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DOI 10.1378/chest.11-2300 2012;141;e691S-e736S Chest Anne-Marie Prabulos and Per Olav Vandvik Shannon M. Bates, Ian A. Greer, Saskia Middeldorp, David L. Veenstra, Evidence-Based Clinical Practice Guidelines ed: American College of Chest Physicians Therapy and Prevention of Thrombosis, 9th Therapy, 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 prior Dundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2012by the American College of Chest Physicians, 3300 Physicians. It has been published monthly since 1935. is the official journal of the American College of Chest Chest © 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012 chestjournal.chestpubs.org Downloaded from

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Page 1: VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy ... · VTE, instead of UFH (Grade 1B) . 3.0.1. For women receiving anticoagulation for the treatment of VTE who become pregnant,

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

Page 2: VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy ... · VTE, instead of UFH (Grade 1B) . 3.0.1. For women receiving anticoagulation for the treatment of VTE who become pregnant,

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

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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

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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-

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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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www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e695S

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

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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

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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

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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

Page 10: VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy ... · VTE, instead of UFH (Grade 1B) . 3.0.1. For women receiving anticoagulation for the treatment of VTE who become pregnant,

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

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e700S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy

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s de

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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

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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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e704S VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy

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

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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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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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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.

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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

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2© 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

—[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 (

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c Q

ual

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y/Ye

arIn

terv

entio

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e L

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arch

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nclu

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ies

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ided

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essm

ent o

f Q

ualit

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clud

ed S

tudi

es

App

ropr

iate

Met

hods

U

sed

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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

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ies

betw

een

1966

and

199

7 ex

amin

ing

the

use

of V

KA

s an

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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

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e of

VK

As

and

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H o

r no

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tion

in p

regn

ant w

omen

with

m

echa

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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)

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pari

ng a

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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

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in g

iven

alo

ne in

27

tria

ls

(n 5

31,

678;

98%

of w

omen

). M

eta-

anal

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of i

ndiv

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l pa

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dat

a

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Koz

er e

t al 4 /2

002

Con

trol

led

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ies

(n 5

2 c

ase

cont

rolle

d st

udie

s, n

5 5

coh

ort

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sk o

f m

ater

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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

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t al 5 /2

003

Ran

dom

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(n 5

38)

exa

min

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posu

re to

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irin

