels 4 to 6 h after injection with dose adjustment to maintain a therapeutic anti-Xa level (0.6-1.0 units/mL if a bid regimen is used and higher
of pregnancy-related episodes of PE appear to occur in the 4 to 6 weeks after delivery. 139,148 Because the antepartum period is substantially longer than the 6-week postpartum period, the daily risk of PE, as well as DVT, is considerably higher following delivery than antepartum.
7.1 Treatment of VTE During Pregnancy
Based on safety data for the fetus, heparin com-pounds are preferred over vitamin K antagonists for the treatment of VTE in pregnancy (see section 3.0). LMWH is the preferred option for most patients because of its better bioavailability, longer plasma half-life, more predictable dose response, and improved maternal safety profi le with respect to osteoporosis and thrombocytopenia (see section 2.0). 35-38 Further, LMWH is a more convenient option because it can be given once daily, and unlike UFH, LMWH does not require aPTT monitoring. 6
A systematic review of LMWH use in pregnancy 38 and subsequent observational studies 36,150,174 confi rm the safety and effi cacy of LMWH in this patient popu-lation when used for treatment of VTE. Our strong recommendation for LMWH over vitamin K antago-nists in the treatment of VTE in pregnancy is further supported by evidence showing that in the nonpreg-nant population, LMWH is more effective than vita-min K antagonists in preventing recurrent VTE and postthrombotic syndrome without increasing the risk
Table 5— [Section 7.1.2] Summary of Findings: Should LMWH Rather Than VKA Be Used for Long-term Treatment of VTE in Pregnant Women?
OutcomesParticipants
(Studies), Follow-upQuality of the Evidence
(GRADE)Relative Effect
(95% CI) a
Anticipated Absolute Effects During Pregnancy b
Risk With VKARisk Difference With LMWH
(95% CI)
Recurrent symptomatic VTE, DVT, and pulmonary embolism
2496 (7 RCTs); median, 6 mo
Moderate due to risk of bias a
RR 0.62 (0.46-0.84)
30 VTE per 1,000 b 11 fewer VTE per 1,000 (from 16 fewer to 5 fewer)
Major bleeding 2727 (8 RCTs); median, 6 mo
Moderate due to imprecision c
RR 0.81 (0.55-1.2)
20 bleeding events per 1,000 d
4 fewer bleeding events per 1,000 (from 9 fewer to 4 more)
PTS self-reported leg symptoms and signs
100 (1 RCT); median, 3 mo
Low due to risk of bias a and indirectness e
RR 0.85 (0.77-0.94)
480 PTS per 1,000 f 38 fewer bleeding events per 1,000 (from 110 fewer to 29 fewer)
Limited to LMWH regimens that used � 50% of the acute treatment dose during the extended phase of treatment. Meta-analysis is based on RCTs as referenced in Kearon et al 178 in this guideline. PTS 5 postthrombotic syndrome; VKA 5 vitamin K antagonist. See Table 2 legend for expansion of other abbreviations. a Risk of bias due to lack of blinding. b Control group risk estimate for VTE with VKAs comes from cohort study by Prandoni et al, 179 adjusted to the 6-mo time frame considered applicable to the pregnancy period. c Rated down for imprecision because CI includes both benefi t and harm. Borderline decision not to rate down for risk of bias (considered this outcome less subjective, so lack of blinding not serious threat to validity). d Control group risk estimate for major bleeding events comes from cohort studies by Prandoni et al 179 and Beyth et al, 180 adjusted to a 6-mo time frame considered applicable to the pregnancy period. e Predictive value from 3 mo (follow-up in study) to long term is uncertain. f Control group risk estimate for PTS comes from observational study of pregnant women (most mild). 171
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nant population), suffi cient to recommend treatment throughout pregnancy and the postpartum period for a minimum total duration of 3 months.
The delivery options in women using anticoagu-lants are best considered by a multidisciplinary team. Several options are possible, including spontaneous labor and delivery, induction of labor, and elective cesarean section. The plan for delivery should take into account obstetric, hematologic, and anesthetic issues. In order to avoid an unwanted anticoagulant effect during delivery (especially with neuraxial anes-thesia) in women receiving adjusted-dose subcuta-neous UFH 11 or LMWH who have a planned delivery; twice-daily subcutaneous UFH or LMWH should be discontinued 24 h before induction of labor or cesarean section, whereas patients taking once-daily LMWH should take only 50% of their dose on the morning of the day prior to delivery (see Kunz et al 189 in this guideline). If spontaneous labor occurs in women receiving anticoagulation, neuraxial anesthesia should not be used. Where the level of anticoagulation is uncertain and where laboratory support allows for rapid assessment of heparin levels, then testing can be considered to guide anesthetic and surgical man-agement. In women receiving subcutaneous UFH, careful monitoring of the aPTT is required and, if it is markedly prolonged, protamine sulfate 190 may be required to reduce the risk of bleeding. If bleeding occurs that is considered secondary to LMWH rather than to an obstetric cause, protamine sulfate may provide partial neutralization. 191
Women with a very high risk for recurrent VTE (eg, proximal DVT or PE close to the expected date of delivery) may benefi t by having a planned delivery by induction or cesarean section, as appropriate, so that the duration of time without anticoagulation can be minimized. Those at the highest risk of recurrence (eg, proximal DVT or PE within 2 weeks) can be switched to therapeutic IV UFH, which is then dis-continued 4 to 6 h prior to the expected time of deli very or epidural insertion. Alternatively, a tempo-rary inferior vena caval fi lter can be inserted and removed postpartum. However, the latter may be best restricted to women with proven DVT who have recurrent PE despite adequate anticoagulation because experience with these devices during preg-nancy is limited, 192-194 and the risk of fi lter migration and inferior vena cava perforation may be increased during pregnancy. 193,194
Recommendations
7.1.1. For pregnant women with acute VTE, we recommend therapy with adjusted-dose subcutaneous LMWH over adjusted-dose UFH (Grade 1B) .
if a once-daily regimen is chosen). However, other researchers have demonstrated that few women require dose adjustment when therapeutic doses of LMWH are used. 184-186 Given the absence of large studies using clinical end points that demonstrate an optimal therapeutic anti-Xa LMWH range or that dose adjustments increase the safety or effi cacy of therapy, the lack of accuracy and reliability of the measurement, 187 the lack of correlation with risk of bleeding and recurrence, 188 and the cost of the assay, routine monitoring with anti-Xa levels is diffi cult to justify.
Where LMWH cannot be used or when UFH is preferred (eg, in patients with renal dysfunction), UFH can be used through one of two alternatives: (1) initial IV therapy followed by adjusted-dose subcutaneous UFH given every 12 h or (2) bid adjusted-dose sub-cutaneous UFH. With subcutaneous therapy, UFH doses should be adjusted to prolong a midinterval (6 h postinjection) aPTT into therapeutic range, although it is recognized that aPTT monitoring is less reliable in pregnancy. 6 As previously discussed, the use of fondaparinux is inadvisable in pregnancy (see section 3.5). In this guideline, Linkins et al 14 and Kearon et al 178 present evidence regarding platelet count monitoring for the detection of HIT and the role of compression stockings in the acute manage-ment of DVT.
It remains unclear whether the dose of LMWH (or UFH) can be reduced after an initial phase of therapeutic anticoagulation. Some suggest that full-dose anticoagulation should be maintained through-out pregnancy and the puerperium because of the ongoing risk of recurrent VTE. However, regimens in which the intensity of LMWH is reduced later during the course of therapy to an intermediate-dose regimen 26 or 75% of a full-treatment dose 177 have been used successfully in the nonpregnant popula-tion, including in cancer patients who have a much higher risk of recurrence. A similar approach when using LMWH in pregnancy may reduce the small risks of anticoagulant-related bleeding and heparin-induced osteoporosis. Although there have been no studies directly compar ing full-dose LMWH with one of these modifi ed dos ing strategies in pregnant women, a modifi ed dosing regimen may be useful in pregnant women at increased risk of either of these two complications.
No studies have assessed optimal duration of anti-coagulant therapy for treatment of pregnancy-related VTE. In nonpregnant patients with VTE, evidence supports a minimum duration of 3 months treatment (see Kearon et al 178 in this guideline). We consider the additional fi vefold to 10-fold increase in risk for VTE in pregnant women, coupled with the high rate of proximal thrombi (compared with the nonpreg-
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of objectively diagnosed VTE in whom antepartum heparin was withheld and anticoagulants (usually warfa-rin with a target INR of 2.0-3.0 with an initial short course of UFH or LMWH) were given in the post-partum period for 4 to 6 weeks. 203 In this study, the incidence of antepartum recurrence was 2.4% (95% CI, 0.2%-6.9%), whereas that during the post-partum period was 2.5% (95% CI, 0.5%-7.0%). The advanced median gestational age at enrollment ( � 15 weeks) and the exclusion of women with known thrombophilia might have resulted in an underesti-mation of the risk of pregnancy-related recurrent VTE.
In subsequently published large retrospective cohort studies, the probability of antepartum VTE in women not given prophylaxis was � 6%, whereas for postpar-tum VTE, the observed incidence ranged from 6% to 8%. 204,205 Differences in study population (inclusion of women with more than one prior episode of VTE and inclusion of pregnancies not ending in live birth [ie, miscarriages]) and failure to independently adju-dicate recurrent events might account for the higher risk of recurrence. However, as shown in Table S16, the overall risk of recurrent VTE antepartum in both prospective and retrospective studies was , 10%, and CIs around the risk estimates of individual studies are overlapping.
Data regarding prognostic factors for recurrent VTE during pregnancy are inconsistent. A post hoc subgroup analysis of the prospective cohort study described previously identifi ed women without thrombophilia who had a temporary risk factor (including oral con-traceptive therapy or pregnancy) at the time of their prior VTE event as being at low risk of recurrence, with no recurrent events in 44 patients (0%; 95% CI, 0.0%-8.0%). 203 Antepartum recurrences occurred in three of 51 women with abnormal thrombophilia testing, a previous episode of thrombosis that was unprovoked, or both (5.9%; 95% CI, 1.2%-16.0%).
In the retrospective studies, the association between the presence or absence of temporary risk factors or of a defi nable thrombophilia and the risk of recurrent VTE associated with pregnancy was not consistent (Table S16). In these studies, it appears that women who had their fi rst episode of VTE provoked by use of oral contraceptives or related to pregnancy or the postpartum period had a higher risk of recurrent VTE in a subsequent pregnancy than women whose fi rst VTE was unprovoked or associated with a non-hormonal transient risk factor, although these differ-ences did not reach statistical signifi cance in the individual studies. 204,205 These fi ndings are consis-tent with those from a large population-based cohort study that used administrative data 206 in which women who had their fi rst VTE associated with pregnancy or the postpartum period had a higher risk of recurrence
7.1.2. For pregnant women with acute VTE, we recommend LMWH over vitamin K antagonist treatment antenatally (Grade 1A) .
7.1.3. For pregnant women with acute VTE, we suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 3 months) in com-parison with shorter durations of treatment (Grade 2C) .
7.1.4. For pregnant women receiving adjusted-dose LMWH or UFH therapy and where deli-very is planned, we recommend discontinuation of the heparin at least 24 h prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia) rather than continuing LMWH up until the time of delivery (Grade 1B) .
8.0 Prevention of VTE in Pregnant Women With Prior DVT or PE
Compared with individuals without a history of VTE, patients with previous events are at increased risk of future episodes of DVT and PE. 195 Women with a history of VTE have a threefold to fourfold higher risk of VTE during subsequent pregnancies than out-side pregnancy. 196 Thromboprophylaxis during preg-nancy involves long-term parenteral LMWH, which is expen sive, inconvenient, and painful to adminis-ter. Although bleeding, osteoporosis, and HIT are very uncommon in patients receiving prophylactic LMWH, 37-40,197 injec tion site skin reactions may occur. 45 The threshold for recommending postpartum pro-phylaxis is lower than for antepartum prophylaxis because of the shorter length of required treatment (ie, 6 weeks) and the higher average daily risk of VTE in the postpartum period. 137,173 Given the distribution of DVT throughout all three trimesters, 173 antepar-tum prophylaxis, if used, should be instituted early in the fi rst trimester.
8.1 Prior VTE and Pregnancy
Cohort studies evaluating the risk of recurrent VTE during pregnancy in women with a history of VTE in whom no prophylaxis is given have shown variable results (Table S16). The higher risk estimates from retrospective studies of nonconsecutive patients in which objective testing was not used routinely to con-fi rm the diagnosis of recurrent VTE likely represent overdiagnosis. 198,199 Prospective studies provide lower estimates. 200-203
The largest prospective study to date investigated 125 pregnant women with a single previous episode
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estimated the recurrence rate because objective diag-nostic testing was not used. 199
Given the low quality of the direct evidence, we use indirect evidence about the relative effects of thrombo-prophylaxis from other patient populations to inform our recommendations for antenatal prevention of VTE. Table 6 and Table S19 summarizes the quality of the evidence and main fi ndings from a systematic review of thromboprophylaxis in orthopedic patients at high risk for VTE. 136 Our choice of indirect evi-dence is based on similarities in risk of VTE, the type and duration of intervention (extended prophylactic-dose LMWH), and outcomes (symptomatic VTE and major bleeding events). Our baseline risk estimates are based on observational studies of pregnant women with previous VTE (Table S16). We have catego-rized patients into groups at low risk (major tran-sient risk factor for VTE), intermediate (hormone- or pregnancy-related or unprovoked VTE), or high risk (multiple prior unprovoked VTE or persistent risk factors, such as paralysis) during pregnancy. Clini-cians can use these risk groups to determine the anti-cipated absolute effects of treatment with LMWH in their patients. Given the evidence of similar absolute risks for VTE antepartum and postpartum outlined
during a subsequent pregnancy than women with an unprovoked fi rst VTE (ie, 4.5% vs 2.7%; RR, 1.71; 95% CI, 1.0-2.8).
8.2 Prevention of Recurrent VTE in Pregnant Women
A systematic review of the effects of thrombo-prophylaxis in pregnant women 157 identifi ed two ran-domized controlled trials that evaluated the safety and effi cacy of prophylaxis (compared with placebo or no treatment) in pregnant women with prior VTE. 158,202 Both studies have major methodologic weaknesses, including very small sample sizes (n 5 40 and n 5 16). 158,202 A third, unblended randomized trial compared LMWH prophylaxis with UFH prophylaxis in a selected group of pregnant women with prior VTE 207 (Table S17).
Several observational studies have evaluated the risk of recurrent VTE with various treatment regi-mens 36-38,44,199,204,208-212 (Table S18). Some of these stud-ies stratifi ed patients according to their perceived risk of recurrence. The estimates of the risk of recur-rent VTE while using some form of pharmacologic prophylaxis range from 0% to 15%, with the higher results seen in an older study that may have over-
Table 6— [Section 8.2.2, 8.2.3] Summary of Findings: Antepartum and Postpartum Prevention of VTE With Prophylactic-Dose LMWH vs No Prophylaxis in Pregnant Women With Prior VTE
OutcomesParticipants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI) a
Anticipated Absolute Effects During Pregnancy
Risk Without Prophylaxis
Risk Difference With LMWH (95% CI)
Symptomatic VTE, DVT, and pulmonary embolism
1,953 (6 RCTs), 27-35 d postoperative
Low due to indirectness c and imprecision a
RR 0.36 (0.20-0.67)
Low risk (transient risk factor)20 VTE per 1,000 a 13 fewer VTE per 1,000
(from 16 fewer to 7 fewer)Intermediate and high risk (pregnancy- or
estrogen-related, idiopathic or multiple prior VTE but discontinued VKAs)
80 VTE per 1,000 a 51 fewer VTE per 1,000 (from 65 fewer to 30 fewer)
Major bleeding b 1,953 (6 RCTs), 27-35 d postoperative
Low due to indirectness c and imprecision d
RR 0.43 (0.11-1.65)
Antepartum period5 bleeding events
per 1,000 e No signifi cant difference; 3 fewer
bleeding events per 1,000 (from 3 fewer to 3 more)
Postpartum period20 bleeding events
per 1,000 e No signifi cant difference; 11 fewer
bleeding events per 1,000 (from 18 fewer to 13 more)
See Table 2 and 5 legends for expansion of abbreviations. a Control group risk estimates for VTE in the antepartum and postpartum period come from studies summarized in Table S16. Quality of evidence is rated down because of imprecision in these risk estimates. We consider the distribution of VTE antepartum and postpartum to be equal. b Nonfatal maternal hemorrhage (according to section 1.0) defi ned as a symptomatic bleeding complication noted during pregnancy or within 6 wk postpartum that involved bleeding into a critical site, bleeding causing a fall in hemoglobin level of � 2 g/dL, or bleeding leading to transfusion of � 2 units of whole blood or red cells. c Population is indirect (ie, did not include pregnant women). Different doses of LMWH were used. Treatment was initiated variably before or after surgery with a duration of � 7 days (in hospital). Outcomes variably reported. Meta-analysis also provides other outcomes such as mortality, asymptomatic DVT, and specifi c bleed outcomes (wound hematoma, transfusion). Follow-up varied between trials from 3 wk to 9 mo. d Wide CIs for absolute effect of LMWH in high-risk group included benefi t and harm. e Control group risk estimate for major bleeding events comes from a systematic review by Greer et al. 38
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rence could occur between ultrasounds. We recom-mend that women should be investigated aggressively if symptoms suspicious of DVT or PE occur. That said, the performance of a baseline compression ultra-sound of a previously affected leg prior to or early on in pregnancy may be useful to help differentiate residual thrombosis from new disease in women presenting with symptoms during pregnancy (see Bates et al 218 in this guideline).
Recommendations
8.2.1. For all pregnant women with prior VTE, we suggest postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted at INR 2.0 to 3.0 rather than no prophylaxis (Grade 2B) .
8.2.2. For pregnant women at low risk of recur-rent VTE (single episode of VTE associated with a transient risk factor not related to pregnancy or use of estrogen), we suggest clinical vigilance antepartum rather than antepartum prophylaxis (Grade 2C) .
8.2.3. For pregnant women at moderate to high risk of recurrent VTE (single unprovoked VTE, pregnancy- or estrogen-related VTE, or multiple prior unprovoked VTE not receiving long-term anticoagulation), we suggest antepar-tum prophylaxis with prophylactic- or interme-diate-dose LMWH rather than clinical vigilance or routine care (Grade 2C) .
8.2.4. For pregnant women receiving long-term vitamin K antagonists, we suggest adjusted-dose LMWH or 75% of a therapeutic dose of LMWH throughout pregnancy followed by resumption of long-term anticoagulants post-partum rather than prophylactic-dose LMWH (Grade 2C) .
9.0 Prevention of VTE in Pregnant Women With Thrombophilia and No Prior VTE
9.1 Risk of Pregnancy-Related VTE in Women With Thrombophilia
A number of studies have examined the association between hereditary thrombophilias and pregnancy-related VTE. Table 7 presents estimated and observed pooled risks for pregnant women with thrombo-philia in the absence and presence of a positive family history.
In a systematic review of nine studies that assessed the risk of VTE in pregnant women with inherited thrombophilias but not necessarily a family history of
previously herein, the absolute effects of LMWH shown in Table 6 and Table S19 are applicable both to the 9-month antepartum period and the 6-week postpartum period.
LMWH is the preferred agent for prophylaxis (see section 2.0). Dose regimens include subcutaneous enox-aparin 40 mg every 24 h, 27,158 dalteparin 5,000 units every 24 h, 207 and dose-adjusted LMWH to achieve a peak anti-Xa level of 0.2 to 0.6 units/mL 213-215 (Table S18). Although all of the studies evaluating these regimens reported low recurrence rates, most were cohort studies and, therefore, no comparative data from untreated controls are available. Further, because different doses of anticoagulant prophylaxis have not been compared directly, the optimal dose of LMWH is unknown. Although indirect evidence ( Table 6 , Table S19) suggests that prophylactic-dose LMWH is effective (ie, RR of 0.36) in high-risk settings, some investigators have reported recurrent pregnancy-associated VTE in pregnant women pre-scribed prophylactic LMWH 36,37,204,208,216 However, it is unclear whether these represent true failures or were due to compliance issues with long-term daily subcutaneous injections.
Women who have an indication for long-term vita-min K antagonists, mostly because of multiple epi-sodes of VTE, are considered at very high risk of recurrent VTE during pregnancy and the postpartum period. Dose-adjusted LMWH is a rational option for anticoagulant therapy during pregnancy, with resumption of long-term vitamin K antagonists after delivery. Alternatively, a reduced therapeutic-dose regimen ( � 75% of the usual therapeutic dose) may represent a reasonable option given evidence of the superior effectiveness of LMWH compared with vitamin K antagonists observed in the treatment of VTE in cancer patients. 177
Increased renal clearance of LMWH during preg-nancy has led to suggestions that clinicians monitor the anticoagulant effect of prophylactic-dose LMWH using anti-Xa levels. 209,214 However, the appropriate target range for prophylaxis is uncertain, and there is no evidence to support any specifi c target range. Moreover, routine monitoring of anti-Xa levels is expensive, inconvenient, and possibly unreliable 187,217 (see Garcia et al 188 in this guideline).
An alternate strategy for DVT prevention is repeated screening during the antepartum period with noninvasive tests for DVT, such as compression ultra-sonography. This strategy generally is not justifi ed for two reasons. First, if we postulate rates of recurrent VTE of 5%, given an ultrasound sensitivity of 96% and specifi city of 98%, we would anticipate that 28% of positive results would be false positives. Second, there is no evidence to guide the timing of screening, and it is possible that a clinically important recur-
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Table 7— [Section 9.2.1-9.2.4] Risk of Pregnancy-Related VTE in Women With Thrombophilia Stratifi ed by Family History for VTE
Thrombophilic Defect, n/No. Women With ThrombophiliaEstimated Relative Risk,
OR (95% CI) a
Observed or Estimated Absolute Risk of VTE Antepartum and Postpartum
Combined, % Pregnancies (95% CI) b,c
Antithrombin/protein C/protein S defi ciency combined Family studies, 7/169 219 … 4.1 (1.6-8.3)Antithrombin defi ciency Family studies, 1/33 219 … 3.0 (0.08-15.8) Nonfamily studies, 8/11 151 4.7 (1.3-17.0) 0.7 (0.2-2.4)Protein C defi ciency Family studies, 1/60 219 … 1.7 (0.4-8.9) Nonfamily studies, 23/32 151 4.8 (2.2-10.6) 0.7 (0.3-1.5)Protein S defi ciency Family studies, 5/76 219 … 6.6 (2.2-14.7) Nonfamily studies, 16/28 151 3.2 (1.5-6.9) 0.5 (0.2-1.0)Factor V Leiden, heterozygous Family studies, 26/828 220-222, 223 … 3.1 (2.1-4.6) Nonfamily studies, 96/226 151 8.3 (5.4-12.7) 1.2 (0.8-1.8)Factor V Leiden, homozygous Family studies, 8/57 224-226 … 14.0 (6.3-25.8) Nonfamily studies, 29/91 153 34.4 (9.9-120.1) 4.8 (1.4-16.8)Prothrombin G20201A mutation, heterozygous Family studies, 6/228 227,228 … 2.6 (0.9-5.6) Nonfamily studies, 42/61 151 6.8 (2.5-18.8) 1.0 (0.3-2.6)Prothrombin G20201A mutation, homozygous Family studies, n/a … … Nonfamily studies, 2/2 151 26.4 (1.2-559.3) 3.7 (0.2-78.3)
a Data from Robertson et al 151 ; number of VTE cases in women with the thrombophilia in question vs VTE cases in women without the specifi ed thrombophilia. b In the family studies, number of women with VTE out of number of women with thrombophilia. Observed absolute risks for family studies are risks observed in cohorts of families from a proband with symptomatic VTE and thrombophilia. Study numbers are pooled. Incidence is derived by adding number of events and dividing by number of pregnancies. c Estimated absolute risks for nonfamily studies are derived by multiplying the pooled ORs with their corresponding 95% CIs from Robertson et al 151 with the overall baseline VTE incidence (ie, antepartum and until 6 wk postpartum combined) of 1.40 per 1,000 from a group of women aged 25 to 34 y (I. A. Greer, MD, personal communication, November 2010).
was similar to that in the fi rst systematic review (OR, 8.6; 95% CI, 4.8-12.6). 229 However, cohort studies, which are likely to be more reliable, showed a lower pooled OR of 4.5 (95% CI, 1.8-10.9). 229 Given a background incidence of VTE during pregnancy of � 1/1,000 deliveries, the absolute risk of VTE in women without a prior event or family history remains low (in the range of 5-12/1,000 deliveries) for most of the inherited thrombophilias, except perhaps for homozygous carriers of the factor V Leiden or the prothrombin mutations where the OR from case-control studies suggest baseline risks of pregnancy-related VTE of � 4%.
Regardless of the presence of thrombophilia, a positive family history of VTE increases the risk for VTE twofold to fourfold. 230 Several family-based cohort studies found that women with inherited throm-bophilia and a positive family history who have not had a previous episode of VTE have a risk of devel-oping a fi rst VTE during pregnancy or the postpar-tum period of between 1.7% for protein C defi ciency 219 and 14.0% for homozygous carriers of the factor V
VTE, all with the exception of homozygosity for the thermolabile methylene tetrahydrofolate reductase variant (MTHFR C677T) were associated with a sta-tistically signifi cant increase in the risk of pregnancy-related VTE ( Table 7 ). 151 The highest risks were associated with homozygosity for factor V Leiden (OR, 34.4; 95% CI, 9.9-120.1) or the prothrombin G20210A variant (OR, 26.4; 95% CI, 1.2-559.3). The most common inherited thrombophilias (ie, heterozy-gosity for factor V Leiden [OR, 8.3; 95% CI, 5.4-12.7], prothrombin G20210A variant [OR, 6.8; 95% CI, 2.5-18.8]) were associated with lower risks. Defi cien-cies of the endogenous anticoagulants were associ-ated with similar risk increases (ORs for antithrombin, protein S, and protein C defi ciency, 4.7 [95% CI, 1.30-17.0], 4.8 [95% CI, 2.2-10.7], and 3.2 [95% CI, 1.5-6.0], respectively).
In a subsequently published meta-analysis under-taken to provide an estimate of the association of the factor V Leiden mutation with pregnancy-related VTE that used slightly different study entry criteria, the risk estimate obtained from case-control studies
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agents in preventing VTE in this population, we used indirect evidence to inform our treatment rec-ommendations. Given the low risk for VTE in women with thrombophilia but no family history, we restricted our analysis to women with thrombophilia and a family history of VTE ( Table 8, Table S20). We esti-mated the baseline VTE incidence (ie, antepartum and until 6 weeks postpartum combined) as 1.40 of 1,000 (I. A. Greer, MD, personal communication, November 8, 2010). Evidence about relative effects of treatment is taken from a meta-analysis of throm-boprophylaxis in patients undergoing hip arthro-plasty. 136 We have rated the quality of evidence as low because of indirectness of the population and intervention as well as the considerable imprecision in baseline risk estimates for VTE in women with thrombophilias.
Estimates of absolute effects are relatively large in women with a positive family history of VTE who are homozygous for the factor V Leiden mutation—47 fewer VTE/1,000 antepartum and 47 fewer VTE of 1,000 postpartum when prophylaxis is used, with no increased risk of major bleeding ( Table 8 , Table S20). In women with a positive family history for VTE and antithrombin, protein C, or protein S defi ciency, these fi gures are approximately 13 of 1,000 antepar-tum and 13 of 1,000 postpartum. For the other thrombophilias, the estimated number of VTE pre-vented is 10 of 1,000 both antepartum and postpartum. The evidence is, however, low quality and includes imprecise estimates.
The increased risk in women with thrombophilia and a family history of VTE begins early in preg-nancy 173 ; therefore, when antepartum prophylaxis is used, it should be commenced as early as possible in the fi rst trimester. The burden of self-injecting with LMWH over several months and the risk of skin reactions weigh into our weak recommendation for antepartum thromboprophylaxis. For postpartum prophylaxis, we consider vitamin K antagonist therapy targeted to an INR of 2.0 to 3.0 an appropriate alter-native to LMWH, except in patients with protein C or S defi ciency who are at risk for developing warfarin-induced skin necrosis. 241-243
Recommendations
9.2.1. For pregnant women with no prior his-tory of VTE who are known to be homozygous for factor V Leiden or the prothrombin 20210A mutation and have a positive family history for VTE, we suggest antepartum prophylaxis with prophylactic- or intermediate-dose LMWH and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted at INR 2.0 to 3.0 rather than no prophylaxis (Grade 2B) .
Leiden mutation 224-226 ( Table 7 ). 219-228,231,232 These estimates are, however, imprecise, particularly for the less common thrombophilias (see wide CIs in Table 7 ).
Although the defi ciencies of the natural anticoagu-lants (and in particular, antithrombin defi ciency) are usually labeled as high-risk thrombophilias, this per-ception is based on older studies with important methodological limitations. For instance, Conard et al 233 reported a very high risk of pregnancy-related VTE in women with antithrombin and protein C or protein S defi ciency, but many patients included in this report had a history of recurrent VTE, and all episodes of VTE were not objectively confi rmed. More rigorous recent studies included in Table 7 do not support the high risk of recurrence from previous studies. Two small studies that investigated the risk in women with both the factor V Leiden and prothrombin muta-tions found similar risk estimates to those seen in single heterozygous carriers. 226,234 Based on these esti-mates, we suggest that serious consideration of pro-phylaxis is warranted only in (1) homozygous carriers of the factor V Leiden or prothrombin gene muta-tions (regardless of family history) and (2) women with the other inherited thrombophilias with a family history of VTE.
Acquired thrombophilias have been less well stud-ied, but repeated positivity at least 12 weeks apart for APLAs (lupus anticoagulants [nonspecifi c inhibitors], moderate- or high-titer IgG or IgM anticardiolipin antibodies [ . 40 GPL or MPL or . 99th percentile], or moderate- of high-titer IgG or IgM anti- b 2 -glyco-protein I antibodies [ . 99th percentile]) is associated with an increased risk of VTE. 235,236 The VTE risk in women with APLAs and no previous venous throm-bosis is uncertain. 237,238
Hyperhomocysteinemia is associated with an increased risk of VTE in nonpregnant women. 239 How-ever, it does not appear that homozygosity for MTHFR C667T (the genetic abnormality most com-monly associated with hyperhomocysteinemia) alone leads to an increased risk of VTE in pregnant women. 151 As clinical events in homozygotes are likely to refl ect the interaction of the genotype with a relative defi ciency of vitamins, such as B12 and folic acid, the absence of an association of this geno-type with gestational VTE may refl ect pregnancy-related physiological reduction in homocysteine levels and the effects of folic acid supplements that are now taken widely by women in pregnancy for prevention of neural tube defects. 240
9.2 Prevention of Pregnancy-Related VTE in Women With Thrombophilia
Because of a paucity of high-quality evidence mea-suring the effectiveness and safety of antithrombotic
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Table 8— [Section 9.2.1-9.2.4] Summary of Findings: Antepartum and Postpartum Prophylactic-Dose LMWH vs No Thromboprophylaxis for Pregnant Women With a Known Thrombophilia
Outcomes
Participants (Studies), Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI) a
Anticipated Absolute Effects Antepartum and Postpartum (Different Risk Estimates for Bleeding Events)
Risk Without Prophylaxis
Risk Difference With LMWH (95% CI)
Symptomatic VTE, DVT, and pulmonary embolism
1,953 (6 RCTs), 27-35 d
postoperative
Low due to indirectness b
and imprecision a
RR 0.36 (0.20-0.67)
Positive family history VTE and heterozygous factor V Leiden or prothrombin 202010A
15 VTE per 1,000 c 10 fewer VTE per 1,000 (from 12 fewer to 5 fewer)
Positive family history VTE and antithrombin, protein C, or protein S defi ciency
20 VTE per 1,000 c 13 fewer VTE per 1,000 (from 16 fewer to 6 fewer)
Positive family history VTE and homozygous factor V Leiden or prothrombin 20210A
70 VTE per 1,000 c 47 fewer per 1,000 (from 56 fewer to 31 fewer)
No family history of VTE but homozygous factor V Leiden or prothrombin 20210A
20 VTE per 1,000 c 13 fewer VTE per 1,000 (from 16 fewer to 6 fewer)
Major bleeding 5,456 (7 RCTs), 3 wks-9 mo
Moderate due to indirectness b
RR 0.43 (0.11-1.65)
Antepartum period5 bleeding events per 1,000 d
No signifi cant difference; 3 fewer bleeding events per 1,000
(from 3 fewer to 3 more)Postpartum period
20 bleeding events per 1,000 d
No signifi cant difference; 11 fewer bleeding events per 1,000
(from 18 fewer to 13 more)
See Table 2 legend for expansion of abbreviations. a Imprecision in control group risk estimates for all thrombophilias (see Table S20 ) results in imprecise anticipated absolute effects. b The population did not include pregnant women. Different doses of LMWH were used; treatment was initiated variably before or after surgery with a duration of � 7 days in hospital and 25 d out of hospital. Outcomes were variably reported. c Control group risk estimate for VTE comes from observational studies summarized in Table S20 . Our antepartum risk estimate is based on assumed equal distribution of antepartum and postpartum VTE events based on data from observational studies (I. A. Greer, MD, personal communication, November 8, 2010). d Control group risk estimate for major bleeding events antepartum comes from systematic review by Greer. 38
9.2.4. For pregnant women with all other throm-bophilias and no prior VTE who do not have a positive family history for VTE, we suggest antepartum and postpartum clinical vigilance rather than pharmacologic prophylaxis (Grade 2C) .
10.0 Thrombophilia and Pregnancy Complications
Various pregnancy complications have been linked to thrombophilic states. Unfortunately, adverse preg-nancy outcomes are not infrequent in the general population. Fifteen percent of clinically recognized pregnancies end in miscarriage, but total repro-ductive loss may be as high as 50%. 244 Five percent of women experience two or more losses, and 1% to 2% have three or more consecutive losses. Other placental-mediated pregnancy complications include preeclampsia, fetal growth restriction, and placental abruption.
9.2.2. For pregnant women with all other thrombophilias and no prior VTE who have a positive family history for VTE, we suggest antepartum clinical vigilance and postpartum prophylaxis with prophylactic- or intermediate-dose LMWH or, in women who are not pro-tein C or S defi cient, vitamin K antagonists targeted at INR 2.0 to 3.0 rather than routine care (Grade 2C) .
9.2.3. For pregnant women with no prior his-tory of VTE who are known to be homozygous for factor V Leiden or the prothrombin 20210A mutation and who do not have a positive family history for VTE, we suggest antepartum clin-ical vigilance and postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or vitamin K antagonists tar-geted at INR 2.0 to 3.0 rather than routine care (Grade 2B) .
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loss and severe preeclampsia are also associated with inherited thrombophilia, 151,274,275 whereas the presence of an association is controversial in women with fetal growth restriction or placental abruption. 151,277
Table 9 summarizes the fi ndings of a meta-analysis of 25 studies (predominantly case control) 151 exam-ining the association between thrombophilia and var-ious pregnancy complications. The wide CIs around the point estimates of some associations illustrate the uncertainty of the fi ndings, particularly for the less-prevalent thrombophilias. In a meta-analysis limited to prospective cohort studies, 277 the pooled OR for pregnancy loss in women with factor V Leiden (abso-lute risk, 4.2%) compared with women without this mutation (absolute risk, 3.2%) was 1.52 (95% CI, 1.06-2.19). The meta-analysis was unable to estab-lish or refute an association between the presence of factor V Leiden and preeclampsia (OR, 1.23; 95% CI, 0.89-1.70) or fetal growth restriction (OR, 1.0; 95% CI, 0.80-1.25). Results also failed to demon-strate or exclude an association between the pro-thrombin mutation and either preeclampsia (OR, 1.25; 95% CI, 0.79-1.99), fetal growth restriction (OR, 1.25; 95% CI, 0.92-1.70), or pregnancy loss (OR, 1.13; 95% CI, 0.64-2.01). Given these results, it remains unclear whether screening for inherited thrombo-philias is in the best interests of women with preg-nancy complications.
10.2 Prevention of Pregnancy Complications in Women With Thrombophilia
Clinicians are increasingly using antithrombotic therapy in women at risk for these complications (Tables S21, S22). 278-299 With respect to acquired thrombophilias, of the interventions examined in a systematic review 252 (up to date in February 2005) that summarized the data from 13 randomized or quasi-randomized trials, including a total of 849 preg-nant women with APLA and a history of at least two unexplained pregnancy losses, only UFH combined with aspirin (two trials, n 5 150) reduced the inci-dence of pregnancy loss. 278,279 Consistent fi ndings of a third study (n 5 72), 290 when included, yielded an relative risk of 0.44 (95% CI, 0.30-0.66) for UFH combined with aspirin compared with aspirin alone ( Table 10, Table S23). The use of higher-dose UFH and aspirin did not decrease the risk of pregnancy loss compared with low-dose UFH and aspirin (one trial, n 5 50; RR, 0.83; 95% CI, 0.29-2.38). 252,280 On its own, aspirin (three trials, n 5 71) failed to demonstrate or exclude an effect on pregnancy loss compared with usual care 281 or placebo 282,283 (RR, 1.05; 95% CI, 0.66-1.68). 252 In one trial, the combination of LMWH with aspirin had also failed to demonstrate or exclude an effect on pregnancy loss when compared with
Successful pregnancy outcome depends on tropho-blast invasion into the uterine vasculature and on the development and maintenance of an adequate utero-placental circulatory system. Inadequate placentation and damage to the spiral arteries with impaired fl ow, an increased maternal infl ammatory response, and pro-thrombotic changes may lead to placental-medicated pregnancy complications. 245 Animal studies suggest that the hemostatic system plays an important role in placental and fetal development, although hyper-coagulability is unlikely to be the sole mechanism by which thrombophilia increases the risk of pregnancy failure. It is more likely that effects on trophoblast differentiation and early placentation may be involved through as yet unknown mechanisms. Interestingly, both aspirin and heparin appear to infl uence these early trophoblast and placentation mechanisms in vitro as well as in a hypercoagulability mouse model. 246-248
10.1 Risk of Pregnancy Complications in Women With Thrombophilia
Pregnancy complications occur with increased fre-quency in women with APLAs. APLA syndrome can be diagnosed in women who test positive for lupus anticoagulant (nonspecifi c inhibitor) or moderate- to high-titer antibodies to IgG or IgM anticardiolipin ( . 40 GPL or MPL or . 99th percentile) or IgG or IgM b 2 -glycoprotein I ( . 99th percentile) on two occa-sions at least 12 weeks apart and who experience at least one unexplained fetal death (later than 10 weeks of gestation); three or more unexplained consecu-tive miscarriages (before 10 weeks of gestation); or one or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or pla-cental insuffi ciency. 235
There is convincing evidence that APLAs are asso-ciated with an increased risk of recurrent and late pregnancy loss. 151,249-253 Lupus anticoagulants (non-specifi c inhibitors) are more strongly related to preg-nancy loss than are the other antibodies against phospholipids; although associations have also been seen with moderate- to high-titer IgG and IgM anti-bodies ( . 5 SDs above normal, . 99th percentile, or . 20 GPL/MPL units). 253 The importance of anti- b 2 -glycoprotein I antibodies is not clearly estab-lished. 253 Furthermore, there is less agreement on the association between the presence of APLAs and the occurrence of other pregnancy complications, including preeclampsia, placental abruption, and intrauterine growth restriction. 151,243,254-268
The association between inherited thrombophilic disorders and miscarriage, fi rst observed in women from families with venous thrombosis, has been con-fi rmed in many studies. 151,228,269-277 A single late fetal
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e720S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Tabl
e 9—
[10.
2.1,
10.2
.2]
Ass
ocia
tion
Bet
wee
n P
regn
ancy
Com
plic
atio
ns a
nd T
hrom
bop
hili
a
Type
of T
hrom
boph
ilia
Ear
ly L
oss
Rec
urre
nt F
irst
Tr
imes
ter
Los
sN
onre
curr
ent S
econ
d Tr
imes
ter
Los
sL
ate
Los
sPr
eecl
amps
iaPl
acen
tal A
brup
tion
Fet
al G
row
th
Res
tric
tion
Fac
tor
V L
eide
n (h
omoz
ygou
s)2.
71 (1
.32-
5.58
) a
a 1.
98 (0
.40-
9.69
)1.
87 (0
.44-
7.88
)8.
43 (0
.41-
171.
20)
4.64
(0.1
9-11
5.68
)F
acto
r V
Lei
den
(het
eroz
ygou
s)1.
68 (1
.09-
2.58
)1.
91 (1
.01-
3.61
) a 4.
12 (1
.93-
8.81
) a 2.
06 (1
.10-
3.86
)2.
19 (1
.46-
3.27
)4.
70 (1
.13-
19.5
9)2.
68 (0
.59-
12.1
3)Pr
othr
ombi
n ge
ne m
utat
ion
(het
eroz
ygou
s)2.
49 (1
.24-
5.00
)2.
70 (1
.37-
5.34
)8.
60 (2
.18-
33.9
5)2.
66 (1
.28-
5.53
)2.
54 (1
.52-
4.23
)7.
71 (3
.01-
19.7
6)2.
92 (0
.62-
13.7
0)M
TH
FR
C67
7T (h
omoz
ygou
s)1.
40 (0
.77-
2.55
)0.
86 (0
.44-
1.69
)N
A1.
31 (0
.89-
1.91
)1.
37 (1
.07-
1.76
)1.
47 (0
.40-
5.35
)1.
24 (0
.84-
1.82
)A
ntith
rom
bin
defi c
ienc
y0.
88 (0
.17-
4.48
)N
AN
A7.
63 (0
.30-
196.
36)
3.89
(0.1
6-97
.19)
1.08
(0.0
6-18
.12)
NA
Prot
ein
C d
efi c
ienc
y2.
29 (0
.20-
26.4
3)N
AN
A3.
05 (0
.24-
38.5
1)5.
15 (0
.26-
102.
22)
5.93
(0.2
3-15
1.58
)N
APr
otei
n S
defi c
ienc
y3.
55 (0
.35-
35.7
2)N
AN
A20
.09
(3.7
0-10
9.15
)2.
83 (0
.76-
10.5
7)2.
11 (0
.47-
9.34
)N
AA
ntic
ardi
olip
in a
ntib
odie
s3.
40 (1
.33-
8.68
)5.
05 (1
.82-
14.0
1)N
A3.
30 (1
.62-
6.70
)2.
73 (1
.65-
4.51
)1.
42 (0
.42-
4.77
)6.
91 (2
.70-
17.6
8)L
upus
ant
icoa
gula
nts
(non
spec
ifi c
inhi
bito
r)2.
97 (1
.03-
9.76
)N
A14
.28
(4.7
2-43
.20)
2.38
(0.8
1-6.
98)
1.45
(0.7
0-4.
61)
NA
N
AH
yper
hom
ocys
tein
emia
6.25
(1.3
7-28
.42)
4.21
(1.2
8-13
.87)
NA
0.98
(0.1
7-5.
55)
3.49
(1.2
1-10
.11)
2.40
(0.3
6-15
.89)
NA
Dat
a ar
e pr
esen
ted
as O
R (9
5% C
I) a
nd d
eriv
ed fr
om R
ober
tson
et a
l. 151 M
TH
FR
5 m
ethy
lene
tetr
ahyd
rofo
late
red
ucta
se v
aria
nt; N
A 5
not
ava
ilabl
e. a H
omoz
ygou
s an
d he
tero
zygo
us c
arri
ers
wer
e gr
oupe
d to
geth
er; i
t is
not p
ossi
ble
to e
xtra
ct d
ata
for
each
sta
te.
aspirin alone (RR, 0.78; 95% CI, 0.39-1.57). 252,284 Sim-ilar results were obtained when LMWH and aspirin was compared with IV g -globulin (RR, 0.37; 95% CI, 0.12-1.16). 252,281
A subsequent meta-analysis that combined data from randomized trials testing the effi cacy of a com-bination of heparin (either UFH or LMWH) and aspirin vs aspirin alone in patients with APLAs and recurrent pregnancy loss 292 included an additional LMWH study published since the fi rst systematic review. 293 When data from fi ve trials (n 5 334) were combined, the frequency of live births was signifi -cantly higher in the aspirin and heparin group (74.3%) than in those randomized to aspirin alone (55.8%) (RR, 1.3; 95% CI, 1.0-1.7; NNT to achieve one live birth, 5.6). 292 When studies that used LMWH and UFH were analyzed separately, there was just a trend of higher birth rate in patients receiving aspirin and LMWH (RR, 1.1; 95% CI, 0.9-1.3). Although the rel-ative effectiveness of UFH vs LMWH with respect to prevention of recurrent pregnancy loss in women with APLAs is not established, the results of two small pilot studies (n 5 26 and n 5 50) suggest that the combination of LMWH and aspirin might at least be equivalent to UFH and aspirin in preventing recur-rent pregnancy loss (RR, 0.44 [95% CI, 0.17-1.00] 285 and 0.8 [95% CI, 0.26-2.48] 286 in women receiving LMWH vs UFH, respectively). Given the absence of evidence that women with APLA syndrome and a single late pregnancy loss, preeclampsia, or fetal growth restriction benefi t from the addition of UFH or LMWH to aspirin, we do not recommend for or against screening for APLAs in women with these pregnancy complications.
The data addressing the use of antithrombotic ther-apy in women with inherited thrombophilia and pregnancy loss consists of predominantly small uncon-trolled trials or observational studies with impor-tant methodological limitations. 288,289,294-302 Gris et al 297 reported that enoxaparin in women with factor V Leiden, the prothrombin gene mutation, or protein S defi ciency and one previous pregnancy loss increased the live birth rate (86%) compared with low-dose aspirin alone (29%); however, the methodology and results of this randomized trial have generated much controversy, 300,303-305 and we have not included it in the evidence we used to make recommendations. A subsequent cohort study found the live birth rate of subsequent pregnancies after a single pregnancy loss at or later than 12 weeks gestation in carriers of factor V Leiden or the prothrombin mutation was, without intervention, 68% (95% CI, 46%-85%). 306
Tables S21 and S22 summarize the methodology and results of randomized trials and nonrandomized observational studies (excluding those that used a historical control group). These data do not provide
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coagulation 307 as well as widespread endothelial dys-function. 308-310 The manifestations of this disease are protean, 310 and preeclampsia should not be consid-ered as a single disease entity but rather as a maternal response to abnormal placentation. 311,312 Women with a thrombophilic disorder, whether it be acquired or heritable, may be more likely to develop preeclampsia, but for heritable thrombophilias, this association is largely based on retrospective case-control ( Table 9 ) and cohort studies 151 ; prospective investigations have not confi rmed these fi ndings. 275,313
11.1 Prevention of Recurrent Preeclampsia in Women With No Thrombophilia
The observations of endothelial dysfunction and platelet dysfunction in preeclampsia led to the hypothesis that antiplatelet agents might prevent or delay the development of this condition. Systematic review results suggest that the use of antiplatelet agents (primarily low-dose aspirin) is associated with modest reductions in the relative risk of preeclampsia. Table 11 314,315 and Table S24 summarize the evidence and main fi ndings from the most recent Cochrane review of 43 randomized trials with 32,590 women, 314 providing moderate-quality evidence of a signifi cant reduction (RR, 0.83; 95% CI, 0.77-0.89) in the risk of preeclampsia associated with the use of antiplate-let agents. The relative effect of antiplatelet therapy appears to be similar in women at low and high risk for preeclampsia (ie, no evidence of subgroup effect). However, as shown in Table 11 and Table S24, the baseline risk of preeclampsia determines the absolute effect of antiplatelet therapy, and women at low risk have a substantially lower benefi t (NNT, 100) than
evidence that LMWH improves pregnancy outcome in women with inherited thrombophilia and recur-rent pregnancy loss.
Recommendations
10.2.1. For women with recurrent early preg-nancy loss (three or more miscarriages before 10 weeks of gestation), we recommend screening for APLAs (Grade 1B) .
10.2.2. For women with a history of pregnancy complications, we suggest not to screen for inher-ited thrombophilia (Grade 2C) .
10.2.3. For women who fulfi ll the laboratory cri-teria for APLA syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic- or intermediate-dose UFH or prophylactic LMWH combined with low-dose aspirin, 75 to 100 mg/d, over no treat-ment (Grade 1B) .
10.2.4. For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C) .
11.0 Management of Women With a History of Preeclampsia or Recurrent
Fetal Loss and No Thrombophilia
Preeclampsia is associated with microvascular fi brin deposition indicative of activation of platelets and
Table 10— [Section 10.2.1,10.2.3] Summary of Findings: Should UFH Plus Aspirin or Aspirin Alone Be Used for Pregnant Women With APLA and Recurrent Pregnancy Loss
OutcomesParticipants
(Studies), Follow-upQuality of the Evidence
(GRADE)Relative Effect
(95% CI) a
Anticipated Absolute Effects During Pregnancy
Risk With AspirinRisk Difference With UFH 1 Aspirin
(95% CI)
Pregnancy loss 212 (3 RCTs), not reported
Moderate due to risk of bias b
RR 0.44 (0.33- 0.66)
500 losses per 1,000 a 283 fewer losses per 1,000 (from 353 fewer to 172 fewer)
IUGR c 134 (3 RCTs), not reported
Low due to risk of bias b and imprecision d
RR 1.71 (0.48-6.17)
56 IUGR per 1,000 a No signifi cant difference; 39 more IUGR per 1,000 (from 29 fewer to 287 more)
Preeclampsia not clearly defi ned
134 (3 RCTs), not reported
Low due to risk of bias b and imprecision d
RR 0.43 (0.09-2.08)
74 cases per 1,000 a No signifi cant difference; 30 fewer cases per 1,000 (from 67 fewer to 80 more)
Data from unpublished meta-analysis based on three trials. 278,279,290 Major bleeding is a critical outcome that was not reported in the three trials. APLA 5 antiphospholipid antibody; IUGR 5 intrauterine growth restriction; UFH 5 unfractionated heparin. See Table 2 legend for expansion of other abbreviations. a Control group risk estimates with aspirin come from the meta-analysis of three trials. b Risk of bias due to issues of randomization, allocation concealment, and blinding. c Estimated fetal weight below the 10th percentile for gestational age. d Wide CIs include benefi t and harm.
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e722S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Table 11— [11.1.1] Summary of Findings: Should Aspirin Rather Than No Treatment Be Used for Prevention of Preeclampsia in Women Without Thrombophilia
OutcomesParticipants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI) a
Anticipated Absolute Effects During Pregnancy
Risk Without Antiplatelet Therapy
Risk Difference With Antiplatelet Therapy (95% CI)
Preeclampsia defi ned as proteinuric preeclampsia in Cochrane Systematic Review
32,590 (43 RCTs), not reported
Moderate due to inconsistency b
RR 0.83 (0.77-0.89)
Low risk for preeclampsia c 60 cases per 1,000 a 10 fewer cases per 1,000
(from 14 fewer to 7 fewer)High risk for preeclampsia c
210 cases per 1,000 a 36 fewer losses per 1,000 (from 46 fewer to 23 fewer)
Major bleeding events d
95,000 (6 RCTs), 3.8-10 y
Moderate due to indirectness e
RR 1.54 (1.30-1.82)
15 bleeding events per 1,000 f
8 more bleeding events per 1,000 (from 5 more to 12 more)
Data from Duley et al 314 and ATT Collaboration. 315 See Table 2 legend for expansion of abbreviations. a Control group risk estimates for preeclampsia is based on control event rates in studies included in subgroup analyses in the meta-analysis. b Heterogeneity ( I 2 5 46%, P , .001) might be related to different types and doses of antiplatelet agents, the lack of placebo in the control group in many of the trials, different populations of pregnant women concerning risk of preeclampsia, and effect of treatment. c High risk was defi ned in the systematic review: Women who were either normotensive or had chronic hypertension without superimposed preeclampsia at trial entry were classifi ed as being at high risk if they had one or more of the following: previous severe preeclampsia, diabetes, chronic hypertension, renal disease, or autoimmune disease. Low risk constitutes women without these characteristics. d Major antenatal nonfatal hemorrhage. e Rated down for indirectness due to population (primary prevention cardiovascular disease). 315 The Cochrane Review does not report the effects of antiplatelet therapy on major bleeding events in pregnant women. f Control group risk estimate for major bleeding events antepartum from systematic review by Greer et al. 38
risk of preeclampsia between those treated with LMWH and low-dose aspirin vs those treated with low-dose aspirin alone or no prophylactic therapy. 319 In a ran-domized trial of 80 nonthrombophilic women consid-ered to be at increased risk for preeclampsia on the basis of both a history and an underlying angiotensin-converting enzyme insertion/deletion polymorphism that examined the effect of prophylactic LMWH (dalteparin 5,000 units/d) on the pregnancy outcome, maternal BP, and uteroplacental fl ow, 320 women receiv-ing LMWH had a lower incidence of adverse out-comes, with a 74.1% reduction in preeclampsia (RR, 0.26; 95% CI, 0.08-0.86) and a 77.5% reduction in fetal growth restriction (RR, 0.14; 95% CI, 0.03-0.56). A subsequent pilot study of 116 pregnant women with no detectable thrombophilia and previous severe preeclampsia, small for gestational age baby, placen-tal abruption, or intrauterine fetal demise random-ized to prophylactic-dose dalteparin or no dalteparin reported that dalteparin was associated with a lower rate of a composite of one or more of severe pre-eclampsia, birth weight in the fi fth percentile or less, or major abruption (adjusted OR, 0.15; 95% CI, 0.03-0.70). 321
The results of these studies need to be interpreted with some caution. First, it is not clear whether the positive effects of LMWH on prevention of pre-eclampsia in women with underlying angiotensin-converting enzyme insertion/deletion polymorphisms are broadly generalizable. Second, the pilot study
women at high risk (NNT, 28). Current data from the Cochrane review do not show a difference in effect when low-dose aspirin is started before or after 20 weeks gestation. 314
What constitutes high risk for preeclampsia is not always immediately clear, as available studies have used different risk stratifi cation schemes. In iden-tifying levels of risk, studies quantifying the risk of preeclampsia 312,316,317 suggested a relative risk of more than sevenfold with APLAs and previous preeclampsia and an approximately twofold increase in relative risk associated with a BMI � 35 kg/m 2 , preexisting diabetes, twin pregnancy, and a family history of preeclampsia. According to the Cochrane systematic review, women who were either normotensive or had chronic hyper-tension without superimposed preeclampsia at trial entry were classifi ed as being at high risk if they had one or more of the following: previous severe preeclampsia, diabetes, chronic hypertension, renal disease, or autoimmune disease. 314
Some have suggested anticoagulant therapy with LMWH or UFH for women at very high risk for pre-eclampsia. An effect of anticoagulant therapy on the risk of preeclampsia is biologically plausible not only because of a reduction in thrombosis formation but also because LMWH has been shown to have an anti-apoptotic effect on trophoblasts, 248,318 a potential trigger for preeclampsia. However, an observational study of 58 women with previous preeclampsia and an underlying thrombophilia found no difference in the
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subsequently been published that provide relevant evidence on the effects of LMWH plus aspirin vs aspirin or placebo/no treatment on recurrent idio-pathic pregnancy loss. 327,328
11.2.1 LMWH and Aspirin vs No Treatment or Placebo : Table 12 and Table S25 summarize the quality of evidence and main fi ndings from our meta-analysis of the two randomized trials that included 538 women with at least two miscarriages. 327,328 The meta-analysis provides moderate-quality evidence that LMWH and aspirin do not reduce miscarriage or increase major bleeding events in women with at least two recurrent miscarriages.
Women with three or more pregnancy losses might benefi t from anticoagulant therapy. Two randomized trials of women with three or more pregnancy losses reported a substantial benefi t of LMWH therapy on miscarriages. 329,330 However, both of these studies had important methodologic limitations, including a lack of blinding 329 or uncertain blinding, 330 relatively high rates of loss to follow-up, 329,330 lack of prospective trial registration, 329,330 and an unexpectedly low live birth rate in the placebo arm. 330 These fi ndings are chal-lenged by fi ndings from the more recent high-quality randomized trials described previously in the present article. In one of these studies, a prespecifi ed subgroup analysis of women with three or more miscarriages showed no evidence of a different relative effect of LMWH and aspirin vs placebo (test for interaction P 5 .85). 327 The other study provided data for the same subgroup of women and found no difference in effect (27% miscarriages in treatment group vs 24% in con-trol group), although no formal subgroup analysis was performed. 326 We consider these fi ndings more cred-ible than those of the two lower-quality randomized
was stopped before reaching its planned sample size of 276 when an interim analysis performed because of slow accrual suggested a statistically signifi cant decrease in the primary outcome, potentially exagger-ating the treatment effect. 322,323
Recommendation
11.1.1. For women considered at risk for pre-eclampsia, we recommend low-dose aspirin throughout pregnancy, starting from the second trimester, over no treatment (Grade 1B) .
11.2 Women Without Known Thrombophilia and at Least Two Prior Pregnancy Losses
A Cochrane systematic review from 2009 that examined the use of aspirin and anticoagulation for recurrent pregnancy loss in women without APLA syndrome 324 identifi ed two randomized trials: one com-paring aspirin to placebo (n 5 54) 283 and the other comparing enoxaparin to aspirin (n 5 107). 325 Neither of the studies found signifi cant differences in live birth rates, which ranged from 81% to 84%. Another systematic review, published in 2010, of LMWH vs aspirin or LMWH vs no treatment/placebo iden-tifi ed fi ve randomized trials (n 5 757). 326 The studies reviewed varied in terms of defi nition of early or late pregnancy loss, thrombophilic risk factors, and number of prior pregnancy losses. No meta-analysis was performed in the systematic review due to clinical heterogeneity of the studies. Risk ratios for pregnancy loss in the individual studies ranged from 0.95 to 3.0. The authors of this systematic review concluded that there was low-quality evidence, suggesting no effect of LMWH or aspirin. Two randomized trials have
Table 12— [Section 11.2.1] Summary of Findings: Should LMWH and Aspirin Rather Than No Treatment Be Used for Prevention of Recurrent Pregnancy Loss in Women Without Thrombophilia
OutcomesParticipants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI) a
Anticipated Absolute Effects During Pregnancy
Risk Without TreatmentRisk Difference With
LMWH 1 Aspirin (95% CI)
Miscarriage 496 (2 RCTs), 9 mo Moderate due to imprecision b
RR 1.01 (0.84-1.38)
300 cases of miscarriage per 1,000 c
No signifi cant difference; 3 more cases per 1,000 (from 48 fewer to 114 more)
Major bleeding events d
294 (1 RCTs), 9 mo Moderate due to imprecision b
RR 1.00 (0.42-2.33)
15 bleeding events per 1,000 e
No signifi cant difference; 0 more bleeding events per 1,000 (from 9 fewer to 20 more)
Data from unpublished meta-analysis 1 of two RCTs by Kaandorp et al 327 and Clark et al. 328 See Table 2 for expansion of abbreviations. a Wide CIs include benefi t and harm. b Meta-analysis performed in RevMan version 5 with fi xed-effects model for heterogeneity. c Control group risk for miscarriage comes from study event rates in the two available randomized trials. 327,328 d Antepartum maternal major hemorrhage. Bleeding outcomes variably reported in the two trials. We use data from Clark et al 328 on serious adverse events and antepartum hemorrhage both to generate relative risks and baseline risks for anticipated absolute effects. Kaandorp et al 327 reported nosebleed, GI problems, hematuria, and bleeding gums. There were no major bleeding events (S. Middeldorp, MD, personal communication, October 2010 ). e Control group risk estimate for major bleeding events antepartum with aspirin comes from systematic review by Greer et al. 38
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Table 13— [Section 11.2.1] Summary of Findings: Should Aspirin Rather Than No Treatment Be Used for Prevention of Recurrent Pregnancy Loss in Women Without Thrombophilia
OutcomesParticipants (Studies),
Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI) a
Anticipated Absolute Effects During Pregnancy
Risk Without AspirinRisk Difference With Aspirin
(95% CI)
Miscarriage 202 (1 RCT), 9 mo Moderate due to imprecision a
RR 1.16 (0.80-1.69)
300 cases of miscarriage per 1,000 b
No signifi cant difference; 48 more cases per 1,000 (from 60 fewer to 207 more)
Major bleeding events c
95 000 (6), 3.8-10 y Moderate due to indirectness d
RR 1.54 (1.30-1.82)
15 bleeding events per 1,000 e
8 more bleeding events per 1,000 (from 5 more to 12 more)
Data from Kaandorp et al, 327 the only study identifi ed that compared aspirin to placebo in this population, and ATT Collaboration, 315 for relative effect estimate of major bleeding events. See Table 2 legend for expansion of abbreviations. a Wide CIs include benefi t and harm of aspirin on miscarriage. b Baseline risk for miscarriage comes from study event rates in the two available randomized trials. 327,328 c Major antenatal nonfatal hemorrhage. d Rated down for indirectness due to population (primary prevention cardiovascular disease). 315 There were no major bleeding events in the Anticoagulants for LIving Fetuses (ALIFE) Study 327 (S. Middeldorp, MD, personal communication, October 2010 ). e Control group risk estimate for major bleeding events antepartum comes from systematic review by Greer et al. 38
doubt has been raised about their effectiveness for prevention of systemic embolism in this setting. Unfor-tunately, properly designed trials have not been per-formed, and even the small amount of data available is limited by signifi cant heterogeneity for valve type; valve position; valve area; and presence of comorbid conditions, such as atrial fi brillation.
12.1 Anticoagulant Management of Mechanical Prosthetic Valves in Pregnant Women
Tables S27 and S28 present the available data regarding maternal outcomes in this setting. 49,50,332-340 In a systematic review of observational studies between 1966 and 1997 that reported on outcomes with var-ious anticoagulant regimens in pregnant women with mechanical prosthetic valves, the regimen associated with the lowest risk of valve thrombosis/systemic embo-lism was the use of vitamin K antagonists throughout pregnancy (3.9%). 49 The use of UFH in the fi rst tri-mester and near term was associated with a higher risk of valve thrombosis (9.2%). 49 The risk of throm-boembolic complications was highest when UFH was used throughout pregnancy (33.3%), 49 and events occurred in women receiving both IV and adjusted-dose subcutaneous UFH and in those treated with low-dose heparin. Although these data suggest that vitamin K antagonists are more effective than UFH for thromboembolic prophylaxis of pregnant women with mechanical heart valves, some of the thrombo-embolic events in women treated with UFH might be explained by inadequate dosing, use of an inappro-priate target aPTT range, or differences in risk profi le in the patient populations treated with UFH vs those treated with vitamin K antagonists.
LMWH has advantages over UFH in terms of the maternal side effect profi le, and there is increasing use of LMWH in pregnant women with prosthetic heart
trials; however, a possible deleterious effect of aspirin on pregnancy outcome when used in combination with LMWH cannot be excluded.
11.2.2 Aspirin vs Placebo: Table 13 and Table S26 summarize the main fi ndings from a randomized comparison of 104 women allocated to aspirin and 103 women with two or more unexplained recurrent miscarriages allocated to placebo. 327 This trial pro-vides moderate-quality evidence that aspirin does not improve live birth rates among women with two or more unexplained recurrent miscarriages. Similarly, the randomized trial of low-dose aspirin vs placebo 283 that included 54 women with three or more preg-nancy losses did not fi nd a signifi cant difference in miscarriages (RR, 1.00; 95% CI, 0.78-1.29).
Recommendation
11.2.1. For women with two or more miscar-riages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B) .
12.0 Maternal and Fetal Risks Related to Anticoagulation During Pregnancy
for Mechanical Prosthetic Valves
Patients with a mechanical heart valve not receiv-ing antithrombotic therapy face a high risk of valve thrombosis and death or systemic embolism (see Whitlock et al 331 in this guideline). However, as out-lined in section 3.0, the use of vitamin K antagonists during pregnancy carries potential for risks to the fetus, especially if these drugs are administered dur-ing the fi rst trimester or at term. Although LMWH or UFH can be substituted for vitamin K antagonists,
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Thus, it appears that there is no single optimal treatment approach for managing pregnant women with mechanical prosthetic valves. Given the limited and sometimes confl icting data, several approaches remain acceptable ( Table 14 ). The decision about which regimen to use should be made after full dis-cussion with the patient. Additional risk factors for thromboembolism as well as patient preference should be taken into consideration. For example, women at very high risk (eg, fi rst-generation mechan-ical valve in the mitral position, history of throm-boembolism, associated atrial fi brillation) may prefer vitamin K antagonist use throughout pregnancy. If warfarin is used, the dose should be adjusted as rec-ommended by Whitlock et al. 331 If subcutaneous UFH is used, it should be initiated in high doses (17,500-20,000 units every 12 h) and adjusted to prolong a 6-h postinjection aPTT into the therapeutic range. If LMWH is used, it should be administered bid and dosed to achieve the manufacturer’s peak anti-Xa level 4 h after subcutaneous injection. Extrapolating from data in nonpregnant patients with mechanical valves receiving warfarin therapy, 342 for the same high-risk women, the addition of aspirin 75 to 100 mg/d can be considered in an attempt to reduce the risk of throm-bosis, recognizing that it increases the risk of bleeding.
Recommendations
12.1.1. For pregnant women with mechanical heart valves, we recommend one of the follow-ing anticoagulant regimens in preference to no anticoagulation (all Grade 1A) :
(a) Adjusted-dose bid LMWH through out preg-nancy. We suggest that doses be adjusted
valves. The safety of LMWH for this indication was questioned in a warning from an LMWH manufac-turer. 341 This warning was based on postmarketing reports of valve thrombosis in an undisclosed number of patients receiving this LMWH as well as on clinical outcomes in an open randomized study comparing LMWH (enoxaparin) with warfarin and UFH in preg-nant women with prosthetic heart valves. 341 Because of two deaths in the LMWH arm, the study was termi-nated after 12 of the planned 110 patients were enrolled.
In a systematic review of observational studies published between 2000 and 2009, the use of LMWH (or UFH) during the fi rst trimester and near term or throughout pregnancy was associated with a higher risk of valve thrombosis or maternal thromboem-bolism (7.2% and 13.4%, respectively) than the use of vitamin K antagonists alone (2.9%). 50 Maternal bleed-ing risks were similar across the various treatment regimens.
In a review of case series and cohort studies between 1996 and 2006 involving pregnant women with mechan-ical heart valves who were converted to LMWH prior to pregnancy or by the end of the fi rst trimester, mater-nal valve thrombosis or thromboembolism occurred in 17 of 76 (22.4%) pregnancies. 332 Another system-atic review of LMWH use in pregnant women with mechanical prosthetic heart valves that used slightly different eligibility criteria found that valve throm-bosis occurred in seven of 81 pregnancies (8.6%; 95% CI, 2.5%-14.8%), and the overall thromboem-bolic rate was 10 of 81 pregnancies (12.4%; 95% CI, 5.2%-19.5%). 333 However, nine of the 10 patients with thromboembolic complications received a fi xed dose of LMWH, and in two of these, a fi xed low dose was used. Among 51 pregnancies in which anti-Xa LMWH levels were monitored and doses adjusted according to the result, only one patient was reported to have experienced a thromboembolic complication. Two sub-sequent case series 334,335 and one cohort study without internal control 336 that evaluated LMWH given every 12 h and adjusted to maintain therapeutic peak anti-Xa LMWH levels reported risks of maternal valve throm-bosis or systemic thromboembolism ranging between 4.3% and 16.7%.
As outlined in Table S29, the use of UFH or LMWH throughout pregnancy essentially eliminates the risk of congenital malformation. 49,50,332-336 Most pub-lished studies suggest that risks of malformation are also low ( , 2%) if UFH or LMWH are substituted for vitamin K antagonists during the fi rst trimester (pref-erably before the 6th week of gestation). 49,50,332-336 The number of pregnancy losses appears higher in those patients who receive either vitamin K antago-nists or a heparin throughout pregnancy than in those in whom UFH or LMWH are substituted for vitamin K antagonists in the fi rst trimester and at term. 49,50,332-340
Table 14— [12.1.1-12.1.3] Recommended Anticoagulant Regimens in Pregnant Women With Mechanical
Heart Valves
Adjusted-dose bid LMWH throughout pregnancy, with doses adjusted to achieve the manufacturer’s peak anti-Xa LMWH 4 h postsubcutaneous injection (Grade 1A).
Adjusted-dose UFH throughout pregnancy administered subcutaneously every 12 h in doses adjusted to keep the midinterval aPTT at least twice control or attain an anti-Xa heparin level of 0.35-0.70 units/mL (Grade 1A).
UFH or LMWH (as above) until the 13th week with substitution by vitamin K antagonists until close to delivery when UFH or LMWH is resumed (Grade 1A).
For women judged to be at very high risk of thromboembolism in whom concerns exist about the effi cacy and safety of UFH or LMWH as dosed above (eg, older-generation prosthesis in the mitral position or history of thromboembolism), vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH (as above) close to delivery (Grade 2C).
aPTT 5 activated partial thromboplastin time. See Table 2 and 10 legends for expansion of abbreviations.
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article is still generally of low quality. Most recom-mendations are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies to inform us of the risk of recurrent pregnancy-associated VTE and of fi rst VTE in thrombophilic women and those undergoing cesarean section and assisted repro-ductive technology. Further research is needed to optimize regimens for the prevention of VTE and mechanical valve thrombosis. Given the uncertainty of baseline estimates for both the risks of the various conditions discussed in this article and the benefi ts of prophylactic and therapeutic interventions, knowl-edge of pregnant women’s values and treatment pref-erences are crucial when making recommendations. Although investigators have explored patient values and preferences with respect to antithrombotic therapy in other contexts, no studies have been performed in pregnant women.
Although the performance of clinical trials involv-ing pregnant women is challenging, there is a clear need for methodologically strong studies in this patient population. All pregnant women are best protected when evidence about conditions that affect them is gathered in a scientifi cally rigorous manner that max-imizes participant safety. 343
Acknowledgments Author contributions: As Topic Editor, Dr Vandvik oversaw the development of this article, including the data analysis and subse-quent development of the recommendations contained herein. Dr Bates: contributed as Deputy Editor . Dr Greer: contributed as a panelist. Dr Middeldorp: contributed as a panelist. Dr Veenstra: contributed as a resource consultant. Dr. Prabulos: contributed as a front line clinician. Dr Vandvik: contributed as Topic Editor. Financial/nonfi nancial disclosures: The authors of this guide-line provided detailed confl ict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e691S/suppl/DC1. In summary, the authors have reported to CHEST the following confl icts of interest: Dr Bates has received honoraria for lectures from Leo Pharma, Inc. (anti-coagulant manufacturer), Sanofi -Aventis Canada (anticoagulant manufacturer), Boehringer Ingelheim GmbH (anticoagulant manu-facturer), and Thrombosis Education, Ltd. Dr Greer has received honoraria for lectures and advisory board contributions from Leo Pharma and Sanofi-Aventis. Dr Middeldorp has received unrestricted research funding from GlaxoSmithKline plc and MedaPharma for the ALIFE study and has received speakers fees from GlaxoSmithKline plc; Boehringer Ingelheim GmbH; Bayer Healthcare Pharmaceuticals; Leo Pharma, Inc. Dr Vandvik is a member of and prominent contributor to the GRADE Working Group. Drs Veenstra and Prabulos have reported that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed in this article . Role of sponsors: The sponsors played no role in the develop-ment of these guidelines. Sponsoring organizations cannot recom-mend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Sci-ence Policy Committee are blinded to the funding sources. Fur-ther details on the Confl ict of Interest Policy are available online at http://chestnet.org.
to achieve the manufacturer’s peak anti-Xa LMWH 4 h postsubcutaneous injection; or (b) Adjusted-dose UFH throughout pregnancy administered subcutaneously every 12 h in doses adjusted to keep the midinterval aPTT at least twice control or attain an anti-Xa heparin level of 0.35 to 0.70 units/mL; or (c) UFH or LMWH (as above) until the 13th week with substitution by vitamin K antagonists until close to delivery when UFH or LMWH is resumed.
Remarks: For pregnant women with mechanical heart valves, the decision regarding the choice of anticoag-ulant regimen is so value and preference dependent (risk of thrombosis vs risk of fetal abnormalities) that we consider the decision to be completely individ-ualized. Women of childbearing age and pregnant women with mechanical valves should be counseled about potential maternal and fetal risks associated with various anticoagulant regimens, including con-tinuation of vitamin K antagonists with substitution by LMWH or UFH close to term, substitution of vitamin K antagonists by LMWH or UFH until the 13th week and then close to term, and use of LMWH or UFH throughout pregnancy. Usual long-term anticoagulants should be resumed postpartum when adequate hemostasis is assured.
12.1.2. In women judged to be at very high risk of thromboembolism in whom concerns exist about the effi cacy and safety of UFH or LMWH as dosed above (eg, older-generation prosthesis in the mitral position or history of thrombo-embolism), we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH (as above) close to delivery rather than one of the regimens above (Grade 2C) .
Remarks: The recommendation for women at very high risk of thromboembolism places a higher value on avoiding maternal complications (eg, catastrophic valve thrombosis) than on avoiding fetal complica-tions. Women who place a higher risk on avoiding fetal risk will choose LMWH or UFH over vitamin K antagonists.
12.1.3. For pregnant women with prosthetic valves at high risk of thromboembolism, we suggest the addition of low-dose aspirin 75 to 100 mg/d (Grade 2C) .
13.0 Recommendations for Research
Although new information has been published since our last review, the available evidence in this
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weight heparin or unfractionated heparin . N Engl J Med . 1995 ; 332 ( 20 ): 1330 - 1335 .
14 . Linkins L-A, Dans AL, Moores LK, et al. Treatment and pre-vention of heparin-induced thrombocytopenia: antithrom-botic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 141(2)(suppl):e495S-e530S.
15 . de Valk HW , Banga JD , Wester JWJ , et al . Comparing subcu-taneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A random-ized controlled trial . Ann Intern Med . 1995 ; 123 ( 1 ): 1 - 9 .
16 . Peeters LLH , Hobbelen PMJ , Verkeste CM , et al . Pla-cental transfer of Org 10172, a low-molecular weight hepa-rinoid, in the awake late-pregnant guinea pig . Thromb Res . 1986 ; 44 ( 3 ): 277 - 283 .
17 . Henny CP , ten Cate H , ten Cate JW , Prummel MF , Peters M , Büller HR . Thrombosis prophylaxis in an AT III defi cient pregnant woman: application of a low molecular weight heparinoid . Thromb Haemost . 1986 ; 55 ( 2 ): 301 .
18 . Greinacher A , Eckhardt T , Mussmann J , Mueller-Eckhardt C . Pregnancy complicated by heparin associated thrombocy-topenia: management by a prospectively in vitro selected heparinoid (Org 10172) . Thromb Res . 1993 ; 71 ( 2 ): 123 - 126 .
19 . Magnani HN . Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172) . Thromb Haemost . 1993 ; 70 ( 4 ): 554 - 561 .
20 . Rubin N , Rubin J . Treatment of heparin induced thrombo-cytopenia with thrombosis (HITT) in pregnancy with fonda-parinux [abstract]. Paper presented at: the 45th Annual Meeting of the American Society of Hematology; December 6-9, 2003 ; San Diego, CA.
21 . Parody R , Oliver A , Souto JC , Fontcuberta J . Fondaparinux (ARIXTRA) as an alternative anti-thrombotic prophylaxis when there is hypersensitivity to low molecular weight and unfractionated heparins . Haematologica . 2003 ; 88 ( 11 ): ECR32 .
22 . Douketis JD , Ginsberg JS , Burrows RF , Duku EK , Webber CE , Brill-Edwards P . The effects of long-term heparin therapy during pregnancy on bone density. A prospec-tive matched cohort study . Thromb Haemost . 1996 ; 75 ( 2 ): 254 - 257 .
23 . Dahlman TC . Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with hep-arin . Am J Obstet Gynecol . 1993 ; 168 ( 4 ): 1265 - 1270 .
24 . Ginsberg JS , Kowalchuk G , Hirsh J , et al . Heparin effect on bone density . Thromb Haemost . 1990 ; 64 ( 2 ): 286 - 289 .
25 . Dahlman TC , Lindvall N , Hellgren M . Osteopenia in pregnancy during long-term heparin treatment: a radiolog-ical study post partum . Br J Obstet Gynaecol . 1990 ; 97 ( 3 ): 221 - 228 .
26 . Monreal M , Lafoz E , Olive A , del Rio L , Vedia C . Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous throm-boembolism and contraindications to coumarin . Thromb Haemost . 1994 ; 71 ( 1 ): 7 - 11 .
27 . Pettilä V , Leinonen P , Markkola A , Hiilesmaa V , Kaaja R . Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin . Thromb Haemost . 2002 ; 87 ( 2 ): 182 - 186 .
28 . Muir JM , Andrew M , Hirsh J , et al . Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo . Blood . 1996 ; 88 ( 4 ): 1314 - 1320 .
29 . Muir JM , Hirsh J , Weitz JI , Andrew M , Young E , Shaughnessy SG . A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats . Blood . 1997 ; 89 ( 9 ): 3236 - 3242 .
Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clin-ical Pharmacy, the American Society of Health-System Pharma-cists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additionally, the guide-lines presented in this article have been endorsed by the American College of Obstetricians and Gynecologists. Additional Information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e691S/suppl/DC1.
References 1 . Schulman S , Kearon C ; Subcommittee on Control of Anti-
coagulation of the Scientifi c and Standardization Committee of the International Society on Thrombosis and Haemostasis . Defi nition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients . J Thromb Haemost . 2005 ; 3 ( 4 ): 692 - 694 .
2 . Guyatt GH , Oxman AD , Vist GE , et al ; GRADE Working Group . GRADE: an emerging consensus on rating quality of evidence and strength of recommendations . BMJ . 2008 ; 336 ( 7650 ): 924 - 926 .
3 . Guyatt G , Gutterman D , Baumann MH , et al . Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force . Chest . 2006 ; 129 ( 1 ): 174 - 181 .
4 . Guyatt GH, Norris SL, Schulman S, et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: antithrombotic therapy and pre-vention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):53S-70S.
5 . MacLean S , Mulla S , Akl E , et al. Patient values and pref-erences in decision making for antithrombotic therapy: a systematic review: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e1S-e23S.
6 . Chunilal SD , Young E , Johnston MA , et al . The APTT response of pregnant plasma to unfractionated heparin . Thromb Haemost . 2002 ; 87 ( 1 ): 92 - 97 .
7 . Ginsberg JS , Kowalchuk G , Hirsh J , Brill-Edwards P , Burrows R . Heparin therapy during pregnancy. Risks to the fetus and mother . Arch Intern Med . 1989 ; 149 ( 10 ): 2233 - 2236 .
8 . Hull RD , Delmore TJ , Carter CJ , et al . Adjusted subcu-taneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis . N Engl J Med . 1982 ; 306 ( 4 ): 189 - 194 .
9 . Hull RD , Hirsh J , Jay R , et al . Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis . N Engl J Med . 1982 ; 307 ( 27 ): 1676 - 1681 .
10 . Kearon C , Ginsberg JS , Kovacs MJ , et al; Extended Low-Intensity Anticoagulation for Thrombo-Embolism Inves-tigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term pre-vention of recurrent venous thromboembolism. N Engl J Med . 2003 ;349(7):631-639.
11 . Anderson DR , Ginsberg JS , Burrows R , Brill-Edwards P . Subcutaneous heparin therapy during pregnancy: a need for concern at the time of delivery . Thromb Haemost . 1991 ; 65 ( 3 ): 248 - 250 .
12 . Burrows RF , Kelton JG . Incidentally detected thrombocy-topenia in healthy mothers and their infants . N Engl J Med . 1988 ; 319 ( 3 ): 142 - 145 .
13 . Warkentin TE , Levine MN , Hirsh J , et al . Heparin-induced thrombocytopenia in patients treated with low-molecular-
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e728S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
30 . Shaughnessy SG , Hirsh J , Bhandari M , Muir JM , Young E , Weitz JI . A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treat-ment in rats . Blood . 1999 ; 93 ( 4 ): 1231 - 1236 .
31 . Harenberg J , Hoffmann U , Huhle G , Winkler M , Bayerl C . Cutaneous reactions to anticoagulants. Recognition and man-agement . Am J Clin Dermatol . 2001 ; 2 ( 2 ): 69 - 75 .
32 . Gould MK , Dembitzer AD , Doyle RL , Hastie TJ , Garber AM . Low-molecular-weight heparins compared with unfraction-ated heparin for treatment of acute deep venous throm-bosis. A meta-analysis of randomized, controlled trials . Ann Intern Med . 1999 ; 130 ( 10 ): 800 - 809 .
33 . Quinlan DJ , McQuillan A , Eikelboom JW . Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials . Ann Intern Med . 2004 ; 140 ( 3 ): 175 - 183 .
34 . Eikelboom JW , Anand SS , Malmberg K , Weitz JI , Ginsberg JS , Yusuf S . Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis . Lancet . 2000 ; 355 ( 9219 ): 1936 - 1942 .
35 . Weitz JI . Low-molecular-weight heparins [published cor-rection appears in N Engl J Med. 1997;337(21):1567]. N Engl J Med . 1997 ; 337 ( 10 ): 688 - 698 .
36 . Lepercq J , Conard J , Borel-Derlon A , et al . Venous throm-boembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies . BJOG . 2001 ; 108 ( 11 ): 1134 - 1140 .
37 . Sanson BJ , Lensing AWA , Prins MH , et al . Safety of low-molecular-weight heparin in pregnancy: a systematic review . Thromb Haemost . 1999 ; 81 ( 5 ): 668 - 672 .
38 . Greer IA , Nelson-Piercy C . Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thrombo-embolism in pregnancy: a systematic review of safety and effi cacy . Blood . 2005 ; 106 ( 2 ): 401 - 407 .
39 . Carlin AJ , Farquharson RG , Quenby SM , Topping J , Fraser WD . Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control . Hum Reprod . 2004 ; 19 ( 5 ): 1211 - 1214 .
40 . Rodger MA , Kahn SR , Cranney A , et al ; TIPPS investigators . Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial . J Thromb Haemost . 2007 ; 5 ( 8 ): 1600 - 1606 .
41 . Lefkou E , Khamashta M , Hampson G , Hunt BJ . Review: Low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity? Lupus . 2010 ; 19 ( 1 ): 3 - 12 .
42 . Byrd LM , Shiach CR , Hay CRM , Johnston TA . Osteo penic fractures in pregnancy: is low molecular weight heparin (LMWH) implicated? J Obstet Gynaecol . 2008 ; 28 ( 5 ): 539 - 542 .
43 . Hunt BJ , Doughty HA , Majumdar G , et al . Thrombo-prophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies . Thromb Haemost . 1997 ; 77 ( 1 ): 39 - 43 .
44 . Bauersachs RM , Dudenhausen J , Faridi A , et al ; EThIG Investigators . Risk stratifi cation and heparin prophylaxis to prevent venous thromboembolism in pregnant women . Thromb Haemost . 2007 ; 98 ( 6 ): 1237 - 1245 .
45 . Bank I , Libourel EJ , Middeldorp S , Van Der Meer J , Büller HR . High rate of skin complications due to low-molecular-weight heparins in pregnant women . J Thromb Haemost . 2003 ; 1 ( 4 ): 859 - 861 .
46 . Wütschert R , Piletta P , Bounameaux H . Adverse skin reac-tions to low molecular weight heparins: frequency, manage-ment and prevention . Drug Saf . 1999 ; 20 ( 6 ): 515 - 525 .
47 . Ginsberg JS , Hirsh J , Turner DC , Levine MN , Burrows R . Risks to the fetus of anticoagulant therapy during preg-nancy . Thromb Haemost . 1989 ; 61 ( 2 ): 197 - 203 .
48 . Hall JG , Pauli RM , Wilson KM . Maternal and fetal sequelae of anticoagulation during pregnancy . Am J Med . 1980 ; 68 ( 1 ): 122 - 140 .
49 . Chan WS , Anand S , Ginsberg JS . Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature . Arch Intern Med . 2000 ; 160 ( 2 ): 191 - 196 .
50 . Hassouna A , Allam H . Anticoagulation of pregnant women with mechanical heart valve prosthesis: a systematic review of the literature (2000-2009) . J Coagul Disorders . 2010 ; 2 ( 1 ): 81 - 88 .
51 . Pauli RM , Haun J . Intrauterine effects of coumarin deriva-tives . Dev Brain Dysfunct . 1993 ; 6 : 229 - 247 .
52 . Ben Ismail M , Abid F , Trabelsi S , Taktak M , Fekih M . Cardiac valve prostheses, anticoagulation, and pregnancy . Br Heart J . 1986 ; 55 ( 1 ): 101 - 105 .
53 . Born D , Martinez EE , Almeida PAM , et al . Pregnancy in patients with prosthetic heart valves: the effects of anti-coagulation on mother, fetus, and neonate . Am Heart J . 1992 ; 124 ( 2 ): 413 - 417 .
54 . Pavankumar P , Venugopal P , Kaul U , et al . Pregnancy in patients with prosthetic cardiac valve. A 10-year experience . Scand J Thorac Cardiovasc Surg . 1988 ; 22 ( 1 ): 19 - 22 .
55 . Larrea JL , Núñez L , Reque JA , Gil Aguado M , Matarros R , Minguez JA . Pregnancy and mechanical valve prostheses: a high-risk situation for the mother and the fetus . Ann Thorac Surg . 1983 ; 36 ( 4 ): 459 - 463 .
56 . Al-Lawati AAM , Venkitraman M , Al-Delaime T , Valliathu J . Pregnancy and mechanical heart valves replacement; dilemma of anticoagulation . Eur J Cardiothorac Surg . 2002 ; 22 ( 2 ): 223 - 227 .
57 . Iturbe-Alessio I , Fonseca MC , Mutchinik O , Santos MA , Zajarías A , Salazar E . Risks of anticoagulant therapy in pregnant women with artifi cial heart valves . N Engl J Med . 1986 ; 315 ( 22 ): 1390 - 1393 .
58 . Schaefer C , Hannemann D , Meister R , et al . Vitamin K antagonists and pregnancy outcome. A multi-centre pro-spective study . Thromb Haemost . 2006 ; 95 ( 6 ): 949 - 957 .
59 . Wesseling J , Van Driel D , Heymans HS , et al . Coumarins during pregnancy: long-term effects on growth and develop-ment of school-age children . Thromb Haemost . 2001 ; 85 ( 4 ): 609 - 613 .
60 . van Driel D , Wesseling J , Sauer PJJ , van Der Veer E , Touwen BC , Smrkovsky M . In utero exposure to cou-marins and cognition at 8 to 14 years old . Pediatrics . 2001 ; 107 ( 1 ): 123 - 129 .
61 . Hirsh J , Cade JF , O’Sullivan EF . Clinical experience with anticoagulant therapy during pregnancy . BMJ . 1970 ; 1 ( 5691 ): 270 - 273 .
62 . Vitale N , De Feo M , De Santo LS , Pollice A , Tedesco N , Cotrufo M . Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves . J Am Coll Cardiol . 1999 ; 33 ( 6 ): 1637 - 1641 .
63 . Flessa HC , Kapstrom AB , Glueck HI , Will JJ . Placental trans-port of heparin . Am J Obstet Gynecol . 1965 ; 93 ( 4 ): 570 - 573 .
64 . Clark NP , Delate T , Witt DM , Parker S , McDuffi e R . A descriptive evaluation of unfractionated heparin use during pregnancy . J Thromb Thrombolysis . 2009 ; 27 ( 3 ): 267 - 273 .
65 . Forestier F , Daffos F , Capella-Pavlovsky M . Low molecular weight heparin (PK 10169) does not cross the placenta dur ing the second trimester of pregnancy study by direct fetal blood sampling under ultrasound . Thromb Res . 1984 ; 34 ( 6 ): 557 - 560 .
66 . Forestier F , Daffos F , Rainaut M , Toulemonde F . Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy . Thromb Haemost . 1987 ; 57 ( 2 ): 234 .
67 . Lindhoff-Last E , Kreutzenbeck H-J , Magnani HN . Treat-ment of 51 pregnancies with danaparoid because of heparin intolerance . Thromb Haemost . 2005 ; 93 ( 1 ): 63 - 69 .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e729S
68 . Lagrange F , Vergnes C , Brun JL , et al . Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro . Thromb Haemost . 2002 ; 87 ( 5 ): 831 - 835 .
69 . Dempfl e CE . Minor transplacental passage of fondaparinux in vivo . N Engl J Med . 2004 ; 350 ( 18 ): 1914 - 1915 .
70 . Harenberg J . Treatment of a woman with lupus and throm-boembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy . Thromb Res . 2007 ; 119 ( 3 ): 385 - 388 .
71 . Mazzolai L , Hohlfeld P , Spertini F , Hayoz D , Schapira M , Duchosal MA . Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy . Blood . 2006 ; 108 ( 5 ): 1569 - 1570 .
72 . Wijesiriwardana A , Lees DA , Lush C . Fondaparinux as anti-coagulant in a pregnant woman with heparin allergy . Blood Coagul Fibrinolysis . 2006 ; 17 ( 2 ): 147 - 149 .
73 . Gerhardt A , Zotz RB , Stockschlaeder M , Scharf RE . Fonda-parinux is an effective alternative anticoagulant in pregnant women with high risk of venous thromboembolism and intolerance to low-molecular-weight heparins and hepari-noids . Thromb Haemost . 2007 ; 97 ( 3 ): 496 - 497 .
74 . Schapkaitz E , Jacobson BF . Delayed hypersensitivity to low-molecular-weight heparin (LMWH) in pregnancy . S Afr Med J . 2007 ; 97 ( 12 ): 1255 - 1257 .
75 . Winger EE , Reed JL . A retrospective analysis of fondaparinux versus enoxaparin treatment in women with infertility or preg-nancy loss . Am J Reprod Immunol . 2009 ; 62 ( 4 ): 253 - 260 .
76 . Knol HM , Schultinge L , Erwich JJHM , Meijer K . Fonda-parinux as an alternative anticoagulant therapy during preg-nancy . J Thromb Haemost . 2010 ; 8 ( 8 ): 1876 - 1879 .
77 . Lindhoff-Last E , Bauersachs R . Heparin-induced thrombocytopenia-alternative anticoagulation in pregnancy and lactation . Semin Thromb Hemost . 2002 ; 28 ( 5 ): 439 - 446 .
78 . Markwardt F , Fink G , Kaiser B , et al . Pharmacological survey of recombinant hirudin . Pharmazie . 1988 ; 43 ( 3 ) 202 - 207 .
79 . Mehta R , Golichowski A . Treatment of heparin induced thrombocytopenia and thrombosis during the fi rst trimester of pregnancy . J Thromb Haemost . 2004 ; 2 ( 9 ): 1665 - 1666 .
80 . Furlan A , Vianello F , Clementi M , Prandoni P . Heparin- induced thrombocytopenia occurring in the fi rst trimester of pregnancy: successful treatment with lepirudin. A case report . Haematologica . 2006 ; 91 ( suppl 8 ): ECR40 .
81 . Taniguchi S , Fukuda I , Minakawa M , Watanabe K , Daitoku K , Suzuki Y . Emergency pulmonary embolectomy during the second trimester of pregnancy: report of a case . Surg Today . 2008 ; 38 ( 1 ): 59 - 61 .
82 . Young SK , Al-Mondhiry HA , Vaida SJ , Ambrose A , Botti JJ . Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature . Pharmacotherapy . 2008 ; 28 ( 12 ): 1531 - 1536 .
83 . Ekbatani A , Asaro LR , Malinow AM . Anticoagulation with argatroban in a parturient with heparin-induced throm-bocytopenia . Int J Obstet Anesth . 2010 ; 19 ( 1 ): 82 - 87 .
84 . Boehringer Ingelheim . Summary of product characteristics: dabigatran etexilate. Date of text revision: March 2009
85 . Bayer Schering Pharma AG . Summary of product charac-teristics: rivaroxaban. Date of text revision: May 2009
86 . Askie LM , Duley L , Henderson-Smart DJ , Stewart LA ; PARIS Collaborative Group . Antiplatelet agents for preven-tion of pre-eclampsia: a meta-analysis of individual patient data . Lancet . 2007 ; 369 ( 9575 ): 1791 - 1798 .
87 . Kozer E , Nikfar S , Costei A , Boskovic R , Nulman I , Koren G . Aspirin consumption during the fi rst trimester of preg-nancy and congenital anomalies: a meta-analysis . Am J Obstet Gynecol . 2002 ; 187 ( 6 ): 1623 - 1630 .
88 . Kozer E , Costei AM , Boskovic R , Nulman I , Nikfar S , Koren G . Effects of aspirin consumption during pregnancy on pregnancy outcomes: meta-analysis . Birth Defects Res B Dev Reprod Toxicol . 2003 ; 68 ( 1 ): 70 - 84 .
89 . Li DK , Liu L , Odouli R . Exposure to non-steroidal anti-infl ammatory drugs during pregnancy and risk of miscar-riage: population based cohort study . BMJ . 2003 ; 327 ( 7411 ): 368 - 372 .
90 . James AH , Brancazio LR , Price T . Aspirin and reproductive outcomes . Obstet Gynecol Surv . 2008 ; 63 ( 1 ): 49 - 57 .
91 . Pfeifer GW . Distribution and placental transfer of 131-I streptokinase . Australas Ann Med . 1970 ; 19 ( suppl 1 ): 17 - 18 .
92 . Leonhardt G , Gaul C , Nietsch HH , Buerke M , Schleussner E . Thrombolytic therapy in pregnancy . J Thromb Thrombolysis . 2006 ; 21 ( 3 ): 271 - 276 .
93 . Ahearn GS , Hadjiliadis D , Govert JA , Tapson VF . Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options . Arch Intern Med . 2002 ; 162 ( 11 ): 1221 - 1227 .
94 . te Raa GD , Ribbert LSM , Snijder RJ , Biesma DH . Treat-ment options in massive pulmonary embolism during preg-nancy; a case-report and review of literature . Thromb Res . 2009 ; 124 ( 1 ): 1 - 5 .
95 . Holden EL , Ranu H , Sheth A , Shannon MS , Madden BP . Thrombolysis for massive pulmonary embolism in pregnancy—a report of three cases and follow up over a two year period . Thromb Res . 2011 ; 127 ( 1 ): 58 - 59 .
96 . Berlin CM , Briggs GG . Drugs and chemicals in human milk . Semin Fetal Neonatal Med . 2005 ; 10 ( 2 ): 149 - 159 .
97 . Clark SL , Porter TF , West FG . Coumarin derivatives and breast-feeding . Obstet Gynecol . 2000 ; 95 ( 6 Pt 1 ): 938 - 940 .
98 . Orme ML , Lewis PJ , de Swiet M , et al . May mothers given warfarin breast-feed their infants? BMJ . 1977 ; 1 ( 6076 ): 1564 - 1565 .
99 . McKenna R , Cole ER , Vasan U . Is warfarin sodium con-traindicated in the lactating mother? J Pediatr . 1983 ; 103 ( 2 ): 325 - 327 .
100 . Houwert-de Jong M , Gerards LJ , Tetteroo-Tempelman CA , de Wolff FA . May mothers taking acenocoumarol breast feed their infants? Eur J Clin Pharmacol . 1981 ; 21 ( 1 ): 61 - 64 .
101 . Fondevila CG , Meschengieser S , Blanco A , Peñalva L , Lazzari MA . Effect of acenocoumarine on the breast-fed infant . Thromb Res . 1989 ; 56 ( 1 ): 29 - 36 .
102 . O’Reilly R . Anticoagulant, antithrombotic and thrombolytic drugs . In: Gillman AG , Goodman LS, Gillman A, eds. The Pharmacologic Basis of Therapeutics . 6th ed. New York : Macmillan ; 1980 : 1347 .
103 . Richter C , Sitzmann J , Lang P , Weitzel H , Huch A , Huch R . Excretion of low molecular weight heparin in human milk . Br J Clin Pharmacol . 2001 ; 52 ( 6 ): 708 - 710 .
104 . GlaxoSmithKline. Arixtra prescribing information. Date of test revision: January 2010
105 . Vetter A , Perera G , Leithner K , Klima G , Bernkop-Schnürch A . Development and in vivo bioavailability study of an oral fondaparinux delivery system . Eur J Pharm Sci . 2010 ; 41 ( 3-4 ): 489 - 497 .
106 . Lindhoff-Last E , Willeke A , Thalhammer C , Nowak G , Bauersachs R . Hirudin treatment in a breastfeeding woman . Lancet . 2000 ; 355 ( 9202 ): 467 - 468 .
107 . Bar-Oz B , Bulkowstein M , Benyamini L , et al . Use of anti-biotic and analgesic drugs during lactation . Drug Saf . 2003 ; 26 ( 13 ): 925 - 935 .
108 . Unsworth J , d’Assis-Fonseca A , Beswick DT , Blake DR . Serum salicylate levels in a breast fed infant . Ann Rheum Dis . 1987 ; 46 ( 8 ): 638 - 639 .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e730S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
109 . Needs CJ , Brooks PM . Antirheumatic medication during lactation . Br J Rheumatol . 1985 ; 24 ( 3 ): 291 - 297 .
110 . Clark JH , Wilson WG . A 16-day-old breast-fed infant with metabolic acidosis caused by salicylate . Clin Pediatr (Phila) . 1981 ; 20 ( 1 ): 53 - 54 .
111 . Stuart MJ , Gross SJ , Elrad H , Graeber JE . Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis . N Engl J Med . 1982 ; 307 ( 15 ): 909 - 912 .
112 . Louden KA , Broughton Pipkin F , Heptinstall S , et al . Neonatal platelet reactivity and serum thromboxane B2 production in whole blood: the effect of maternal low dose aspirin . Br J Obstet Gynaecol . 1994 ; 101 ( 3 ): 203 - 208 .
113 . Ito S , Blajchman A , Stephenson M , Eliopoulos C , Koren G . Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication . Am J Obstet Gynecol . 1993 ; 168 ( 5 ): 1393 - 1399 .
114 . Chan WS , Dixon ME . The “ART” of thromboembolism: a review of assisted reproductive technology and thromboem-bolic complications . Thromb Res . 2008 ; 121 ( 6 ): 713 - 726 .
115 . Nelson SM . Prophylaxis of VTE in women-during assisted reproductive techniques . Thromb Res . 2009 ; 123 ( suppl 3 ): S8 - S15 .
116 . Mára M , Koryntová D , Rezábek K , et al . Thromboembolic complications in patients undergoing in vitro fertilization: retrospective clinical study [in Czech] . Ceska Gynekol . 2004 ; 69 ( 4 ): 312 - 316 .
117 . Aurousseau MH , Samama MM , Belhassen A , Herve F , Hugues JN . Risk of thromboembolism in relation to an in-vitro fertilization programme: three case reports . Hum Reprod . 1995 ; 10 ( 1 ): 94 - 97 .
118 . Delvigne A , Demoulin A , Smitz J , et al . The ovarian hyper-stimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features . Hum Reprod . 1993 ; 8 ( 9 ): 1353 - 1360 .
119 . Morris RS , Miller C , Jacobs L , Miller K . Conservative man-agement of ovarian hyperstimulation syndrome . J Reprod Med . 1995 ; 40 ( 10 ): 711 - 714 .
120 . Bergh T , Lundkvist O . Clinical complications during in-vitro fertilization treatment . Hum Reprod . 1992 ; 7 ( 5 ): 625 - 626 .
121 . Jacobsen AF , Skjeldestad FE , Sandset PM . Ante- and post-natal risk factors of venous thrombosis: a hospital-based case-control study . J Thromb Haemost . 2008 ; 6 ( 6 ): 905 - 912 .
122 . Chan WS . The ‘ART’ of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology . Curr Opin Obstet Gynecol . 2009 ; 21 ( 3 ): 207 - 218 .
123 . Dessole S , Rubattu G , Ambrosini G , Miele M , Nardelli GB , Cherchi PL . Blood loss following noncomplicated trans-vaginal oocyte retrieval for in vitro fertilization . Fertil Steril . 2001 ; 76 ( 1 ): 205 - 206 .
124 . Shalev J , Davidi O , Fisch B . Quantitative three-dimensional sonographic assessment of pelvic blood after transvaginal ultrasound-guided oocyte aspiration: factors predicting risk . Ultrasound Obstet Gynecol . 2004 ; 23 ( 2 ): 177 - 182 .
125 . Ragni G , Scarduelli C , Calanna G , Santi G , Benaglia L , Somigliana E . Blood loss during transvaginal oocyte retrieval . Gynecol Obstet Invest . 2009 ; 67 ( 1 ): 32 - 35 .
126 . Bennett SJ , Waterstone JJ , Cheng WC , Parsons J . Com-plications of transvaginal ultrasound-directed follicle aspi-ration: a review of 2760 consecutive procedures . J Assist Reprod Genet . 1993 ; 10 ( 1 ): 72 - 77 .
127 . Dicker D , Ashkenazi J , Feldberg D , Levy T , Dekel A , Ben-Rafael Z . Severe abdominal complications after trans-vaginal ultrasonographically guided retrieval of oocytes for in vitro fertilization and embryo transfer . Fertil Steril . 1993 ; 59 ( 6 ): 1313 - 1315 .
128 . Tureck RW , García CR , Blasco L , Mastroianni L Jr . Perioperative complications arising after transvaginal oocyte retrieval . Obstet Gynecol . 1993 ; 81 ( 4 ): 590 - 593 .
129 . Govaerts I , Devreker F , Delbaere A , Revelard P , Englert Y . Short-term medical complications of 1500 oocyte retrievals for in vitro fertilization and embryo transfer . Eur J Obstet Gynecol Reprod Biol . 1998 ; 77 ( 2 ): 239 - 243 .
130 . Ludwig AK , Glawatz M , Griesinger G , Diedrich K , Ludwig M . Perioperative and post-operative complications of transvaginal ultrasound-guided oocyte retrieval: prospec-tive study of . 1000 oocyte retrievals . Hum Reprod . 2006 ; 21 ( 12 ): 3235 - 3240 .
131 . Bodri D , Guillén JJ , Polo A , Trullenque M , Esteve C , Coll O . Complications related to ovarian stimulation and oocyte retrieval in 4052 oocyte donor cycles . Reprod Biomed Online . 2008 ; 17 ( 2 ): 237 - 243 .
132 . Baber R , Porter R , Picker R , Robertson R , Dawson E , Saunders D . Transvaginal ultrasound directed oocyte col-lection for in vitro fertilization: successes and complications . J Ultrasound Med . 1988 ; 7 ( 7 ): 377 - 379 .
133 . Yinon Y , Pauzner R , Dulitzky M , Elizur SE , Dor J , Shulman A . Safety of IVF under anticoagulant therapy in patients at risk for thrombo-embolic events . Reprod Biomed Online . 2006 ; 12 ( 3 ): 354 - 358 .
134 . Qublan H , Amarin Z , Dabbas M , et al . Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial . Hum Fertil . 2008 ; 11 ( 4 ): 246 - 253 .
135 . Stern C , Chamley L , Norris H , Hale L , Baker HW . A ran-domized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies . Fertil Steril . 2003 ; 80 ( 2 ): 376 - 383 .
136 . Hull RD , Pineo GF , Stein PD , et al . Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthro-plasty: a systematic review . Ann Intern Med . 2001 ; 135 ( 10 ): 858 - 869 .
137 . Pomp ER , Lenselink AM , Rosendaal FR , Doggen CJ . Preg-nancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study . J Thromb Haemost . 2008 ; 6 ( 4 ): 632 - 637 .
138 . Heit JA , Kobbervig CE , James AH , Petterson TM , Bailey KR , Melton LJ III . Trends in the incidence of venous throm-boembolism during pregnancy or postpartum: a 30-year population-based study . Ann Intern Med . 2005 ; 143 ( 10 ): 697 - 706 .
139 . Gherman RB , Goodwin TM , Leung B , Byrne JD , Hethumumi R , Montoro M . Incidence, clinical character-istics, and timing of objectively diagnosed venous thrombo-embolism during pregnancy . Obstet Gynecol . 1999 ; 94 ( 5 pt 1 ): 730 - 734 .
140 . Macklon NS , Greer IA . Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience . Scott Med J . 1996 ; 41 ( 3 ): 83 - 86 .
141 . Blondon MB , Perrier A , Nendaz M , et al . Thromboprophylaxis with low-molecular-weight heparin after cesarean delivery . Thromb Haemost . 2010 ; 103 ( 1 ): 129 - 137 .
142 . Bergqvist A , Bergqvist D , Hallböök T . Acute deep vein thrombosis (DVT) after cesarean section . Acta Obstet Gynecol Scand . 1979 ; 58 ( 5 ): 473 - 476 .
143 . Chan LY , Lam KY , Metreweli C , Lau TK . Duplex ultrasound screening for deep vein thrombosis in Chinese after cesarean section . Acta Obstet Gynecol Scand . 2005 ; 84 ( 4 ): 368 - 370 .
144 . Jacobsen AF , Drolsum A , Klow NE , Dahl GF , Qvigstad E , Sandset PM . Deep vein thrombosis after elective cesarean section . Thromb Res . 2004 ; 113 ( 5 ): 283 - 288 .
145 . Kalro BN , Davidson RA , Owen P . Low incidence of asymp-tomatic deep venous thrombosis following caesarean sec-tion: a colour Doppler study . Health Bull (Edinb) . 1999 ; 57 ( 6 ): 418 - 421 .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e731S
146 . Lindqvist P , Dahlbäck B , Marŝál K . Thrombotic risk dur-ing pregnancy: a population study . Obstet Gynecol . 1999 ; 94 ( 4 ): 595 - 599 .
147 . Sia WW , Powrie RO , Cooper AB , et al . The incidence of deep vein thrombosis in women undergoing cesarean delivery . Thromb Res . 2009 ; 123 ( 3 ): 550 - 555 .
148 . Simpson EL , Lawrenson RA , Nightingale AL , Farmer RD . Venous thromboembolism in pregnancy and the puerpe-rium: incidence and additional risk factors from a London perinatal database . BJOG . 2001 ; 108 ( 1 ): 56 - 60 .
149 . White RH , Brickner LA , Scannell KA . ICD-9-CM codes poorly indentifi ed venous thromboembolism during preg-nancy . J Clin Epidemiol . 2004 ; 57 ( 9 ): 985 - 988 .
150 . Knight M ; UKOSS . Antenatal pulmonary embolism: risk factors, management and outcomes . BJOG . 2008 ; 115 ( 4 ): 453 - 461 .
151 . Robertson L , Wu O , Langhorne P , et al ; Thrombosis Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review . Br J Haematol . 2005 ; 132 ( 2 ):1 71 - 196 .
152 . James AH , Jamison MG , Brancazio LR , Myers ER . Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality . Am J Obstet Gynecol . 2006 ; 194 ( 5 ): 1311 - 1315 .
153 . McColl MD , Ramsay JE , Tait RC , et al . Risk factors for pregnancy associated venous thromboembolism . Thromb Haemost . 1997 ; 78 ( 4 ): 1183 - 1188 .
154 . Einstein MH , Kushner DM , Connor JP , et al . A protocol of dual prophylaxis for venous thromboembolism preven-tion in gynecologic cancer patients . Obstet Gynecol . 2008 ; 112 ( 5 ): 1091 - 1097 .
155 . Kakkos SK , Caprini JA , Geroulakos G , Nicolaides AN , Stansby GP , Reddy DJ . Combined intermittent pneumatic leg compression and pharmacological prophylaxis for pre-vention of venous thromboembolism in high-risk patients . Cochrane Database Syst Rev . 2008 ;( 4 ): CD005258 .
156 . Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guide-lines. Chest . 2012;141(2)(suppl):e227S-e277S.
157 . Tooher R , Gates S , Dowswell T , Davis LJ . Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period . Cochrane Database Syst Rev . 2010 ; 5 ( 5 ): CD001689 .
158 . Gates S , Brocklehurst P , Ayers S , Bowler U ; Thrombo-prophylaxis in Pregnancy Advisory Group . Thrombopro-phylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin . Am J Obstet Gynecol . 2004 ; 191 ( 4 ): 1296 - 1303 .
159 . Burrows RF , Gan ET , Gallus AS , Wallace EM , Burrows EA . A randomised double-blind placebo controlled trial of low molecular weight heparin as prophylaxis in preventing venous thrombolic events after caesarean section: a pilot study . BJOG . 2001 ; 108 ( 8 ): 835 - 839 .
160 . Hill NC , Hill JG , Sargent JM , Taylor CG , Bush PV . Effect of low dose heparin on blood loss at caesarean section . BMJ . 1988 ; 296 ( 6635 ): 505 - 506 .
161 . Welti H . Prophylaxie thrombo-embolique par physiothera-pie avec et sans heparine a faibles doses en gynecologie-obstetrique . Rev Med Suisse Romande . 1981 ; 101 ( 11 ): 925 - 934 .
162 . Mismetti P , Laporte S , Darmon JY , Buchmüller A , Decousus H . Meta-analysis of low molecular weight hep-arin in the prevention of venous thromboembolism in gen-eral surgery . Br J Surg . 2001 ; 88 ( 7 ): 913 - 930 .
163 . White RH , Zhou H , Romano PS . Incidence of symptom-atic venous thromboembolism after different elective or
urgent surgical procedures . Thromb Haemost . 2003 ; 90 ( 3 ): 446 - 455 .
164 . Bergqvist D . Prolonged prophylaxis in postoperative medi-cine . Semin Thromb Hemost . 1997 ; 23 ( 2 ): 149 - 154 .
165 . Bergqvist D , Agnelli G , Cohen AT , et al ; ENOXACAN II Investigators . Duration of prophylaxis against venous throm-boembolism with enoxaparin after surgery for cancer . N Engl J Med . 2002 ; 346 ( 13 ): 975 - 980 .
166 . Rasmussen MS , Jorgensen LN , Wille-Jørgensen P , et al ; FAME Investigators . Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter ran-domized open-label study . J Thromb Haemost . 2006 ; 4 ( 11 ): 2384 - 2390 .
167 . Casele H , Grobman WA . Cost-effectiveness of thrombo-prophylaxis with intermittent pneumatic compression at cesarean delivery . Obstet Gynecol . 2006 ; 108 ( 3 pt 1 ): 535 - 540 .
168 . Chang J , Elam-Evans LD , Berg CJ , et al . Pregnancy-related mortality surveillance—United States, 1991-1999 . MMWR Surveill Summ . 2003 ; 52 ( 2 ): 1 - 8 .
169 . Lewis G , ed. Confi dential Enquiry Into Maternal and Child Health. Saving Mothers’ Lives—Reviewing Maternal Deaths To Make Motherhood Safer 2003-2005 . London, England : CEMACH ; 2007 .
170 . McColl MD , Ellison J , Greer IA , Tait RC , Walker ID . Prevalence of the post-thrombotic syndrome in young women with previous venous thromboembolism . Br J Haematol . 2000 ; 108 ( 2 ): 272 - 274 .
171 . Rosfors S , Norén A , Hjertberg R , Persson L , Lillthors K , Törngren S . A 16-year haemodynamic follow-up of women with pregnancy-related medically treated iliofemoral deep venous thrombosis . Eur J Vasc Endovasc Surg . 2001 ; 22 ( 5 ): 448 - 455 .
172 . Andersen BS , Steffensen FH , Sørensen HT , Nielsen GL , Olsen J . The cumulative incidence of venous thromboembo-lism during pregnancy and puerperium—an 11 year Danish population-based study of 63,300 pregnancies . Acta Obstet Gynecol Scand . 1998 ; 77 ( 2 ): 170 - 173 .
173 . Ray JG , Chan WS . Deep vein thrombosis during preg-nancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation . Obstet Gynecol Surv . 1999 ; 54 ( 4 ): 265 - 271 .
174 . Voke J , Keidan J , Pavord S , Spencer HN, Hunt BJ; British Society of Haematology Obstetric Haematology Group. The management of antenatal venous thromboembolism in the UK and Ireland: a prospective multicentre observational study . Br J Haematol . 2007 ; 139 (4): 545 - 558 .
175 . Lopaciuk S , Bielska-Falda H , Noszczyk W , et al . Low- molecular-weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis . Thromb Haemost . 1999 ; 81 (1): 26 - 31 .
176 . Hutten BA , Büller HR , Prins MH , van Der Heijden JF . Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboem-bolism . Cochrane Database Syst Rev . 2000 ;( 4 ): CD002001 .
177 . Lee AYY , Levine MN , Baker RI , et al ; Randomized Com-parison of Low-Molecular-Weight Heparin versus Oral Anti-coagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investi-gators . Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer . N Engl J Med . 2003 ; 349 ( 2 ): 146 - 153 .
178 . Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic ther-apy for VTE disease: antithrombotic therapy and preven-tion of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e419S-e494S.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e732S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
179 . Prandoni P , Lensing AWA , Piccioli A , et al . Recurrent venous thromboembolism and bleeding complications dur-ing anticoagulant treatment in patients with cancer and venous thrombosis . Blood . 2002 ; 100 ( 10 ): 3484 - 3488 .
180 . Beyth RJ , Quinn LM , Landefeld CS . Prospective evalua-tion of an index for predicting the risk of major bleeding in outpatients treated with warfarin . Am J Med . 1998 ; 105 ( 2 ): 91 - 99 .
181 . Crowther MA , Spitzer K , Julian J , et al . Pharmacokinetic profi le of a low-molecular weight heparin (reviparin) in pregnant patients. A prospective cohort study . Thromb Res . 2000 ; 98 ( 2 ): 133 - 138 .
182 . Barbour LA , Oja JL , Schultz LK . A prospective trial that demonstrates that dalteparin requirements increase in preg-nancy to maintain therapeutic levels of anticoagulation . Am J Obstet Gynecol . 2004 ; 191 ( 3 ): 1024 - 1029 .
183 . Jacobsen AF , Qvigstad E , Sandset PM . Low molecular weight heparin (dalteparin) for the treatment of venous thromboem-bolism in pregnancy . BJOG . 2003 ; 110 ( 2 ): 139 - 144 .
184 . Rodie VA , Thomson AJ , Stewart FM , Quinn AJ , Walker ID , Greer IA . Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series . BJOG . 2002 ; 109 ( 9 ): 1020 - 1024 .
185 . Rey E , Rivard GE . Prophylaxis and treatment of thrombo-embolic diseases during pregnancy with dalteparin . Int J Gynaecol Obstet . 2000 ; 71 ( 1 ): 19 - 24 .
186 . Smith MP , Norris LA , Steer PJ , Savidge GF , Bonnar J . Tinzaparin sodium for thrombosis treatment and preven-tion during pregnancy . Am J Obstet Gynecol . 2004 ; 190 ( 2 ): 495 - 501 .
187 . Kovacs MJ , Keeney M , MacKinnon K , Boyle E . Three dif-ferent chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin . Clin Lab Haematol . 1999 ; 21 ( 1 ): 55 - 60 .
188 . Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e24S-e43S.
189 . Douketis JD, Spyropoulos AC, Spencer FA, et al. Peri opera-tive management of antithrombotic therapy: antithrom-botic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e326S-e350S.
190 . Chargaff E , Olson KB . Studies on chemistry of blood coag-ulation. VI. Studies on the action of heparin and other anti-coagulants. The infl uence of protamine on the anticoagulant effect in vivo . J Biol Chem . 1937 ; 122 : 163 - 167 .
191 . Massonnet-Castel S , Pelissier E , Bara L , et al . Partial rever-sal of low molecular weight heparin (PK 10169) anti-Xa acti-vity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation . Haemostasis . 1986 ; 16 ( 2 ): 139 - 146 .
192 . Gupta S , Ettles DF , Robinson GJ , Lindow SW . Inferior vena cava fi lter use in pregnancy: preliminary experience. BJOG . 2008 ;115(6):785-788.
193 . Cheung MC , Asch MR , Gandhi S , Kingdom JCP . Tempor-ary inferior vena caval fi lter use in pregnancy . J Thromb Haemost . 2005 ; 3 ( 5 ): 1096 - 1097 .
194 . Ganguli S , Tham JC , Komlos F , Rabkin DJ . Fracture and migration of a suprarenal inferior vena cava fi lter in a preg-nant patient . J Vasc Interv Radiol . 2006 ; 17 ( 10 ): 1707 - 1711 .
195 . López JA , Kearon C , Lee AY . Deep venous thrombosis . Hematology (Am Soc Hematol Educ Program) . 2004 : 439 - 456 .
196 . Pabinger I , Grafenhofer H , Kyrle PA , et al . Temporary increase in the risk for recurrence during pregnancy in
women with a history of venous thromboembolism . Blood . 2002 ; 100 ( 3 ): 1060 - 1062 .
197 . Warkentin TE , Greinacher A . Heparin-induced thrombocy-topenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy . Chest . 2004 ; 126 ( 3 suppl ): 311S - 337S .
198 . Badaracco MA , Vessey MP . Recurrence of venous throm-boembolic disease and use of oral contraceptives . BMJ . 1974 ; 1 ( 5901 ): 215 - 217 .
199 . Tengborn L , Bergqvist D , Mätzsch T , Bergqvist A , Hedner U . Recurrent thromboembolism in pregnancy and puerpe-rium. Is there a need for thromboprophylaxis? Am J Obstet Gynecol . 1989 ; 160 ( 1 ): 90 - 94 .
200 . Lao TT , de Swiet M , Letsky SE , Walters BN . Prophylaxis of thromboembolism in pregnancy: an alternative . Br J Obstet Gynaecol . 1985 ; 92 ( 3 ): 202 - 206 .
201 . de Swiet M , Floyd E , Letsky E . Low risk of recurrent throm-boembolism in pregnancy . Br J Hosp Med . 1987 ; 38 ( 3 ): 264 .
202 . Howell R , Fidler J , Letsky E , de Swiet M . The risks of ante-natal subcutaneous heparin prophylaxis: a controlled trial . Br J Obstet Gynaecol . 1983 ; 90 ( 12 ): 1124 - 1128 .
203 . Brill-Edwards P , Ginsberg JS , Gent M , et al ; Recurrence of Clot in This Pregnancy Study Group . Safety of withholding heparin in pregnant women with a history of venous throm-boembolism . N Engl J Med . 2000 ; 343 ( 20 ): 1439 - 1444 .
204 . Pabinger I , Grafenhofer H , Kaider A , et al . Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis . J Thromb Haemost . 2005 ; 3 ( 5 ): 949 - 954 .
205 . De Stefano V , Martinelli I , Rossi E , et al . The risk of recurrent venous thromboembolism in pregnancy and puer-perium without antithrombotic prophylaxis . Br J Haematol . 2006 ; 135 ( 3 ): 386 - 391 .
206 . White RH , Chan WS , Zhou H , Ginsberg JS . Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism . Thromb Haemost . 2008 ; 100 ( 2 ): 246 - 252 .
207 . Pettilä V , Kaaja R , Leinonen P , Ekblad U , Kataja M , Ikkala E . Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy . Thromb Res . 1999 ; 96 ( 4 ): 275 - 282 .
208 . Rozanski C , Lazo-Langner A , Kovacs M. Prevention of venous thromboembolism (VTE) associated with pregnancy in women with a past history of VTE [abstract]. Blood . 2009;114(suppl):3132.
209 . Blombäck M , Bremme K , Hellgren M , Siegbahn A , Lindberg H . Thromboprophylaxis with low molecular mass heparin, ‘Fragmin’ (dalteparin), during pregnancy—a longi-tudinal safety study . Blood Coagul Fibrinolysis . 1998 ; 9 ( 1 ): 1 - 9 .
210 . Brennand JE , Walker ID , Greer IA . Anti-activated factor X profi les in pregnant women receiving antenatal thrombopro-phylaxis with enoxaparin . Acta Haematol . 1999 ; 101 ( 1 ): 53 - 55 .
211 . Dargaud Y , Rugeri L , Vergnes MC , et al . A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study . Br J Haematol . 2009 ; 145 ( 6 ): 825 - 835 .
212 . Folkeringa N , Brouwer JL , Korteweg FJ , Veeger NJ , Erwich JJ , van der Meer J . High risk of pregnancy-related venous thromboembolism in women with multiple throm-bophilic defects . Br J Haematol . 2007 ; 138 ( 1 ): 110 - 116 .
213 . Dulitzki M , Pauzner R , Langevitz P , Pras M , Many A , Schiff E . Low-molecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies . Obstet Gynecol . 1996 ; 87 ( 3 ): 380 - 383 .
214 . Casele HL , Laifer SA , Woelkers DA , Venkataramanan R . Changes in the pharmacokinetics of the low-molecular-weight
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e733S
heparin enoxaparin sodium during pregnancy . Am J Obstet Gynecol . 1999 ; 181 ( 5 pt 1 ): 1113 - 1117 .
215 . Ellison J , Thomson AJ , Conkie JA , McCall F , Walker D , Greer A . Thromboprophylaxis following caesarean section—a comparison of the antithrombotic properties of three low molecular weight heparins—dalteparin, enoxaparin and tinzaparin . Thromb Haemost . 2001 ; 86 ( 6 ): 1374 - 1378 .
216 . Roeters van Lennep JE , Meijer E , Klumper FJ , Middeldorp JM , Bloemenkamp KW , Middeldorp S . Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective? J Thromb Haemost . 2011 ; 9 ( 3 ): 473 - 480 .
217 . Kitchen S , Iampietro R , Woolley AM , Preston FE . Anti Xa monitoring during treatment with low molecular weight hep-arin or danaparoid: inter-assay variability . Thromb Haemost . 1999 ; 82 ( 4 ): 1289 - 1293 .
218 . Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e351S-e418S.
219 . Friederich PW , Sanson BJ , Simioni P , et al . Frequency of pregnancy-related venous thromboembolism in anticoagu-lant factor-defi cient women: implications for prophylaxis . Ann Intern Med . 1996 ; 125 ( 12 ): 955 - 960 .
220 . Middeldorp S , Henkens CMA , Koopman MMW , et al . The incidence of venous thromboembolism in family mem-bers of patients with factor V Leiden mutation and venous thrombosis . Ann Intern Med . 1998 ; 128 ( 1 ): 15 - 20 .
221 . Simioni P , Sanson BJ , Prandoni P , et al . Incidence of venous thromboembolism in families with inherited thrombophilia . Thromb Haemost . 1999 ; 81 ( 2 ): 198 - 202 .
222 . Middeldorp S , Meinardi JR , Koopman MMW , et al . A pro-spective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thrombo-embolism . Ann Intern Med . 2001 ; 135 ( 5 ): 322 - 327 .
223 . Couturaud F , Leroyer C , Mottier D ; Groupe dEtude de la Thrombose de Bretagne Occidentale (G.E.T.B.O) . Risk factors and clinical presentation of venous thrombo-embolism according to the age of relatives of patients with factor V Leiden . Thromb Haemost . 2008 ; 99 ( 4 ): 793 - 794 .
224 . Middeldorp S , Libourel EJ , Hamulyak K, van der MJ, Buller HR. The risk of pregnancy-related venous throm-boembolism in women who are homozygous for factor V Leiden . Br J Haematol . 2001 ; 113(2 ): 553 - 555 .
225 . Martinelli I , Legnani C , Bucciarelli P , Grandone E , De Stefano V , Mannucci PM . Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombo-philia . Thromb Haemost . 2001 ; 86 ( 3 ): 800 - 803 .
226 . Tormene D , Simioni P , Prandoni P , et al . Factor V Leiden mutation and the risk of venous thromboembolism in preg-nant women . Haematologica . 2001 ; 86 ( 12 ): 1305 - 1309 .
227 . Bank I , Libourel EJ , Middeldorp S , et al . Prothrombin 20210A mutation: a mild risk factor for venous thromboembo-lism but not for arterial thrombotic disease and pregnancy-related complications in a family study . Arch Intern Med . 2004 ; 164 ( 17 ): 1932 - 1937 .
228 . Coppens M , van de Poel MH , Bank I , et al . A prospective cohort study on the absolute incidence of venous thrombo-embolism and arterial cardiovascular disease in asymptom-atic carriers of the prothrombin 20210A mutation . Blood . 2006 ; 108 ( 8 ): 2604 - 2607 .
229 . Biron-Andreani C , Schved JF , Daures JP , Factor V Leiden mutation and pregnancy-related venous thromboembolism: what is the exact risk? Results from a meta-analysis . Thromb Haemost . 2006 ; 96 ( 1 ): 14 - 18 .
230 . Bezemer ID , van der Meer FJ , Eikenboom JC , Rosendaal FR , Doggen CJ . The value of family history as a risk indi-
cator for venous thrombosis . Arch Intern Med . 2009 ; 169 ( 6 ): 610 - 615 .
231 . Simioni P , Tormene DF , Prandoni PF , et al . Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study . Blood . 2002 ; 99 ( 6 ): 1938 - 1942 .
232 . De Stefano V , Martinelli I , Mannucci PM , et al . The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation . Br J Haematol . 2001 ; 113 ( 3 ): 630 - 635 .
233 . Conard J , Horellou MH , Van Dreden P , Lecompte T , Samama M . Thrombosis and pregnancy in congenital defi ciencies in AT III, protein C or protein S: study of 78 women . Thromb Haemost . 1990 ; 63 ( 2 ): 319 - 320 .
234 . Martinelli I , Battaglioli T , De Stefano V , et al ; GIT (Gruppo Italiano Trombofi lia) . The risk of fi rst venous thromboem-bolism during pregnancy and puerperium in double het-erozygotes for factor V Leiden and prothrombin G20210A . J Thromb Haemost . 2008 ; 6 ( 3 ): 494 - 498 .
235 . Miyakis S , Lockshin MD , Atsumi T , et al . International con-sensus statement on an update of the classifi cation criteria for defi nite antiphospholipid syndrome (APS) . J Thromb Haemost . 2006 ; 4 ( 2 ): 295 - 306 .
236 . Galli M , Barbui T . Antiphospholipid syndrome: clinical and diagnostic utility of laboratory tests . Semin Thromb Hemost . 2005 ; 31 ( 1 ): 17 - 24 .
237 . Bergrem A , Jacobsen EM , Skjeldestad FE , Jacobsen AF , Skogstad M , Sandset PM . The association of antiphospho-lipid antibodies with pregnancy-related fi rst time venous thrombosis—a population-based case-control study . Thromb Res . 2010 ; 125 ( 5 ): e222 - e227 .
238 . Quenby S , Farquharson RG , Dawood F , Hughes AM , Topping J . Recurrent miscarriage and long-term throm-bosis risk: a case-control study . Hum Reprod . 2005 ; 20 ( 6 ): 1729 - 1732 .
239 . den Heijer M , Koster T , Blom HJ , et al . Hyperhomocysteine-mia as a risk factor for deep-vein thrombosis . N Engl J Med . 1996 ; 334 ( 12 ): 759 - 762 .
240 . Greer IA . The challenge of thrombophilia in maternal-fetal medicine . N Engl J Med . 2000 ; 342 ( 6 ): 424 - 425 .
241 . Broekmans AW , Bertina RM , Loeliger EA , Hofmann V , Klingemann HG . Protein C and the development of skin necrosis during anticoagulant therapy . Thromb Haemost . 1983 ; 49 ( 3 ): 251 .
242 . Locht H , Lindström FD . Severe skin necrosis following warfarin therapy in a patient with protein C defi ciency . J Intern Med . 1993 ; 233 ( 3 ): 287 - 289 .
243 . Berkompas DC . Coumadin skin necrosis in a patient with a free protein S defi ciency: case report and literature review . Indiana Med . 1991 ; 84 ( 11 ): 788 - 791 .
244 . Rai R , Regan L. Recurrent miscarriage. Lancet . 2006 ;368(9535):601-611.
245 . Nelson SM , Greer IA . The potential role of heparin in assisted conception . Hum Reprod Update . 2008 ; 14 ( 6 ): 623 - 645 .
246 . Bose P , Black S , Kadyrov M , et al . Heparin and aspirin attenuate placental apoptosis in vitro: implications for early pregnancy failure . Am J Obstet Gynecol . 2005 ; 192 ( 1 ): 23 - 30 .
247 . Di Simone N , Caliandro D , Castellani R , Ferrazzani S , De Carolis S , Caruso A . Low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome . Hum Reprod . 1999 ; 14 ( 2 ): 489 - 495 .
248 . Ganapathy R , Whitley GS , Cartwright JE , Dash PR , Thilaganathan B . Effect of heparin and fractionated hep-arin on trophoblast invasion . Hum Reprod . 2007 ; 22 ( 9 ): 2523 - 2527 .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e734S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
249 . Ginsberg JS , Brill-Edwards P , Johnston M , et al . Relation-ship of antiphospholipid antibodies to pregnancy loss in patients with systemic lupus erythematosus: a cross-sectional study . Blood . 1992 ; 80 ( 4 ): 975 - 980 .
250 . Laskin CA , Bombardier C , Hannah ME , et al . Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss . N Engl J Med . 1997 ; 337 ( 3 ): 148 - 153 .
251 . Rai RS , Clifford K , Cohen H , Regan L . High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies . Hum Reprod . 1995 ; 10 ( 12 ): 3301 - 3304 .
252 . Empson M , Lassere M , Craig JC , Scott JR . Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant . Cochrane Database Syst Rev . 2005 ;( 2 ): CD002859 .
253 . Opatrny L , David M , Kahn SR , Shrier I , Rey E . Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis . J Rheumatol . 2006 ; 33 ( 11 ): 2214 - 2221 .
254 . Branch DW , Andres R , Digre KB , Rote NS , Scott JR . The association of antiphospholipid antibodies with severe pre-eclampsia . Obstet Gynecol . 1989 ; 73 ( 4 ): 541 - 545 .
255 . Polzin WJ , Kopelman JN , Robinson RD , Read JA , Brady K . The association of antiphospholipid antibodies with preg-nancies complicated by fetal growth restriction . Obstet Gynecol . 1991 ; 78 ( 6 ): 1108 - 1111 .
256 . Lockwood CJ , Romero R , Feinberg RF , Clyne LP , Coster B , Hobbins JC . The prevalence and biologic signifi cance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population . Am J Obstet Gynecol . 1989 ; 161 ( 2 ): 369 - 373 .
257 . Lockshin MD , Druzin ML , Goei S , et al . Antibody to car-diolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus . N Engl J Med . 1985 ; 313 ( 3 ): 152 - 156 .
258 . Reece EA , Gabrielli S , Cullen MT , Zheng XZ , Hobbins JC , Harris EN . Recurrent adverse pregnancy outcome and antiphospholipid antibodies . Am J Obstet Gynecol . 1990 ; 163 ( 1 pt 1 ): 162 - 169 .
259 . Milliez J , Lelong F , Bayani N , et al . The prevalence of auto-antibodies during third-trimester pregnancy complicated by hypertension or idiopathic fetal growth retardation . Am J Obstet Gynecol . 1991 ; 165 ( 1 ): 51 - 56 .
260 . el-Roeiy A , Myers SA , Gleicher N . The relationship between autoantibodies and intrauterine growth retardation in hyper-tensive disorders of pregnancy . Am J Obstet Gynecol . 1991 ; 164 ( 5 pt 1 ): 1253 - 1261 .
261 . von Tempelhoff GF , Heilmann L , Spanuth E , Kunzmann E , Hommel G . Incidence of the factor V Leiden-mutation, coagulation inhibitor defi ciency, and elevated antiphospholipid-antibodies in patients with preeclampsia or HELLP-syndrome. Hemolysis, elevated liver-enzymes, low platelets . Thromb Res . 2000 ; 100 ( 4 ): 363 - 365 .
262 . Sletnes KE , Wisløff F , Moe N , Dale PO . Antiphospholipid antibodies in pre-eclamptic women: relation to growth retar-dation and neonatal outcome . Acta Obstet Gynecol Scand . 1992 ; 71 ( 2 ): 112 - 117 .
263 . Lynch A , Marlar R , Murphy J , et al . Antiphospholipid anti-bodies in predicting adverse pregnancy outcome. A pro-spective study . Ann Intern Med . 1994 ; 120 ( 6 ): 470 - 475 .
264 . Harris EN , Spinnato JA . Should anticardiolipin tests be performed in otherwise healthy pregnant women? Am J Obstet Gynecol . 1991 ; 165 ( 5 pt 1 ): 1272 - 1277 .
265 . Branch DW , Porter TF , Rittenhouse L , et al ; National Insti-tute of Child Health and Human Development Maternal-Fetal Medicine Units Network . Antiphospholipid antibodies
in women at risk for preeclampsia . Am J Obstet Gynecol . 2001 ; 184 ( 5 ): 825 - 832, discussion 832-834.
266 . Out HJ , Bruinse HW , Christiaens GC , et al . A prospective, controlled multicenter study on the obstetric risks of preg-nant women with antiphospholipid antibodies . Am J Obstet Gynecol . 1992 ; 167 ( 1 ): 26 - 32 .
267 . Faux JA , Byron MA , Chapel HM . Clinical relevance of spe-cifi c IgG antibodies of cardiolipin . Lancet . 1989 ; 2 ( 8677 ): 1457 - 1458 .
268 . Taylor PV , Skerrow SM , Redman CW . Pre-eclampsia and anti-phospholipid antibody . Br J Obstet Gynaecol . 1991 ; 98 ( 6 ): 604 - 606 .
269 . Sanson BJ , Friederich PW , Simioni P , et al . The risk of abor-tion and stillbirth in antithrombin-, protein C-, and protein S-defi cient women . Thromb Haemost . 1996 ; 75 ( 3 ): 387 - 388 .
270 . Preston FE , Rosendaal FR , Walker ID , et al . Increased fetal loss in women with heritable thrombophilia . Lancet . 1996 ; 348 ( 9032 ): 913 - 916 .
271 . Meinardi JR , Middeldorp S , de Kam PJ , et al . Increased risk for fetal loss in carriers of the factor V Leiden mutation . Ann Intern Med . 1999 ; 130 ( 9 ): 736 - 739 .
272 . Tormene D , Simioni P , Prandoni P , et al . The risk of fetal loss in family members of probands with factor V Leiden mutation . Thromb Haemost . 1999 ; 82 ( 4 ): 1237 - 1239 .
273 . Middeldorp S , van de Poel MH , Bank I , et al . Unselected women with elevated levels of factor VIII:C or homocysteine are not at increased risk for obstetric complications . Thromb Haemost . 2004 ; 92 ( 4 ): 787 - 790 .
274 . Rey E , Kahn SR , David M , Shrier I . Thrombophilic disor-ders and fetal loss: a meta-analysis . Lancet . 2003 ; 361 ( 9361 ): 901 - 908 .
275 . Morrison ER , Miedzybrodzka ZH , Campbell DM , et al . Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review . Thromb Haemost . 2002 ; 87 ( 5 ): 779 - 785 .
276 . Pabinger I , Vormittag R . Thrombophilia and pregnancy out-comes . J Thromb Haemost . 2005 ; 3 ( 8 ): 1603 - 1610 .
277 . Rodger MA , Betancourt MT , Clark P , et al . The associa-tion of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a system-atic review and meta-analysis of prospective cohort studies . PLoS Med . 2010 ; 7 ( 6 ): e1000292 .
278 . Kutteh WH . Antiphospholipid antibody-associated recur-rent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone . Am J Obstet Gynecol . 1996 ; 174 ( 5 ): 1584 - 1589 .
279 . Rai R , Cohen H , Dave M , Regan L . Randomised con-trolled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phos-pholipid antibodies (or antiphospholipid antibodies) . BMJ . 1997 ; 314 ( 7076 ): 253 - 257 .
280 . Kutteh WH , Ermel LD . A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin . Am J Reprod Immunol . 1996 ; 35 ( 4 ): 402 - 407 .
281 . Cowchock S , Reece EA . Do low-risk pregnant women with antiphospholipid antibodies need to be treated? Organizing Group of the Antiphospholipid Antibody Treatment Trial . Am J Obstet Gynecol . 1997 ; 176 ( 5 ): 1099 - 1100 .
282 . Pattison NS , Chamley LW , Birdsall M , Zanderigo AM , Liddell HS , McDougall J . Does aspirin have a role in improving pregnancy outcome for women with the antiphos-pholipid syndrome? A randomized controlled trial . Am J Obstet Gynecol . 2000 ; 183 ( 4 ): 1008 - 1012 .
283 . Tulppala M , Marttunen M , Söderstrom-Anttila V , et al . Low-dose aspirin in prevention of miscarriage in women
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e735S
with unexplained or autoimmune related recurrent miscar-riage: effect on prostacyclin and thromboxane A2 produc-tion . Hum Reprod . 1997 ; 12 ( 7 ): 1567 - 1572 .
284 . Farquharson RG , Quenby S , Greaves M . Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment . Obstet Gynecol . 2002 ; 100 ( 3 ): 408 - 413 .
285 . Noble LS , Kutteh WH , Lashey N , Franklin RD , Herrada J . Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight hep-arin versus unfractionated heparin . Fertil Steril . 2005 ; 83 ( 3 ): 684 - 690 .
286 . Stephenson MD , Ballem PJ , Tsang P , et al . Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin . J Obstet Gynaecol Can . 2004 ; 26 ( 8 ): 729 - 734 .
287 . Gris JC , Quéré I , Monpeyroux F , et al . Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent—the Nîmes Obstetricians and Haematologists Study 5 (NOHA5) . Thromb Haemost . 1999 ; 81 ( 6 ): 891 - 899 .
288 . Carp H , Dolitzky M , Inbal A . Thromboprophylaxis improves the live birth rate in women with consecutive recurrent mis-carriages and hereditary thrombophilia . J Thromb Haemost . 2003 ; 1 ( 3 ): 433 - 438 .
289 . Kupferminc MJ , Fait G , Many A , et al . Low-molecular-weight heparin for the prevention of obstetric complica-tions in women with thrombophilias . Hypertens Pregnancy . 2001 ; 20 ( 1 ): 35 - 44 .
290 . Goel N , Tuli A , Choudhry R . The role of aspirin versus aspi-rin and heparin in cases of recurrent abortions with raised anticardiolipin antibodies . Med Sci Monit . 2006 ; 12 ( 3 ): CR132 - CR136 .
291 . Triolo G , Ferrante A , Ciccia F , et al . Randomized study of subcutaneous low molecular weight heparin plus aspi-rin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid anti-bodies . Arthritis Rheum . 2003 ; 48 ( 3 ): 728 - 731 .
292 . Mak A , Cheung MW-L , Cheak AA , Ho RC . Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and posi-tive anti-phospholipid antibodies: a meta-analysis of random-ized controlled trials and meta-regression . Rheumatology (Oxford) . 2010 ; 49 ( 2 ): 281 - 288 .
293 . Laskin CA , Spitzer KA , Clark CA , et al . Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial . J Rheumatol . 2009 ; 36 ( 2 ): 279 - 287 .
294 . Brenner B , Hoffman R , Blumenfeld Z , Weiner Z , Younis JS . Gestational outcome in thrombophilic women with recur-rent pregnancy loss treated by enoxaparin . Thromb Haemost . 2000 ; 83 ( 5 ): 693 - 697 .
295 . Brenner B , Hoffman R , Carp H , Dulitsky M , Younis J ; LIVE-ENOX Investigators . Effi cacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study . J Thromb Haemost . 2005 ; 3 ( 2 ): 227 - 229 .
296 . Brenner B , Bar J , Ellis M , Yarom I , Yohai D , Samueloff A ; Live-Enox Investigators . Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study . Fertil Steril . 2005 ; 84 ( 3 ): 770 - 773 .
297 . Gris JC , Mercier E , Quéré I , et al . Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder . Blood . 2004 ; 103 ( 10 ): 3695 - 3699 .
298 . Tzafettas J , Petropoulos P , Psarra A , et al. Early antiplate-let and antithrombotic therapy in patients with a history of recurrent miscarriages of known and unknown aeti-ology. Eur J Obstet Gynecol Reprod Biol . 2005 ;120(1):22-26.
299 . Leduc L , Dubois E , Takser L , Rey E , David MJ . Dalteparin and low-dose aspirin in the prevention of adverse obstetric outcomes in women with inherited thrombophilia . J Obstet Gynaecol Can . 2007 ; 29 ( 10 ): 787 - 793 .
300 . Middeldorp S . Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost . 2007 ; 5 ( suppl 1 ): 276 - 282 .
301 . Walker ID , Kujovich JL , Greer IA , et al . The use of LMWH in pregnancies at risk: new evidence or perception? J Thromb Haemost . 2005 ; 3 ( 4 ): 778 - 793 .
302 . Lindqvist PG , Merlo J . Low molecular weight heparin for repeated pregnancy loss: is it based on solid evidence? J Thromb Haemost . 2005 ; 3 ( 2 ): 221 - 223 .
303 . Rodger M . Important publication missing key information . Blood . 2004 ; 104 ( 10 ): 3413 , author reply 3413-3414.
304. Gris JC , Quere I , Dauzat M , Mares P . Response: thrombo-prophylaxis for fi rst fetal loss. Blood . 2004 ;104(10):3413-3414
305 . Rodger MA , Paidas MJ , McLintock C , et al . Inherited throm-bophilia and pregnancy complications revisited . Obstet Gynecol . 2008 ; 112 ( 2 pt 1 ): 320 - 324 .
306 . Coppens M , Folkeringa N , Teune M , et al. Natural course of the subsequent pregnancy after a single loss in women with and without the factor V Leiden or prothrombin 20210A mutations. J Thromb Haemost . 2007 ;5(7):1444-1448.
307 . Sheppard BL , Bonnar J . An ultrastructural study of utero-placental spiral arteries in hypertensive and normoten-sive pregnancy and fetal growth retardation . Br J Obstet Gynaecol . 1981 ; 88 ( 7 ): 695 - 705 .
308 . Steegers EA , von Dadelszen P , Duvekot JJ , Pijnenborg R . Pre-eclampsia . Lancet . 2010 ; 376 ( 9741 ): 631 - 644 .
309 . Young BC , Levine RJ , Karumanchi SA . Pathogenesis of pre-eclampsia . Annu Rev Pathol . 2010 ; 5 : 173 - 192 .
310 . Greer IA . Platelets and coagulation abnormalities in pre-eclampsia . In: Rubin P , ed. Handbook of Hypertension: Hypertension in Pregnancy . Amsterdam, The Netherlands : Elsevier Science ; 1999 : 163 - 181 .
311 . Sattar N , Greer IA . Pregnancy complications and mater-nal cardiovascular risk: opportunities for intervention and screening? BMJ . 2002 ; 325 ( 7356 ): 157 - 160 .
312 . Duckitt K , Harrington D . Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies . BMJ . 2005 ; 330 ( 7491 ): 565 - 572 .
313 . Clark P , Walker ID , Govan L , Wu O , Greer IA . The GOAL study: a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemor-rhagic and thrombotic pregnancy outcomes . Br J Haematol . 2008 ; 140 ( 2 ): 236 - 240 .
314 . Duley L , Henderson-Smart DJ , Meher S , King JF . Antiplatelet agents for preventing pre-eclampsia and its complications . Cochrane Database Syst Rev . 2007 ; ( 2 ): CD004659 .
315 . Antithrombotic Trialists’ (ATT) Collaboration; Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and sec-ondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials . Lancet . 2009 ; 373 (9678): 1849 - 1860 .
316 . Greer IA . Pre-eclampsia matters . BMJ . 2005 ; 330 ( 7491 ): 549 - 550 .
317 . Kaaja R . Predictors and risk factors of pre-eclampsia . Minerva Ginecol . 2008 ; 60 ( 5 ): 421 - 429 .
318 . Hills FA , Abrahams VM , González-Timón B , et al . Heparin prevents programmed cell death in human trophoblast . Mol Hum Reprod . 2006 ; 12 ( 4 ): 237 - 243 .
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
e736S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
331 . Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Anti-thrombotic and thrombolytic therapy for valvular dis ease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest . 2012;141(2)(suppl):e576S-e600S.
332 . James AH , Brancazio LR , Gehrig TR , Wang A , Ortel TL . Low-molecular-weight heparin for thromboprophylaxis in pregnant women with mechanical heart valves . J Matern Fetal Neonatal Med . 2006 ; 19 ( 9 ): 543 - 549 .
333 . Oran B , Lee-Parritz A , Ansell J . Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy . Thromb Haemost . 2004 ; 92 ( 4 ): 747 - 751 .
334 . Abildgaard U , Sandset PM , Hammerstrøm J , Gjestvang FT , Tveit A . Management of pregnant women with mechanical heart valve prosthesis: thromboprophylaxis with low molec-ular weight heparin . Thromb Res . 2009 ; 124 ( 3 ): 262 - 267 .
335 . Quinn J , Von Klemperer K , Brooks R , Peebles D , Walker F , Cohen H . Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves dur-ing pregnancy: a single-center experience . Haematologica . 2009 ; 94 ( 11 ): 1608 - 1612 .
336 . Yinon Y , Siu SC , Warshafsky C , et al . Use of low molecular weight heparin in pregnant women with mechanical heart valves . Am J Cardiol . 2009 ; 104 ( 9 ): 1259 - 1263 .
337 . Kawamata K , Neki R , Yamanaka K , et al . Risks and preg-nancy outcome in women with prosthetic mechanical heart valve replacement . Circ J . 2007 ; 71 ( 2 ): 211 - 213 .
338 . Khamooshi AJ , Kashfi F , Hoseini S , Tabatabaei MB , Javadpour H , Noohi F . Anticoagulation for prosthetic heart valves in pregnancy. Is there an answer? Asian Cardiovasc Thorac Ann . 2007 ; 15 ( 6 ): 493 - 496 .
339 . Lee JH , Park NH , Keum DY , Choi SY , Kwon KY , Cho CH . Low molecular weight heparin treatment in pregnant women with a mechanical heart valve prosthesis . J Korean Med Sci . 2007 ; 22 ( 2 ): 258 - 261 .
340 . McLintock C , McCowan LME , North RA . Maternal com-plications and pregnancy outcome in women with mechan-ical prosthetic heart valves treated with enoxaparin . BJOG . 2009 ; 116 ( 12 ): 1585 - 1592 .
341 . Injection L . ( package insert ). Bridgewater, NJ : Aventis Pharmaceuticals ; 2004 .
342 . Turpie AGG , Gent M , Laupacis A , et al . A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement . N Engl J Med . 1993 ; 329 ( 8 ): 524 - 529 .
343 . Macklin R . Enrolling pregnant women in biomedical research . Lancet . 2010 ; 375 ( 9715 ): 632 - 633 .
319 . Kalk JJ , Huisjes AJ , de Groot CJ , et al . Recurrence rate of pre-eclampsia in women with thrombophilia infl uenced by low-molecular-weight heparin treatment? Neth J Med . 2004 ; 62 ( 3 ): 83 - 87 .
320 . Mello G , Parretti E , Fatini C , et al . Low-molecular-weight hep-arin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women . Hypertension . 2005 ; 45 ( 1 ): 86 - 91 .
321 . Rey E , Garneau P , David M , et al . Dalteparin for the pre-vention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot random-ized controlled trial . J Thromb Haemost . 2009 ; 7 ( 1 ): 58 - 64 .
322 . Dao V , Rodger M . Anticoagulants to prevent placenta-mediated pregnancy complications: a review of current evi-dence . Curr Opin Hematol . 2009 ; 16 ( 5 ): 386 - 390 .
323 . Bassler D , Briel M , Montori VM , et al ; STOPIT-2 Study Group . Stopping randomized trials early for benefi t and esti-mation of treatment effects: systematic review and meta-regression analysis . JAMA . 2010 ; 303 ( 12 ): 1180 - 1187 .
324 . Kaandorp S , Di Nisio M , Goddijn M , Middeldorp S . Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome . Cochrane Database Syst Rev . 2009 ;( 1 ): CD004734 .
325 . Dolitzky M , Inbal A , Segal Y , Weiss A , Brenner B , Carp H . A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages . Fertil Steril . 2006 ; 86 ( 2 ): 362 - 366 .
326 . Mantha S , Bauer KA , Zwicker JI . Low molecular weight hep-arin to achieve live birth following unexplained pregnancy loss: a systematic review . J Thromb Haemost . 2010 ; 8 ( 2 ): 263 - 268 .
327 . Kaandorp SP , Goddijn M , van der Post JAM , et al . Aspirin plus heparin or aspirin alone in women with recurrent mis-carriage . N Engl J Med . 2010 ; 362(17 ): 1586 - 1596 .
328 . Clark P , Walker ID , Langhorne P , et al; Scottish Pregnancy Intervention Study (SPIN) Collaborators. SPIN (Scottish Pregnancy Intervention) study: a multicentre randomised controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage . Blood . 2010 ; 115 ( 21 ): 4162 - 4167 .
329 . Badawy AM , Khiary M , Sherif LS , Hassan M , Ragab A , Abdelall I . Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology . J Obstet Gynaecol . 2008 ; 28 ( 3 ): 280 - 284 .
330 . Fawzy M , Shokeir T , El-Tatongy M , Warda O , El-Refaiey A-A , Mosbah A . Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a ran-domized placebo-controlled study . Arch Gynecol Obstet . 2008 ; 278 ( 1 ): 33 - 38 .
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CHEST
1
Online Data Supplement
© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http :// www . chestpubs . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.11-2300
VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Shannon M. Bates , MDCM ; Ian A. Greer , MD, FCCP ; Saskia Middeldorp , MD, PhD ; David L. Veenstra , PharmD, PhD ; Anne-Marie Prabulos , MD ; and Per Olav Vandvik , MD, PhD
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S1
—[3
.0.1
] Sy
stem
atic
Rev
iew
s E
xam
inin
g F
etal
Saf
ety
of M
ater
nal
The
rapy
Wit
h O
ral
Ant
icoa
gula
nts
or A
spir
in (
Met
hodo
logi
c Q
ual
ity)
Stud
y/Ye
arIn
terv
entio
n
Incl
usiv
e L
itera
ture
Se
arch
Dup
licat
e St
udy
Sele
ctio
n an
d D
ata
Ext
ract
ion
Lis
t of S
tudi
es
(Inc
lude
d an
d E
xclu
ded)
Pro
vide
d
Cha
ract
eris
tics
of I
nclu
ded
Stud
ies
Prov
ided
Ass
essm
ent o
f Q
ualit
y of
In
clud
ed S
tudi
es
App
ropr
iate
Met
hods
U
sed
To C
ombi
ne
Stud
y F
indi
ngs
Ass
essm
ent o
f L
ikel
ihoo
d of
Pu
blic
atio
n B
ias
Cha
n et
al 1 /2
000
Stud
ies
betw
een
1966
and
199
7 ex
amin
ing
the
use
of V
KA
s an
d U
FH
or
no a
ntic
oagu
latio
n in
pre
gnan
t wom
en w
ith
mec
hani
cal h
eart
val
ves
Yes
No
No
No
No
Yes
No
Has
soun
a an
d A
llam
2 /201
0St
udie
s be
twee
n 20
00 a
nd 2
009
exam
inin
g th
e us
e of
VK
As
and
UF
H o
r no
ant
icoa
gula
tion
in p
regn
ant w
omen
with
m
echa
nica
l hea
rt v
alve
s
No
No
No
No
No
Yes
No
Ask
ie e
t al 3 /2
007
Ran
dom
ized
tria
ls (n
5 3
1)
com
pari
ng a
ntip
late
let a
gent
s (lo
w-d
ose
aspi
rin
or d
ypyr
idam
ole)
w
ith e
ither
pla
cebo
or
no
antip
late
let a
gent
in p
regn
ant
wom
en (n
5 3
2,21
7) fo
r pr
imar
y pr
even
tion
of p
reec
lam
psia
.A
spir
in g
iven
alo
ne in
27
tria
ls
(n 5
31,
678;
98%
of w
omen
). M
eta-
anal
ysis
of i
ndiv
idua
l pa
tient
dat
a
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Koz
er e
t al 4 /2
002
Con
trol
led
stud
ies
(n 5
2 c
ase
cont
rolle
d st
udie
s, n
5 5
coh
ort
stud
ies,
n 5
1 r
ando
miz
ed c
ontr
ol
stud
y) e
xam
inin
g th
e ri
sk o
f m
ater
nal e
xpos
ure
to a
spir
in
duri
ng th
e fi r
st tr
imes
ter
of
preg
nanc
y an
d re
port
ed o
n co
ngen
ital m
alfo
rmat
ions
Yes
Yes
Incl
uded
stu
dies
on
lyYe
sN
oYe
sN
o
Koz
er e
t al 5 /2
003
Ran
dom
ized
con
trol
led
stud
ies
(n 5
38)
exa
min
ing
mat
erna
l ex
posu
re to
asp
irin
dur
ing
preg
nanc
y an
d re
port
ing
on
seve
n pr
espe
cifi e
d ou
tcom
es
Yes
Yes
Incl
uded
stu
dies
on
lyYe
sN
oYe
sN
o
UF
H 5
unf
ract
iona
ted
hepa
rin;
VK
A 5
vita
min
K a
ntag
onis
t.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Table S2 —[Section 3.0.1] Systematic Reviews Examining Fetal Safety of Maternal Therapy With Oral Anticoagulants and Aspirin (Results)
Anticoagulation RegimenSpontaneous
AbortionsTotal Fetal Wastage a
Congenital Fetal Anomalies
Fetal or Neonatal Hemorrhage
VKAs throughout with or without heparin at term
Chan et al 1 /2000 196/792 (24.7) 266/792 (33.6) 35/549 (6.4) Hassouna and Allam 2 /2010 194/833 (23.3) 274/833 (32.9) 21/559 (3.7) Not reported
Heparin in fi rst trimester, then VKAs throughout with or without heparin near term
Heparin use at/before 6 wk Chan et al 1 /2000 19/129 (14.7) 21/129 (16.3) 0/108 (0.0) Not reported Heparin use after 6 wk Chan et al 1 /2000 19/56 (33.9) 20/56 (35.7) 4/36 (11.1) Not reported
Heparin use at unknown time in fi rst trimester
Chan et al 1 /2000 19/45 (42.2) 20/45 (44.4) 2/30 (6.7) Not reported Hassouna and Allam 2 /2010 42/322 (13.0) 64/322 (19.9) 1/258 (0.4) Not reported
Adjusted-dose heparin Chan et al 1 /2000 4/16 (25.0) 7/16 (43.8) 0/12 (0.0) Not reported Low-dose heparin Chan et al 1 /2000 1/5 (20.0) 2/5 (40.0) 0/5 (0.0) Not reported Regimen not specifi ed Hassouna and Allam 2 /2010 31/157 (21.6) 61/157 (38.8) 0/96 (0.0) Not reported
No anticoagulation
Nothing Chan et al 1 /2000 2/35 (5.7) 7/35 (20.0) 2/33 (6.1) Not reported Antiplatelet agent Chan et al 1 /2000 8/67 (11.9) 13/67 (19.4) 1/59 (1.7) Not reported Nothing or antiplatelet agent Hassouna and Allam 2 /2010 2/31 (6.4) 4/31 (12.9) 0/27 (0.0) Not reported
Data are presented as n/N (%). See Table S1 legend for expansion of abbreviation. a Wastage due to abortions, stillbirths, and neonatal deaths.
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Tabl
e S3
—[S
ecti
on 3
.0.1
] Sy
stem
atic
Rev
iew
s of
the
Eff
ect
of M
ater
nal
Asp
irin
Use
on
Ant
ithr
omb
otic
The
rapy
on
Fet
al O
utc
omes
(C
lini
cal
Des
crip
tion
and
R
esu
lts)
Ref
eren
ceIn
terv
entio
nN
eona
tal H
emor
rhag
ePr
egna
ncy
Los
sC
onge
nita
l Mal
form
atio
nD
evel
opm
enta
l Del
aySm
all f
or G
esta
tiona
l Age
Ask
ie e
t al 3 /2
007
Mat
erna
l asp
irin
(98%
) and
dy
pyri
dam
ole
vs p
lace
bo
or n
o an
tipla
tele
t age
nt
Ant
ipla
tele
t: 28
7/14
,583
; co
ntro
l: 30
8/14
,563
; RR
0.
93 (9
5% C
I, 0
.80-
1.09
)
Fet
al/n
eona
tal d
eath
an
tipla
tele
t: 48
4/15
,412
; co
ntro
l: 11
1/15
,523
; RR
0.
90 (9
5% C
I, 0
.83-
0.98
)
Not
rep
orte
dN
ot r
epor
ted
Ant
ipla
tele
t: 56
8/10
,772
; C
ontr
ol: 6
24/1
0,65
4; R
R
0.90
(95%
CI,
0.8
1-1.
01)
Koz
er e
t al 4 /2
002
Mat
erna
l asp
irin
use
dur
ing
the
fi rst
trim
este
r vs
m
ater
nal u
se o
f oth
er
drug
s or
no
othe
r dr
ugs
Not
rep
orte
dN
ot r
epor
ted
Ove
rall:
asp
irin
, 888
/15,
138;
co
ntro
l, 1,
935/
49,8
90;
OR
1.3
3 (9
5% C
I,
0.94
-1.8
9)
Not
rep
orte
dN
ot r
epor
ted
C
onge
nita
l hea
rt d
efec
ts:
aspi
rin,
580
/17,
197;
co
ntro
l, 2,
406/
44,7
74; O
R
1.03
(95%
CI,
0.9
4-1.
13)
G
astr
osch
isis
: asp
irin
, 52
/261
con
trol
, 523
/2,4
49
OR
2.3
7 (9
5% C
I,
1.44
-3.8
8)
Koz
er e
t al 5 /2
003
Mat
erna
l asp
irin
use
dur
ing
preg
nanc
y vs
pla
cebo
or
no a
spir
in
Asp
irin
: 238
/13,
003;
co
ntro
l: 23
1/13
,055
; R
R 1
.03
(95%
CI,
0.
86-1
.25)
Mis
carr
iage
(exp
osur
e in
fi r
st o
r se
cond
trim
este
r):
aspi
rin,
111
/7,6
15;
cont
rol,
122/
7,61
5; R
R
0.92
(95%
CI,
0.7
1-1.
19)
Not
rep
orte
dN
ot r
epor
ted
Asp
irin
: 417
/3,7
05; c
ontr
ol:
418/
3,60
8; R
R 0
.96
(95%
CI,
0.8
7-1.
07)
M
isca
rria
ge (e
xpos
ure
in th
e fi r
st tr
imes
ter)
: asp
irin
, 13
/53;
con
trol
, 10/
53; R
R
1.3
(95%
CI,
0.6
3-2.
69)
Pe
rina
tal m
orta
lity:
asp
irin
, 40
6/14
,130
; con
trol
, 44
1/14
,078
; RR
0.9
2 (9
5% C
I, 0
.81-
1.05
)
RR
5 ri
sk r
atio
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S4
—[S
ecti
on 4
.0.1
, 4.0
.5]
Pro
spec
tive
Stu
dies
of
the
Eff
ect
of M
ater
nal
Ant
ithr
omb
otic
The
rapy
on
Bre
ast-
fed
Infa
nts
(Met
hodo
logi
c Q
ual
ity)
Ref
eren
ceIn
terv
entio
nSt
udy
Des
ign
Ran
dom
izat
ion
Con
ceal
edB
lindi
ngL
ost t
o F
ollo
w-u
pA
naly
sis
Com
men
ts
Orm
e et
al 6 /1
977
War
fari
n ex
posu
re d
urin
g br
east
-fee
ding
Cas
e se
ries
NA
Patie
nts:
CN
C
areg
iver
s: C
N
Dat
a co
llect
ors:
CN
A
djud
icat
ors:
CN
D
ata
anal
ysts
: CN
0/7
ITT
Lim
ited
by s
mal
l sam
ple
size
McK
enna
et a
l 7 /198
3W
arfa
rin
expo
sure
dur
ing
brea
st-f
eedi
ngC
ase
seri
esN
APa
tient
s: C
N
Car
egiv
ers:
CN
D
ata
colle
ctor
s: C
N
Adj
udic
ator
s: C
N
Dat
a an
alys
ts: C
N
0/2
ITT
Lim
ited
by s
mal
l sam
ple
size
Hou
wer
t-de
Jon
g et
al 8 /1
981
Ace
noco
umar
ol e
xpos
ure
duri
ng b
reas
t-fe
edin
gC
ase
seri
esN
APa
tient
s: C
N
Car
egiv
ers:
CN
D
ata
colle
ctor
s: C
N
Adj
udic
ator
s: C
N
Dat
a an
alys
ts: C
N
0/20
ITT
Lim
ited
by s
mal
l sam
ple
size
Fon
devi
la e
t al 9 /1
989
Ace
noco
umar
ol e
xpos
ure
duri
ng b
reas
t-fe
edin
gC
ase
seri
esN
APa
tient
s: C
N
Car
egiv
ers:
CN
D
ata
colle
ctor
s: C
N
Adj
udic
ator
s: C
N
Dat
a an
alys
ts: C
N
0/7
ITT
Lim
ited
by s
mal
l sam
ple
size
; tw
o m
othe
rs h
ad
two
infa
nts
incl
uded
Ric
hter
et a
l 10 /2
001
LM
WH
exp
osur
e du
ring
br
east
-fee
ding
(mat
erna
l-do
se d
alte
pari
n 2,
500
Inte
rnat
iona
l Uni
ts S
C)
Cas
e se
ries
NA
Patie
nts:
CN
C
areg
iver
s: C
N
Dat
a co
llect
ors:
CN
A
djud
icat
ors:
CN
D
ata
anal
ysts
: CN
0/15
ITT
Lim
ited
by s
mal
l sam
ple
size
Ito
et a
l 11 /1
993
Low
-dos
e as
piri
n ex
posu
re
duri
ng b
reas
t-fe
edin
gSu
bgro
up o
f pr
ospe
ctiv
e co
hort
NA
Patie
nts:
CN
C
areg
iver
s: C
N
Dat
a co
llect
ors:
CN
A
djud
icat
ors:
CN
D
ata
anal
ysts
: CN
0/15
ITT
Lim
ited
by s
mal
l sam
ples
si
ze; e
ffec
t of a
spir
in
on p
late
let f
unct
ion
not a
sses
sed
CN
5 ce
rtai
n no
; IT
T 5
inte
ntio
n to
trea
t; L
MW
H 5
low
-mol
ecul
ar-w
eigh
t hep
arin
; NA
5 n
ot a
pplic
able
; SC
5 su
bcut
aneo
us.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S5
—[S
ecti
on 4
.0.1
, 4.0
.5]
Pro
spec
tive
Stu
dies
of
the
Eff
ect
of M
ater
nal
Ant
ithr
omb
otic
The
rapy
on
Bre
ast-
fed
Infa
nts
(Cli
nica
l D
escr
ipti
on a
nd R
esu
lts)
Ref
eren
ceIn
terv
entio
nsN
umbe
r Pa
tient
s A
naly
zed
Len
gth
of F
ollo
w-u
p Po
stde
liver
yIn
fant
Hem
orrh
age
Pres
ence
in B
reas
t M
ilk (%
)E
ffec
t in
Infa
nt B
lood
Com
men
ts
Orm
e et
al 6 /1
977
War
fari
n ex
posu
re
duri
ng b
reas
t-fe
edin
g
Bre
ast-
fed
infa
nts,
7/7
Up
to 1
0 d
0/7
War
fari
n, 0
/7W
arfa
rin,
0/7
War
fari
n le
vels
mea
sure
d by
chr
omat
ogra
phy
(low
er li
mit
of d
etec
tion,
0.
08 m
mol
/L)
McK
enna
et a
l 7 /198
3W
arfa
rin
expo
sure
du
ring
bre
ast-
feed
ing
Bre
ast-
fed
infa
nts,
2/2
Fir
st: 5
6 d
0/2
War
fari
n, 0
/2E
leva
ted
PT, 0
/2Pr
esen
ce o
f war
fari
n in
br
east
milk
det
ecte
d by
spe
ctro
phot
omet
ry
Se
cond
: 130
d
Hou
wer
t-de
Jon
g et
al 8 /1
981
Ace
noco
umar
ol
expo
sure
dur
ing
brea
st-f
eedi
ng
Bre
ast-
fed
infa
nts,
7/7
Not
sta
ted
Not
rep
orte
dA
ceno
coum
arol
, 0/2
0E
leva
ted
thro
mbo
test
co
mpa
red
with
no
rmal
ran
ge fo
r ag
e, 0
/20
Pres
ence
of
acen
ocou
mar
ol in
br
east
milk
det
ecte
d by
hig
h-pe
rfor
man
ce
liqui
d ch
rom
atog
raph
y (li
mit
of 1
5 ng
/mL
)
Fon
devi
la e
t al 9 /1
989
Ace
noco
umar
ol
expo
sure
dur
ing
brea
st-f
eedi
ng
Bre
ast-
fed
infa
nts,
7/7
(n 5
4
mot
hers
)
Not
sta
ted
No
pred
ispo
sitio
n to
per
inat
al
hem
orrh
agin
g co
mpl
icat
ions
Not
rep
orte
dM
ean
INR
, % P
T, %
fa
ctor
II,
% fa
ctor
V
II-X
not
diff
eren
t fr
om c
ontr
ol in
fant
s
NA
Ric
hter
et a
l 10 /2
001
LM
WH
exp
osur
e du
ring
bre
ast-
feed
ing
(mat
erna
l-dos
e da
ltepa
rin
2,50
0 In
tern
atio
nal
Uni
ts S
C)
Bre
ast-
fed
infa
nts,
15/
15U
p to
8 d
Not
rep
orte
dD
etec
tabl
e an
ti-X
a L
MW
H le
vels
, 11
/15
(ran
ge, 0
.006
-0.
037
Inte
rnat
iona
l U
nits
/mL
)
Not
rep
orte
d T
hera
peut
ic a
nti-X
a L
MW
H le
vel,
0.5-
1.5
Inte
rnat
iona
l Uni
ts/m
L
4-6
h po
stin
ject
ion
Ito
et a
l 11 /1
993
Low
-dos
e as
piri
n ex
posu
re d
urin
g br
east
-fee
ding
Bre
ast-
fed
infa
nts,
15/
15N
ot r
epor
ted
Not
rep
orte
dN
ot r
epor
ted
Not
rep
orte
d 0/
15 w
ith d
iarr
hea,
dr
owsi
ness
, or
irri
tabi
lity
INR
5 in
tern
atio
nal n
orm
aliz
ed r
atio
; PT
5 p
roth
rom
bin
time.
See
Tab
le S
4 le
gend
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S6
—[S
ecti
on 5
.1.1
, 5.1
.2]
Ris
k of
Thr
omb
oem
bol
ism
in
Pat
ient
s U
nder
goin
g A
ssis
ted
Rep
rodu
ctiv
e T
echn
olog
y
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
ts/ I
nter
vent
ion
Fol
low
-up
Ris
k of
Thr
ombo
embo
lism
Stre
ngth
s/L
imita
tions
Már
a et
al 12
/200
4R
etro
spec
tive
coho
rt2,
748
IVF
cyc
les
IVF
cyc
le a
nd p
regn
ancy
Ove
rall:
3/2
,748
(0.1
%;
95%
CI,
0%
-0.3
%);
all
inte
rnal
jugu
lar
DV
TIn
wom
en w
ith s
ever
e ov
aria
n hy
pers
timul
atio
n: 2
/49
(4.1
%; 9
5% C
I, 1
.1%
-13.
7%)
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:
Sing
le c
ente
r
Aur
ouss
eau
et a
l 13 /1
995
Ret
rosp
ectiv
e co
hort
1,10
2 IV
F p
roce
dure
s;
no c
ases
of o
vari
an
hype
rstim
ulat
ion
Not
sta
ted
Ove
rall:
3/1
,102
(0.3
%;
95%
CI,
0.1
%-0
.8%
); tw
o ar
teri
al e
vent
s an
d on
e PE
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:
Sing
le c
ente
r D
urat
ion
of fo
llow
-up,
met
hods
of i
nves
tigat
ion,
diag
nost
ic te
stin
g st
rate
gies
not d
escr
ibed
Del
vign
e et
al 12
/199
3M
ultic
ente
r re
tros
pect
ive
coho
rt12
8 w
omen
with
ova
rian
hy
pers
timul
atio
n (c
ases
)N
ot s
tate
dIn
wom
en w
ith o
vari
an
hype
rstim
ulat
ion:
1/1
28
(0.8
%; 9
5% C
I, 0
.1%
-4.3
%);
cere
bral
thro
mbo
sis
Stre
ngth
s:
Mul
ticen
ter
Dir
ectn
ess
Wea
knes
ses:
Im
prec
isio
n U
ncle
ar w
heth
er c
ases
wer
e
cons
ecut
ive
Dur
atio
n of
follo
w-u
p, m
etho
ds
of
inve
stig
atio
n, d
iagn
ostic
te
stin
g st
rate
gies
not
des
crib
ed
17 p
atie
nts
rece
ived
LM
WH
Mor
ris
et a
l 14 /1
995
Pros
pect
ive
coho
rt13
wom
en w
ith s
ever
e ov
aria
n hy
pers
timul
atio
nD
urin
g ho
spita
lizat
ion
for
trea
tmen
t of s
ever
e ov
aria
n hy
pers
timul
atio
n
In w
omen
with
sev
ere
ovar
ian
hype
rstim
ulat
ion:
0/1
3 (0
%; 9
5% C
I, 0
%-2
2.8%
)
Stre
ngth
s:
D
irec
tnes
s W
eakn
esse
s:
Im
prec
isio
n Sh
ort f
ollo
w-u
p
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
ts/ I
nter
vent
ion
Fol
low
-up
Ris
k of
Thr
ombo
embo
lism
Stre
ngth
s/L
imita
tions
Ber
gh a
nd L
undk
vist
15 /1
992
Surv
ey o
f 12
fert
ility
cl
inic
s10
,125
IV
F c
ycle
s w
ith
7,33
1 em
bryo
tran
sfer
sVa
ried
from
clin
ic to
clin
ic
(ran
ge, 1
-9 y
)O
vera
ll: 1
/10,
125
(0.0
1%; 9
5% C
I, 0
%-0
.1%
); fo
ot th
rom
bosi
s
Stre
ngth
s:
Mul
ticen
ter
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:
Ret
rosp
ectiv
e re
view
D
iagn
ostic
crit
eria
and
inve
stig
ativ
e
prot
ocol
s no
t spe
cifi e
d
Jaco
bsen
et a
l 16 /2
008
Cas
e-co
ntro
l stu
dy w
ith c
ases
fr
om N
orw
egia
n Pa
tient
R
egis
ter
and
cont
rols
from
w
omen
who
gav
e bi
rth
at
a un
iver
sity
hos
pita
l
268
case
s di
agno
sed
with
V
TE
dur
ing
preg
nanc
y;
1,22
9 co
ntro
ls
Preg
nanc
y an
d fi r
st 3
mo
post
part
umA
ntep
artu
m: s
ingl
eton
(a
djus
ted
OR
, 4.3
; 95%
CI,
2.
0-9.
4); t
win
s (a
djus
ted
OR
, 6.6
; 95%
CI,
2.1
-21.
0)Po
stpa
rtum
: sin
glet
on (a
djus
ted
OR
, 2.6
; 95%
CI,
0.8
-8.5
); tw
ins
(adj
uste
d O
R, 0
.6;
95%
CI,
0.1
-7.6
)
Stre
ngth
s:
Va
lidat
ed c
ase
diag
nosi
s an
d
com
orbi
ditie
s
Col
lect
ed d
ata
on p
oten
tial
co
nfou
nder
s an
d po
tent
ial
risk
fact
ors
Wea
knes
ses:
Con
trol
s fr
om s
ingl
e ce
nter
IVF
5 in
vitr
o fe
rtili
zatio
n; P
E 5
pul
mon
ary
embo
lism
. See
Tab
le S
4 fo
r ex
pans
ion
of o
ther
abb
revi
atio
n.
Tabl
e S6
—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
9© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S7
—[S
ecti
on 5
.1.1
, 5.1
.2]
Ris
k of
Ble
edin
g in
Pat
ient
s U
nder
goin
g T
rans
vagi
nal
Ooc
yte
Ret
riev
al
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
ts/ I
nter
vent
ion
Fol
low
-up
Ris
k of
Ble
edin
gSt
reng
ths/
Lim
itatio
ns a
nd C
omm
ents
Ber
gh a
nd L
undk
vist
15 /1
992
Surv
ey o
f 12
fert
ility
ce
nter
s10
,125
ret
riev
als
Vari
ed fr
om c
linic
to
clin
ic (1
-9 y
)M
ajor
ble
edin
g: 2
/10,
125
(0.0
2%; 9
5% C
I,
0%
-0.1
%);
intr
aabd
omin
al b
leed
ing
requ
irin
g la
paro
tom
yVa
gina
l ble
edin
g: 3
3/10
,125
(0.3
%; 9
5% C
I,
0.
2%-0
.5%
)
Stre
ngth
s:
Mul
ticen
ter
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:
Ret
rosp
ectiv
e de
fi niti
ons
and
met
hods
of e
valu
atin
g ou
tcom
es n
ot s
peci
fi ed
Rag
ni e
t al 17
/200
9Pr
ospe
ctiv
e co
hort
150
cons
ecut
ive
retr
ieva
ls72
hM
ajor
ble
edin
g: 0
/150
(0%
; 95%
CI,
0%-2
.4%
)M
edia
n bl
ood
loss
(int
erqu
artil
e ra
nge)
:
72 ( 2
8 to
162
mL
)
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s M
etho
ds fo
r de
tect
ing
bloo
d lo
ss c
lear
ly
de
scri
bed
Ben
nett
et a
l 18 /1
993
Pros
pect
ive
coho
rt2,
670
cons
ecut
ive
retr
ieva
lsN
ot s
tate
dM
ajor
ble
edin
g: 1
/2,6
70 (0
.04%
; 95%
CI,
0%-0
.2%
); in
traa
bdom
inal
ble
edin
g w
ith
hypo
vole
mic
shoc
k ne
cess
itatin
g em
erge
ncy
lapa
roto
my
(1 L
hem
oper
itone
um)
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s Pr
ospe
ctiv
e
Abd
omin
al b
leed
ing
(non
maj
or):
1/2,
670
(0
.04%
; 95%
CI,
0%
-0.2
%);
triv
ial
blee
ding
with
70
mL
blo
od a
spir
ated
fr
om th
e ab
dom
inal
cav
ity
Wea
knes
ses:
F
ollo
w-u
p no
t des
crib
ed
Met
hods
for
asse
ssm
ent o
f blo
od
lo
ss u
ncle
ar
Va
gina
l ble
edin
g: 2
29/2
,670
(8.6
%; 9
5% C
I,
7.
6%-9
.7%
) . 1
00 m
L, 2
2/2,
670
(0.8
%;
95%
CI,
0.5
%-1
.2%
)
Req
uiri
ng lo
cal c
ompr
essi
on, 2
8/2,
670
(1
.0%
; 95%
CI,
0.7
%-1
.5%
)
Dic
ker
et a
l 19 /1
993
Ret
rosp
ectiv
e3,
656
retr
ieva
lsN
ot s
tate
dM
ajor
ble
edin
g: 3
/3,6
56 (0
.08%
; 95%
CI,
0%-0
.2%
); al
l int
raab
dom
inal
; lap
arot
omy
and
4 un
its o
f blo
od r
equi
red
in o
ne
patie
nt; d
rain
age
and
hem
osta
sis
achi
eved
la
paro
scop
ical
ly in
the
othe
r tw
o pa
tient
s.
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:
Ret
rosp
ectiv
e F
ollo
w-u
p no
t des
crib
ed
Ture
ck e
t al 20
/199
3R
etro
spec
tive
674
retr
ieva
lsN
ot s
tate
dVa
gina
l ble
edin
g: 2
/674
(0.3
%; 9
5% C
I,
0.
1%-1
.1%
) . 1
00 m
L, o
ne p
atie
nt
requ
ired
sut
ures
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s
Intr
aabd
omin
al b
leed
ing:
1/6
74 (0
.1%
;
95%
CI,
0%
-0.8
%);
expa
ndin
g br
oad
ligam
ent b
leed
trea
ted
with
dia
gnos
tic
lapa
roto
my
and
obse
rvat
ion
Wea
knes
ses:
R
etro
spec
tive
Fol
low
-up
not d
escr
ibed
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
10© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
ts/ I
nter
vent
ion
Fol
low
-up
Ris
k of
Ble
edin
gSt
reng
ths/
Lim
itatio
ns a
nd C
omm
ents
Gov
aert
s et
al 21
/199
8R
etro
spec
tive
1,50
0 re
trie
vals
At l
east
to
com
plet
ion
of I
VF
Intr
aabd
omin
al b
leed
ing:
3/1
,500
(0.2
%;
95
% C
I, 0
.1%
-0.6
%);
all t
hree
req
uire
d la
paro
scop
y
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:
Ret
rosp
ectiv
e L
udw
ig e
t al 22
/200
6Pr
ospe
ctiv
e co
hort
1,05
8 re
trie
vals
2 m
o po
stre
trie
val
Vagi
nal b
leed
ing:
29/
1,04
9 (2
.8%
; 95%
CI,
1.9%
-3.9
%)
R
equi
ring
com
pres
sion
, 28/
1,04
9
(2.7
%; 9
5% C
I, 1
.9%
-3.9
%)
R
equi
ring
tam
pona
de fo
r .
2 h
, 1/1
,049
(0.1
%; 9
5% C
I, 0
%-0
.5%
)In
traa
bdom
inal
ble
edin
g: 0
/1,0
49 (0
%;
95
% C
I, 0
%-0
.4%
)
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s Pr
ospe
ctiv
e
Bod
ri e
t al 23
/200
8R
etro
spec
tive
4,05
2 re
trie
vals
2 w
kM
ajor
ble
edin
g: 1
/4,0
52 (0
.02%
; 95%
CI,
0%-0
.5%
) int
raab
dom
inal
ble
edin
g re
quir
ing
lapa
roto
my
and
tran
sfus
ion
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:
Ret
rosp
ectiv
e
Oth
er n
onm
ajor
ble
edin
g: 1
3/4,
052
(0.3
%;
95
% C
I, 0
.2%
-0.5
%);
four
pat
ient
s ha
d ab
dom
inal
ble
edin
g re
quir
ing
lapa
rosc
opy;
in th
e re
mai
ning
nin
e pa
tient
s, bl
eedi
ng re
solv
ed sp
onta
neou
sly,
alth
ough
six
wer
e ho
spita
lized
Bab
er e
t al 24
/198
8R
etro
spec
tive
600
retr
ieva
lsN
ot s
tate
dVa
gina
l ble
edin
g: 5
/600
(0.8
%; 9
5% C
I,
0.
4%-1
.9%
); re
quir
ing
inse
rtio
n of
va
gina
l pac
k (n
one
had
sign
ifi ca
nt fa
ll in
hem
oglo
bin
leve
l)
Stre
ngth
s:
Prec
isio
n D
irec
tnes
s W
eakn
esse
s:R
etro
spec
tive
Pe
lvic
hem
atom
a: 3
/600
(0.5
%; 9
5% C
I,
0.
2%-1
.5%
); al
l man
aged
con
serv
ativ
ely
with
no
drop
in h
emog
lobi
n le
vel
O
vert
ble
edin
g: 1
/600
(0.2
%; 9
5% C
I,
0%
-0.9
%);
200-
mL
blo
od lo
ss
requ
irin
g su
ture
Tabl
e S7
—C
onti
nued
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Tabl
e S8
—[S
ecti
on 5
.1.1
, 5.1
.2]
Ris
k of
Thr
omb
osis
and
Ble
edin
g in
Pat
ient
s R
ecei
ving
Pro
phyl
acti
c A
ntic
oagu
lati
on A
rou
nd t
he T
ime
of T
rans
vagi
nal
Ooc
yte
Ret
riev
al
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
ts/I
nter
vent
ion
Fol
low
-up
Out
com
esR
esul
tsSt
reng
ths/
Lim
itatio
ns
and
Com
men
ts
Yino
n et
al 25
/200
6R
etro
spec
tive
Twen
ty-f
our
wom
en c
onsi
dere
d hi
gh r
isk
for
thro
mbo
sis
unde
rgoi
ng 7
3 IV
F c
ycle
s an
d 68
ooc
yte
retr
ieva
l pro
cedu
res
(fi ve
ver
y hi
gh r
isk
used
a c
ontr
olle
d sp
onta
neou
s cy
cle
and
surr
ogac
y). P
atie
nts
rece
ived
L
MW
H (0
.6-1
mg/
kg p
er d
) sta
rtin
g on
th
e da
y of
GnR
H a
goni
st a
dmin
istr
atio
n (w
hen
GnR
H a
goni
st p
roto
cols
wer
e us
ed) a
nd o
n th
e fi r
st d
ay o
f gon
adot
ropi
n ad
min
istr
atio
n in
the
GH
rH a
ntag
onis
t pr
otoc
ol. T
he la
st in
ject
ion
of L
MW
H
was
adm
inis
tere
d 14
-15
h pr
ior
to o
ocyt
e re
trie
val a
nd r
esum
ed 1
2 h
post
proc
edur
e.A
ntic
oagu
latio
n w
as c
ontin
ued
in p
regn
ancy
an
d st
oppe
d af
ter
a ne
gativ
e pr
egna
ncy
test
. Ver
y-hi
gh-r
isk
patie
nts
rece
ived
w
arfa
rin
� a
spir
in p
rior
to o
ocyt
e re
trie
val b
efor
e tr
ansi
tioni
ng to
LM
WH
po
stre
trie
val (
unle
ss p
lann
ed s
urro
gacy
).
Unt
il de
liver
y of
em
bryo
tr
ansf
er if
pre
gnan
cy
not a
chie
ved.
Ble
edin
gT
hrom
boem
bolis
mB
leed
ing:
0/2
4 (0
; 95%
CI,
0%
-13.
8%)
Thr
ombo
embo
lism
: 0/
24 (0
; 95%
CI,
0%
-13.
8%)
Stre
ngth
s:
Dir
ectn
ess
Wea
knes
ses:
Im
prec
isio
n R
etro
spec
tive
Qub
lan
et a
l 26 /2
008
Ran
dom
ized
tr
ial
Eig
hty-
thre
e w
omen
with
at l
east
thre
e fa
iled
assi
sted
rep
rodu
ctio
n cy
cles
and
at
leas
t one
thro
mbo
phili
a.Pa
tient
s w
ere
allo
cate
d to
eno
xapa
rin
40 m
g/d
(n 5
42)
or
plac
ebo
(n 5
41)
st
artin
g on
the
day
of e
mbr
yo tr
ansf
er
and
cont
inue
d un
til c
ompl
etio
n of
pr
egna
ncy.
Unt
il de
liver
y. F
ive
wom
en
in e
ach
grou
p w
ere
lost
to
follo
w-u
p in
the
LM
WH
gro
up, a
nd th
ree
wer
e lo
st to
follo
w-u
p in
th
e no
-tre
atm
ent g
roup
.
Impl
anta
tion
succ
ess,
liv
e bi
rths
, co
mpl
icat
ions
Ble
edin
g: e
noxa
pari
n,
3/42
(7.1
%; 9
5% C
I,
2.5%
-19.
0%)
Thr
ombo
cyto
peni
a:
enox
apar
in, 2
/42
(4.8
%; 9
5% C
I,
1.3%
-15.
8%)
Alle
rgic
rea
ctio
ns:
enox
apar
in, 1
/42
(2.4
%;
95%
CI,
0.4
%-1
2.3%
)
Stre
ngth
s:
D
irec
tnes
s R
ando
miz
ed tr
ial
Wea
knes
ses:
Impr
ecisi
on
Onl
y pa
rtic
ipan
ts w
ere
blin
ded
For
32%
of
part
icip
ants
, the
qu
alify
ing
thro
mbo
phili
a
w
as th
e M
TH
FR
C67
7T
mut
atio
n, w
hich
is n
ot
a ri
sk fa
ctor
for v
enou
s
th
rom
bosis
C
rite
ria
for
blee
ding
an
d th
rom
bocy
tope
nia
not s
peci
fi ed
B
leed
ing
not
spec
ifi ca
lly r
epor
ted
for
plac
ebo
grou
p
Thr
ombo
sis
not
spec
ifi ca
lly r
epor
ted
for
eith
er g
roup
(C
onti
nued
)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
ts/I
nter
vent
ion
Fol
low
-up
Out
com
esR
esul
tsSt
reng
ths/
Lim
itatio
ns
and
Com
men
ts
Ster
n et
al 27
/200
3R
ando
miz
ed, d
oubl
e-bl
ind,
pla
cebo
-co
ntro
lled,
cro
ssov
er
tria
l (tr
ansf
er b
y tr
ansf
er)
One
hun
dred
fort
y-th
ree
wom
en w
ith a
n au
toan
tibod
y (e
ither
APL
A, a
ntin
ucle
ar,
or a
nti- b
2 -gl
ycop
rote
in I
) and
at l
east
10
pri
or u
nsuc
cess
ful e
mbr
yo tr
ansf
ers.
Patie
nts
wer
e al
loca
ted
to e
ither
UF
H 5
,000
un
its b
id S
C a
nd a
spir
in (1
58 tr
ansf
ers
of 2
96 e
mbr
yos)
or
plac
ebo
(142
tran
sfer
s of
259
em
bryo
s) s
tart
ing
the
day
of
embr
yo tr
ansf
er u
ntil
14 w
k ge
stat
ion
or p
regn
ancy
failu
re.
Unt
il de
liver
y or
end
of
pre
gnan
cySu
cces
sful
im
plan
tatio
n,
live
birt
hs,
blee
ding
Sign
ifi ca
nt b
leed
ing:
he
pari
n an
d as
piri
n,
0/15
8 (0
; 95%
CI,
0%
-2.4
%) P
lace
bo, 0
/142
(0
; 95%
CI,
0%
-2.6
%)
Stre
ngth
s:
D
irec
tnes
s R
ando
miz
ed tr
ial
Dou
ble
blin
ding
W
eakn
esse
s:
Cri
teri
a fo
r si
gnifi
cant
blee
ding
not
rep
orte
d T
hrom
bosi
s no
t spe
cifi c
ally
repo
rted
APL
A 5
antip
hosp
holip
id a
ntib
ody;
GH
rH 5
gro
wth
-hor
mon
e-re
leas
ing
horm
one;
GnR
H 5
gon
adot
ropi
n-re
leas
ing
horm
one;
MT
HF
R 5
met
hyle
ne t
etra
hydr
ofol
ate
redu
ctas
e va
rian
t. Se
e Ta
ble
S1 a
nd
S4 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
Tabl
e S8
—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S9
—[S
ecti
on 5
.1.1
, 5.1
.2]
Evi
denc
e P
rofi l
e: P
roph
ylac
tic-
Dos
e L
MW
H v
s N
o T
hrom
bop
roph
ylax
is f
or W
omen
Who
Und
ergo
Ass
iste
d R
epro
duct
ive
The
rapy
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)A
ntic
ipat
ed A
bsol
ute
Eff
ects
b
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Ove
rall
Qua
lity
of
Evi
denc
eW
ithou
t Pr
ophy
laxi
s a W
ith L
WM
H
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
out
Prop
hyla
xis a
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Sym
ptom
atic
VT
E (c
ritic
al o
utco
me)
, DV
T, a
nd P
E
1,95
3 (6
RC
Ts),
27-3
5 d
post
oper
ativ
e
No
seri
ous
risk
of
bias
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss a
orth
oped
ic
surg
ery
Serio
us im
prec
ision
c ; w
ide
CI
for
cont
rol g
roup
ri
sk e
stim
ates
Und
etec
ted
Low
due
to
indi
rect
ness
an
d im
prec
ision
36/8
62 (4
.2)
15/1
,091
(1.4
)R
R 0
.36
(0.2
0-0.
67)
With
out s
ever
e ov
aria
n hy
pers
timul
atio
n sy
ndro
me
2 V
TE
pe
r 1,
000 d
1 fe
wer
VT
E
per
1,00
0 (f
rom
2 fe
wer
to
0 fe
wer
)
W
ith s
ever
e ov
aria
n hy
pers
timul
atio
n sy
ndro
me
40
VT
E
per
1,00
0 d 26
few
er V
TE
pe
r 1,
000
(fro
m 3
2 fe
wer
to
13 fe
wer
)
Maj
or b
leed
(cri
tical
out
com
e)
5,45
6 (7
RC
Ts),
3 w
k-9
mo
No
seri
ous
risk
of
bias
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss a
orth
oped
ic
surg
ery
Serio
us im
prec
ision
c ; w
ide
CI
for
cont
rol g
roup
ri
sk e
stim
ates
Und
etec
ted
Low
2/1,
480
(0.1
4)6/
1,24
5 (0
.48)
RR
0.4
3 (0
.11-
1.65
)30
ble
edin
g ev
ents
pe
r 1,
000 d
17 fe
wer
ble
edin
g ev
ents
per
1,
000
(fro
m 2
7 fe
wer
to
20
mor
e)
Bib
liogr
aphy
: Hul
l RD
, et a
l. E
xten
ded
out o
f hos
pita
l low
mol
ecul
ar w
eigh
t hep
arin
pro
phyl
axis
aga
inst
dee
p ve
in th
rom
bosi
s in
patie
nts a
fter
ele
ctiv
e hi
p ar
thro
plas
ty: a
syst
emat
ic re
view
. Ann
Int
ern
Med
. 20
01;1
35:8
58-8
69. R
CT
5 ra
ndom
ized
con
trol
led
tria
l. Se
e Ta
ble
S4 a
nd S
6 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a The
pop
ulat
ion
did
not i
nclu
de p
regn
ant w
omen
. Diff
eren
t dos
es o
f LM
WH
wer
e us
ed, t
reat
men
t was
initi
ated
var
iabl
y be
fore
or
afte
r su
rger
y w
ith a
dur
atio
n of
� 7
day
s (in
hos
pita
l). O
utco
mes
wer
e va
riab
ly r
epor
ted,
met
a-an
alys
is a
lso
prov
ides
oth
er o
utco
mes
suc
h as
mor
talit
y, a
sym
ptom
atic
DV
T, a
nd s
peci
fi c b
leed
out
com
es (
wou
nd h
emat
oma,
tra
nsfu
sion
). F
ollo
w-u
p va
ried
bet
wee
n tr
ials
fro
m
3 w
k to
9 m
o.
b Tim
e fr
ame
is 9
mo
for
all o
utco
mes
. c I
mpr
ecis
e co
ntro
l gro
up r
isk
estim
ates
for
blee
ding
eve
nts
and
for
VT
E in
the
subs
et o
f wom
en w
ith o
vari
an h
yper
stim
ulat
ion
(Tab
les
S6-S
8).
d Con
trol
gro
up r
isk
for
VT
E a
nd m
ajor
ble
ed c
ome
from
obs
erva
tiona
l stu
dies
of w
omen
und
ergo
ing
assi
sted
rep
rodu
ctiv
e te
chno
logy
(Tab
les
S6-S
8).
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Table S10 —[Section 6.2.1-6.2.4] Risk Factors for Pregnancy-Associated VTE
Risk Factor Adjusted OR 95% CI
Immobility (strict bed rest for � 1 wk in the antepartum period) with BMI � 25 kg/m 2 (antenatal risk) 62.3 11.5-337.0
Immobility (strict bed rest for � 1 wk in the antepartum period) with BMI � 25 kg/m 2 (postpartum risk) 40.1 8.0-201.5
Factor V Leiden homozygosity 34.4 9.9-120.1
Prothrombin G20210A homozygosity 26.4 1.2-559.3
Previous VTE 24.8 17.1-36
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following vaginal delivery 20.2 6.4-63.5
Postpartum hemorrhage � 1,000 mL with surgery 12.0 3.9-36.9
Immobility (strict bed rest for � 1 wk in the antepartum period) with BMI , 25 kg/m 2 (postpartum risk) 10.8 4.0-28.8
Systemic lupus erythematosus 8.7 5.8-13.0
Factor V Leiden heterozygosity 8.3 5.4-12.7
Immobility (strict bed rest for � 1 wk in the antepartum period) with BMI , 25 kg/m 2 (antepartum risk) 7.7 3.2-19.0
Blood transfusion 7.6 6.2-9.4
Heart disease 7.1 6.2-8.3
Prothrombin G20210A heterozygosity 6.8 2.5-18.8
Sickle cell disease 6.7 4.4-10.1
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following cesarean section 6.2 2.4-16.2
Preeclampsia with fetal growth restriction 5.8 2.1-16
Multiple pregnancy 4.2 1.8-9.7
BMI . 30 kg/m 2 5.3 2.1-13.5
Protein C defi ciency 4.8 2.2-10.6
Antithrombin defi ciency 4.7 1.3-17.0
Assisted reproductive techniques 4.3 2.0-9.4
Postpartum hemorrhage . 1 L 4.1 2.3-7.3
Fetal growth restriction (gestational age 1 sex-adjusted birth weight , 2.5th percentile) 3.8 1.4-10.2
Smoking (10-30 cigarettes/d prior to or during pregnancy) (postpartum risk) 3.4 2.0-5.5
Protein S defi ciency 3.2 1.5-6.9
Preeclampsia 3.1 1.8-5.3
Emergency cesarean section 2.7 1.8-4.1
Anemia 2.6 2.2-2.9
Smoking (10-30 cigarettes/d prior to or during pregnancy) (antepartum risk) 2.1 1.3-3.4
Smoking (5-9 cigarettes/d prior to or during pregnancy) (postpartum risk) 2.0 1.1-3.7
Weight gain . 21 kg (vs 7-21 kg) 1.6 1.1-2.6
Parity . 1 1.5 1.1-1.9
Age . 35 y 1.3 1.0-1.7
Cesarean section (nonemergent) 1.3 0.7-2.2
Data are from Jacobsen et al, 16 Jacobsen et al, 28 Lindqvist et al, 29 Simpson et al, 30 Knight, 31 Roberston et al, 32 and James et al. 33
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
15© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Table S11 —[6.2.1-6.2.4] Risk Factors for Postpartum VTE
Risk Factor Adjusted OR 95% CIs
Immobility (strict bed rest for � 1 wk in the antepartum period) with BMI � 25 kg/m 2 40.1 8.0-201.5
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following vaginal delivery 20.2 6.4-63.5
Postpartum hemorrhage � 1,000 mL with surgery 12.0 3.9-36.9
Immobility (strict bed rest for � 1 wk in the antepartum period) with BMI , 25 kg/m 2 10.8 4.0-28.8
Postpartum infection (clinical signs/symptoms 1 fever 1 elevated WBC) following cesarean section 6.2 2.4-16.2
Preeclampsia with fetal growth restriction 5.8 2.1-16
Postpartum hemorrhage . 1 L 4.1 2.3-7.3
Fetal growth restriction (gestational age 1 sex-adjusted birth weight , 2.5th percentile) 3.8 1.4-10.2
Smoking (10-30 cigarettes/d prior to or during pregnancy) 3.4 2.0-5.5
Preeclampsia 3.1 1.8-5.3
Emergency cesarean section 2.7 1.8-4.1
BMI prepregnancy . 25 kg/m 2 2.4 1.7-3.3
Smoking (5-9 cigarettes/d prior to or during pregnancy) 2.0 1.1-3.7
Cesarean section (nonemergent) 1.3 0.7-2.2
Data are from Jacobsen et al. 16
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Tabl
e S1
2 —[S
ecti
on 6
.2.1
-6.2
.4]
Evi
denc
e P
rofi l
e: L
MW
H v
s N
o T
hrom
bop
roph
ylax
is f
or P
reve
ntio
n of
VT
E i
n W
omen
Und
ergo
ing
Ces
area
n Se
ctio
n
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%) a
Ant
icip
ated
Abs
olut
e E
ffec
ts b
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ithou
t Pr
ophy
laxi
sW
ith L
WM
H
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
out
Prop
hyla
xis c
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Sym
ptom
atic
VT
E (c
ritic
al o
utco
me)
, DV
T, a
nd P
E (o
nly
sym
ptom
atic
PE
, not
sym
ptom
atic
DV
T, r
epor
ted
sepa
rate
ly in
met
a-an
alys
is) m
easu
red
at e
nd o
f fol
low
-up
4,89
0 (3
RC
Ts),
3 w
k-9
mo
No
seri
ous
risk
of
bias
c Sel
ectiv
e ou
tcom
e re
port
ing
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss
gene
ral
surg
ery
No
seri
ous
impr
ecis
ion
Und
etec
ted
Mod
erat
e22
/2,4
45 (0
.9)
5/2,
445
(0.0
2)R
R 0
.29
(0.1
1-0.
73)
Low
ris
k
5 V
TE
pe
r 1,
000 d
3 fe
wer
VT
E
per
1,00
0 (f
rom
4 fe
wer
to
1 fe
wer
)
H
igh
risk
30
VT
E
per
1,00
0 d 21
few
er V
TE
pe
r 1,
000
(fro
m 2
7 fe
wer
to
9 fe
wer
)
Maj
or b
leed
(cri
tical
out
com
e)
5,45
6 (7
RC
Ts),
3 w
k-9
mo
No
seri
ous
risk
of
bia
sN
o se
riou
s in
cons
iste
ncy
Seri
ous
indi
rect
ness
e H
eter
ogen
eous
de
fi niti
ons
of b
leed
ing
even
ts
No
seri
ous
impr
ecis
ion
Und
etec
ted
Mod
erat
e37
/2,7
28 (0
.14)
74/2
,728
(0.4
8)R
R 2
.03
(1.3
7-3.
01)
20 b
leed
ing
even
ts
per
1,00
0 f
20 m
ore
blee
ding
ev
ents
per
1,
000
(fro
m
8 m
ore
to
40 m
ore)
Bib
liogr
aphy
: Mis
met
ti P,
Lap
orte
S, D
arm
on J
Y, B
uchm
ülle
r A
, Dec
ousu
s H
. Met
a-an
alys
is o
f low
mol
ecul
ar w
eigh
t hep
arin
in th
e pr
even
tion
of v
enou
s th
rom
boem
bolis
m in
gen
eral
sur
gery
. Br
J Su
rg.
2001
;88:
913-
930.
Blo
ndon
M, P
erri
er A
, Nen
daz
M, e
t al.
Thr
ombo
prop
hyla
xis
wit
h lo
w-m
olec
ular
-wei
ght h
epar
in a
fter
ces
area
n de
liver
y. A
dec
isio
n an
alys
is. T
hrom
b H
aem
ost.
201
0;10
3:12
9-13
7.
See
Tabl
e S3
, S4,
S6,
and
S9
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a The
den
omin
ator
s fo
r L
MW
H a
nd c
ontr
ols
wer
e ex
trac
ted
by d
ivid
ing
tota
l no
of p
artic
ipan
ts b
y tw
o.
b Tim
e fr
ame
is 9
mo
for
all o
utco
mes
. c O
nly
fi ve
of e
ight
RC
Ts o
f LM
WH
vs
plac
ebo/
no tr
eatm
ent r
epor
ted
mor
talit
y. W
e di
d no
t rat
e do
wn
for
risk
of b
ias.
d F
or s
ourc
e of
con
trol
gro
up r
isk
estim
ates
see
text
and
Tab
les
S10
and
S11.
e R
ated
dow
n fo
r in
dire
ctne
ss d
ue to
var
iabl
e bl
eedi
ng d
efi n
ition
s in
tria
ls (b
leed
ing
lead
ing
to d
eath
, tra
nsfu
sion
, reo
pera
tion ,
or
disc
ontin
uatio
n of
ther
apy)
mea
sure
d at
end
of t
hera
py.
f Con
trol
gro
up r
isk
estim
ate
for
maj
or b
leed
ing
even
ts c
omes
from
stu
dy b
y B
lond
on e
t al.
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Tabl
e S1
3 —D
ecis
ion
and
Cos
t-E
ffec
tive
ness
Ana
lyse
s/E
cono
mic
Ana
lyse
s St
udy
: Met
hodo
logi
c K
ey I
nfor
mat
ion
D
ata
Sour
ces
Stud
y/Ye
arTy
pe o
f A
naly
sis
Type
of
Mod
el
All
Rel
evan
t St
rate
gies
C
onsi
dere
d?Pe
rspe
ct.
of A
naly
sis
Tim
e F
ram
e of
A
naly
sis
Prob
abili
ties
and
Rat
esC
osts
QO
L
Mea
sure
s
Ben
efi ts
or
Cos
ts a
nd
Ben
efi ts
C
ompl
etel
y Sp
ecifi
ed?
Are
Cos
ts
and
Ben
efi ts
D
iscou
nted
?
Wer
e Se
nsiti
vity
A
naly
ses
Perf
orm
ed?
Com
men
ts
Cas
ele
and
Gro
bman
34 /2
006
Cos
t- effe
ctiv
eM
arko
v tr
ansi
tion
stat
e m
odel
No,
pha
rmac
ol.
prop
hyla
xis
not
cons
ider
ed
Hea
lth-c
are
paye
rL
ife-t
ime
of c
ohor
tR
CT
from
di
ffer
ent
patie
nt
popu
latio
n
Publ
ishe
d
C/E
an
alys
es
Publ
ishe
d
C/E
or
deci
sion
anal
ysis
Yes
Yes,
3%
Det
erm
inis
tic
Yes
Prob
abili
stic
N
o
Phar
mac
olog
ic
pr
ophy
laxi
s
not i
nclu
ded
as
a
com
para
tor
Mod
erat
e
unce
rtai
nty
in
bas
elin
e
risk
and
effe
ctiv
enes
s Sa
tisfa
ctor
y
qual
ity b
ut
no
t defi
niti
ve
gi
ven
data
unce
rtai
ntie
s
as n
oted
by
au
thor
s
C
osts
incl
uded
:
Und
erly
ing
di
seas
e
trea
tmen
t
Trea
tmen
t
com
plic
atio
ns
QO
L m
etric
s:
Not
sta
ted
Q
ualit
y ca
tego
ry a :
Ve
ry g
ood
G
ood
Sa
tisfa
ctor
y
Uns
atis
fact
ory
QO
L 5
qua
lity
of li
fe. S
ee T
able
S9
lege
nd fo
r ex
pans
ion
of o
ther
abb
revi
atio
n.
a Defi
niti
ons:
ver
y go
od, 9
0% to
100
% o
f qua
lity
item
s pr
esen
t; go
od, 8
0% to
89%
of q
ualit
y ite
ms
pres
ent;
satis
fact
ory,
60%
to 7
9% o
f qua
lity
item
s pr
esen
t; un
satis
fact
ory,
, 6
0% o
f qua
lity
item
s pr
esen
t.
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Table S14 —Decision and Cost-Effectiveness Analyses/Economic Analyses Study: Description of Study
Outcome Measures
Study/YearStrategies Analyzed
Target Populations a Effectiveness Cost b
Funding Sources and Potential Confl icts of
Interest
Study Conclusions, Assessment of
Continued Relevance, Additional Comments c
Casele and Grobman 34 /2006
Pneumatic compression vs no prophylaxis
Pregnant women undergoing cesarean section who were not anticoagulated during pregnancy
QALYs USD 2004 Funding source (if any) not stated
Pharmacologic prophylaxis not included as a comparator
Moderate uncertainty in baseline risk and effectiveness
Satisfactory quality, but not defi nitive given data uncertainties as noted by authors
Results (expected utilities, ICERs, etc)
Delta costs: 1 $ 104 Delta QALYs: 1 0.00263 ICER: 39,545 (range up to
200,000 1 , depending on assumptions)
ICER 5 incremental cost-effectiveness ratio; QALY 5 quality adjusted life year; USD 5 US dollar. a Types of patients/multiple subgroups. b Average wholesale price (eg, Redbook, Bluebook) or average sales price based estimate. c Quality category defi nitions: very good, 90% to 100% of quality items present; good, 80% to 89% of quality items present; satisfactory, 60% to 79% of quality items present; unsatisfactory, , 60% of quality items present .
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Tabl
e S1
5 —[S
ecti
on 7
.1.2
] E
vide
nce
Pro
fi le:
Sho
uld
LM
WH
Rat
her
Tha
n V
KA
s B
e U
sed
for
Lon
g-te
rm T
reat
men
t of
VT
E i
n P
regn
ant
Wom
en?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Dur
ing
Preg
nanc
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith V
KA
With
LM
WH
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
V
KA
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Rec
urre
nt s
ympt
omat
ic V
TE
(cri
tical
out
com
e), D
VT,
and
PE
2,49
6 (7
RC
Ts),
6 m
oSe
riou
s ri
sk
of b
ias
No
stud
ies
wer
e bl
inde
d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate
due
to r
isk
of
bias
202/
1,23
1 (1
6.4)
204/
1,26
5 (1
6.1)
RR
0.6
2 (0
.46-
0.84
)30
VT
E
per
1,00
0 a 11
few
er V
TE
pe
r 1,
000
(fro
m 5
few
er
to 1
6 fe
wer
)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,72
7 (8
RC
Ts),
6 m
oN
o se
riou
s ri
sk o
f bia
sL
ack
of
blin
ding
not
se
riou
s b
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nC
I in
clud
es
impo
rtan
t be
nefi t
an
d ha
rm
Und
etec
ted
Mod
erat
e du
e to
im
prec
isio
n
105/
1,34
9 (7
.8)
67/1
,378
(4.9
)R
R 0
.81
(0.5
5-1.
2)20
ble
edin
g ev
ents
pe
r 1,
000 c
4 fe
wer
ble
edin
g ev
ents
per
1,
000
(fro
m
9 fe
wer
to 4
m
ore)
PTS
(impo
rtan
t out
com
e): s
elf-
repo
rted
leg
sym
ptom
s an
d si
gns
100
(1 R
CT
), no
t rep
orte
dSe
riou
s ri
sk
of b
ias
Patie
nts
and
inve
stig
ator
s no
t blin
ded
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ssPr
edic
tive
valu
e fr
om 3
mo
to lo
ng te
rm
unce
rtai
n
No
seri
ous
impr
ecis
ion
Und
etec
ted
Low
due
to
risk
of
bias
and
in
dire
ctne
ss
31/4
4 (7
0.5)
34/5
6 (6
0.7)
RR
0.8
5 (0
.77-
0.94
)48
0 PT
S pe
r 1,
000 d
72 fe
wer
PT
S pe
r 1,
000
(fro
m
110
few
er to
29
few
er)
Bib
liogr
aphy
: Kea
ron
C, A
kl E
A, C
omer
ato
AJ,
et a
l. A
ntith
rom
botic
ther
apy
for V
TE
dis
ease
: ant
ithro
mbo
tic th
erap
y an
d pr
even
tion
of th
rom
bosi
s, 9
th e
d: A
mer
ican
Col
lege
of C
hest
Phy
sici
ans e
vide
nce-
base
d cl
inic
al p
ract
ice
guid
elin
es. C
hest
. 201
2;14
1(2)
(sup
p 1)
:e41
8S-e
494S
. Pra
ndon
i P, L
ensi
ng A
W, P
icci
oli A
, et a
l. R
ecur
rent
ven
ous t
hrom
boem
bolis
m a
nd b
leed
ing
com
plic
atio
ns d
urin
g an
ticoa
gula
nt
trea
tmen
t in
patie
nts
with
can
cer
and
veno
us th
rom
bosi
s. B
lood
. 200
2;10
0:34
84-3
488.
Bey
th R
J, Q
uinn
LM
, Lan
defe
ld C
S. P
rosp
ectiv
e ev
alua
tion
of a
n in
dex
for
pred
ictin
g th
e ri
sk o
f maj
or b
leed
ing
in
outp
atie
nts
trea
ted
with
war
fari
n. A
m J
Med
. 199
8;10
5:91
-99.
Met
a-an
alys
is is
bas
ed o
n R
CTs
as
refe
renc
ed in
the
text
of K
earo
n et
al 17
8 in
this
gui
delin
e. L
imite
d to
LM
WH
reg
imen
s th
at u
sed
� 5
0% o
f the
acu
te tr
eatm
ent d
ose
duri
ng th
e ex
tend
ed p
hase
of t
reat
-m
ent.
PTS
5 p
ostt
hrom
botic
syn
drom
e. S
ee T
able
S1,
S3,
S4,
S6,
and
S9
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a C
ontr
ol g
roup
ris
k es
timat
e fo
r V
TE
with
VK
As
com
es fr
om c
ohor
t stu
dy b
y Pr
ando
ni e
t al,
adju
sted
to 6
-mo
time
fram
e.
b Out
com
e le
ss s
ubje
ctiv
e: B
orde
rlin
e de
cisi
on.
c Con
trol
gro
up r
isk
estim
ate
for
maj
or b
leed
ing
even
ts c
omes
from
coh
ort s
tudi
es b
y Pr
ando
ni e
t al a
nd B
eyth
et a
l, ad
just
ed to
6-m
o tim
e fr
ame.
d C
ontr
ol g
roup
ris
k es
timat
e fo
r PT
S co
mes
from
obs
erva
tiona
l stu
dy o
f pre
gnan
t wom
en (m
ost m
ild). 17
1
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S1
6 —[S
ecti
on 8
.2.2
, 8.2
.3]
Ris
k of
Rec
urr
ent
VT
E i
n P
regn
ant
Wom
en W
itho
ut
Ant
epar
tum
Thr
omb
osis
Pro
phyl
axis
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
Pros
pect
ive
stud
ies
How
ell
et a
l 35 /1
983
RC
TN
5 4
0; n
5 2
0 in
con
trol
ar
m
No
ante
part
um
prop
hyla
xis;
po
stpa
rtum
U
FH
8,0
00
bid
Ble
edin
gO
steo
peni
aR
ecur
rent
VT
E
6 w
k post
part
umA
ntep
artu
m:
1 (5
%; 9
5% C
I,
0.1%
-25%
)Po
stpa
rtum
: 0
RC
T, c
once
alm
ent
of a
lloca
tion
adeq
uate
Prim
ary
outc
ome
was
sid
e ef
fect
s (o
steo
peni
a, a
nten
atal
bl
eedi
ng) r
athe
r th
an
VT
E, n
o IT
T a
naly
sis,
m
ean
gest
atio
nal a
ge
at e
ntry
14
wk
(ran
ge,
8-37
wk)
, no
obje
ctiv
e di
agno
sis
of fi
rst V
TE
, no
des
crip
tion
of
diag
nost
ic te
chni
ques
fo
r re
curr
ent D
VT
Lao
et a
l 36 /1
985
and
de S
wie
t et
al 37
/198
7 (la
tter
rep
ort
prov
ides
ad
ditio
nal
data
to th
e fi r
st)
Pros
pect
ive
coho
rt
stud
y
N 5
59;
25%
wom
en
had
sing
le p
revi
ous
VT
E r
elat
ed to
pr
egna
ncy;
39%
ha
d si
ngle
pre
viou
s V
TE
dur
ing
OC
P us
e
No
ante
part
um
prop
hyla
xis
(tw
o pr
otoc
ol
viol
atio
ns in
w
hich
pat
ient
s re
ceiv
ed
ante
part
um
antic
oagu
lant
s)
Rec
urre
nt V
TE
6 w
k post
part
umA
ntep
artu
m: 0
Post
part
um: 0
D
extr
an d
urin
g de
liver
y an
d he
pari
n or
w
arfa
rin
for
6 w
k po
stpa
rtum
Bri
ll-E
dwar
ds
et a
l 38 /2
000
Pros
pect
ive
coho
rtN
5 1
25 w
omen
w
ith o
ne
obje
ctiv
ely
diag
nose
d pr
evio
us V
TE
No
ante
part
um
prop
hyla
xis;
po
stpa
rtum
prop
hyla
xis
with
war
fari
n
Rec
urre
nt V
TE
an
tepa
rtum
Rec
urre
nt V
TE
po
stpa
rtum
3 m
o post
part
umA
ntep
artu
m:
3/12
5; 2
.4%
(9
5% C
I,
0.2%
-6.9
%)
Pros
pect
ive,
si
ngle
epi
sode
of
pri
or V
TE
on
ly
Incl
usio
n at
med
ian
gest
atio
nal a
ge o
f 15
wk,
exc
lusi
on o
f w
omen
with
kno
wn
thro
mbo
phili
a (C
onti
nued
)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
N
o re
curr
ence
s in
w
omen
with
no
thro
mbo
phili
a an
d a
prov
oked
fi rs
t VT
E
(0/4
4, 0
%; 9
5% C
I,
0%-8
.0%
); of
wom
en
with
an
idio
path
ic
fi rst
VT
E o
r abn
orm
al
thro
mbo
phili
a te
stin
g, 3
/51
(5.9
%; 9
5% C
I, 1
.2%
-16
.2%
) dev
elop
ed
recu
rren
cePo
stpa
rtum
: 3/1
22
(2.5
%; 9
5% C
I,
0.5%
-7.0
%)
Ret
rosp
ectiv
e st
udie
s
Bad
arac
co
et a
l 39 /1
974
Ret
rosp
ectiv
e co
hort
st
udy
N 5
30
wom
en
with
pre
viou
s V
TE
Not
sta
ted
Rec
urre
nt V
TE
du
ring
pr
egna
ncy
or p
ostp
artu
m
peri
od
Not
sta
ted
Tota
l: 6/
15 (4
0%;
(95%
CI,
16.
3%-
67.7
%);
dist
ribu
tion
betw
een
ante
part
um
and
post
part
um n
ot
prov
ided
Ret
rosp
ectiv
e, in
clud
ed
wom
en w
ith m
ore
than
one
pre
viou
s V
TE
, que
stio
nnai
re
data
, no
obje
ctiv
e di
agno
sis
Teng
born
et
al 40
/198
9R
etro
spec
tive
coho
rt
stud
y
N 5
72
wom
en w
ith
prev
ious
VT
E
(87
preg
nanc
ies;
67
pre
gnan
cies
w
ithou
t ant
epar
tum
pr
ophy
laxi
s)
No
ante
part
um
prop
hyla
xis
Post
part
um: n
o pr
ophy
laxi
s (n
5 3
0)Va
riou
s an
ticoa
gula
nt
regi
men
s,
incl
udin
g U
FH
an
d de
xtra
n (n
5 5
7)
Rec
urre
nt V
TE
;
supe
rfi c
ial
thro
mbo
phle
bitis
(n
ot in
clud
ed in
th
is ta
ble)
Unt
il po
stpa
rtum
; tim
e no
t st
ated
Ant
epar
tum
: 5/6
7 (7
.5%
; 95%
CI,
2%
-14%
)Po
stpa
rtum
: 2/3
0 (6
.7%
; 95%
CI,
0%
-21%
)A
ll re
curr
ence
s in
wom
en w
ith
prev
ious
VT
E
elic
ited
by
preg
nanc
y or
O
CP
use
Ret
rosp
ectiv
e, q
uest
ionn
aire
da
ta, n
o ob
ject
ive
diag
nosi
s, w
omen
with
m
ultip
le p
revi
ous
epis
odes
of V
TE
in
clud
ed, s
ome
wom
en
with
her
edita
ry
thro
mbo
phili
a (a
ntic
oagu
lant
inhi
bito
r de
fi cie
ncie
s n
5 3
; de
fect
ive
fi bri
noly
sis
n 5
18)
, wid
e ra
nge
of
post
part
um r
egim
ens,
po
tent
ial c
onfo
undi
ng
by in
dica
tion
Tabl
e S1
6—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
Pabi
nger
et
al 41
/200
5R
etro
spec
tive
coho
rt
stud
y
N 5
109
wom
en w
ith
prev
ious
VT
E (1
97
preg
nanc
ies;
284
po
stpa
rtum
per
iods
, in
clud
ing
afte
r te
rmin
atio
ns,
mis
carr
iage
s,
still
birt
hs, a
nd
live
birt
hs)
No
ante
part
um
prop
hyla
xis;
in
cons
iste
nt u
se
of p
ostp
artu
m
prop
hyla
xis,
m
ainl
y lo
w-d
ose
LM
WH
(det
ails
no
t sta
ted)
Cum
ulat
ive
inci
denc
e of
re
curr
ent V
TE
an
tepa
rtum
Rec
urre
nt V
TE
po
stpa
rtum
6 w
k post
part
umA
ntep
artu
m: 8
/197
(c
umul
ativ
e in
cide
nce,
6.2
%;
95%
CI,
1.
6%-1
0.6%
)N
o pr
edic
tive
valu
e of
thro
mbo
phili
a or
whe
ther
fi rs
t ep
isod
e w
as
idio
path
ic
Rec
urre
nce
risk
in
sub
grou
p of
w
omen
with
fi rs
t V
TE
ass
ocia
ted
with
OC
P us
e 10
%
vs 2
.7%
if fi
rst V
TE
no
t ass
ocia
ted
with
O
CP
use
(ns)
Post
part
um: o
vera
ll,
15/2
84 (5
.3%
; 95
% C
I, 3.
0%-8
.6%
); w
ithou
t pro
phyl
axis
, 10
/187
(5.4
%;
95%
CI,
2.6%
-9.6
%);
with
pro
phyl
axis
, 5/
97 (5
.2%
; 95%
CI,
1.
7%-1
1.6%
)
Ass
esse
d ri
sk fo
r fu
ll pe
riod
of
preg
nanc
y (ie
. in
clud
ing
earl
y te
rmin
atio
ns,
mis
carr
iage
s)
Ret
rosp
ectiv
e, in
clud
ed
wom
en w
ith m
ore
than
on
e pr
evio
us V
TE
, not
al
l VT
E o
bjec
tivel
y di
agno
sed,
pot
entia
l co
nfou
ndin
g by
in
dica
tion
Tabl
e S1
6—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
De
Stef
ano
et a
l 42 /2
006
Ret
rosp
ectiv
e co
hort
st
udy
N 5
88
wom
en
with
pre
viou
s V
TE
(155
pr
egna
ncie
s)
No
ante
part
um
prop
hyla
xis;
12
0 pr
egna
ncie
s w
ithou
t pos
tpar
tum
pr
ophy
laxi
s
Cum
ulat
ive
inci
denc
e of
rec
urre
nt V
TE
an
tepa
rtum
Rec
urre
nt V
TE
po
stpa
rtum
6 w
k post
part
um
if de
liver
y af
ter
16 w
k ge
stat
iona
l ag
e
Ant
epar
tum
: 9/1
55
(5.8
%; 9
5% C
I,
3.0%
-10.
6%)
Subg
roup
of w
omen
w
ith a
nd w
ithou
t th
rom
boph
ilia:
7.
9% v
s 4.
2%
Subg
roup
of
wom
en
with
fi rs
t VT
E
horm
onal
ly
prov
oked
(ie,
re
late
d to
pr
egna
ncy
or
OC
P us
e), 9
.5%
vs
unp
rovo
ked,
4.
2%, v
s tra
nsie
nt
nonh
orm
onal
ri
sk fa
ctor
, 0%
Post
part
um: 8
.3%
(9
5% C
I,
4.5%
-14.
6%)
Fir
st p
regn
ancy
-re
late
d V
TE
, 15
.5%
vs
fi rst
ev
ent-
rela
ted
to
OC
P us
e, 0
%,
vs u
npro
voke
d,
3.1%
, vs t
rans
ient
no
nhor
mon
al
risk
fact
or, 7
.1%
Ret
rosp
ectiv
e, in
clud
ed
wom
en w
ith
mor
e th
an o
ne
prev
ious
VT
E, n
ot
all V
TE
obj
ectiv
ely
diag
nose
d, p
oten
tial
conf
ound
ing
by
indi
catio
n
ns 5
not
sig
nifi c
ant;
OC
P 5
ora
l con
trac
eptio
n. S
ee T
able
S1,
S4,
and
S9
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.
Tabl
e S1
6—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
24© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S1
7 —[S
ecti
on 8
.2.2
, 8.2
.3]
Ris
k of
Sym
ptom
atic
Rec
urr
ent
VT
E a
nd B
leed
ing
in P
regn
ant
Wom
en R
ecei
ving
Ant
epar
tum
Thr
omb
osis
Pro
phyl
axis
: RC
Ts
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nC
ontr
olO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
How
ell
et a
l 35 /1
983
RC
TN
5 4
0; n
5 2
0 in
pro
phyl
axis
ar
m
Ant
epar
tum
pr
ophy
laxi
s U
FH
10
,000
uni
ts
bid
star
ting
at
enro
llmen
t (m
ean,
14
wk;
ran
ge,
8-37
wk)
Post
part
um U
FH
8,
000
units
bid
fo
r 6
wk
No
ante
part
um
prop
hyla
xis
Post
part
um
UF
H 8
,000
un
its b
id
Ble
edin
gO
steo
peni
aR
ecur
rent
V
TE
6 w
k post
part
umR
ecur
rent
VT
E
Inte
rven
tion
arm
:
Ant
epar
tum
, 0/2
0 Po
stpa
rtum
, 0/2
0
Con
trol
arm
: ant
epar
tum
,
1/20
(5%
; 95%
CI,
0.
1%-2
5%);
post
part
um,
0/20
(0%
; 95%
CI,
0%
-16.
8%);
estim
ate
of e
ffec
t siz
e, R
R 0
.33
(95%
CI,
0.0
1-7.
72)
Ble
edin
g
Inte
rven
tion
arm
,
2/20
(10%
; 95%
CI,
1.
24%
-31.
7%);
cont
rol
arm
, 0/2
0 (0
%, 9
5% C
I,
0%-1
6.8%
); es
timat
e of
eff
ect s
ize,
RR
5.0
0 (9
5% C
I, 0
.26-
98.0
0)
Con
ceal
men
t of
allo
catio
n ad
equa
te
Prim
ary
outc
ome
was
sid
e ef
fect
s (o
steo
peni
a, a
nten
atal
bl
eedi
ng) r
athe
r th
an
VT
E, n
o IT
T a
naly
sis,
m
ean
gest
atio
nal a
ge
at e
ntry
16
wk
(ran
ge 8
-37
wk)
, no
obje
ctiv
e di
agno
sis
of fi
rst V
TE
, no
desc
ript
ion
of
diag
nost
ic te
chni
ques
of
rec
urre
nce
Gat
es
et a
l 43 /2
004
RC
TN
5 1
6E
noxa
pari
n 40
mg
star
ted
from
an
tena
tal
recr
uitm
ent
until
6 w
k po
stpa
rtum
Plac
ebo
(1 m
L
salin
e)Sy
mpt
omat
ic
confi
rm
ed
VT
ESy
mpt
omat
ic
oste
opor
otic
fr
actu
res
6 m
o post
part
umR
ecur
rent
VT
E
Inte
rven
tion
arm
:
ante
part
um, 0
/8 (0
.0%
; 95
% C
I, 0
.0%
-36.
9%);
post
part
um, 0
/8 (0
.0%
; 95
% C
I, 0
.0%
-36.
9%)
C
ontr
ol a
rm: a
ntep
artu
m,
0/
8 (0
.0%
; 95%
CI,
0.
0%-3
6.9%
); po
stpa
rtum
, 1/
8 (1
2.5%
; 95%
CI,
3.
1%-5
2.7%
); es
timat
e of
eff
ect s
ize,
RR
0.3
3 (9
5% C
I, 0
.02-
7.14
)B
leed
ing:
non
e re
port
ed
Ade
quat
e co
ncea
lmen
t of
allo
catio
n A
dequ
ate
blin
ding
of
patie
nts
and
care
give
rs
Pilo
t stu
dy, t
oo s
mal
l to
draw
any
con
clus
ions
, re
crui
tmen
t at a
ll ge
stat
iona
l age
s,
the
maj
ority
. 2
0 w
k,
som
e cr
osso
ver
betw
een
grou
ps
post
part
um
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
25© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nC
ontr
olO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
Pett
ilä
et a
l 44 /1
994
RC
Tn
5 1
02 w
omen
w
ith p
revi
ous
prox
imal
VT
E
or p
revi
ous
dist
al V
TE
an
d pr
otei
n S
and
prot
ein
C d
efi c
ienc
y,
activ
ated
pro
tein
C
resi
stan
ce, o
r as
soci
ated
with
pr
egna
ncy
or O
CP
use
(thr
ee w
omen
w
ith V
TE
dur
ing
curr
ent p
regn
ancy
ex
clud
ed)
Ant
epar
tum
dal
tepa
rin
once
dai
ly a
t st
artin
g do
se o
f 5,
000
Inte
rnat
iona
l U
nits
( , 8
5 kg
) or
7,50
0 In
tern
atio
nal
Uni
ts ( .
85
kg),
then
dos
e ad
just
ed
to m
aint
ain
anti-
Xa
leve
ls .
0.2
0 un
its/m
L 3
h a
fter
in
ject
ion
Ant
epar
tum
UF
H
bid
SC s
tart
ing
at 7
,500
In
tern
atio
nal
Uni
ts, t
hen
dose
adj
uste
d to
mai
ntai
n aP
TT
5-1
5 s
abov
e up
per
limit
of n
orm
al
Rec
urre
nt
VT
EB
leed
ing
epis
odes
6 w
k post
part
umR
ecur
rent
VT
E
Dal
tepa
rin
arm
: 0/4
8
UF
H a
rm: 0
/54
safe
ty,
an
y bl
eedi
ng
com
plic
atio
n
Dal
tepa
rin
arm
: 9/5
0
(18%
; 95%
CI,
7.
0%-2
9%)
U
FH
arm
: 35/
55
(6
4%; 9
5% C
I,
51%
-77%
)
Con
ceal
men
t of
allo
catio
n ad
equa
te,
obje
ctiv
ely
confi
rm
ed
prev
ious
V
TE
Not
blin
ded
aPT
T 5
activ
ated
par
tial t
hrom
bopl
astin
tim
e. S
ee T
able
S1,
S3,
S4,
S16
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.
Tabl
e S1
7—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
26© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S1
8 —[8
.2.2
, 8.2
.3]
Ris
k of
Rec
urr
ent
VT
E i
n P
regn
ant
Wom
en R
ecei
ving
Ant
epar
tum
Thr
omb
osis
Pro
phyl
axis
: Ob
serv
atio
nal
Stu
dies
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
Pros
pect
ive
stud
ies
Blo
mbä
ck
et a
l 45 /1
998
Pros
pect
ive
coho
rt
stud
y
25 w
omen
with
pr
evio
us V
TE
Dal
tepa
rin
wei
ght-
adju
sted
sta
rtin
g do
se, t
hen
adju
sted
to
targ
et a
nti-X
a le
vels
of 0
.20-
0.40
uni
ts/m
L 3
h
post
inje
ctio
n
Rec
urre
nt V
TE
Ant
i-Xa
leve
ls6
wk po
stpa
rtum
Ant
epar
tum
re
curr
ent V
TE
: 0/
25 (0
%;
95%
CI,
0%
-13.
7%)
Obj
ectiv
e di
agno
sis
of fi
rst V
TE
Unc
ontr
olle
d, 1
4 w
omen
w
ere
recr
uite
d in
the
seco
nd tr
imes
ter
of
preg
nanc
y, 3
wom
en
did
not c
ompl
ete
the
stud
y an
d w
ere
with
draw
n fr
om
the
anal
ysis
Bre
nnan
d et
al 46
/199
9Pr
ospe
ctiv
e co
hort
st
udy
16 w
omen
with
an
indi
catio
n fo
r th
rom
bosi
s pr
ophy
laxi
s du
ring
pr
egna
ncy;
14
had
a hi
stor
y of
pr
evio
us V
TE
Eno
xapa
rin
40 m
g on
ce d
aily
; po
stpa
rtum
no
t sta
ted
Ant
i-Xa
leve
lsR
ecur
rent
VT
E
repo
rted
in
the
artic
le
Not
sta
ted
Ant
epar
tum
: 0/1
4 (0
%; 9
5% C
I,
0%-2
3.2%
)Po
stpa
rtum
: 1/1
4 (7
.1%
; 95%
CI,
0.
2%-3
4%)
Phar
mac
odyn
amic
stu
dy
Bau
ersa
chs
et a
l 47 /2
007
Pros
pect
ive
coho
rt
man
agem
ent
stud
y
810
preg
nant
w
omen
at
incr
ease
d ri
sk fo
r V
TE
; 22
5 w
ith
prev
ious
V
TE
Ant
epar
tum
clin
ical
su
rvei
llanc
e;
inte
rmed
iate
- and
hi
gh-d
ose
dalte
pari
n ac
cord
ing
to r
isk
stra
tifi c
atio
n ba
sed
on
hist
ory
(see
lege
nd)
Wom
en w
ith p
revi
ous
VT
E/to
tal:
low
-ris
k gr
oup,
49/
225;
hi
gh-r
isk
grou
p,
339/
469;
ver
y-hi
gh-r
isk
grou
p, 1
04/1
16
Sym
ptom
atic
re
curr
ent
VT
E, c
linic
ally
re
leva
nt
blee
ding
, se
riou
s bl
eedi
ng
Not
sta
ted
Low
-ris
k gr
oup:
0/
49 (9
5% C
I,
0%-7
.3%
)H
igh-
risk
gro
up:
2/33
8 (0
.6%
; 95
% C
I, 0
.0%
-2.1
%)
Very
-hig
h-ri
sk g
roup
: 2/
104
(1.9
%;
95%
CI,
0.
2%-6
.8%
)
Unc
ontr
olle
d, in
clud
ed
wom
en w
ith m
ultip
le
epis
odes
of V
TE
, in
clud
es w
omen
w
ithou
t his
tory
of
VT
E, d
ata
in th
is ta
ble
dedu
ced
from
art
icle
Dar
gaud
et
al 48
/200
9Pr
ospe
ctiv
e co
hort
m
anag
emen
t st
udy
286
preg
nant
w
omen
at
incr
ease
d ri
sk
for
VT
E; 1
83
with
pre
viou
s V
TE
Ant
epar
tum
clin
ical
su
rvei
llanc
e; e
noxa
pari
n 40
mg
once
dai
ly
(60
mg
in B
MI
. 3
5 kg
/m 2 )
sta
rtin
g in
th
e th
ird
trim
este
r or
st
artin
g ea
rly
in
preg
nanc
y ac
cord
ing
to a
ris
k sc
ore
(see
le
gend
); al
l in
addi
tion
to c
lass
2 s
tock
ings
Sym
ptom
atic
re
curr
ent V
TE
, bl
eedi
ng, H
IT,
sym
ptom
atic
os
teop
oros
is,
seri
ous
urtic
aria
l ra
sh r
elat
ed to
he
pari
n
Not
sta
ted,
lik
ely
8 w
k po
stpa
rtum
No
ante
nata
l LM
WH
(r
isk
scor
e ,
3):
0/25
(95%
CI,
0%
-13.
7%)
LM
WH
sta
rt in
thir
d tr
imes
ter
(ris
k sc
ore
3-5)
: ant
epar
tum
, 0/
89 (0
%; 9
5% C
I,
0%-4
.1%
); po
stpa
rtum
, 1/8
9 (1
.1%
; 95%
CI,
0.
0%-6
.1%
)
Unc
ontr
olle
d, m
ay h
ave
incl
uded
wom
en w
ith
mul
tiple
epi
sode
s of
V
TE
, inc
lude
d w
omen
w
ithou
t his
tory
of
VT
E, d
ata
in th
is ta
ble
dedu
ced
from
art
icle
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
27© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S1
8—C
onti
nued
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
N
o an
tena
tal L
WM
H,
n 5
25
Star
t LM
WH
in th
ird
trim
este
r, n
5 8
9L
MW
H th
roug
hout
pr
egna
ncy,
n 5
69
LM
WH
thro
ugho
ut
preg
nanc
y (r
isk
scor
e �
6):
ante
part
um,
0/69
(0%
; 95%
CI,
0%
-5.2
%);
post
part
um, 1
/69
(1.5
%; 9
5% C
I,
0.0%
-7.8
%)
Ble
edin
g: o
ne
post
part
um
hem
orrh
age
in a
wom
an n
ot
rece
ivin
g L
MW
H
Fol
keri
nga
et a
l49/2
007
Pros
pect
ive
coho
rt
stud
y
55 w
omen
from
fa
mili
es w
ith
antit
hrom
bin,
pr
otei
n C
, and
pr
otei
n S
defi c
ienc
y;
22 w
ith a
his
tory
of
VT
E.
19 w
omen
rec
eive
d th
rom
bosi
s pr
ophy
laxi
s du
ring
pr
egna
ncy;
18
wer
e an
tithr
ombi
n,
prot
ein
C, o
r pr
otei
n S
defi c
ient
Adj
uste
d-do
se U
FH
or
LM
WH
bef
ore
16 w
k of
ge
stat
ion
and
afte
r 36
wk
of g
esta
tion,
with
VK
As
in b
etw
een
or a
djus
ted-
dose
LM
WH
th
roug
hout
pre
gnan
cy
Fet
al lo
ss
Sym
ptom
atic
re
curr
ent V
TE
re
port
ed in
the
artic
le
Not
sta
ted
Not
sta
ted
whe
ther
an
tepa
rtum
or
post
part
um: 2
/19
(10.
5%; 9
5% C
I,
1.3%
-33.
1%)
No
maj
or b
leed
ing
repo
rted
Unc
ontr
olle
d, m
ay h
ave
incl
uded
wom
en w
ith
mul
tiple
epi
sode
s of
V
TE
, inc
lude
d w
omen
w
ithou
t his
tory
of
VT
E, d
ata
in th
is ta
ble
dedu
ced
from
art
icle
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
28© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
Roz
ansk
i et
al 50
/200
9Pr
ospe
ctiv
e co
hort
m
anag
emen
t st
udy
90 p
regn
ant w
omen
at
incr
ease
d ri
sk
for
VT
E
Ant
epar
tum
clin
ical
su
rvei
llanc
e in
wom
en
with
pre
viou
s pr
ovok
ed
VT
E (m
ajor
ris
k fa
ctor
), n
5 3
0; 3
7 pr
egna
ncie
sD
alte
pari
n (d
ose
not
stat
ed) i
n w
omen
with
pr
evio
us id
iopa
thic
V
TE
n 5
60;
99
pre
gnan
cies
Sym
ptom
atic
re
curr
ent
VT
E
Not
sta
ted
Prev
ious
pro
voke
d V
TE
, clin
ical
su
rvei
llanc
e:
ante
part
um
recu
rren
t VT
E,
1/37
(2.7
%; 9
5%
CI,
0.5
%-1
3.8%
); po
stpa
rtum
, 0/3
6Pr
evio
us id
iopa
thic
V
TE
, dal
tepa
rin:
an
tepa
rtum
, re
curr
ent V
TE
3/
99 (3
.0%
; 95%
C
I, 1
.0%
-8.5
%);
post
part
um, 0
/96
Maj
or b
leed
ing:
Non
e
Unc
ontr
olle
d, a
bstr
act
only
, defi
niti
on o
f pr
ovok
ed v
s id
iopa
thic
pr
evio
us V
TE
unc
lear
Ret
rosp
ectiv
e st
udie
s
Teng
born
et
al 40
/198
9R
etro
spec
tive
coho
rt
stud
y
72 w
omen
with
pr
evio
us V
TE
, 87
pre
gnan
cies
; 20
pre
gnan
cies
w
ith a
ntep
artu
m
prop
hyla
xis
Ant
epar
tum
: UF
H 5
,000
In
tern
atio
nal U
nits
bi
d (n
5 1
1), 1
0,00
0 In
tern
atio
nal U
nits
bi
d (n
5 1
), 12
,500
In
tern
atio
nal U
nits
bi
d (n
5 2)
, aPT
T-ba
sed
(n 5
2),
Unk
now
n re
gim
en (n
5 1
)U
FH
sta
rted
at m
edia
n of
16t
h (r
ange
, bef
ore
conc
eptio
n-30
wk)
ge
stat
iona
l age
Post
part
um: U
FH
, dos
e no
t sta
ted
(n 5
13)
; de
xtra
n, d
ose
not
stat
ed (n
5 42
); U
FH
an
d de
xtra
n (n
5 1
); U
FH
and
ant
ithro
mbi
n co
ncen
trat
e (n
5 1
)
Rec
urre
nt V
TE
, su
perfi
cia
l th
rom
boph
lebi
tis
(not
incl
uded
in
this
tabl
e)
Unt
il po
stpa
rtum
, tim
e no
t sta
ted
Ant
epar
tum
: 3/2
0 (1
5%, 9
5% C
I,
0%-3
1%);
two
occu
rrin
g in
lo
wes
t UF
H d
ose;
on
e in
wom
an
with
ant
ithro
mbi
n de
fi cie
ncy
who
ha
d aP
TT-
adju
sted
do
se U
FH
Post
part
um: 2
/57
(3.5
%; 9
5% C
I,
0.4%
-12.
1%)
desp
ite p
roph
ylax
isA
ll re
curr
ence
s in
w
omen
with
pr
evio
us V
TE
el
icite
d by
pr
egna
ncy
or
OC
P us
e
Ret
rosp
ectiv
e,
ques
tionn
aire
dat
a,
no o
bjec
tive
diag
nosi
s,
wom
en w
ith m
ultip
le
prev
ious
epi
sode
s of
V
TE
incl
uded
, som
e w
omen
with
her
edita
ry
thro
mbo
phili
a (a
nti c
oagu
lant
inhi
bito
r de
fi cie
ncie
s, n
5 3
; de
fect
ive
fi bri
noly
sis,
n
5 1
8), p
oten
tial
conf
ound
ing
by
indi
catio
n
Tabl
e S1
8—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
29© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
Sans
on
et a
l 51 /1
999
Syst
emat
ic r
evie
w
of p
ublis
hed
coho
rt s
tudi
es
and
coho
rts f
rom
in
tern
atio
nal
inte
rest
gro
up
486
preg
nanc
ies
from
21
repo
rts;
14
9 pr
egna
ncie
s in
wom
en w
ith
prev
ious
VT
E
Seve
ral d
oses
and
type
s of
LM
WH
; low
-dos
e de
fi ned
as
, 7
5 an
ti-X
a un
its/k
g; in
term
edia
te
dose
defi
ned
as
75-1
50
anti-
Xa
units
/kg;
hig
h do
se d
efi n
ed a
s .
150
an
ti-X
a un
its/k
g
Adv
erse
pr
egna
ncy
even
ts; a
dver
se
feta
l/neo
nata
l ev
ents
Se
cond
ary:
VT
E,
thro
mbo
cyto
peni
a,
oste
opor
osis,
he
mor
rhag
ic
epis
odes
Not
sta
ted
3/14
9 (2
%; 9
5% C
I ,
0.7-
5.6%
) had
ph
lebi
tis; 2
had
th
rom
boph
ilia;
1
had
APL
As;
1
low
-dos
e; 2
in
term
edia
te-d
ose
Rev
iew
of s
mal
l cas
e se
ries
and
ad
hoc
iden
tifi e
d co
hort
s,
pote
ntia
l for
pub
licat
ion
and
repo
rtin
g bi
as,
risk
per
dos
e L
MW
H
cann
ot b
e ca
lcul
ated
fr
om th
e pu
blis
hed
data
, dia
gnos
tic c
rite
ria
fi rst
and
rec
urre
nt V
TE
no
t sta
ted,
num
ber
of p
revi
ous
VT
E n
ot
stat
ed
Lep
ercq
et
al 52
/200
1R
etro
spec
tive
coho
rt
stud
y
604
wom
en w
ith
649
preg
nanc
ies
Seve
ral d
oses
and
in
dica
tions
of
enox
apar
in
thro
mbo
sis
prop
hyla
xis
in
574
case
s
Mat
erna
l saf
ety,
pr
egna
ncy
outc
ome,
ne
onat
al
safe
ty, V
TE
re
curr
ence
Ant
epar
tum
rec
urre
nce,
n
5 5
(den
omin
ator
un
clea
r), a
ll in
wom
en
who
had
had
pre
viou
s V
TE
in c
urre
nt
preg
nanc
y w
hile
ta
king
40
mg
Post
part
um
recu
rren
ce,
n 5
3
Prim
ary
outc
ome
safe
ty
rath
er th
an r
ecur
rent
V
TE
D
enom
inat
or o
f wom
en
with
his
tory
of V
TE
ca
nnot
be
extr
acte
d fr
om th
e ar
ticle
, unc
lear
w
heth
er r
ecur
renc
es
are
real
rec
urre
nces
or
exte
nsio
ns fr
om r
ecen
t ac
ute
VT
E, d
iagn
ostic
cr
iteri
a fi r
st a
nd
recu
rren
t VT
E n
ot
stat
ed, n
umbe
r of
pr
evio
us V
TE
not
stat
ed
Tabl
e S1
8—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
30© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arTy
pe o
f Stu
dyPa
rtic
ipan
tsIn
terv
entio
nO
utco
mes
Fol
low
-up
Res
ults
Stre
ngth
sL
imita
tions
Pabi
nger
et
al 41
/200
5R
etro
spec
tive
coho
rt
stud
y
Unk
now
n nu
mbe
r of
wom
en w
ith
prev
ious
VT
E
who
had
87
preg
nanc
ies
with
ant
epar
tum
pr
ophy
laxi
s28
4 po
stpa
rtum
pe
riod
s, in
clud
ing
afte
r te
rmin
atio
ns,
mis
carr
iage
s,
still
birt
hs, a
nd
live
birt
hs
Ant
epar
tum
UF
H
5,00
0 bi
d or
low
-dos
e en
oxap
arin
or d
alte
parin
(d
ose
not s
tate
d);
inco
nsis
tent
use
of
post
part
um p
roph
ylax
is,
mai
nly
low
-dos
e L
MW
H
(det
ails
not
sta
ted)
Cum
ulat
ive
inci
denc
e of
re
curr
ent V
TE
an
tepa
rtum
, re
curr
ent V
TE
po
stpa
rtum
6 w
k post
part
umA
ntep
artu
m: 0
/87
(0%
; 95%
CI,
0%
-4.1
%)
Post
part
um: o
vera
ll,
15/2
84 (5
.3%
; 95
% C
I, 3
.0%
-8.6
%);
with
out p
roph
ylax
is,
10/1
87 (5
.3%
; 95
% C
I, 2
.6%
-9.6
%);
with
pro
phyl
axis
, 5/
97 (5
.2%
; 95%
CI,
1.
7%-1
1.6%
)
Ass
esse
d ri
sk
of fu
ll pe
riod
of
preg
nanc
y (ie
, inc
ludi
ng
earl
y te
rmin
atio
ns,
mis
carr
iage
s)
Incl
uded
wom
en w
ith
mor
e th
an o
ne p
revi
ous
VT
E, n
ot a
ll V
TE
ob
ject
ivel
y di
agno
sed,
po
tent
ial c
onfo
undi
ng
by in
dica
tion
Bau
ersa
chs e
t al 47
: Ris
k st
ratifi
cat
ion
for w
omen
with
pre
viou
s VT
E: (
1) lo
w-r
isk
patie
nts,
pri
or se
cond
ary
VT
E (n
ot a
ssoc
iate
d w
ith th
rom
boph
ilia,
pre
gnan
cy, o
ral c
ontr
acep
tion)
; (2)
hig
h-ri
sk p
atie
nts,
pri
or
VT
E a
nd th
rom
boph
ilia,
pri
or id
iopa
thic
VT
E, p
rior
VT
E d
urin
g pr
egna
ncy
or o
ral c
ontr
acep
tion,
recu
rren
t sec
onda
ry V
TE
; (3)
ver
y-hi
gh-r
isk
patie
nts,
ant
ithro
mbi
n de
fi cie
ncy
and
prio
r VT
E, a
ntip
hosp
ho-
lipid
synd
rom
e an
d pr
ior V
TE
or a
rter
ial t
hrom
boem
bolis
m, a
cute
VT
E in
cur
rent
pre
gnan
cy a
fter
day
11.
Dar
gaud
et a
l 48 : R
isk
stra
tifi c
atio
n us
ing
an in
divi
dual
risk
scor
e, se
e Ta
ble
1 in
ori
gina
l pub
licat
ion.
H
IT 5
hep
arin
-indu
ced
thom
bocy
tope
nia.
See
Tab
le S
1, S
4, S
8, S
16, a
nd S
17 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
Tabl
e S1
8—C
onti
nued
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Tabl
e S1
9 —[S
ecti
on 8
.2.2
, 8.2
.3]
Ant
epar
tum
and
Pos
tpar
tum
Pre
vent
ion
of V
TE
Wit
h P
roph
ylac
tic-
Dos
e L
MW
H v
s N
o P
roph
ylax
is i
n P
regn
ant
Wom
en
Wit
h P
rior
VT
E
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Dur
ing
Preg
nanc
y
Part
icip
ants
(S
tudi
es),
Fol
low
up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ithou
t Pr
ophy
laxi
sW
ith L
WM
H
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
out
Prop
hyla
xis
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Sym
ptom
atic
VT
E (c
ritic
al o
utco
me)
, DV
T a
nd P
E
1,95
3 (6
RC
Ts),
27-3
5 d
post
oper
ativ
e
No
seri
ous
risk
of
bias
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss a
orth
oped
ic
surg
ery
Seri
ous
impr
e cis
ion b
Wid
e C
I fo
r co
ntro
l gro
up
risk
est
imat
es
Und
etec
ted
Low
due
to
indi
rect
ness
an
d im
prec
isio
n
36/8
62 (4
.2)
15/1
,091
(1.4
)R
R 0
.36
(0.2
0-0.
67)
Low
ris
k (t
rans
ient
ris
k fa
ctor
)
20 V
TE
pe
r 1,
000 c
13 fe
wer
VT
E
per
1,00
0 (f
rom
16
few
er to
7
few
er)
In
term
edia
te a
nd h
igh
risk
(p
regn
ancy
or
estr
ogen
rel
ated
, id
iopa
thic
, or
mul
tiple
pri
or V
TE
bu
t dis
cont
inue
d V
KA
)
40
VT
E
per
1,00
0 c 26
few
er V
TE
pe
r 1,
000
(fro
m
32 fe
wer
to
13 fe
wer
) (C
onti
nued
)
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Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Dur
ing
Preg
nanc
y
Part
icip
ants
(S
tudi
es),
Fol
low
up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ithou
t Pr
ophy
laxi
sW
ith L
WM
H
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
out
Prop
hyla
xis
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Maj
or b
leed
(cri
tical
out
com
e)d
5,45
6 (7
RC
Ts),
3 w
k-9
mo
No
seri
ous
risk
of
bias
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss a
orth
oped
ic
surg
ery
Seri
ous
impr
ecis
ion
CI
incl
udes
ben
efi t
and
harm
Und
etec
ted
Low
due
to
indi
rect
ness
an
d im
prec
isio
n
2/1,
480
(0.1
4)6/
1,24
5 (0
.48)
RR
0.4
3 (0
.11-
1.65
)A
ntep
artu
m p
erio
d
5 bl
eedi
ng
even
ts
per
1,00
0 e
3 fe
wer
ble
edin
g ev
ents
per
1,0
00
(fro
m 4
few
er
to 3
mor
e)
Po
stpa
rtum
per
iod
20
ble
edin
g ev
ents
pe
r 1,
000 e
11 fe
wer
ble
edin
g ev
ents
per
1,0
00
(fro
m 1
8 fe
wer
to
13
mor
e)
Hul
l RD
et a
l. E
xten
ded
out o
f hos
pita
l low
mol
ecul
ar w
eigh
t hep
arin
pro
phyl
axis
aga
inst
dee
p ve
in th
rom
bosi
s in
pat
ient
s af
ter
elec
tive
hip
arth
ropl
asty
: a s
yste
mat
ic r
evie
w. A
nn I
nter
n M
ed. 2
001;
135:
858-
869.
Gre
er I
A, N
elso
n-Pi
ercy
C. L
ow m
olec
ular
wei
ght
hepa
rins
for
thr
ombo
prop
hyla
xis
and
trea
tmen
t of
ven
ous
thro
mbo
embo
lism
in p
regn
ancy
: a s
yste
mat
ic r
evie
w o
f sa
fety
and
effi
cacy
. Blo
od.
2005
;106
:401
-407
. See
Tab
le S
3, S
4, S
6, S
9 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a P
opul
atio
n is
indi
rect
; the
pop
ulat
ion
did
not i
nclu
de p
regn
ant w
omen
. Diff
eren
t dos
es o
f LM
WH
wer
e us
ed, t
reat
men
t was
initi
ated
var
iabl
y be
fore
or
afte
r su
rger
y w
ith a
dur
atio
n of
� 7
day
s (in
hos
pi-
tal).
Out
com
es v
aria
bly
repo
rted
. Met
a-an
alys
is a
lso
prov
ides
oth
er o
utco
mes
, suc
h as
mor
talit
y, a
sym
ptom
atic
DV
T, a
nd s
peci
fi c b
leed
out
com
es (w
ound
hem
atom
a, tr
ansf
usio
n). F
ollo
w-u
p va
ried
am
ong
tria
ls fr
om 3
wk
to 9
mo.
b B
asel
ine
risk
est
imat
es fo
r V
TE
in th
e an
tepa
rtum
and
pos
tpar
tum
per
iod
com
e fr
om s
tudi
es s
umm
ariz
ed in
Tab
le S
16. Q
ualit
y of
evi
denc
e is
rat
ed d
own
beca
use
of im
prec
isio
n in
thes
e ri
sk e
stim
ates
. W
e co
nsid
er th
e di
stri
butio
n of
VT
E a
ntep
artu
m a
nd p
ostp
artu
m to
be
equa
l. c B
asel
ine
risk
est
imat
es fo
r V
TE
in th
e an
tepa
rtum
and
pos
tpar
tum
per
iod
com
e fr
om s
tudi
es s
umm
ariz
ed in
Tab
le S
16. W
e co
nsid
er th
e di
stri
butio
n of
VT
E a
ntep
artu
m a
nd p
ostp
artu
m to
be
equa
l. d D
efi n
ed n
onfa
tal m
ater
nal h
emor
rhag
e (a
ccor
ding
to s
ectio
n 1.
0) a
s a
sym
ptom
atic
ble
edin
g co
mpl
icat
ion
note
d du
ring
pre
gnan
cy o
r w
ithin
6 w
eeks
pos
tpar
tum
that
invo
lved
ble
edin
g in
to a
cri
tical
site
, bl
eedi
ng c
ausi
ng a
fall
in h
emog
lobi
n le
vel o
f 2 g
/dL
or
mor
e, a
nd b
leed
ing
lead
ing
to tr
ansf
usio
n of
� 2
uni
ts o
f who
le b
lood
or
red
cells
. e B
asel
ine
risk
est
imat
e fo
r m
ajor
mat
erna
l hem
orrh
age
com
es fr
om a
sys
tem
atic
rev
iew
by
Gre
er e
t al. 38
Tabl
e S1
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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(Con
tinu
ed)
Tabl
e S2
0 —[S
ecti
on 9
.2.1
-9.2
.4]
Evi
denc
e P
rofi l
e: A
ntep
artu
m a
nd P
ostp
artu
m P
roph
ylac
tic-
Dos
e L
MW
H v
s N
o T
hrom
bop
roph
ylax
is f
or P
regn
ant
Wom
en
Wit
h a
Kno
wn
Thr
omb
ophi
lia
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Ant
epar
tum
and
Pos
tpar
tum
(Diff
eren
t R
isk
Est
imat
es fo
r B
leed
ing
Eve
nts)
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ithou
t Pr
ophy
laxi
sW
ith L
WM
H
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ithou
t Pr
ophy
laxi
sR
isk
Diff
eren
ce W
ith
LM
WH
(95%
CI)
Sym
ptom
atic
VT
E (c
ritic
al o
utco
me)
, DV
T, a
nd P
E
1,95
3 (6
RC
Ts),
27-3
5 d
post
oper
ativ
e
No
seri
ous
risk
of
bias
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss a
orth
oped
ic
surg
ery
Seri
ous
impr
e cisi
on b
Wid
e C
I fo
r co
ntro
l gr
oup
risk
es
timat
es
Und
etec
ted
Low
due
to
indi
rect
ness
an
d im
prec
isio
n
36/8
62 (4
.2)
15/1
,091
(1.4
)R
R 0
.36
(0.2
0-0.
67)
Posi
tive
fam
ily h
isto
ry V
TE
and
he
tero
zygo
us fa
ctor
V L
eide
n or
pr
othr
ombi
n 20
2010
A
15 V
TE
pe
r 1,
000 c
10 fe
wer
VT
E p
er 1
,000
(f
rom
12
few
er to
5
few
er)
Po
sitiv
e fa
mily
his
tory
VT
E a
nd
antit
hrom
bin,
pro
tein
C o
r pr
otei
n S
defi c
ienc
y
20
VT
E
per
1,00
0 c 13
few
er V
TE
per
1,0
00
(fro
m 1
6 fe
wer
to
6 fe
wer
)
Po
sitiv
e fa
mily
his
tory
VT
E a
nd
hom
ozyg
ous
fact
or V
Lei
den
or
prot
hrom
bin
2021
0A
70
VT
E
per
1,00
0 c 47
few
er V
TE
per
1,0
00
(fro
m 5
6 fe
wer
to
21 fe
wer
)
N
o fa
mily
his
tory
of V
TE
but
ho
moz
ygou
s fa
ctor
V L
eide
n or
pr
othr
ombi
n 20
210A
20
VT
E p
er
1,00
0 c 13
few
er V
TE
per
1,0
00
(fro
m 1
6 fe
wer
to
6 fe
wer
)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
34© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Ant
epar
tum
and
Pos
tpar
tum
(Diff
eren
t R
isk
Est
imat
es fo
r B
leed
ing
Eve
nts)
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ithou
t Pr
ophy
laxi
sW
ith L
WM
H
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ithou
t Pr
ophy
laxi
sR
isk
Diff
eren
ce W
ith
LM
WH
(95%
CI)
Maj
or b
leed
(cri
tical
out
com
e)
5,45
6 (7
RC
Ts),
3 w
k-9
mo
No
seri
ous
risk
of
bias
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss
orth
oped
ic
surg
ery
Seri
ous
impr
ecis
ion
CI
incl
udes
be
nefi t
and
ha
rm
Und
etec
ted
Low
due
to
indi
rect
ness
an
d im
prec
isio
n
2/1,
480
(0.1
4)6/
1,24
5 (0
.48)
RR
0.4
3 (0
.11-
1.65
)A
ntep
artu
m p
erio
d
5 bl
eedi
ng
even
ts
per
1,00
0 d
3 fe
wer
ble
edin
g ev
ents
pe
r 1,
000
(fro
m 4
fe
wer
to 3
mor
e)
Post
part
um p
erio
d
20
ble
edin
g ev
ents
per
1,
000 d
11 fe
wer
ble
edin
g ev
ents
pe
r 1,
000
(fro
m 1
8 fe
wer
to 1
3 m
ore)
Bib
liogr
aphy
: Hul
l RD
, et a
l. E
xten
ded
out o
f hos
pita
l low
mol
ecul
ar w
eigh
t hep
arin
pro
phyl
axis
aga
inst
dee
p ve
in th
rom
bosi
s in
patie
nts a
fter
ele
ctiv
e hi
p ar
thro
plas
ty: a
syst
emat
ic re
view
. Ann
Int
ern
Med
. 20
01;1
35:8
58-8
69. G
reer
IA
, Nel
son-
Pier
cy C
. Low
mol
ecul
ar w
eigh
t hep
arin
s fo
r th
rom
bopr
ophy
laxi
s an
d tr
eatm
ent o
f ven
ous
thro
mbo
embo
lism
in p
regn
ancy
: a s
yste
mat
ic r
evie
w o
f saf
ety
and
effi c
acy.
B
lood
. 200
5;10
6:40
1-40
7. S
ee T
able
S3,
S4,
S6,
and
S9
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a The
pop
ulat
ion
did
not
incl
ude
preg
nant
wom
en. D
iffer
ent
dose
s of
LM
WH
wer
e us
ed, t
reat
men
t w
as in
itiat
ed v
aria
bly
befo
re o
r af
ter
surg
ery
with
a d
urat
ion
of �
7 d
ays
in h
ospi
tal a
nd 2
5 da
ys o
ut
of h
ospi
tal.
Out
com
es w
ere
vari
ably
rep
orte
d.
b Im
prec
isio
n in
bas
elin
e ri
sk e
stim
ates
for
all t
hrom
boph
ilias
(see
Tab
le S
22) r
esul
ts in
impr
ecis
e an
ticip
ated
abs
olut
e ef
fect
s.
c Bas
elin
e ri
sk e
stim
ate
for V
TE
com
es fr
om o
bser
vatio
nal s
tudi
es su
mm
ariz
ed in
Tab
le S
22. O
ur a
ntep
artu
m ri
sk e
stim
ate
is b
ased
on
assu
med
equ
al d
istr
ibut
ion
of a
ntep
artu
m a
nd p
ostp
artu
m V
TE
eve
nts
base
d on
dat
a fr
om o
bser
vatio
nal s
tudi
es (I
. A. G
reer
, MD
, per
sona
l com
mun
icat
ion,
Nov
embe
r 8,
201
0).
d Bas
elin
e ri
sk e
stim
ate
for
maj
or b
leed
ing
even
ts a
ntep
artu
m a
nd p
ostp
artu
m c
ome
from
sys
tem
atic
rev
iew
by
Gre
er.
Tabl
e S2
0—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
35© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S2
1 —[S
ecti
on 1
0.2.
3. 1
0.2.
4] R
ando
miz
ed T
rial
s an
d O
bse
rvat
iona
l St
udi
es o
f th
e P
reve
ntio
n of
Com
plic
atio
ns i
n P
regn
ant
Wom
en W
ith
Thr
omb
ophi
lia:
C
lini
cal
Des
crip
tion
and
Res
ult
s
Stud
y/Ye
arIn
terv
entio
nN
umbe
r Pa
tient
s A
naly
zed
Len
gth
of
Fol
low
-up
Preg
nanc
y L
oss
(%)
Fet
al G
row
th
Res
tric
tion
(%)
Pree
clam
psia
(%)
Plac
enta
l A
brup
tion
(%)
Mat
erna
l B
leed
ing
(%)
Com
men
ts
Ran
dom
ized
tria
ls
Thr
ombo
phili
a-A
PLA
Asp
irin
vs
plac
ebo
Cow
choc
k an
d R
eece
53 /1
997
Asp
irin
81
mg/
dA
spir
in 5
11
Preg
nanc
y lo
ss
or d
eliv
ery
Asp
irin
5 1
/11
(9
.1)
Asp
irin
5 0
/10
NR
NR
NR
U
sual
car
eU
sual
5 8
Usu
al 5
0/8
Usu
al 5
1/8
(12.
5)
R
R 2
.25
(0
.10-
49.0
4)R
R 0
.27
(0.0
1-5.
92)
Tulp
pala
et
al 54
/199
7A
spir
in 5
0 m
g/d
Asp
irin
5 6
Preg
nanc
y lo
ss
or d
eliv
ery
Asp
irin
5 5
/6 (8
3)N
RN
RN
RN
RPr
egna
ncy
loss
es
in
clud
e: A
SA
1/6
5 b
light
ed
ov
um; c
ontr
ol
3/6
5 b
light
ed
ov
um o
r ec
topi
c pr
egna
ncy
Pl
aceb
oPl
aceb
o 5
6Pl
aceb
o 5
3/6
(50.
0)
R
R 1
.20
(0
.48-
2.99
)
Patt
ison
et
al 55
/200
0A
spir
in 7
5 m
g/d
Asp
irin
5 2
0/25
(8
0.0%
)Pr
egna
ncy
loss
or
del
iver
yA
spir
in 5
4/2
0
(20.
0)A
spir
in 5
1/1
6 (6
.2)
Asp
irin
5 3
/20
(15.
0)N
RA
spir
in 5
9/2
0 (4
5.0)
All
blee
ding
even
ts m
inor
Pl
aceb
oPl
aceb
o 5
20/
25
(80.
0%)
Plac
ebo
5 3
/20
(1
5.0)
Plac
ebo
5 4
/17
(23.
5)Pl
aceb
o 5
3/2
0 (1
5.0)
Plac
ebo
5 7
/20
(35.
0)
R
R 1
.33
(0
.34-
5.21
)R
R 0
.27
(0.0
3- 2
.13)
RR
1.0
0 (0
.23-
4.3
7)R
R 1
.29
(0.6
-2.7
2)
UF
H 1
aspi
rin
vs a
spir
in a
lone
Rai
et a
l 56 /1
997
UF
H 5
,000
uni
ts
SC b
id 1
aspi
rin
75 m
g/d
UF
H 1
as
piri
n 5
45/
45Pr
egna
ncy
loss
or
del
iver
yU
FH
1
as
pirin
5 13
/45
(28.
9)
UF
H 1
as
piri
n 5
3/3
2 (9
.4)
UF
H 1
as
piri
n 5
0/3
2 (0
.0)
NR
NR
A
spir
in 7
5 m
g/d
Asp
irin
5 4
5/45
Asp
irin
5 2
6/45
(57.
8)A
spir
in 5
1/1
9 (5
.3)
Asp
irin
5 1
/19
(2.2
)
R
R 0
.50
(0
.30-
0.8
4)R
R 1
.78
(0.2
0-15
.93)
RR
0.3
3 (0
.01-
7.92
)
Goe
l et a
l 57 /2
006
UF
H 5
,000
In
tern
atio
nal
Uni
ts S
C b
id 1
as
piri
n 80
mg/
d
UF
H 1
as
piri
n 5
33/
33
(100
%)
Preg
nanc
y lo
ss
or d
eliv
ery
Ove
rall:
U
FH
1
as
pirin
5 5/
33
(15.
2)
UF
H 1
as
piri
n 5
2/2
8 (1
5)
UF
H 1
as
piri
n 5
0/2
8 (0
)
NR
No
maj
or
blee
ding
du
e to
he
pari
n
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
36© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arIn
terv
entio
nN
umbe
r Pa
tient
s A
naly
zed
Len
gth
of
Fol
low
-up
Preg
nanc
y L
oss
(%)
Fet
al G
row
th
Res
tric
tion
(%)
Pree
clam
psia
(%)
Plac
enta
l A
brup
tion
(%)
Mat
erna
l B
leed
ing
(%)
Com
men
ts
A
spir
in 8
0 m
g/d
Asp
irin
5 3
9/39
(1
00%
)
Asp
irin
5 1
5/39
(38.
5)A
spir
in 5
1/2
4 (4
.2)
Asp
irin
5 2
/24
(8.3
)
RR
0.3
9
(0.1
6-0.
97)
F
irst
trim
este
r
loss
:
UF
H 1
aspi
rin 5
4/33
(1
2.1)
Asp
irin
5 1
3/39
(33.
3)
Kut
teh 58
/199
6U
FH
5,0
00 u
nits
SC
bid
adj
uste
d to
att
ain
6 h
post
inje
ctio
n aP
TT
at 1
.2-1
.5
times
bas
elin
e 1
as
piri
n 81
mg/
dA
spir
in 8
1 m
g/d
UF
H 1
as
piri
n 5
25/
25
Asp
irin
5 2
5/25
Preg
nanc
y lo
ss
or d
eliv
ery
UF
H 1
aspi
rin 5
5/25
(2
0.0)
Asp
irin
5 1
4/25
(56.
0)R
R 0
.36
(0
.15-
0.8
4)
UF
H 1
aspi
rin
5 3
/20
(15.
0)
Asp
irin
5 1
/11
(9.1
)R
R 1
.65
(0.1
9-14
.03)
UF
H 1
as
piri
n 5
2/2
0 (1
0.0)
Asp
irin
5 1
/11
(9.1
)R
R 1
.10
(0.1
1-10
.81)
NR
UF
H 1
as
piri
n 5
3/2
0 (1
5.05
)
Asp
irin
5 1
/11
(9.1
)R
R 1
.65
(0.1
9- 1
4.03
)
All
blee
ding
even
ts
cons
ider
ed
min
or
LM
WH
1 as
piri
n vs
asp
irin
alo
ne
Far
quha
rson
et
al 59
/200
2L
MW
H 5
,000
un
its/d
SC
unt
il de
liver
y 1
aspi
rin
75 m
g/d
Asp
irin
75
mg/
d
LM
WH
1
aspi
rin 5
51/
51
Asp
irin
5 4
7/47
Preg
nanc
y lo
ss
or d
eliv
ery
LM
WH
1
as
pirin
5 11
/51
(21.
6)
Asp
irin
5 1
3/47
(27.
6)
NR
NR
NR
NR
R
R 0
.78
(0
.39-
1.5
7)
Las
kin
et a
l 60 /2
009
LM
WH
5,0
00
Inte
rnat
iona
l U
nits
SC
dai
ly
until
del
iver
y 1
aspi
rin
81 m
g/d
LM
WH
1
as
pirin
5 22
/22
(100
%)
Preg
nanc
y lo
ss
or d
eliv
ery
LM
WH
1
as
pirin
5 5/
22
(22.
7)
LM
WH
1
aspi
rin
5 3
/17
(17.
6)
NR
NR
NR
Ear
ly lo
sses
not
stra
tifi e
d by
th
rom
boph
ilia
type
Tabl
e S2
1—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
37© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arIn
terv
entio
nN
umbe
r Pa
tient
s A
naly
zed
Len
gth
of
Fol
low
-up
Preg
nanc
y L
oss
(%)
Fet
al G
row
th
Res
tric
tion
(%)
Pree
clam
psia
(%)
Plac
enta
l A
brup
tion
(%)
Mat
erna
l B
leed
ing
(%)
Com
men
ts
A
spir
in 8
1 m
g/d
Asp
irin
5 2
0/20
(1
00%
)A
spir
in 5
5/2
0
(25.
0)A
spir
in 5
6/1
5 (4
0)
(IU
GR
num
bers
in
clud
e on
e tw
in w
ho w
as
still
born
)
R
R 0
.91
(0
.31-
2.68
)
LM
WH
1 as
piri
n vs
UF
H 1
aspi
rin
Step
hens
on
et a
l 61 /2
004
Asp
irin
81
mg/
d st
artin
g pr
ior
to
conc
eptio
n 1
L
MW
H lu
teal
ph
ase
or fi
rst
trim
este
r dal
tepa
rin
2,50
0 In
tern
atio
nal
Uni
ts S
C o
nce
daily
; sec
ond
trim
este
r dal
tepa
rin
5,00
0 In
tern
atio
nal
Uni
ts S
C o
nce
daily
; thi
rd tr
imes
ter
dalte
pari
n 7,
500
Inte
rnat
iona
l Uni
ts
SC o
nce
daily
LM
WH
1
aspi
rin
5 1
4/14
(1
00.0
)
Preg
nanc
y lo
ss
or d
eliv
ery
LM
WH
1
as
pirin
5 4/
13
(30.
7)
NR
LM
WH
1
aspi
rin
5 1
/9
(11.
1)
NR
NR
A
spir
in 8
1 m
g/d
star
ting
prio
r to
co
ncep
tion
1 U
FH
lu
teal
pha
se o
r fi r
st
trim
este
r 5,
000
units
SC
bid
; se
cond
trim
este
r 7,
500
units
SC
bid
; th
ird
trim
este
r 10
,000
uni
ts S
C b
id
UF
H 1
as
piri
n 5
14/
14
(100
.0)
UF
H 1
aspi
rin 5
9/13
(6
9.2)
RR
0.4
4
(0.1
8-1.
08)
UF
H 1
as
piri
n 5
0/4
(0
.0)
RR
3.0
0 (0
.13-
67.5
2)
Tabl
e S2
1—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
38© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arIn
terv
entio
nN
umbe
r Pa
tient
s A
naly
zed
Len
gth
of
Fol
low
-up
Preg
nanc
y L
oss
(%)
Fet
al G
row
th
Res
tric
tion
(%)
Pree
clam
psia
(%)
Plac
enta
l A
brup
tion
(%)
Mat
erna
l B
leed
ing
(%)
Com
men
ts
Her
edita
ry th
rom
boph
ilia
LM
WH
vs
aspi
rin
Gri
s et
al 62
/200
4L
MW
H (e
noxa
pari
n 40
mg/
d SC
) 1
folic
aci
d 5
mg/
d
LM
WH
5 8
0/80
Preg
nanc
y lo
ss
or d
eliv
ery
LM
WH
5 1
1/80
(13.
7)L
MW
H 5
7/7
1 (9
.9)
LM
WH
5 4
/71
(5.6
)N
RN
R
A
spir
in 1
00 m
g/d
1
folic
aci
d 5
mg/
dA
spir
in 5
80/
80A
spir
in 5
57/
80
(7
1.2)
Asp
irin
5 7
/23
(30.
4)A
spir
in 5
3/2
3 (1
3)
R
R 0
.19
(0
.11-
0.3
4)R
R 0
.32
(0.1
3-0.
83)
RR
1.3
3 (4
.77-
0.69
)
Obs
erva
tiona
l Stu
dies
Thr
ombo
phili
a–A
PLA
LM
WH
1 a
spir
in v
s U
FH
1 as
piri
n
Nob
le
et a
l 63 /2
005
Asp
irin
81
mg
daily
st
artin
g pr
ior
to
conc
eptio
n 1
L
MW
H
(eno
xapa
rin
40 m
g/d
SC)
Asp
irin
81
mg
daily
st
artin
g pr
ior
to
conc
eptio
n 1
UF
H
(5,0
00-6
,000
uni
ts
SC b
id, d
epen
ding
on
wei
ght)
LM
WH
1
aspi
rin
5 2
5/25
UF
H 1
asp
irin
5 2
5/25
2 w
k post
deliv
ery
LM
WH
1
as
pirin
5 4/
25
(16.
0)
UF
H 1
aspi
rin
5 5
/25
(20.
0)
RR
0.8
0
(0.2
4-2.
64)
LM
WH
1
aspi
rin
5 1
/21
(4.8
)
UF
H 1
as
piri
n 5
1/2
0 (5
.0)
RR
0.9
5 (0
.06-
14.2
2)
LM
WH
1
aspi
rin
5 0
/21
(0)
UF
H 1
as
piri
n 5
0/2
0 (0
)
RR
1.0
0 (0
.02-
48.5
3)
NR
LM
WH
1
aspi
rin
5 3
/25
(12.
0)
UF
H 1
as
piri
n 5
2/2
5 (5
.0)
RR
1.5
(0
.27-
8.22
)
All
blee
ding
even
ts
clas
sifi e
d as
min
or
UF
H h
ighe
r do
se 1
aspi
rin
vs U
FH
low
er d
ose
1 as
piri
n
Kut
teh
and
Erm
el 64
/199
6U
FH
5,0
00 u
nits
SC
bi
d ad
just
ed to
m
aint
ain
aPT
T a
t 1.
2-1.
5 3
bas
elin
e (h
ighe
r do
se) 1
as
piri
n 81
mg/
d
UF
H h
ighe
r do
se 1
as
piri
n 5
25/
25
Preg
nanc
y lo
ss
or d
eliv
ery
UF
H h
ighe
r
dose
1
aspi
rin 5
5/25
(2
0.0)
NR
NR
NR
NR
Tabl
e S2
1—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
39© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S2
1—C
onti
nued
Stud
y/Ye
arIn
terv
entio
nN
umbe
r Pa
tient
s A
naly
zed
Len
gth
of
Fol
low
-up
Preg
nanc
y L
oss
(%)
Fet
al G
row
th
Res
tric
tion
(%)
Pree
clam
psia
(%)
Plac
enta
l A
brup
tion
(%)
Mat
erna
l B
leed
ing
(%)
Com
men
ts
U
FH
5,0
00 u
nits
SC
bi
d ad
just
ed to
m
aint
ain
aPT
T
at u
pper
lim
it of
no
rmal
(low
er
dose
) 1 as
piri
n 81
mg/
d
UF
H lo
wer
do
se 1
as
piri
n 5
25/
25
UF
H lo
wer
dose
1
aspi
rin 5
6/25
(2
4.0)
RR
0.8
3
(0.2
9-2.
38)
Her
edita
ry th
rom
boph
ilia
LM
WH
vs
cont
rol
Car
p et a
l 65 /2
003
LM
WH
(e
noxa
pari
n 40
mg/
d SC
)R
etro
spec
tive
cont
rol (
no
prop
hyla
xis)
LM
WH
5 3
7/37
(1
00%
)
Con
trol
5 4
8/48
(1
00%
)
Preg
nanc
y lo
ss
or d
eliv
ery
LM
WH
5 1
1/37
(29.
7)
Con
trol
5 2
7/48
(56.
3)
RR
1.8
9
(1.0
9-3.
29)
NR
LM
WH
5 2
/26
(7.6
)
Con
trol
5 1
/21
(4.8
)
RR
2.0
0 (0
.19-
0.72
)
NR
NR
LM
WH
vs
cont
rol (
untr
eate
d)
Led
uc
et a
l 66 /2
007
LM
WH
(dal
tepa
rin)
va
ried
bet
wee
n 3,
500
and
7,50
0 In
tern
atio
nal
Uni
ts S
C b
idA
spir
in 8
0 m
g/d
LM
WH
5 1
3/13
(1
00%
)
Asp
irin
5 1
1/11
(1
00%
)
Cha
rt r
evie
w
1994
-200
1D
ata
on
pr
egna
ncy
loss
not
st
ratifi
ed
by
trea
tmen
t
LM
WH
O
R 0
.81
Asp
irin
OR
0.8
8
LM
WH
OR
0.
92 A
spir
in
OR
0.8
7
Dat
a on
pla
cent
al
abru
ptio
n no
t st
ratifi
ed
by
trea
tmen
t
No
maj
or
blee
ding
or
mat
erna
l m
orta
lity
repo
rted
OR
: the
pro
babi
lity
of
dev
elop
ing
an o
bste
tric
co
mpl
icat
ion
desp
ite
prop
hyla
ctic
th
erap
y (in
terp
rete
d to
mea
n th
e od
ds o
f co
mpl
icat
ion
com
pare
d w
ith n
o tr
eatm
ent)
(C
onti
nued
)
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40© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Stud
y/Ye
arIn
terv
entio
nN
umbe
r Pa
tient
s A
naly
zed
Len
gth
of
Fol
low
-up
Preg
nanc
y L
oss
(%)
Fet
al G
row
th
Res
tric
tion
(%)
Pree
clam
psia
(%)
Plac
enta
l A
brup
tion
(%)
Mat
erna
l B
leed
ing
(%)
Com
men
ts
LM
WH
1 as
piri
n vs
con
trol
(unt
reat
ed)
Led
uc
et a
l 66 /2
007
LM
WH
(dal
tepa
rin)
va
ried
bet
wee
n 35
00 I
U S
C a
nd
7500
IU
SC
bid
1
aspi
rin
80 m
g/d
LM
WH
(dal
tepa
rin)
va
ried
bet
wee
n 35
00 a
nd 7
,500
In
tern
atio
nal
Uni
ts S
C b
id
LM
WH
1
aspi
rin
5 2
6/26
(1
00%
)
LM
WH
5 1
3/13
(1
00%
)
Cha
rt r
evie
w
1994
-200
1N
RL
MW
H 1
as
piri
n O
R 0
.70
LM
WH
O
R 0
.81
LM
WH
1
aspi
rin
OR
0.8
0
LM
WH
O
R 0
.92
NR
NR
OR
: the
pro
babi
lity
of
dev
elop
ing
an o
bste
tric
co
mpl
icat
ion
desp
ite
prop
hyla
ctic
th
erap
y (in
terp
rete
d to
mea
n th
e od
ds o
f co
mpl
icat
ion
com
pare
d w
ith n
o tr
eatm
ent)
Asp
irin
vs
cont
rol (
untr
eate
d)
Led
uc
et a
l 66 /2
007
LM
WH
(dal
tepa
rin)
va
ried
bet
wee
n 3,
500
and
7,50
0 In
tern
atio
nal
Uni
ts S
C b
id 1
as
piri
n 80
mg/
dA
spir
in 8
0 m
g/d
LM
WH
1
aspi
rin
5 2
6/26
(1
00%
)
Asp
irin
5 1
1/11
(1
00%
)
Cha
rt r
evie
w
1994
-200
1N
RL
MW
H 1
as
piri
n O
R 0
.70
Asp
irin
0.8
8
LM
WH
1
aspi
rin
OR
0.8
0
Asp
irin
0.8
7
NR
NR
OR
: the
pro
babi
lity
of
dev
elop
ing
an o
bste
tric
co
mpl
icat
ion
desp
ite
prop
hyla
ctic
th
erap
y (in
terp
rete
d to
mea
n th
e od
ds o
f co
mpl
icat
ion
com
pare
d w
ith n
o tr
eatm
ent)
ASA
5 ac
etyl
salic
yclic
aci
d; I
UG
R 5
intr
aute
rine
gro
wth
res
tric
tion;
NR
5 n
ot r
epor
ted.
See
Tab
le S
1, S
3, S
4, S
8, S
9, a
nd S
17 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
Tabl
e S2
1—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
41© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S2
2 —[S
ecti
on 1
0.2.
3, 1
0.2.
4] R
ando
miz
ed T
rial
s an
d O
bse
rvat
iona
l St
udi
es o
f th
e P
reve
ntio
n of
Com
plic
atio
ns i
n P
regn
ant
Wom
en W
ith
Thr
omb
ophi
lia:
M
etho
dolo
gic
Qu
alit
y
Ran
dom
ized
Tri
als
Stud
y/Ye
arIn
terv
entio
nSt
udy
Des
ign
Ran
dom
ize
Con
ceal
edB
lindi
ngL
ost t
o F
ollo
w-u
pA
naly
sis
Com
men
ts
Thr
ombo
phili
a-A
PLA
Asp
irin
vs
plac
ebo
Cow
choc
k et
al 53
/199
7A
spir
in 8
1 m
g/d
Usu
al c
are
RC
T,
mul
ticen
ter
PNPa
tient
s: P
N
Car
egiv
ers:
PN
D
ata
Col
lect
ors:
PN
A
djud
icat
ors:
PN
D
ata
Ana
lyst
s: P
N
Asp
irin
5 0
/11
Usu
al c
are
5 0
/9IT
TPo
pula
tion:
pre
gnan
t wom
en
with
APL
A a
nd e
ither
0 (1
0/19
pa
tient
s) o
r 1
(9/1
9 pa
tient
s) p
rior
sp
onta
neou
s ab
ortio
n. W
omen
w
ith th
rom
bosi
s hi
stor
y or
lupu
s ex
clud
ed.
N
o de
fi niti
on o
f usu
al c
are.
Tulp
pala
et
al 54
/199
7A
spir
in 5
0 m
g/d
Plac
ebo
RC
T, s
ingl
e ce
nter
PYPa
tient
s: C
Y C
areg
iver
s: P
Y D
ata
Col
lect
ors:
PY
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
Asp
irin
5 0
/6Pl
aceb
o 5
0/6
ITT
Popu
latio
n: s
ubgr
oup
of 6
6 pr
egna
nt
wom
en w
ith th
ree
to e
ight
co
nsec
utiv
e lo
sses
: 12
preg
nant
w
omen
with
APL
A o
f who
m tw
o ha
d bl
ight
ed o
va (o
ne in
eac
h tr
eatm
ent a
rm),
and
two
had
ecto
pic
preg
nanc
ies (
plac
ebo
grou
p).
Patt
ison
et
al 55
/200
0A
spir
in 7
5 m
g/d
Plac
ebo
RC
T, s
ingl
e ce
nter
CY
Patie
nts:
CY
Car
egiv
ers:
CY
Dat
a C
olle
ctor
s: C
Y A
djud
icat
ors:
PN
D
ata
Ana
lyst
s: P
N
Asp
irin
5 5
/25
Plac
ebo
5 5
/25
(5 p
ostr
ando
miz
atio
n ex
clus
ions
from
eac
h tr
eatm
ent a
rm)
Not
IT
TPo
pula
tion:
pre
gnan
t wom
en w
ith
APL
A a
nd th
ree
or m
ore
feta
l lo
sses
. Wom
en w
ith th
rom
bosi
s hi
stor
y or
lupu
s ex
clud
ed.
Ten
excl
usio
ns a
fter
ran
dom
izat
ion
beca
use
of in
appr
opria
te in
clus
ion.
R
ando
miz
atio
n no
t bal
ance
d fo
r m
ean
grav
idity
and
num
ber
of fi
rst t
rim
este
r lo
sses
(b
oth
favo
ring
asp
irin
).
UF
H 1
aspi
rin
vs a
spir
in a
lone
Rai
et a
l 56 /1
997
UF
H 5
,000
uni
ts
SC b
id 1
as
piri
n 75
mg/
dA
spir
in 7
5 m
g/d
RC
T, s
ingl
e ce
nter
PNPa
tient
s: C
N
Car
egiv
ers:
C
N D
ata
Col
lect
ors:
PN
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
UF
H 1
as
piri
n 5
0/4
5A
spir
in 5
0/4
5
ITT
Popu
latio
n: p
regn
ant w
omen
with
A
PLA
and
thre
e or
mor
e co
n sec
utiv
e m
isca
rria
ges.
W
omen
with
pri
or th
rom
bosi
s or
lupu
s ex
clud
ed.
Trea
tmen
t sto
pped
at 3
4 w
k or
m
isca
rria
ge.
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
42© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Ran
dom
ized
Tri
als
Stud
y/Ye
arIn
terv
entio
nSt
udy
Des
ign
Ran
dom
ize
Con
ceal
edB
lindi
ngL
ost t
o F
ollo
w-u
pA
naly
sis
Com
men
ts
Goe
l et a
l 57 /2
006
UF
H 5
,000
In
tern
atio
nal
Uni
ts S
C b
id 1
as
piri
n 80
mg/
dA
spir
in 8
0 m
g/d
RC
T,
mul
ticen
ter
NR
Patie
nts:
DN
C
areg
iver
s: D
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
UF
H 1
as
piri
n 5
0/3
9A
spir
in 5
0/3
3
ITT
Popu
latio
n: p
regn
ant w
omen
with
A
PLA
(ant
icar
diol
ipin
) with
two
or m
ore
fi rst
or
seco
nd tr
imes
ter
mis
carr
iage
s.
Trea
tmen
t dis
cont
inue
d at
36
wk
gest
atio
n.
Kut
teh 58
/199
6
UF
H 5
,000
uni
ts
SC b
id a
djus
ted
to a
ttai
n 6
h po
stin
ject
ion
aPT
T a
t 1.2
-1.5
tim
es b
asel
ine
1
aspi
rin
81 m
g/d
Asp
irin
81
mg/
d
RC
T, s
ingl
e ce
nter
Qua
si-r
ando
miz
edPa
tient
s: D
N
Car
egiv
ers:
DN
D
ata
Col
lect
ors:
PN
A
djud
icat
ors:
PN
D
ata
Ana
lyst
s: P
N
UF
H 1
as
piri
n 5
0/2
5A
spir
in 5
0/2
5
No
Popu
latio
n: p
regn
ant w
omen
with
A
PLA
and
thre
e or
mor
e co
nsec
utiv
e m
isca
rria
ges
(wom
en w
ith N
SI o
r lu
pus
excl
uded
). A
ltern
ate
assi
gnm
ent o
f tre
atm
ent.
USP
STF
rat
ing
of e
vide
nce
is I
I-1.
LM
WH
1 as
piri
n vs
asp
irin
alo
ne
Far
quha
rson
et
al 59
/200
2L
MW
H 5
,000
uni
ts/d
SC
unt
il de
liver
y 1
aspi
rin
75 m
g/d
Asp
irin
75
mg/
d
RC
T, s
ingl
e ce
nter
CY
Patie
nts:
CN
C
areg
iver
s: C
N
Dat
a C
olle
ctor
s: C
N
Adj
udic
ator
s: C
N
Dat
a A
naly
sts:
CN
LM
WH
5 0
/51
Asp
irin
5 0
/47
ITT
Popu
latio
n: p
regn
ant w
omen
with
A
PLA
and
at l
east
thre
e co
nsec
utiv
e lo
sses
or
two
loss
es
with
feta
l dea
th a
fter
10
wk.
Las
kin
et a
l 60 /2
009
LM
WH
5,0
00
Inte
rnat
iona
l Uni
ts
SC d
aily
unt
il de
liver
y 1 as
piri
n 81
mg/
dA
spir
in 8
1 m
g/d
Ope
n la
bel,
RC
T, s
ingl
e ce
nter
Not
NR
Patie
nts:
DN
C
areg
iver
s: D
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
LM
WH
1
aspi
rin
5 0
/22
(0%
)A
spir
in 5
0/2
0 (0
%)
ITT
Popu
latio
n: p
regn
ant w
omen
with
A
PLA
or
inhe
rite
d th
rom
boph
ilia
or A
NA
(onl
y A
PLA
abl
e to
be
con s
ider
ed h
ere)
with
two
or
mor
e un
expl
aine
d co
nsec
utiv
e pr
egna
ncy
loss
es p
rior
to 3
2 w
k.
Trea
tmen
t with
LM
WH
st
oppe
d at
35
wk
or d
eliv
ery.
Tabl
e S2
2—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
43© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Ran
dom
ized
Tri
als
Stud
y/Ye
arIn
terv
entio
nSt
udy
Des
ign
Ran
dom
ize
Con
ceal
edB
lindi
ngL
ost t
o F
ollo
w-u
pA
naly
sis
Com
men
ts
LM
WH
1 as
piri
n vs
UF
H 1
aspi
rin
Step
hens
on
et a
l 61 /2
004
Asp
irin
81
mg/
d st
artin
g pr
ior
to c
once
ptio
n 1
LM
WH
(lut
eal
phas
e or
fi rs
t tri
mes
ter
dalte
pari
n 2,
500
Inte
rnat
iona
l Uni
ts
SC o
nce
daily
; sec
ond
trim
este
r da
ltepa
rin
5,00
0 In
tern
atio
nal
Uni
ts S
C o
nce
daily
; th
ird
trim
este
r da
ltepa
rin
7,50
0 In
tern
atio
nal U
nits
SC
onc
e da
ily)
Ope
n-la
bel,
RC
T, s
ingl
e ce
nter
CY
Patie
nts:
CN
C
areg
iver
s: C
N
Dat
a C
olle
ctor
s: C
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
In p
atie
nts
who
be
cam
e pr
egna
nt:
LM
WH
1
aspi
rin
5 0
/13
UF
H 1
as
piri
n 5
0/1
3
Unc
lear
w
heth
er
ITT
Popu
latio
n: w
omen
with
A
PLA
and
rec
urre
nt
loss
es.
Patie
nts
rand
omiz
ed p
rior
to
conc
eptio
n (o
ne p
atie
nt in
ea
ch g
roup
did
not
bec
ome
preg
nant
dur
ing
stud
y).
Her
edita
ry th
rom
boph
ilia.
A
spir
in 8
1 m
g/d
star
ting
prio
r to
con
cept
ion
1
UF
H (l
utea
l pha
se o
r fi r
st tr
imes
ter
5,00
0 un
its S
C b
id; s
econ
d tr
imes
ter
7,50
0 un
its
SC b
id; t
hird
trim
este
r 10
,000
uni
ts S
C b
id)
Her
edita
ry th
rom
phili
a
LM
WH
vs
aspi
rin
alon
e
Gri
s et
al 62
/200
4
LM
WH
(eno
xapa
rin
40 m
g/d
SC) a
nd
folic
aci
d 5
mg/
dA
spir
in 1
00 m
g/d
and
folic
aci
d 5
mg/
d
RC
TC
YPa
tient
s: C
N
Car
egiv
ers:
CN
D
ata
Col
lect
ors:
PN
A
djud
icat
ors:
PN
D
ata
Ana
lyst
s: P
N
14/1
74 (8
%) l
ost
prio
r to
al
loca
tion
LM
WH
5 0
/80
Asp
irin
5 0
/80
Unc
lear
w
heth
er
ITT
Popu
latio
n: w
omen
with
fact
or V
L
eide
n, p
roth
rom
bin
gene
m
utat
ion,
or
prot
ein
S de
fi cie
ncy
and
a si
ngle
loss
aft
er 1
0 w
k.
Wom
en w
ith o
ther
her
edita
ry
thro
mbo
phili
a, lu
pus,
APL
A,
or p
rior
thro
mbo
sis
wer
e ex
clud
ed.
Tabl
e S2
2—C
onti
nued
(Con
tinu
ed)
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Tabl
e S2
2—C
onti
nued
Obs
erva
tiona
l Stu
dies
Stud
y/Ye
arIn
terv
entio
nSt
udy
Des
ign
Inte
rven
tion/
Con
trol
Se
ttin
g Si
mila
r?In
terv
entio
n/C
ontr
ol
Tim
e F
ram
e Si
mila
r?A
djus
tmen
t
Eff
ectiv
ely
Blin
ded
Ass
essm
ent
of O
utco
me
Los
t to
Fol
low
-up
Com
men
ts
Nob
le e
t al 63
/200
5A
spir
in 8
1 m
g/d
star
ting
prio
r to
co
ncep
tion
1
LM
WH
(eno
xapa
rin
40 m
g/d
SC)
Asp
irin
81
mg/
d st
artin
g pr
ior
to c
once
ptio
n 1
U
FH
(5,0
00-6
,000
un
its S
C b
id,
depe
ndin
g on
wei
ght)
Pros
pect
ive
coho
rt,
two
cent
er
Very
Iden
tical
All
rele
vant
vari
able
s
No
LM
WH
1
aspi
rin
5 0
/25
UF
H 1
aspi
rin
5 0
/25
Popu
latio
n: w
omen
with
A
PLA
and
thre
e or
mor
e pr
egna
ncy
loss
es b
efor
e 20
wk.
Tr
eatm
ent r
egim
en b
ased
on
enr
ollin
g ce
nter
. L
MW
H s
topp
ed 3
wk
befo
re
estim
ated
due
dat
e or
5 d
pr
ior
to s
ched
uled
in
duct
ion
or
cesa
rean
sec
tion.
U
FH
dis
cont
inue
d w
ith
spon
tane
ous
labo
r.
UF
H h
ighe
r do
se 1
aspi
rin
vs U
FH
low
er d
ose
1 as
piri
n
Kut
teh
and
Erm
el 64
/199
6U
FH
5,0
00 u
nits
SC
bid
adj
uste
d to
mai
ntai
n aP
TT
at
1.2
to 1
.5 ti
mes
ba
selin
e (h
ighe
r do
se) 1
aspi
rin
81 m
g/d
UF
H 5
,000
uni
ts S
C
bid
adju
sted
to
mai
ntai
n aP
TT
at
uppe
r lim
it of
nor
mal
(lo
wer
dos
e) 1
as
piri
n 81
mg/
d
Pros
pect
ive
coho
rt,
sing
le c
ente
r
Very
Clo
seA
ll re
leva
nt
va
riab
les
No
UF
H (h
ighe
r do
se) 1
as
piri
n 5
0/2
5U
FH
(low
er
dose
) 1
aspi
rin
5 0
/25
Popu
latio
n: p
regn
ant w
omen
w
ith A
PLA
and
at l
east
th
ree
cons
ecut
ive
mis
carr
iage
s. W
omen
w
ith N
SI o
r lu
pus
excl
uded
. A
ltern
ate
assi
gnm
ent o
f tr
eatm
ents
.
(Con
tinu
ed)
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Her
edita
ry th
rom
boph
ilia
LM
WH
vs
cont
rol
Car
p et
al 65
/200
3L
MW
H (e
noxa
pari
n 40
mg/
d SC
)R
etro
spec
tive
cont
rol
(no
prop
hyla
xis)
Pros
pect
ive
coho
rt,
sing
le c
ente
r
Very
Clo
seM
ost
No
LM
WH
5 0
/37
Con
trol
5 0
/48
Popu
latio
n: w
omen
with
he
redi
tary
thro
mbo
phili
a an
d th
ree
or m
ore
con s
ecut
ive
loss
es in
fi r
st o
r se
cond
trim
este
rs.
Patie
nts w
ere
excl
uded
if
prio
r th
rom
bosi
s or
APL
A.
Con
trol
s w
ere
wom
en
retr
ieve
d fr
om a
da
taba
se, m
atch
ed
for
num
ber
of
mis
carr
iage
s, m
ater
nal
age,
and
tim
e ta
ken
to c
once
ive.
LM
WH
1 as
piri
n vs
asp
irin
vs
LM
WH
Led
uc e
t al 66
/200
7L
MW
H (d
alte
pari
n)
vari
ed b
etw
een
3,50
0 an
d 7,
500
Inte
rnat
iona
l Uni
ts
SC b
id 1
aspi
rin
80 m
g/d
Asp
irin
80
mg/
dL
MW
H (d
alte
pari
n)
vari
ed b
etw
een
3,50
0 an
d 7,
500
Inte
rnat
iona
l U
nits
SC
bid
Ret
rosp
ectiv
e co
hort
, sin
gle
cent
er
Very
Iden
tical
Som
e: u
se
of L
MW
H
or A
SA a
nd
gest
atio
n ag
e
No
LM
WH
1
aspi
rin
5 0
/26
Asp
irin
5 0
/11
LM
WH
5 0
/13
Popu
latio
n: w
omen
who
re
ceiv
ed a
ntith
rom
botic
pr
ophy
laxi
s du
ring
pr
egna
ncy
betw
een
1997
an
d 20
01 o
r a
hist
ory
of p
revi
ous
preg
nanc
y co
mpl
icat
ed b
y se
vere
pr
eecl
amps
ia, p
lace
ntal
ab
rupt
ion,
feta
l gro
wth
re
stri
ctio
n, s
econ
d or
th
ird
trim
este
r fe
tal l
oss,
an
d as
soci
ated
her
edita
ry
thro
mbo
phili
a. E
xclu
ded
if pr
evio
us th
rom
boem
bolic
di
sord
er o
r A
PLA
.
AN
A 5
antin
ucle
ar a
ntib
ody;
CY
5 ce
rtai
n ye
s; D
N 5
defi
nite
no;
NSI
5 n
onsp
ecifi
c in
hibi
tor;
PN
5 p
roba
ble
no;
PY 5
pro
babl
e ye
s. S
ee T
able
S1,
S4,
S8,
S9,
and
leg
ends
S17
for
exp
ansi
on o
f ot
her
abbr
evia
tions
.
Tabl
e S2
2—C
onti
nued
Obs
erva
tiona
l Stu
dies
Stud
y/Ye
arIn
terv
entio
nSt
udy
Des
ign
Inte
rven
tion/
Con
trol
Se
ttin
g Si
mila
r?In
terv
entio
n/C
ontr
ol
Tim
e F
ram
e Si
mila
r?A
djus
tmen
t
Eff
ectiv
ely
Blin
ded
Ass
essm
ent
of O
utco
me
Los
t to
Fol
low
-up
Com
men
ts
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Tabl
e S2
3 —[S
ecti
on 1
0.2.
1,10
.2.3
] E
vide
nce
Pro
fi le:
Sho
uld
UF
H P
lus
Asp
irin
or
Asp
irin
Alo
ne B
e U
sed
for
Pre
gnan
t W
omen
Wit
h A
PL
A a
nd R
ecu
rren
t P
regn
ancy
L
oss?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)A
ntic
ipat
ed A
bsol
ute
Eff
ects
a
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
eW
ith
Asp
irin
b
With
U
FH
1
Asp
irin
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in b
Ris
k D
iffer
ence
W
ith A
dditi
on o
f U
FH
(95%
CI)
Preg
nanc
y lo
ss (c
ritic
al o
utco
me)
212
(3 R
CTs
), no
t re
port
ed
Seri
ous
risk
of
bias
Issu
es o
f ra
ndom
izat
ion,
al
loca
tion
conc
ealm
ent,
and
blin
ding
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate
due
to r
isk
of b
ias
55/1
09 (5
0)23
/103
(22)
RR
0.4
4 (0
.30-
0.66
)50
0 pr
egna
ncy
loss
es
per
1,00
0
283
few
er p
regn
ancy
lo
sses
per
1,0
00
(fro
m 1
72 fe
wer
to
353
few
er)
IUG
R (c
ritic
al o
utco
me)
est
imat
ed fe
tal w
eigh
t , 1
0th
perc
entil
e fo
r ge
stat
iona
l age
134
(3 R
CTs
), no
t re
port
ed
Seri
ous
risk
of
bia
sIs
sues
of
rand
omiz
atio
n,
allo
catio
n co
ncea
lmen
t, an
d bl
indi
ng
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us
impr
ecis
ion
CI
incl
udes
im
port
ant
bene
fi t a
nd
harm
Und
etec
ted
Very
low
due
to
ris
k of
bi
as a
nd
impr
ecisi
on
3/54
(5.6
)8/
80 (1
0)R
R 1
.71
(0.4
8-6.
17)
56 I
UG
R
per
1,00
039
mor
e IU
GR
pe
r 1,
000
(fro
m
29 fe
wer
to
287
mor
e)
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)A
ntic
ipat
ed A
bsol
ute
Eff
ects
a
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
eW
ith
Asp
irin
b
With
U
FH
1
Asp
irin
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
A
spir
in b
Ris
k D
iffer
ence
W
ith A
dditi
on o
f U
FH
(95%
CI)
Pree
clam
psia
(cri
tical
out
com
e) n
ot c
lear
ly d
efi n
ed
134
(3 R
CTs
), no
t re
port
ed
Seri
ous
risk
of
bias
Issu
es o
f ra
ndom
izat
ion,
al
loca
tion
conc
ealm
ent,
and
blin
ding
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nC
I in
clud
es
impo
rtan
t be
nefi t
and
ha
rm
Und
etec
ted
Low
due
to
risk
of
bias
and
im
prec
isio
n
4/54
(7.4
)2/
80 (2
.5)
RR
0.4
3 (0
.09-
2.08
)74
pre
ecla
mps
ia
per
1,00
042
few
er
pree
clam
psia
per
1,
000
(fro
m 6
7 fe
wer
to 8
0 m
ore)
Maj
or B
leed
ing
(cri
tical
out
com
e) n
ot r
epor
ted c
Bib
liogr
aphy
: D
ata
from
unp
ublis
hed
met
a-an
alys
is b
ased
on
thre
e tr
ials
: K
utte
h W
H.
Ant
ipho
spho
lipid
ant
ibod
y-as
soci
ated
rec
urre
nt p
regn
ancy
los
s: t
reat
men
t w
ith h
epar
in a
nd l
ow-d
ose
aspi
rin
is
supe
rior
to
low
-dos
e as
piri
n al
one.
Am
J O
bste
t G
ynec
ol. 1
996;
174:
1584
-158
9. R
ai R
, Coh
en H
, Dav
e M
, et
al. R
ando
mis
ed c
ontr
olle
d tr
ial o
f as
piri
n an
d as
piri
n pl
us h
epar
in in
pre
gnan
t w
omen
with
re
curr
ent m
isca
rria
ge a
ssoc
iate
d w
ith p
hosp
holip
id a
ntib
odie
s (o
r an
tipho
spho
lipid
ant
ibod
ies)
. BM
J. 1
997;
314:
253-
257.
Goe
l N, T
uli A
, Cho
udhr
y R
. The
rol
e of
asp
irin
ver
sus
aspi
rin
and
hepa
rin
in c
ases
of
rec
urre
nt a
bort
ions
with
rai
sed
antic
ardi
olip
in a
ntib
odie
s. M
ed S
ci M
onit
. 200
6(3)
:CR
132-
CR
136.
PO
Van
dvik
, MD
, per
sona
l com
mun
icat
ion,
Oct
ober
201
0. S
ee T
able
S1,
S3,
S9,
and
S21
lege
nds
for
expa
nsio
n of
abb
revi
atio
n.
a Tim
e fr
ame
is 9
mo
for
all o
utco
mes
. b E
stim
ates
for
base
line
risk
with
asp
irin
com
es fr
om th
e m
eta-
anal
ysis
of t
hree
tria
ls.
c Alth
ough
a p
atie
nt im
port
ant o
utco
me
defi n
ed a
s in
1, n
one
of th
e th
ree
tria
ls r
epor
ted
maj
or b
leed
ing
even
ts.
Tabl
e S2
3—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S2
4 —[S
ecti
on 1
1.1.
1] E
vide
nce
Pro
fi le:
Sho
uld
Asp
irin
Rat
her
Tha
n N
o Tr
eatm
ent
Be
Use
d fo
r P
reve
ntio
n of
Pre
ecla
mps
ia in
Wom
en W
itho
ut T
hrom
boph
ilia
?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Dur
ing
Preg
nanc
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
eW
ithou
t Pr
ophy
laxi
sW
ith L
WM
H
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
out
Prop
hyla
xis
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Pree
clam
psia
(cri
tical
out
com
e) d
efi n
ed a
s pr
otei
nuri
c pr
eecl
amps
ia in
Coc
hran
e sy
stem
atic
rev
iew
32,5
90
(43
RC
Ts,)
not r
epor
ted
No
seri
ous
risk
of b
ias
Vari
abili
ty
acro
ss tr
ials
bu
t not
co
nsid
ered
to
intr
oduc
e bi
as
Seri
ous
inco
nsis
tenc
y a I 2 5
46,
P
, .0
01
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion
Ben
efi t
even
at
low
er
end
of C
I
Und
etec
ted
Mod
erat
e du
e to
in
cons
iste
ncy
1,29
2/16
,194
(8
)1,
081/
16,3
96
(6.6
)R
R 0
.83
(0.7
7-0.
89)
Low
ris
k fo
r pr
eecl
amps
ia
60 c
ases
pe
r 1,
000 b
10 fe
wer
per
1,0
00
(fro
m 1
4 fe
wer
to
7 fe
wer
)
H
igh
risk
for
pree
clam
psia
210 pe
r 1,
000 b
38 fe
wer
per
1,0
00
(fro
m 4
6 fe
wer
to
23
few
er)
Maj
or b
leed
(cri
tical
out
com
e) c
95,0
00
(6 R
CTs
), 3.
8-10
y
No
seri
ous
risk
of
bia
sN
o se
riou
s in
cons
iste
ncy
Seri
ous
indi
rect
ness
d Pr
imar
y pr
even
tion
card
iova
scul
ar
dise
ase
No
seri
ous
impr
ecis
ion
Und
etec
ted
Mod
erat
e du
e to
in
dire
ctne
ss
219/
47,5
00
(0.5
)33
5/47
,500
(0
.7)
RR
1.5
4 (1
.30-
1.82
)15
ble
edin
g ev
ents
pe
r 1,
000 e
8 m
ore
blee
ding
ev
ents
per
1,0
00
(fro
m 5
mor
e to
12
mor
e)
Bib
liogr
aphy
: Dul
ey L
, Hen
ders
on-S
mar
t D
J, M
eher
S, K
ing
JF. A
ntip
late
let
agen
ts f
or p
reve
ntin
g pr
e-ec
lam
psia
and
its
com
plic
atio
ns. C
ochr
ane
Dat
abas
e Sy
st R
ev. 2
007;
(2):C
D00
4659
. Gre
er I
A,
Nel
son-
Pier
cy C
. Low
mol
ecul
ar w
eigh
t he
pari
ns f
or t
hrom
bopr
ophy
laxi
s an
d tr
eatm
ent
of v
enou
s th
rom
boem
bolis
m in
pre
gnan
cy: a
sys
tem
atic
rev
iew
of
safe
ty a
nd e
ffi ca
cy. B
lood
. 200
5;10
6:40
1-40
7.
See
Tabl
e S3
, S4,
and
S9
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Het
erog
enei
ty m
ight
be
rela
ted
to d
iffer
ent t
ypes
and
dos
es o
f ant
ipla
tele
t age
nts,
the
lack
of p
lace
bo in
the
cont
rol g
roup
in m
any
of th
e tr
ials
, diff
eren
t pop
ulat
ions
of p
regn
ant w
omen
con
cern
ing
risk
of
pre
ecla
mps
ia, a
nd e
ffec
t of t
reat
men
t. b C
ontr
ol g
roup
ris
k es
timat
e fo
r pr
eecl
amps
ia is
bas
ed o
n co
ntro
l eve
nt r
ates
in s
tudi
es in
clud
ed in
sub
grou
p an
alys
es in
the
met
a-an
alys
is. H
igh
risk
was
defi
ned
in th
e sy
stem
atic
rev
iew
as
wom
en w
ho
eith
er w
ere
norm
oten
sive
or
had
chro
nic
hype
rten
sion
with
out s
uper
impo
sed
pree
clam
psia
at t
rial
ent
ry a
nd w
ere
clas
sifi e
d as
bei
ng a
t hig
h ri
sk if
they
had
one
or
mor
e of
the
follo
win
g: p
revi
ous
seve
re
pree
clam
psia
, dia
bete
s, c
hron
ic h
yper
tens
ion,
ren
al d
isea
se, o
r au
toim
mun
e di
seas
e.
c Maj
or a
nten
atal
mat
erna
l hem
orrh
age.
d R
ated
dow
n fo
r in
dire
ctne
ss d
ue to
pop
ulat
ion
(peo
ple
incl
uded
in tr
ials
of p
rim
ary
prev
entio
n ca
rdio
vasc
ular
dis
ease
). T
he C
ochr
ane
revi
ew d
oes
not r
epor
t the
eff
ects
of a
ntip
late
let t
hera
py o
n m
ajor
bl
eedi
ng e
vent
s in
pre
gnan
t wom
en.
e Con
trol
gro
up r
isk
estim
ate
for
maj
or b
leed
ing
even
ts a
ntep
artu
m fr
om s
yste
mat
ic r
evie
w b
y G
reer
et a
l.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
49© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S2
5 —[S
ecti
on 1
1.2.
1] E
vide
nce
Pro
fi le:
Sho
uld
LM
WH
and
Asp
irin
Rat
her
Tha
n N
o T
reat
men
t B
e U
sed
for
Pre
vent
ion
of R
ecu
rren
t P
regn
ancy
Los
s in
W
omen
Wit
hou
t T
hrom
bop
hili
a?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Dur
ing
Preg
nanc
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
eW
ithou
t Tr
eatm
ent
With
LM
WH
an
d A
spir
in
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
out
Trea
tmen
t
Ris
k D
iffer
ence
W
ith L
MW
H a
nd
Asp
irin
(95%
CI)
Mis
carr
iage
(cri
tical
out
com
e)
294
(2 R
CTs
), 9
mo
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nC
I in
clud
es
impo
rtan
t be
nefi t
and
ha
rm
Und
etec
ted
Mod
erat
e du
e to
impr
ecis
ion
62/2
50 (2
5.2)
62/2
44 (2
5.4)
RR
1.0
1 (0
.84-
1.38
)30
0 ca
ses
per
1,00
0 a 3
mor
e pe
r 1,
000
(fro
m 4
8 fe
wer
to
114
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e) a
ntep
artu
m h
emor
rhag
e b , c
294
(1 R
CT
), 9
mo
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nC
I in
clud
es
bene
fi t a
nd
harm
Und
etec
ted
Mod
erat
e du
e to
impr
ecis
ion
10/1
47 (6
.8)
10/1
47 (6
.8)
RR
1.0
0 (0
.42-
2.33
)15
ble
edin
g ev
ents
per
1,
000 c
0 m
ore
blee
ding
ev
ents
per
1,0
00
(fro
m 9
few
er to
20
mor
e)
Bib
liogr
aphy
: Gre
er I
A, N
elso
n-Pi
ercy
C. L
ow m
olec
ular
wei
ght h
epar
ins f
or th
rom
bopr
ophy
laxi
s and
trea
tmen
t of v
enou
s thr
ombo
embo
lism
in p
regn
ancy
: a sy
stem
atic
revi
ew o
f saf
ety
and
effi c
acy.
Blo
od.
2005
;106
:401
-407
. Dat
a fr
om a
n un
publ
ishe
d m
eta-
anal
ysis
d of t
wo
RC
Ts b
y K
aand
orp
SP, M
arië
tte
God
dijn
M, v
an d
er P
ost J
AM
, et a
l. A
spir
in c
ombi
ned
with
low
-mol
ecul
ar-w
eigh
t hep
arin
and
asp
irin
al
one
in w
omen
with
recu
rren
t mis
carr
iage
. A ra
ndom
ized
pla
cebo
-con
trol
led
tria
l: th
e A
LIF
E st
udy.
N E
ngl J
Med
. 201
0;29
:158
6-15
96 a
nd C
lark
P, W
alke
r ID
, Lan
ghor
ne P
, et a
l. SP
IN (S
cott
ish
Preg
nanc
y In
terv
entio
n) s
tudy
: a m
ultic
ente
r, ra
ndom
ized
con
trol
led
tria
l of l
ow-m
olec
ular
-wei
ght h
epar
in a
nd lo
w-d
ose
aspi
rin
in w
omen
with
rec
urre
nt m
isca
rria
ge. B
lood
. 201
0;11
5:41
62-4
167.
See
Tab
le S
3, S
4,
and
S9 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a C
ontr
ol g
roup
ris
k fo
r m
isca
rria
ge c
omes
from
stu
dy e
vent
rat
es in
the
two
avai
labl
e ra
ndom
ized
tria
ls b
y K
aand
orp
and
Cla
rk.
b Ble
edin
g ou
tcom
es v
aria
bly
repo
rted
in th
e tw
o tr
ials
. We
use
data
from
Cla
rk e
t al o
n se
riou
s ad
vers
e ev
ents
and
ant
epar
tum
hem
orrh
age
to g
ener
ate
both
rel
ativ
e ri
sks
and
base
line
risk
s fo
r an
ticip
ated
ab
solu
te e
ffec
ts. K
aand
orp
et a
l rep
orte
d no
se b
leed
, GI
prob
lem
, hem
atur
ia, a
nd b
leed
ing
gum
s. T
here
wer
e no
maj
or b
leed
ing
even
ts (S
. Mid
deld
orp,
MD
, per
sona
l com
mun
icat
ion,
Oct
ober
201
0 ).
c Con
trol
gro
up r
isk
estim
ate
for
maj
or b
leed
ing
even
ts a
ntep
artu
m c
omes
from
sys
tem
atic
rev
iew
by
Gre
er e
t al.
d Met
a-an
alys
is p
erfo
rmed
in R
evM
an v
ersi
on 5
with
fi xe
d-ef
fect
s m
odel
for
hete
roge
neity
.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
50© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S2
6 —[S
ecti
on 1
1.2.
1] E
vide
nce
Pro
fi le:
Sho
uld
Asp
irin
Rat
her
Tha
n N
o T
reat
men
t B
e U
sed
for
Pre
vent
ion
of R
ecu
rren
t P
regn
ancy
Los
s in
Wom
en
Wit
hou
t T
hrom
bop
hili
a?
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Dur
ing
Preg
nanc
y
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ithou
t Tr
eatm
ent
With
Asp
irin
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ithou
t Tr
eatm
ent
Ris
k D
iffer
ence
W
ith A
spir
in
(95%
CI)
Mis
carr
iage
(cri
tical
out
com
e)
202
(1 R
CTs
), 9
mo
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s im
prec
isio
nC
I in
clud
es
impo
rtan
t be
nefi t
an
d ha
rm
Und
etec
ted
Mod
erat
e du
e to
impr
ecis
ion
34/1
03 (3
3)38
/99
(38)
RR
1.1
6 (0
.80-
1.69
)30
0 ca
ses
per
1,00
0 a 48
mor
e pe
r 1,
000
(fro
m 6
0 fe
wer
to
207
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e) a
ntep
artu
m h
emor
rhag
e b , c
95,0
00 (6
RC
Ts),
3.8-
10 y
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
ySe
riou
s in
dire
ctne
ss c
Prim
ary
prev
entio
n ca
rdio
vasc
ular
di
seas
e
No
seri
ous
impr
ecis
ion
Und
etec
ted
Mod
erat
e du
e to
indi
rect
ness
219/
47,5
00 (0
.5)
335/
47,5
00 (0
.7)
RR
1.5
4 (1
.30-
1.82
)15
ble
edin
g ev
ents
pe
r 1,
000 d
8 m
ore
blee
ding
ev
ents
per
1,0
00
(fro
m 5
mor
e to
12
mor
e)
Bib
liogr
aphy
: Kaa
ndor
p SP
, Mar
iëtt
e G
oddi
jn M
, van
der
Pos
t JA
M e
t al.
Asp
irin
com
bine
d w
ith lo
w-m
olec
ular
-wei
ght h
epar
in a
nd a
spir
in a
lone
in w
omen
with
rec
urre
nt m
isca
rria
ge. A
ran
dom
ized
pl
aceb
o-co
ntro
lled
tria
l: th
e A
LIF
E s
tudy
. New
Eng
l J M
ed. 2
010;
29;3
62:1
586-
1596
. Cla
rk P
, Wal
ker
ID, L
angh
orne
P, e
t al
. SPI
N (
Scot
tish
Preg
nanc
y In
terv
entio
n) s
tudy
: a m
ultic
ente
r, ra
ndom
ized
co
ntro
lled
tria
l of
low
-mol
ecul
ar-w
eigh
t he
pari
n an
d lo
w-d
ose
aspi
rin
in w
omen
with
rec
urre
nt m
isca
rria
ge.
Blo
od.
2010
;115
:416
2-41
67.
Gre
er I
A,
Nel
son-
Pier
cy C
. L
ow m
olec
ular
wei
ght
hepa
rins
fo
r th
rom
bopr
ophy
laxi
s an
d tr
eatm
ent
of v
enou
s th
rom
boem
bolis
m i
n pr
egna
ncy:
a s
yste
mat
ic r
evie
w o
f sa
fety
and
effi
cacy
. B
lood
. 20
05;1
06:4
01-4
07.
See
Tabl
e S3
and
S9
lege
nds
for
expa
nsio
n of
ab
brev
iatio
ns.
a Bas
elin
e ri
sk fo
r m
isca
rria
ge c
omes
from
stu
dy e
vent
rat
es in
the
two
avai
labl
e ra
ndom
ized
tria
ls b
y K
aand
orp
et a
l and
Cla
rk e
t al.
b Maj
or a
nten
atal
non
fata
l hem
orrh
age.
c R
ated
dow
n fo
r in
dire
ctne
ss d
ue to
pop
ulat
ion
(pri
mar
y pr
even
tion
card
iova
scul
ar d
isea
se).
The
re w
ere
no m
ajor
ble
edin
g ev
ents
in th
e A
LIF
E S
tudy
(per
sona
l com
mun
icat
ion
with
aut
hors
). d C
ontr
ol g
roup
ris
k es
timat
e fo
r m
ajor
ble
edin
g ev
ents
ant
epar
tum
com
es fr
om s
yste
mat
ic r
evie
w b
y G
reer
et a
l. e O
nly
stud
y id
entifi
ed
that
com
pare
d as
piri
n to
pla
cebo
in th
is p
opul
atio
n.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S2
7 —[S
ecti
on 1
2.1.
1-12
.1.3
] Sy
stem
atic
Rev
iew
s E
xam
inin
g M
ater
nal
and
Fet
al S
afet
y of
Ant
icoa
gula
nt R
egim
ens
in P
regn
ant
Wom
en W
ith
Mec
hani
cal
Hea
rt V
alve
s (M
etho
dolo
gic
Qu
alit
y)
Stud
y/Ye
arIn
terv
entio
n
Incl
usiv
e L
itera
ture
Se
arch
Dup
licat
e St
udy
Sele
ctio
n an
d D
ata
Ext
ract
ion
Lis
t of S
tudi
es
(Inc
lude
d an
d E
xclu
ded)
Pr
ovid
ed
Cha
ract
eris
tics
of
Incl
uded
Stu
dies
Pr
ovid
edA
sses
smen
t of Q
ualit
y of
Inc
lude
d St
udie
s
App
ropr
iate
M
etho
ds U
sed
to
Com
bine
Stu
dy
Fin
ding
s
Ass
essm
ent o
f L
ikel
ihoo
d of
Pu
blic
atio
n B
ias
Cha
n et
al 1 /2
000
Stud
ies
betw
een
1966
and
19
97 e
xam
inin
g th
e us
e of
VK
As
and
UF
H o
r no
ant
icoa
gula
tion
in
preg
nant
wom
en w
ith
mec
hani
cal h
eart
val
ves
Yes
No
No
No
No
Yes
No
Has
soun
a an
d A
llam
2 /201
0St
udie
s be
twee
n 20
00 a
nd
2009
exa
min
ing
the
use
of V
KA
s an
d U
FH
or
no a
ntic
oagu
latio
n in
pr
egna
nt w
omen
with
m
echa
nica
l hea
rt v
alve
s
No
Bi
No
No
No
Yes
No
Jam
es e
t al 67
/200
6St
udie
s be
twee
n 19
66 a
nd
2006
invo
lvin
g pr
egna
nt
wom
en w
ith m
echa
nica
l he
art v
alve
s re
ceiv
ing
LM
WH
No
No
No
Yes
No
N/A
No
Ora
n et
al 68
/200
4St
udie
s be
twee
n 19
89 a
nd
2004
invo
lvin
g pr
egna
nt
wom
en w
ith m
echa
nica
l he
art v
alve
s w
ho r
ecei
ved
hepa
rin
Yes
No
No
Yes
No
N/A
No
See
Tabl
e S1
and
S4
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
52© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Tabl
e S2
8 —[S
ecti
on 1
2.1.
1-12
.1.3
] A
ntit
hrom
bot
ic T
hera
py i
n P
regn
ant
Wom
en W
ith
Mec
hani
cal
Hea
rt V
alve
s—M
ater
nal
Ou
tcom
es (
Cli
nica
l D
escr
ipti
on a
nd R
esu
lts)
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
Coh
ort s
tudi
es w
ith c
ompa
rato
r gr
oups
Iran
, ret
rosp
ectiv
e,
Kha
moo
shi
et a
l 69 /2
007
110
wom
en19
6 pr
egna
ncie
sPr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
Valv
e ty
pe
Tilti
ng: 9
8 B
ileafl
et:
98Va
lve
posi
tion
Aor
tic: 2
6 M
itral
: 128
A
ortic
and
mitr
al: 4
2
Reg
imen
1 w
arfa
rin
th
roug
hout
pre
gnan
cy;
INR
che
cked
mon
thly
an
d ke
pt 2
.5-3
.5
Reg
imen
1,
5/14
2 (3
.5)
Reg
imen
1,
0/14
2 (0
.0)
Reg
imen
1, 0
/142
(0.0
)R
egim
en 1
, 6/1
42 (3
.1)
(3 v
alve
thro
mbo
sis,
3
embo
lism
)
R
egim
en 2
SC
UF
H fo
r
the
fi rst
trim
este
r, w
arfa
rin
until
wee
k 36
, th
en U
FH
for
rem
aind
er
of p
regn
ancy
; aPT
T
kept
2 ti
mes
con
trol
Reg
imen
2,
2/54
(3.7
)R
egim
en 2
, 0/
54 (0
.0)
Reg
imen
2, 2
/54
(3.7
) (2
vag
inal
ble
edin
g ev
ents
trea
ted
cons
erva
tivel
y)
Reg
imen
2, 9
/54
(16.
7)
(7 v
alve
thro
mbo
sis,
2
embo
lism
)
N
o fa
tal
mat
erna
l bl
eedi
ng
even
ts
No
maj
or G
I or
maj
or
obst
etri
cal b
leed
ing
even
ts
Kor
ea, r
etro
spec
tive,
L
ee e
t al 70
/200
725
wom
en31
pre
gnan
cies
Preg
nant
wom
en
w
ith m
echa
nica
l he
art v
alve
sVa
lve
posi
tion
Aor
tic: 4
M
itral
: 21
Dou
ble
valv
e
repl
acem
ent:
5
Reg
imen
1 c
oum
arin
and
aspi
rin
thro
ugho
ut
preg
nanc
y w
ith
targ
et I
NR
2.5
-3.5
, the
n na
drop
arin
7,5
00 u
nits
SC
q12
h fo
r 2
wk
befo
re d
ue d
ate
Reg
imen
1,
0/8
(0)
Reg
imen
1,
0/8
(0.0
)R
egim
en 1
, 0/2
3 (0
.0)
Reg
imen
1, 2
/8 (2
5.0)
(1
val
ve th
rom
bosi
s,
1 T
IA)
R
egim
en 2
nad
ropa
rin
7,
500
units
SC
q12
h un
til w
eek
12, t
hen
coum
arin
s un
til w
eek
38 w
hen
nadr
opar
in
resu
med
.
Reg
imen
2,
0/23
(0)
Reg
imen
2,
0/23
(0.0
)R
egim
en 2
, 023
(0.0
)R
egim
en 2
, 3/2
3 (1
3.0)
(2
val
ve th
rom
bosi
s,
1 T
IA)
A
spir
in 1
00 m
g/d
th
roug
hout
pre
gnan
cyN
o fa
tal
mat
erna
l bl
eedi
ng
even
ts
No
mat
erna
l maj
or G
I or
maj
or o
bste
tric
al
blee
ding
eve
nts
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
53© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
New
Zea
land
, re
tros
pect
ive
audi
t, M
cLin
tock
et a
l 71 /2
009
31 w
omen
47 p
regn
anci
esPr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
Valv
e ty
pe
Star
r-E
dwar
ds: 1
2 Ti
lting
dis
c or
bile
afl e
t: 19
Valv
e po
sitio
n
Mitr
al:1
4
Aor
tic: 4
Mitr
al a
nd
ao
rtic
: 13
Reg
imen
1 p
redo
min
antly
war
fari
n an
d as
piri
n (1
00-1
50 m
g) th
roug
hout
w
ith e
noxa
pari
n (1
mg/
kg S
C q
12h)
an
d as
piri
n su
bstit
uted
be
twee
n w
eeks
6 a
nd
12 a
nd a
t 34
and
36 w
k ge
stat
ion
Reg
imen
2 e
noxa
pari
n
(1 m
g/kg
SC
q12
h) a
nd
aspi
rin
(100
-150
mg)
pr
edom
inan
tlyIn
bot
h re
gim
ens,
enox
apar
in m
onito
red
by a
nti-X
a le
vels
eve
ry
3-7
d; d
ose
adju
sted
to
atta
in a
targ
et p
redo
se
leve
l: 0.
4-0.
7 In
tern
atio
nal U
nits
/mL
Reg
imen
1,
0/13
(0.0
)
Reg
imen
2,
0/34
(0.0
)
No
fata
l m
ater
nal
blee
ding
ev
ents
Reg
imen
1,
0/13
(0.0
)
Reg
imen
2,
0/34
(0.0
)
Una
ble
to s
epar
ate
by r
egim
enM
ater
nal m
ajor
G
I bl
eedi
ng e
vent
s:
0/47
(1 m
inor
he
mat
emes
is w
ith
enox
apar
in)
Mat
erna
l maj
or
obst
etri
cal b
leed
ing
even
ts: 1
9/47
(2
abr
uptio
ns a
nd
1 an
tepa
rtum
he
mor
rhag
e w
ith
enox
apar
in;
1 ad
ditio
nal
abru
ptio
n du
ring
IV
U
FH
aro
und
deliv
ery;
1 a
dditi
onal
m
inor
ant
epar
tum
he
mor
rhag
e w
ith
enox
apar
in; 6
pri
mar
y po
stpa
rtum
he
mor
rhag
es a
nd
9 se
cond
ary
post
part
um
hem
orrh
ages
)M
ajor
ble
edin
g fr
om
othe
r si
te: 1
/47
(rec
tus
shea
th a
nd
epis
taxi
s w
ith I
V
UF
H a
roun
d de
liver
y)
Reg
imen
1, 0
/13
(0)
Reg
imen
2, 5
/34
(14.
7)
(1 v
alve
thro
mbo
sis,
4
TIA
, 3/5
ass
ocia
ted
with
non
com
plia
nce,
2
even
ts p
ostp
artu
m)
(Con
tinu
ed)
Tabl
e S2
8—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
54© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
Sing
le-g
roup
coh
ort s
tudi
es
Nor
way
, ret
rosp
ectiv
e,
Abi
ldga
ard
et a
l 72 /2
009
11 w
omen
12 p
regn
anci
esPr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
Valv
e po
sitio
n
Mitr
al: 4
Aor
tic: 6
Aor
tic a
nd
m
itral
: 2
The
rape
utic
dos
es o
f
LM
WH
q12
h th
roug
hout
pr
egna
ncy.
Asp
irin
75
mg/
d re
com
men
ded
but d
isco
ntin
ued
1 w
k be
fore
exp
ecte
d de
liver
y da
teD
oses
adj
uste
d to
att
ain
pe
ak a
nti-X
a le
vel o
f 0.
7-1.
2 un
its/m
L
0/12
(0.0
)1
subj
ect w
ho
died
sud
denl
y at
11
wk
with
no
aut
opsy
ev
iden
ce o
f bl
eedi
ng o
r th
rom
bosi
s ex
clud
ed fr
om
anal
ysis
No
mat
erna
l fa
tal b
leed
ing
even
ts r
epor
ted
0/12
(0.0
)4/
12 (3
3.3)
No
mat
erna
l maj
or
GI
blee
ding
eve
nts
Mat
erna
l maj
or
obst
etri
cal b
leed
ing
even
ts: 4
(all
post
part
um o
r po
stce
sare
an s
ectio
n)
2/12
(16.
7) (b
oth
asso
ciat
ed w
ith
subt
hera
peut
ic
dosi
ng o
f LM
WH
) M
ater
nal i
sche
mic
st
roke
: 1
Mat
erna
l non
stro
ke
syst
emic
em
bolis
m: 0
M
ater
nal v
alve
th
rom
bosi
s: 1
Japa
n, r
etro
spec
tive,
K
awam
ata
et a
l 73 /2
007
12 w
omen
16 p
regn
anci
esPr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
Valv
e po
sitio
n
Mitr
al: 7
Aor
tic: 2
Tric
uspi
d: 7
Subs
titut
ion
of w
arfa
rin
w
ith U
FH
sta
rtin
g be
twee
n 6-
13 w
k an
d un
til te
rmD
oses
adj
uste
d to
mai
ntai
n
aPT
T le
vels
2-3
tim
es
cont
rol (
betw
een
20,0
00
and
30,0
00 I
nter
natio
nal
Uni
ts/d
)
1/16
(6.3
) (de
ath
of m
othe
r an
d fe
tus
duri
ng
repl
acem
ent
of th
rom
bose
d va
lve)
No
fata
l mat
erna
l bl
eedi
ng e
vent
s
2/16
(12.
5)7/
16 (4
3.8)
No
mat
erna
l maj
or
GI
blee
ding
eve
nts
Mat
erna
l maj
or
obst
etri
cal b
leed
ing
even
ts: 7
(4 p
erin
atal
bl
eedi
ng, 3
sub
chor
ioni
c bl
eedi
ng e
vent
s)
3/16
(13.
8)
Mat
erna
l isc
hem
ic
stro
ke: 0
N
o m
ater
nal n
onst
roke
sy
stem
ic
embo
lism
: 0
Mat
erna
l val
ve
thro
mbo
sis:
2
(Con
tinu
ed)
Tabl
e S2
8—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
55© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
Eng
land
, pro
spec
tive,
Q
uinn
et a
l 74 /2
009
11 w
omen
12 p
regn
anci
esPr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
Valv
e po
sitio
n
Mitr
al: 4
Aor
tic: 2
Aor
tic a
nd m
itral
: 3
Sy
stem
ic r
ight
atri
oven
tric
ular
va
lve:
2
Dal
tepa
rin
100
Inte
rnat
iona
l
Uni
ts/k
g q1
2h (8
) or
enox
apar
in 1
mg/
kg q
12h
(4) 1
aspi
rin
81 m
g/d
LM
WH
dos
es a
djus
ted
to
at
tain
an
anti-
Xa
leve
l 1.
0-1.
2 un
its/m
L
0/12
(0.0
)N
o m
ater
nal
feta
l ble
edin
g ev
ents
rep
orte
d
Not
rep
orte
d6/
12 (5
0.0)
(3 m
inor
, ep
ista
xis,
pla
cent
al
hem
atom
a, s
econ
dary
po
stpa
rtum
hem
orrh
age;
3
maj
or a
s be
low
)N
o m
ater
nal m
ajor
G
I bl
eedi
ng e
vent
s re
port
edM
ater
nal m
ajor
ob
stet
rica
l ble
edin
g ev
ents
: 3 (a
ntep
artu
m
hem
orrh
age
with
pl
acen
ta p
revi
a,
pers
iste
nt c
ervi
cal
hem
atom
a an
d va
gina
l bl
eedi
ng le
adin
g to
ce
sare
an s
ectio
n,
post
part
um h
emor
rhag
e)
1/12
(8.3
) (as
soci
ated
w
ith s
ubth
erap
eutic
an
ti-X
a le
vels
) N
o m
ater
nal i
sche
mic
st
roke
rep
orte
d.
No
mat
erna
l non
stro
ke
syst
emic
em
bolis
m
repo
rted
. M
ater
nal v
alve
th
rom
bosi
s: 1
Can
ada,
pro
spec
tive,
Yi
non
et a
l 75 /2
009
17 w
omen
23 p
regn
anci
esPr
egna
nt w
omen
with
mec
hani
cal
hear
t val
ves
Valv
e po
sitio
n
Mitr
al: 1
4
Aor
tic: 8
Aor
tic a
nd m
itral
: 1
LM
WH
SC
q12
h.
L
ow-d
ose
aspi
rin
(81
mg/
d) a
dmin
iste
red
to a
ll pa
tient
sLW
MH
dos
e ad
just
ed to
mai
ntai
n 4
h po
stin
ject
ion
anti-
Xa
leve
l 1-1
.2
Inte
rnat
iona
l Uni
ts/m
L
1/23
(4.3
) (fa
tal
TIA
/val
ve
thro
mbo
sis)
No
fata
l mat
erna
l bl
eedi
ng e
vent
s
0/23
(0.0
)3/
23 (1
3.0)
(2 m
inor
po
stpa
rtum
and
1 m
ajor
bl
eedi
ng e
vent
s as
bel
ow)
No
maj
or m
ater
nal
GI
blee
ding
eve
nts
Maj
or m
ater
nal o
bste
tric
al
blee
ding
eve
nts:
1/2
3 (la
rge
uter
ine
hem
atom
a po
stce
sare
an s
ectio
n re
quir
ing
tran
sfus
ion)
1/23
(4.3
) M
ater
nal i
sche
mic
st
roke
: 1
Mat
erna
l non
stro
ke
syst
emic
em
bolis
m: 0
M
ater
nal v
alve
th
rom
bosi
s: 1
Tabl
e S2
8—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
56© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
(Con
tinu
ed)
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
Syst
emat
ic r
evie
ws
Can
ada,
Cha
n 1 /200
0
976
wom
enSt
udie
s be
twee
n
1966
and
199
7 in
volv
ing
preg
nant
w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
type
Cag
e an
d ba
ll: 4
33
Sing
le-t
iltin
g
disc
: 356
B
ileafl
et:
62
Oth
er: 2
0
Het
erog
raft
: 1
Unk
now
n: 1
04Po
sitio
n
Mitr
al: 6
47
A
ortic
: 202
Tric
uspi
d: 1
. 1
val
ve: 1
26Va
lve
posi
tion
M
itral
: 647
Aor
tic: 2
02
Tr
icus
pid:
1
.
1 v
alve
: 126
Tota
l: 97
6
Reg
imen
1 o
ral
an
ticoa
gula
nts
thro
ugho
ut p
regn
ancy
Reg
imen
2 s
ubst
itutio
n of
UF
H in
the
fi rst
trim
este
r ei
ther
at o
r be
fore
6 w
k,
afte
r 6
wk,
or
at u
nkno
wn
time
in th
e fi r
st tr
imes
ter
Reg
imen
3 U
FH
thro
ugho
ut p
regn
ancy
-ad
just
ed d
ose
or lo
w
dose
( � 1
5,00
0 un
its/d
)
Reg
imen
4 n
o an
ticoa
gula
nts,
incl
udin
g us
e of
an
tipla
tele
t age
nts
alon
e
Ove
rall:
25
/854
(2.9
%)
Reg
imen
1,
10/5
61 (1
.8)
Reg
imen
2,
7/16
7, (4
.2)
Reg
imen
3, 3
/20
(15.
0)
Adj
uste
d-do
se
UF
H:
1/15
(6.7
) L
ow-d
ose
UF
H:
2/5
(40)
Reg
imen
4, 5
/106
, (4
.7) N
othi
ng:
2/3,
(5.4
) A
ntip
late
let:
3/69
(4.3
)F
atal
mat
erna
l bl
eedi
ng
even
ts: 2
Ove
rall:
0/
1234
(0.0
)O
vera
ll m
ajor
ble
edin
g ev
ents
: 31/
1234
(2.5
) (2
5 at
del
iver
y, 6
out
side
de
liver
y); u
nabl
e to
se
para
te b
y re
gim
en
or s
peci
fi c lo
catio
nR
egim
en 1
, 31
/788
(3.9
)
Reg
imen
2,
21/2
29 (9
.2)
Reg
imen
3, 7
/21
(33.
3)
Adj
uste
d-do
se
UF
H: 4
/16
(25.
0)
Low
-dos
e U
FH
: 3/
5 (6
0.0)
Reg
imen
4, 2
6/10
7 (2
4.3)
Not
hing
: 6/
38 (1
5.8)
A
ntip
late
let:
20/6
9 (2
9)
Mat
erna
l isc
hem
ic
stro
ke: 0
M
ater
nal n
onst
roke
sy
stem
ic
embo
lism
: 0
Mat
erna
l val
ve
thro
mbo
sis:
17
[all
fata
l]
1,23
4 pr
egna
ncie
s
Tabl
e S2
8—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
57© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
Uni
ted
Stat
es,
Jam
es e
t al 67
/200
6
76 p
regn
anci
esSt
udie
s be
twee
n
1966
and
200
6 in
volv
ing
preg
nant
wom
en
with
mec
hani
cal
hear
t val
ves
rece
ivin
g L
MW
HVa
lve
type
C
age
and
ball:
4
Sing
le-t
iltin
g di
sc: 2
B
ileafl
et:
8 So
rin:
1
Unk
now
n: 6
1Va
lve
posi
tion
Mitr
al: 2
4 A
ortic
: 12
Bjo
rk-S
hile
y: 2
U
nkno
wn:
40
Con
vers
ion
to L
MW
H p
rior
to p
regn
ancy
or
by th
e en
d of
fi rs
t tri
mes
ter
LM
WH
Eno
xapa
rin:
32
N
adro
pari
n: 2
0
Dal
tepa
rin:
13
Ti
nzap
arin
: 2
R
evip
arin
: 1
U
nkno
wn:
8A
dditi
on o
f low
-dos
e as
piri
n:
13
Var
ying
reg
imen
s ra
ngin
g fr
om a
fi xe
d su
bthe
rape
utic
dos
e to
wei
ght-
adju
sted
th
erap
eutic
dos
esM
onito
ring
of a
nti-f
acto
r
Xa
leve
ls: 4
3. T
he m
inim
um
valu
e fo
r th
e ta
rget
ran
ges
was
0.5
, and
the
max
imum
w
as 1
.2.
3/76
(3.9
)F
atal
mat
erna
l bl
eedi
ng e
vent
s:
1 (1
intr
acra
nial
bl
eed
duri
ng
conv
ersi
on to
w
arfa
rin
post
deliv
ery)
1/76
(1.3
) (1
intr
acra
nial
bl
eed
duri
ng
conv
ersi
on
to w
arfa
rin
post
deliv
ery)
6/76
(7.9
) (4
min
or b
leed
ing
even
ts [2
hem
atom
as,
1 su
bcho
rion
ic h
emat
oma,
1
dela
yed
broa
d lig
amen
t he
mat
oma]
and
2 m
ajor
bl
eedi
ng e
vent
s as
bel
ow)
No
maj
or m
ater
nal
GI
blee
ding
eve
nts
Maj
or m
ater
nal o
bste
tric
al
blee
ding
eve
nts:
2
(1 p
erip
artu
m h
emor
-rh
age
requ
irin
g tr
ansf
usio
n,
1 de
laye
d po
stpa
rtum
he
mor
rhag
e re
quir
ing
tran
sfus
ion)
17/7
6 (2
2.4)
M
ater
nal i
sche
mic
st
roke
: 2
Mat
erna
l non
stro
ke
syst
emic
em
bolis
m:
2 (m
yoca
rdia
l in
farc
tion)
M
ater
nal v
alve
th
rom
bosi
s:
13 (2
fata
l) (Con
tinu
ed)
Tabl
e S2
8—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
58© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
Uni
ted
Stat
es,
Ora
n et
al 68
/200
4
75 w
omen
81 p
regn
anci
esSt
udie
s be
twee
n 19
89
an
d 20
04 in
volv
ing
preg
nant
wom
en
with
mec
hani
cal
hear
t val
ves
who
re
ceiv
ed L
MW
HVa
lve
posi
tion
M
itral
: 44
A
ortic
: 8
M
itral
and
aort
ic: 5
Unk
now
n: 1
8
Cas
es w
ere
incl
uded
if L
MW
H w
as r
ecei
ved
duri
ng p
regn
ancy
ir
resp
ectiv
e of
this
type
, do
se a
nd d
urat
ion
and
adm
inis
trat
ion
of d
iffer
ent
antic
oagu
lant
reg
imen
s ot
her
than
LM
WH
dur
ing
the
sam
e pr
egna
ncy.
Con
vers
ion
to L
MW
H o
ccur
red
1
mo
befo
re c
once
ptio
n in
2
wom
en; i
n th
e re
mai
nder
, co
nver
sion
to L
MW
H
occu
rred
dur
ing
preg
nanc
yL
MW
H u
se d
urin
g se
cond
half
of fi
rst t
rim
este
r an
d at
term
: 21
LM
WH
th
roug
hout
pre
gnan
cy: 6
0.L
MW
H E
noxa
pari
n:
35
Nad
ropa
rin: 2
1 D
alta
parin
: 11
Tin
zapa
rin:
3 R
evip
arin
: 1
Unk
now
n: 1
0D
ose
adju
sted
to
th
erap
eutic
ant
i-Xa
leve
l: 51
Fix
ed d
ose:
30
1/81
(1.2
)F
atal
mat
erna
l bl
eedi
ng e
vent
s:
1 (in
trac
rani
al
blee
d 3
mo
post
part
um w
ith
no m
onito
ring
of
IN
Rs)
1/81
(1.2
) (in
trac
rani
al
blee
d 3
mo
post
part
um
with
no
mon
itori
ng
of I
NR
s)
3/81
(3.7
)A
nti-X
a-ad
just
ed L
MW
H:
2 (h
emat
omas
at c
esar
ean
inci
sion
)F
ixed
-dos
e L
MW
H:
1 (p
erip
artu
m
hem
orrh
age)
No
maj
or m
ater
nal
GI
blee
ding
eve
nts
Maj
or m
ater
nal
obst
etri
cal b
leed
ing
even
ts: 1
(per
ipar
tum
)
10/8
1 (1
2.3)
A
nti-X
a-ad
just
ed
LM
WH
: 1 (v
alve
th
rom
bosi
s)
Fix
ed-d
ose
LM
WH
: 9
(6 v
alve
th
rom
bosi
s,
2 ce
rebr
ovas
cula
r ac
cide
nts,
1
embo
lism
) M
ater
nal i
sche
mic
st
roke
: 2
Mat
erna
l non
stro
ke
embo
lism
(typ
e no
t re
port
ed):
1 M
ater
nal v
alve
th
rom
bosi
s:
7 (8
.64%
) (Con
tinu
ed)
Tabl
e S2
8—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
59© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, Stu
dy/Y
ear
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Mat
erna
l D
eath
s, n
/N (%
)
Mat
erna
l In
trac
rani
al
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l E
xtra
cran
ial
Ble
edin
g ev
ents
, n/
N (%
)
Mat
erna
l Sy
stem
ic
Thr
ombo
embo
lism
, n/
N (%
)
Egy
pt, H
asso
una
and
Alla
m 2 /2
009
892
wom
en1,
231
preg
nanc
ies
Stud
ies
publ
ishe
d
betw
een
Janu
ary
2000
and
Se
ptem
ber
2009
in
volv
ing
preg
nant
w
omen
with
m
echa
nica
l hea
rt
valv
es w
ho
rece
ived
defi
ned
an
ticoa
gula
nt
regi
men
sVa
lve
type
C
age
and
ball:
134
Ti
lting
dis
c: 3
82
Bile
afl e
t: 34
1 U
ndefi
ned
: 256
Valv
e po
sitio
n M
itral
: 671
A
ortic
: 141
M
itral
and
ao
rtic
: 147
1 1
47
Tric
uspi
d: 7
Reg
imen
1 V
KA
s th
roug
hout
preg
nanc
y w
ith a
nd
with
out U
FH
or
LM
WH
su
bstit
utio
n ne
ar te
rmR
egim
en 2
UF
H o
r L
MW
H
su
bstit
utio
n du
ring
the
fi rst
trim
este
r an
d ne
ar
term
Reg
imen
3 U
FH
or
LM
WH
thro
ugho
ut p
regn
ancy
Reg
imen
4
no
ant
icoa
gula
nts
Ove
rall:
16
/974
, (1.
6)R
egim
en 1
, 7/
605
(1.1
)
Reg
imen
2,
4/23
6 (1
.7)
Reg
imen
3,
5/10
7 (4
.7)
Reg
imen
4,
0/26
(0)
Fat
al m
ater
nal
fata
l ble
edin
g ev
ents
: 2F
atal
mat
erna
l th
rom
bosi
s: 8
Not
rep
orte
dO
vera
ll:
65/1
343
(4.8
)R
egim
en 1
, 35
/833
(4.2
)
Reg
imen
2,
11/3
22 (3
.4)
Reg
imen
3,
17/1
57 (1
0.8)
Reg
imen
4,
2/31
(6.4
)M
ajor
mat
erna
l G
I bl
eedi
ng e
vent
s:
not r
epor
ted
Mat
erna
l maj
or
obst
etri
cal b
leed
ing
even
ts: 5
5 (o
ccur
red
at d
eliv
ery)
Ove
rall:
77/
1343
(5.7
)
Reg
imen
1,
24/8
33 (2
.9%
)
Reg
imen
2,
23/3
22 (7
.2%
)
Reg
imen
3,
21/1
57 (1
3.4%
) R
egim
en 4
, 9/
31 (2
9%)
Mat
erna
l isc
hem
ic
stro
ke a
nd
nons
trok
e sy
stem
ic
embo
lism
: 26
Mat
erna
l val
ve
thro
mbo
sis:
51
TIA
5 tr
ansi
ent i
sche
mic
att
ack.
See
Tab
les
S1, S
4, a
nd S
17 fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
Tabl
e S2
8—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S2
9 —[S
ecti
on 1
2.1.
1-12
.1.3
] A
ntit
hrom
bot
ic T
hera
py i
n P
regn
ant
Wom
en W
ith
Mec
hani
cal
Hea
rt V
alve
s—F
etal
and
Neo
nata
l O
utc
omes
(C
lini
cal
Des
crip
tion
and
Res
ult
s)
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Coh
ort s
tudi
es w
ith c
ompa
rato
r gr
oups
Iran
, re
tros
pect
ive,
K
ham
oosh
i et
al 75
/200
7
110
wom
en19
6 pr
egna
ncie
sPr
egna
nt w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
type
Ti
lting
: 98
B
ileafl
et:
98Va
lve
posi
tion
A
ortic
: 26
M
itral
: 128
A
ortic
and
mitr
al: 4
2
Reg
imen
1 w
arfa
rin
th
roug
hout
pr
egna
ncy;
IN
R
chec
ked
mon
thly
an
d ke
pt 2
.5-3
.5R
egim
en 2
SC
UF
H fo
r th
e fi r
st tr
imes
ter,
war
fari
n un
til
wee
k 36
, the
n U
FH
for
rem
aind
er
of p
regn
ancy
; aP
TT
kep
t 2
times
co
ntro
l
Reg
imen
1,
7/
142
(4.9
)
Reg
imen
2,
1/
54 (1
.9)
Mal
form
atio
ns
in
clud
ed
hydr
ocep
halu
s (2
), st
abism
us (3
), te
lebr
achy
dact
yly
(1),
nasa
l hy
popl
asia
(1)
Not
repo
rted
Reg
imen
1,
71
/142
(5
0)
Reg
imen
2,
10
/54
(18.
5)
Reg
imen
1,
66
/142
(4
6.5)
Reg
imen
2,
8/
54
(14.
8)
Reg
imen
1,
5/
142
(3.5
)
Reg
imen
2,
2
/54
(3.7
)
Una
ble
to
sepa
rate
ne
onat
al
deat
hs fr
om
prem
atur
e bi
rths
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
61© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Kor
ea,
retr
ospe
ctiv
e,
Lee
et
al 73
/200
7
25 w
omen
31 p
regn
anci
esPr
egna
nt w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
posi
tion
A
ortic
: 4
Mitr
al: 2
1
Dou
ble
valv
e
repl
acem
ent:
5
Reg
imen
1 c
oum
arin
and
aspi
rin
thro
ugho
ut
preg
nanc
y w
ith
targ
et IN
R 2
.5-3
.5,
then
nad
ropa
rin
7,50
0 un
its S
C
q12h
for
2 w
k be
fore
due
dat
eR
egim
en 2
nad
ropa
rin
7,
500
units
SC
q12
un
til w
eek
12,
then
cou
mar
ins
until
wee
k 38
w
hen
nadr
opar
in
resu
med
Asp
irin
100
mg/
d
thro
ugho
ut
preg
nanc
y
Reg
imen
1,
1/
23 (3
.2)
(hyd
roce
phal
us)
Reg
imen
2,
0/
8 (0
.0)
Not
repo
rted
Reg
imen
1,
4/
8 (5
0)
(1 lo
ss w
as
asso
ciat
ed
with
m
ater
nal
valv
e th
rom
bosis
)
Reg
imen
2,
2/
23 (8
.7)
(1 lo
ss w
as
asso
ciat
ed
with
m
ater
nal
valv
e th
rom
bosis
)
Not
spec
ifi ed
Not
spe
cifi e
dN
ot s
peci
fi ed
(Con
tinu
ed)
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
62© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
New
Zea
land
, re
tros
pect
ive,
M
cLin
tock
et
al 71
/200
9
31 w
omen
47 p
regn
anci
esPr
egna
nt w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
type
St
arr-
E
dwar
ds: 1
2
Tilti
ng d
isc
or
bi
leafl
et:
19Va
lve
posi
tion
M
itral
:14
A
ortic
: 4
Mitr
al a
nd
ao
rtic
: 13
Reg
imen
1
pr
edom
inan
tly
war
fari
n an
d as
piri
n (1
00-1
50 m
g)
thro
ugho
ut w
ith
enox
apar
in (1
mg/
kg
SC q
12h)
and
as
piri
n su
bstit
uted
be
twee
n w
eeks
6
and
12 a
nd a
t 34
-36
wk
gest
atio
nR
egim
en 2
eno
xapa
rin
(1
mg/
kg S
C
q12h
) and
asp
irin
(1
00-1
50 m
g)
pred
omin
antly
In b
oth
regi
men
s,
en
oxap
arin
m
onito
red
by a
nti-X
a le
vels
ev
ery
3-7
d; d
ose
adju
sted
to a
ttai
n a
targ
et p
redo
se
leve
l: 0.
4-0.
7 In
tern
atio
nal
Uni
ts/m
L
Reg
imen
1,
3/13
(23.
1)
(war
fari
n
em
byro
path
y, hy
droc
epha
lus,
card
iac
anom
alie
s)
Reg
imen
2,
0/34
(0.0
)
Reg
imen
1,
2/13
(15.
3)
(f
etal
in
trac
ereb
ral
hem
orrh
age
resu
lting
in
still
birt
h)
Reg
imen
2,
0/34
(0.0
)
Reg
imen
s 1
an
d 2,
11/4
7 (2
3.4)
Reg
imen
s 1
an
d 2,
8/47
(1
7.0)
Reg
imen
1,
2/13
(15.
3)
(fet
al
intra
cere
bral
he
mor
rhag
e re
sulti
ng in
st
illbi
rth)
Reg
imen
2,
1/34
(2.9
)
Reg
imen
1,
2/13
(15.
3)
(w
arfa
rin
embr
yopa
thy,
com
plex
co
ngen
ital
hear
t di
seas
e)
Reg
imen
2,
0/34
(0/0
)
(Con
tinu
ed)
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
63© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Sing
le-g
roup
coh
ort s
tudi
es
Nor
way
, re
tros
pect
ive,
A
bild
gaar
d et
al 72
/200
9
11 w
omen
12 p
regn
anci
esPr
egna
nt w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
posi
tion
M
itral
: 4
Aor
tic: 6
A
ortic
and
mitr
al: 2
The
rape
utic
dos
es
of
LM
WH
q12
h th
roug
hout
pr
egna
ncy
Asp
irin
75
mg/
d
reco
mm
ende
d bu
t di
scon
tinue
d 1
wk
befo
re e
xpec
ted
deliv
ery
date
Dos
es a
djus
ted
to
att
ain
peak
an
ti-X
a le
vel o
f 0.
7-1.
2 un
its/m
L
1/12
(8.3
) (pa
tent
du
ctus
ar
teri
osus
)
Not
rep
orte
d0/
12 (0
.0)
0/12
(0.0
%)
0/12
(0.0
)0/
12 (0
.0)
Japa
n,
retr
ospe
ctiv
e,
Kaw
amat
a et
al 73
/200
7
12 w
omen
16 p
regn
anci
esPr
egna
nt w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
posi
tion
M
itral
: 7
Aor
tic: 2
Tr
icus
pid:
7
Subs
titut
ion
of
w
arfa
rin
with
U
FH
sta
rtin
g be
twee
n 6
and
13 w
k an
d un
til
term
Dos
es a
djus
ted
to
m
aint
ain
aPT
T le
vels
2-
3 tim
es c
ontr
ol
(bet
wee
n 20
,000
an
d 30
,000
In
tern
atio
nal
Uni
ts/d
)
1/16
(6.3
)
(h
ydro
ceph
alus
)2/
16 (1
2.5)
(intr
aven
tric
ular
he
mor
rhag
e,
intr
aven
tric
ular
an
d pu
lmon
ary
hem
orrh
age)
5/16
(31.
3)4/
16 (2
5)1/
16 (8
.3)
(intr
aute
rine
fe
tal d
eath
du
ring
ex
trac
orpo
real
ci
rcul
atio
n)
2/16
(12.
5)
(see
und
er
F
etal
an
d/or
N
eona
tal
Hem
orrh
age)
(Con
tinu
ed)
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
64© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Eng
land
, pr
ospe
ctiv
e,
Qui
nn
et a
l 74 /2
009
11 w
omen
12 p
regn
anci
esPr
egna
nt w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
posi
tion
M
itral
: 4
Aor
tic :2
A
ortic
and
mitr
al: 3
Sy
stem
ic
ri
ght
atrio
vent
ricul
ar
valv
e: 2
Dal
tepa
rin
100
Inte
rnat
iona
l U
nits
/kg
q12h
(8
) or
enox
apar
in
1 m
g/kg
q12
h (4
) 1 as
pirin
81
mg/
dD
oses
adj
uste
d to
att
ain
an
anti-
Xa
leve
l 1.
0-1.
2 un
its/m
L
Not
rep
orte
dN
ot r
epor
ted
1/12
(8.3
)0/
12 (0
.0)
1/12
(8.3
)0/
12 (0
.0)
Can
ada,
pr
ospe
ctiv
e,
Yino
n et
al 75
/200
9
17 w
omen
23 p
regn
anci
esPr
egna
nt
w
omen
with
m
echa
nica
l he
art v
alve
sVa
lve
posi
tion
M
itral
: 14
A
ortic
: 8
Aor
tic a
nd
m
itral
: 1
LM
WH
SC
q12
hL
ow-d
ose
aspi
rin
(81
mg/
d)
adm
inis
tere
d to
all
patie
nts
LWM
H d
ose
adju
sted
to
mai
ntai
n 4
h po
stin
ject
ion
anti-
Xa
leve
l 1-1
.2
Inte
rnat
iona
l U
nits
/mL
0/23
(0.0
)N
ot r
epor
ted
Tota
l
preg
nanc
y lo
ss:
4 (1
7.4)
2/23
(8.7
)2/
23 (8
.7)
1/12
(4.3
)
(Con
tinu
ed)
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
65© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Syst
emat
ic r
evie
ws
Can
ada,
Cha
n et
al 1 /2
000
976
wom
en1,
234
preg
nanc
ies
Stud
ies
betw
een
19
66-1
997
invo
lvin
g pr
egna
nt
wom
en w
ith
mec
hani
cal
hear
t val
ves:
Valv
e ty
pe
Cag
e an
d
ball:
433
Si
ngle
-tilt
ing
di
sc: 3
56
Bile
afl e
t: 62
O
ther
: 20
Het
erog
raft
: 1U
nkno
wn:
104
Posi
tion
M
itral
: 647
A
ortic
: 202
Tr
icus
pid:
1
. 1
val
ve: 1
26Va
lve
posi
tion
M
itral
: 647
A
ortic
: 202
Tr
icus
pid:
1
. 1
val
ve: 1
26
Tota
l: 97
6
Reg
imen
1 o
ral
an
ticoa
gula
nts
thro
ugho
ut
preg
nanc
yR
egim
en 2
subs
titut
ion
of
UF
H in
the
fi rst
tr
imes
ter
eith
er
at o
r be
fore
6 w
k,
afte
r 6
wk,
or
at
unkn
own
time
in th
e fi r
st tr
imes
ter
Reg
imen
3 U
FH
thro
ugho
ut
preg
nanc
y, ad
just
ed
dose
, or
low
dos
e ( �
15,
000
units
/d)
Reg
imen
1,
35
/549
(6.4
)
Reg
imen
2,
6/
174
(3.4
)
� 6
wk:
0/1
08 (0
)
. 6
wk:
4/3
6 (1
1.1)
U
nkno
wn:
2/30
(6.7
)
Reg
imen
3,
0/
12 (0
)
Adj
uste
d do
se:
0/
12 (0
)
Low
dos
e: 0
/5 (0
)
Not
rep
orte
dR
egim
en 1
,
266/
792
(3
3.6%
)
Reg
imen
2,
61
/230
(26.
5)
� 6
wk:
21/
129
(1
6.3)
.
6 w
k: 2
0/56
(35.
37)
U
nkno
wn:
20/4
5
(44.
4)
Reg
imen
3,
9/
21 (4
2.9)
A
djus
ted
do
se:
7/16
(4
3.8)
Low
-dos
e:
2/
5 (4
0)
Reg
imen
1,
19
6/79
2
(24.
7)
Reg
imen
2,
57
/230
(24.
8)
� 6
w:
19
/129
(1
4.7)
.
6 w
k:
19
/56
(33.
9)
Unk
now
n:
19
/45
(42.
2)R
egim
en 3
,
5/21
(2
3.8)
A
djus
ted
do
se:
4/16
(25)
L
ow-d
ose:
1/5
(20)
Not
spe
cifi e
dN
ot s
peci
fi ed
(Con
tinu
ed)
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
66© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Reg
imen
4, n
o
antic
oagu
lant
s,
incl
udin
g us
e of
an
tipla
tele
t age
nts
alon
e
Reg
imen
4,
3/
92 (3
.3)
N
othi
ng:
2/
33 (6
.1)
A
ntip
late
let:
1/
59 (1
.7)
Mal
form
atio
ns
in
clud
e w
arfa
rin
embr
yopa
thy
(29)
, CN
S ab
norm
aliti
es
(4),
clef
t lip
and
cl
eft p
alat
e (4
), le
ft v
entr
icul
ar
hypo
plas
ia (1
), co
rnea
l leu
kom
a (1
), bi
late
ral h
and
poly
dact
yly
(1),
sing
le k
idne
y-to
e-fi n
ger
defo
rmity
(1)
Reg
imen
4,
20
/102
(1
9.6)
N
othi
ng:
7/
35 (2
0)
Ant
ipla
tele
t:
13/6
7
(19.
4)
Reg
imen
4,
10
/102
(9
.8)
N
othi
ng:
2/
35 (5
.7)
A
ntip
late
let:
8/
67
(11.
9)
Tabl
e S2
9—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
67© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Uni
ted
Stat
es,
Jam
es
et a
l 67 /2
006
76 p
regn
anci
esSt
udie
s be
twee
n
1966
and
20
06
invo
lvin
g pr
egna
nt
wom
en
with
m
echa
nica
l he
art v
alve
s re
ceiv
ing
LM
WH
Valv
e ty
pe
Cag
e an
d
ball:
4
Sing
le-t
iltin
g
disc
: 2
Bile
afl e
t: 8
So
rin:
1
Unk
now
n: 6
1Va
lve
posi
tion
M
itral
: 24
A
ortic
: 12
B
jork
-Shi
ley:
2
Unk
now
n: 4
0
Con
vers
ion
to L
MW
H
pr
ior
to p
regn
ancy
or
by
the
end
of
fi rst
trim
este
rL
MW
H
Eno
xapa
rin:
32
N
adro
pari
n: 2
0
Dal
tepa
rin:
13
Ti
nzap
arin
: 2
Rev
ipar
in: 1
U
nkno
wn:
8A
dditi
on o
f low
-dos
e
aspi
rin:
13
Vary
ing
regi
men
s
rang
ing
from
a
fi xed
subt
hera
peut
ic
dose
to w
eigh
t-ad
just
ed th
erap
eutic
do
ses
Mon
itori
ng o
f ant
i-fac
tor
X
a le
vels
: 43
The
m
inim
um v
alue
for
the
targ
et ra
nges
was
0.
5 an
d th
e m
axim
um
was
1.2
0/76
(0.0
)N
ot r
epor
ted
12 (1
5.8)
8/76
(10.
5)2/
76 (2
.6)
∗ Add
ition
al 2
dem
ises
se
cond
ary
to fa
tal
mat
erna
l va
lve
thro
mbo
sis
∗ ∗ N
ot in
clud
ed
el
ectiv
e te
rmin
atio
n at
14
wk
Not
rep
orte
d
Uni
ted
Stat
es,
Ora
n et
al 68
/200
4
75 w
omen
81 p
regn
anci
esSt
udie
s be
twee
n
1989
and
20
04 in
volv
ing
preg
nant
w
omen
w
ith
mec
hani
cal
hear
t val
ves
who
rec
eive
d L
MW
H
Cas
es w
ere
incl
uded
if L
MW
H w
as
rece
ived
dur
ing
preg
nanc
y ir
resp
ectiv
e of
this
type
, dos
e,
and
dura
tion
and
adm
inis
trat
ion
of
diffe
rent
ant
icoa
gula
nt
regi
men
s ot
her
than
L
MW
H d
urin
g th
e sa
me
preg
nanc
y
1/81
(1.2
)
(h
ydro
ceph
alus
,
LM
WH
re
ceiv
ed
duri
ng fi
rst
trim
este
r, w
arfa
rin
subs
eque
nt
to th
at)
Not
rep
orte
d9/
81 (1
1.1)
Ant
i-Xa
ad
just
ed
dose
: 3/
81 (3
.7)
Fix
ed d
ose:
4/81
(4.9
)U
nkno
wn:
2/81
(3.7
)
6/81
(7.4
)A
nti-X
a
adju
sted
do
se:
3/81
(3.7
)F
ixed
dos
e:
3/
81 (3
.7)
3/81
(3.7
)A
nti-X
a
adju
sted
do
se:
0/81
(0.0
)F
ixed
dos
e:
1/
81 (1
.2)
Unk
now
n:
2/
81 (3
.7)
Not
rep
orte
d
(Con
tinu
ed)
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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(Con
tinu
ed)
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Valv
e po
sitio
n
Mitr
al: 4
4
Aor
tic: 8
M
itral
and
aort
ic: 5
U
nkno
wn:
18
Con
vers
ion
to
L
MW
H o
ccur
red
1 m
o be
fore
co
ncep
tion
in
2 w
omen
; in
the
rem
aind
er,
conv
ersio
n to
LM
WH
oc
curr
ed d
urin
g pr
egna
ncy
LM
WH
use
dur
ing
se
cond
hal
f of fi
rst
tr
imes
ter
and
at te
rm: 2
1L
MW
H th
roug
hout
preg
nanc
y: 6
0L
MW
H e
noxa
parin
: 35
N
adro
pari
n: 2
1
Dal
tapa
rin:
11
Ti
nzap
arin
: 3
Rev
ipar
in: 1
U
nkno
wn:
10
Dos
e ad
just
ed to
ther
apeu
tic a
nti-X
a le
vel:
51F
ixed
dos
e: 3
0
∗ Not
incl
uded
: 1
fi rst
tr
imes
ter
elec
tive
term
inat
ion
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
69© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
Cou
ntry
, St
udy/
Year
Num
ber
of
Patie
nts
and
Preg
nanc
ies
Popu
latio
nTr
eatm
ent R
egim
ens
Con
geni
tal
Mal
form
atio
ns,
n/N
(%)
Fet
al a
nd/o
r N
eona
tal
Hem
orrh
age,
n/
N (%
)
Tota
l Pr
egna
ncy
Los
s,
n/N
(%)
Ear
ly
Preg
nanc
y L
oss,
n/
N (%
)
Lat
e Pr
egna
ncy
Los
s,
n/N
(%)
Neo
nata
l Dea
th
Egy
pt,
Has
soun
a an
d A
llam
2 /200
9
892
wom
en1,
231
preg
nanc
ies
Stud
ies
publ
ishe
d
betw
een
Janu
ary
2000
-Se
ptem
ber
2009
invo
lvin
g pr
egna
nt
wom
en
with
m
echa
nica
l he
art v
alve
s w
ho r
ecei
ved
defi n
ed
antic
oagu
lant
re
gim
ens
Valv
e ty
pe
Cag
e an
d
ball:
134
Ti
lting
dis
c: 3
82
Bile
afl e
t: 34
1
Und
efi n
ed: 2
56Va
lve
posi
tion
M
itral
: 671
A
ortic
: 141
M
itral
and
aor
tic:
14
7 1
147
Tr
icus
pid:
7
Reg
imen
1 V
KA
s
thro
ugho
ut
preg
nanc
y w
ith
and
with
out
UF
H o
r L
MW
H
subs
titut
ion
near
term
Reg
imen
2 U
FH
or L
MW
H
subs
titut
ion
duri
ng th
e fi r
st
trim
este
r an
d ne
ar te
rmR
egim
en 3
UF
H
or
LM
WH
th
roug
hout
pr
egna
ncy
Reg
imen
4
no a
ntic
oagu
lant
s
Ove
rall
22
/942
(2.3
) ∗
Reg
imen
1
21
/559
(3.7
)
Reg
imen
2
1/25
8 (0
.4)
Reg
imen
3
0/96
(0)
Reg
imen
4
0/27
(0)
∗ Inc
lude
s
hydr
ocep
halu
s (4
), na
sal
hypo
plas
ia,
epip
hyse
al
stip
plin
g (7
) st
rabi
smus
(3),
men
tal
reta
rdat
ion
(2),
clef
t lip
/pa
late
(2),
tele
brac
hyda
ctyl
y (1
), an
d ot
her
(3)
Not
rep
orte
dO
vera
ll
403/
1343
(3
0)R
egim
en 1
27
4/83
3 (3
2.9)
Reg
imen
2
64/3
22
(19.
9)
Reg
imen
3
61/1
57
(38.
8)
Reg
imen
4
4/31
(1
2.9)
Ove
rall
27
2/13
43
(20.
2)R
egim
en 1
19
4/83
3 (2
3.3)
Reg
imen
2
42/3
22
(13)
Reg
imen
3
34/1
57
(21.
6)
Reg
imen
4
2/31
(1
2.9)
Not
spe
cifi e
dN
ot r
epor
ted
∗ an
d ∗∗
den
ote
addi
tiona
l dat
a re
ferr
ing
to th
e nu
mbe
r of
late
loss
es tw
o of
76
(2.6
). Se
e Ta
bles
S1,
S4,
and
S17
for
expa
nsio
n of
abb
revi
atio
ns.
Tabl
e S2
9—C
onti
nued
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
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References 1 . Chan WS , Anand S , Ginsberg JS . Anticoagulation of pregnant
women with mechanical heart valves: a systematic review of the literature . Arch Intern Med . 2000 ; 160 ( 2 ): 191 - 196 .
2 . Hassouna A , Allam H . Anticoagulation of pregnant women with mechanical heart valve prosthesis: a systematic review of the literature (2000-2009) . J Coagul Disorders . 2010 ; 2 ( 1 ): 81 - 88 .
3 . Askie LM , Duley L , Henderson-Smart DJ , Stewart LA ; PARIS Collaborative Group. Antiplatelet agents for preven-tion of pre-eclampsia: a meta-analysis of individual patient data . Lancet . 2007 ; 369 ( 9575 ): 1791 - 1798 .
4 . Kozer E , Nikfar S , Costei A , Boskovic R , Nulman I , Koren G . Aspirin consumption during the fi rst trimester of pregnancy and congenital anomalies: a meta-analysis . Am J Obstet Gynecol . 2002 ; 187 ( 6 ): 1623 - 1630 .
5 . Kozer E , Costei AM , Boskovic R , Nulman I , Nikfar S , Koren G . Effects of aspirin consumption during pregnancy on pregnancy outcomes: meta-analysis . Birth Defects Res B Dev Reprod Toxicol . 2003 ; 68 ( 1 ): 70 - 84 .
6 . Orme ML , Lewis PJ , de Swiet M , et al . May mothers given warfarin breast-feed their infants? BMJ . 1977 ; 1 ( 6076 ): 1564 - 1565 .
7 . McKenna R , Cole ER , Vasan U . Is warfarin sodium con-traindicated in the lactating mother? J Pediatr . 1983 ; 103 ( 2 ): 325 - 327 .
8 . Houwert-de Jong M , Gerards LJ , Tetteroo-Tempelman CA , de Wolff FA . May mothers taking acenocoumarol breast feed their infants? Eur J Clin Pharmacol . 1981 ; 21 ( 1 ): 61 - 64 .
9 . Fondevila CG , Meschengieser S , Blanco A , Peñalva L , Lazzari MA . Effect of acenocoumarine on the breast-fed infant . Thromb Res. . 1989 ; 56 ( 1 ): 29 - 36 .
10 . Richter C , Sitzmann J , Lang P , Weitzel H , Huch A , Huch R . Excretion of low molecular weight heparin in human milk . Br J Clin Pharmacol . 2001 ; 52 ( 6 ): 708 - 710 .
11 . Ito S , Blajchman A , Stephenson M , Eliopoulos C , Koren G . Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication . Am J Obstet Gynecol . 1993 ; 168 ( 5 ): 1393 - 1399 .
12 . Delvigne A , Demoulin A , Smitz J , et al . The ovarian hyper-stimulation syndrome in in-vitro fertilization: a Belgian multi-centric study. I. Clinical and biological features . Hum Reprod . 1993 ; 8 ( 9 ): 1353 - 1360 .
13 . Aurousseau MH , Samama MM , Belhassen A , Herve F , Hugues JN . Risk of thromboembolism in relation to an in-vitro fertilization programme: three case reports . Hum Reprod . 1995 ; 10 ( 1 ): 94 - 97 .
14 . Morris RS , Miller C , Jacobs L , Miller K . Conservative man-agement of ovarian hyperstimulation syndrome . J Reprod Med . 1995 ; 40 ( 10 ): 711 - 714 .
15 . Bergh T , Lundkvist O . Clinical complications during in-vitro fertilization treatment . Hum Reprod . 1992 ; 7 ( 5 ): 625 - 626 .
16 . Jacobsen AF , Skjeldestad FE , Sandset PM . Ante- and post-natal risk factors of venous thrombosis: a hospital-based case-control study . J Thromb Haemost . 2008 ; 6 ( 6 ): 905 - 912 .
17 . Ragni G , Scarduelli C , Calanna G , Santi G , Benaglia L , Somigliana E . Blood loss during transvaginal oocyte retrieval . Gynecol Obstet Invest . 2009 ; 67 ( 1 ): 32 - 35 .
18 . Bennett SJ , Waterstone JJ , Cheng WC , Parsons J . Compli-cations of transvaginal ultrasound-directed follicle aspiration: a review of 2760 consecutive procedures . J Assist Reprod Genet . 1993 ; 10 ( 1 ): 72 - 77 .
19 . Dicker D , Ashkenazi J , Feldberg D , Levy T , Dekel A , Ben-Rafael Z . Severe abdominal complications after trans-vaginal ultrasonographically guided retrieval of oocytes for in vitro fertilization and embryo transfer . Fertil Steril . 1993 ; 59 ( 6 ): 1313 - 1315 .
20 . Tureck RW , García CR , Blasco L , Mastroianni L Jr. Perioper-ative complications arising after transvaginal oocyte retrieval . Obstet Gynecol . 1993 ; 81 ( 4 ): 590 - 593 .
21 . Govaerts I , Devreker F , Delbaere A , Revelard P , Englert Y . Short-term medical complications of 1500 oocyte retrievals for in vitro fertilization and embryo transfer . Eur J Obstet Gynecol Reprod Biol . 1998 ; 77 ( 2 ): 239 - 243 .
22 . Ludwig AK , Glawatz M , Griesinger G , Diedrich K , Ludwig M . Perioperative and post-operative complications of transvaginal ultrasound-guided oocyte retrieval: prospective study of . 1000 oocyte retrievals . Hum Reprod . 2006 ; 21 ( 12 ): 3235 - 3240 .
23 . Bodri D , Guillén JJ , Polo A , Trullenque M , Esteve C , Coll O . Complications related to ovarian stimulation and oocyte retrieval in 4052 oocyte donor cycles . Reprod Biomed Online . 2008 ; 17 ( 2 ): 237 - 243 .
24 . Baber R , Porter R , Picker R , Robertson R , Dawson E , Saunders D . Transvaginal ultrasound directed oocyte collec-tion for in vitro fertilization: successes and complications . J Ultrasound Med . 1988 ; 7 ( 7 ): 377 - 379 .
25 . Yinon Y , Pauzner R , Dulitzky M , Elizur SE , Dor J , Shulman A . Safety of IVF under anticoagulant therapy in patients at risk for thrombo-embolic events . Reprod Biomed Online . 2006 ; 12 ( 3 ): 354 - 358 .
26 . Qublan H , Amarin Z , Dabbas M , et al . Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial . Hum Fertil . 2008 ; 11 ( 4 ): 246 - 253 .
27 . Stern C , Chamley L , Norris H , Hale L , Baker HW . A ran-domized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies . Fertil Steril . 2003 ; 80 ( 2 ): 376 - 383 .
28 . Jacobsen AF , Drolsum A , Klow NE , Dahl GF , Qvigstad E , Sandset PM . Deep vein thrombosis after elective cesarean section . Thromb Res . 2004 ; 113 ( 5 ): 283 - 288 .
29 . Lindqvist P , Dahlbäck B . Marŝál K. Thrombotic risk dur-ing pregnancy: a population study . Obstet Gynecol . 1999 ; 94 ( 4 ): 595 - 599 .
30 . Simpson EL , Lawrenson RA , Nightingale AL , Farmer RD . Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database . BJOG . 2001 ; 108 ( 1 ): 56 - 60 .
31 . Knight M ; UKOSS . Antenatal pulmonary embolism: risk factors, management and outcomes . BJOG . 2008 ; 115 ( 4 ): 453 - 461 .
32 . Robertson L , Wu O , Langhorne P , et al ; Thrombosis Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review . Br J Haematol . 2005 ; 132 ( 2 ): 171 - 196 .
33 . James AH , Jamison MG , Brancazio LR , Myers ER . Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality . Am J Obstet Gynecol . 2006 ; 194 ( 5 ): 1311 - 1315 .
34 . Casele H , Grobman WA . Cost-effectiveness of thrombopro-phylaxis with intermittent pneumatic compression at cesarean delivery . Obstet Gynecol . 2006 ; 108 ( 3 pt 1 ): 535 - 540 .
35 . Howell R , Fidler J , Letsky E , de Swiet M . The risks of ante-natal subcutaneous heparin prophylaxis: a controlled trial . Br J Obstet Gynaecol . 1983 ; 90 ( 12 ): 1124 - 1128 .
36 . Lao TT , de Swiet M , Letsky SE , Walters BN . Prophylaxis of thromboembolism in pregnancy: an alternative . Br J Obstet Gynaecol . 1985 ; 92 ( 3 ): 202 - 206 .
37 . de Swiet M , Floyd E , Letsky E . Low risk of recurrent throm-boembolism in pregnancy . Br J Hosp Med . 1987 ; 38 ( 3 ): 264 .
38 . Brill-Edwards P , Ginsberg JS , Gent M , et al ; Recurrence of Clot in This Pregnancy Study Group. Safety of withholding
© 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from
71© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2300
heparin in pregnant women with a history of venous throm-boembolism . N Engl J Med . 2000 ; 343 ( 20 ): 1439 - 1444 .
39 . Badaracco MA , Vessey MP . Recurrence of venous thrombo-embolic disease and use of oral contraceptives . BMJ . 1974 ; 1 ( 5901 ): 215 - 217 .
40 . Tengborn L , Bergqvist D , Mätzsch T , Bergqvist A , Hedner U . Recurrent thromboembolism in pregnancy and puerperium. Is there a need for thromboprophylaxis? Am J Obstet Gynecol . 1989 ; 160 ( 1 ): 90 - 94 .
41 . Pabinger I , Grafenhofer H , Kaider A , et al . Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis . J Thromb Haemost . 2005 ; 3 ( 5 ): 949 - 954 .
42 . De Stefano V , Martinelli I , Rossi E , et al . The risk of recurrent venous thromboembolism in pregnancy and puerperium with-out antithrombotic prophylaxis . Br J Haematol . 2006 ; 135 ( 3 ): 386 - 391 .
43 . Gates S , Brocklehurst P , Ayers S , Bowler U ; Thrombopro-phylaxis in Pregnancy Advisory Group. Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin . Am J Obstet Gynecol . 2004 ; 191 ( 4 ): 1296 - 1303 .
44 . Pettilä V , Kaaja R , Leinonen P , Ekblad U , Kataja M , Ikkala E . Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy . Thromb Res . 1999 ; 96 ( 4 ): 275 - 282 .
45 . Blombäck M , Bremme K , Hellgren M , Siegbahn A , Lindberg H . Thromboprophylaxis with low molecular mass heparin, ‘Fragmin’ (dalteparin), during pregnancy—a longitudinal safety study . Blood Coagul Fibrinolysis . 1998 ; 9 ( 1 ): 1 - 9 .
46 . Brennand JE , Walker ID , Greer IA . Anti-activated factor X profi les in pregnant women receiving antenatal thrombopro-phylaxis with enoxaparin . Acta Haematol . 1999 ; 101 ( 1 ): 53 - 55 .
47 . Bauersachs RM , Dudenhausen J , Faridi A , et al ; EThIG Investigators. Risk stratifi cation and heparin prophylaxis to prevent venous thromboembolism in pregnant women . Thromb Haemost . 2007 ; 98 ( 6 ): 1237 - 1245 .
48 . Dargaud Y , Rugeri L , Vergnes MC , et al . A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study . Br J Haematol . 2009 ; 145 ( 6 ): 825 - 835 .
49 . Folkeringa N , Brouwer JL , Korteweg FJ , Veeger NJ , Erwich JJ , van der Meer J . High risk of pregnancy-related venous throm-boembolism in women with multiple thrombophilic defects . Br J Haematol . 2007 ; 138 ( 1 ): 110 - 116 .
50 . Rozanski C , Lazo-Langner A , Kovacs M . Prevention of venous thromboembolism (VTE) associated with pregnancy in women with a past history of VTE [abstract] . Blood . 2009 ; 114 ( suppl ): 3132 .
51 . Sanson BJ , Lensing AWA , Prins MH , et al . Safety of low-molecular-weight heparin in pregnancy: a systematic review . Thromb Haemost . 1999 ; 81 ( 5 ): 668 - 672 .
52 . Lepercq J , Conard J , Borel-Derlon A , et al . Venous throm-boembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies . BJOG . 2001 ; 108 ( 11 ): 1134 - 1140 .
53 . Cowchock S , Reece EA . Do low-risk pregnant women with antiphospholipid antibodies need to be treated? Organizing Group of the Antiphospholipid Antibody Treatment Trial . Am J Obstet Gynecol . 1997 ; 176 ( 5 ): 1099 - 1100 .
54 . Tulppala M , Marttunen M , Söderstrom-Anttila V , et al . Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production . Hum Reprod . 1997 ; 12 ( 7 ): 1567 - 1572 .
55 . Pattison NS , Chamley LW , Birdsall M , Zanderigo AM , Liddell HS , McDougall J . Does aspirin have a role in improv-ing pregnancy outcome for women with the antiphospholipid
syndrome? A randomized controlled trial . Am J Obstet Gynecol . 2000 ; 183 ( 4 ): 1008 - 1012 .
56 . Rai R , Cohen H , Dave M , Regan L . Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies) . BMJ . 1997 ; 314 ( 7076 ): 253 - 257 .
57 . Goel N , Tuli A , Choudhry R . The role of aspirin versus aspirin and heparin in cases of recurrent abortions with raised anticar-diolipin antibodies . Med Sci Monit . 2006 ; 12 ( 3 ): CR132 - CR136 .
58 . Kutteh WH . Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone . Am J Obstet Gynecol . 1996 ; 174 ( 5 ): 1584 - 1589 .
59 . Farquharson RG , Quenby S , Greaves M . Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment . Obstet Gynecol . 2002 ; 100 ( 3 ): 408 - 413 .
60 . Laskin CA , Spitzer KA , Clark CA , et al . Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial . J Rheumatol . 2009 ; 36 ( 2 ): 279 - 287 .
61 . Stephenson MD , Ballem PJ , Tsang P , et al . Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin . J Obstet Gynaecol Can . 2004 ; 26 ( 8 ): 729 - 734 .
62 . Gris JC , Quéré I , Monpeyroux F , et al . Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent—the Nîmes Obstetricians and Haematologists Study5 (NOHA5) . Thromb Haemost . 1999 ; 81 ( 6 ): 891 - 899 .
63 . Noble LS , Kutteh WH , Lashey N , Franklin RD , Herrada J . Antiphospholipid antibodies associated with recurrent preg-nancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin ver-sus unfractionated heparin . Fertil Steril . 2005 ; 83 ( 3 ): 684 - 690 .
64 . Kutteh WH , Ermel LD . A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin . Am J Reprod Immunol . 1996 ; 35 ( 4 ): 402 - 407 .
65 . Carp H , Dolitzky M , Inbal A . Thromboprophylaxis improves the live birth rate in women with consecutive recurrent mis-carriages and hereditary thrombophilia . J Thromb Haemost . 2003 ; 1 ( 3 ): 433 - 438 .
66 . Leduc L , Dubois E , Takser L , Rey E , David MJ . Dalteparin and low-dose aspirin in the prevention of adverse obstetric outcomes in women with inherited thrombophilia . J Obstet Gynaecol Can . 2007 ; 29 ( 10 ): 787 - 793 .
67 . James AH , Brancazio LR , Gehrig TR , Wang A , Ortel TL . Low-molecular-weight heparin for thromboprophylaxis in pregnant women with mechanical heart valves . J Matern Fetal Neonatal Med . 2006 ; 19 ( 9 ): 543 - 549 .
68 . Oran B , Lee-Parritz A , Ansell J . Low molecular weight hep-arin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy . Thromb Haemost . 2004 ; 92 ( 4 ): 747 - 751 .
69 . Khamooshi AJ , Kashfi F , Hoseini S , Tabatabaei MB , Javadpour H , Noohi F . Anticoagulation for prosthetic heart valves in pregnancy. Is there an answer? Asian Cardiovasc Thorac Ann . 2007 ; 15 ( 6 ): 493 - 496 .
70 . Lee JH , Park NH , Keum DY , Choi SY , Kwon KY , Cho CH . Low molecular weight heparin treatment in pregnant women with a mechanical heart valve prosthesis . J Korean Med Sci . 2007 ; 22 ( 2 ): 258 - 261 .
71 . McLintock C , McCowan LME , North RA . Maternal com-plications and pregnancy outcome in women with mechan-ical prosthetic heart valves treated with enoxaparin . BJOG . 2009 ; 116 ( 12 ): 1585 - 1592 .
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72 . Abildgaard U , Sandset PM , Hammerstrøm J , Gjestvang FT , Tveit A . Management of pregnant women with mechan-ical heart valve prosthesis: thromboprophylaxis with low molecular weight heparin . Thromb Res . 2009 ; 124 ( 3 ): 262 - 267 .
73 . Kawamata K , Neki R , Yamanaka K , et al . Risks and pregnancy outcome in women with prosthetic mechanical heart valve replacement . Circ J . 2007 ; 71 ( 2 ): 211 - 213 .
74 . Quinn J , Von Klemperer K , Brooks R , Peebles D , Walker F , Cohen H . Use of high intensity adjusted dose low molec-ular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience . Haematologica . 2009 ; 94 ( 11 ): 1608 - 1612 .
75 . Yinon Y , Siu SC , Warshafsky C , et al . Use of low molecular weight heparin in pregnant women with mechanical heart valves . Am J Cardiol . 2009 ; 104 ( 9 ): 1259 - 1263 .
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DOI 10.1378/chest.11-2300 2012;141; e691S-e736SChest
Anne-Marie Prabulos and Per Olav VandvikShannon M. Bates, Ian A. Greer, Saskia Middeldorp, David L. Veenstra,
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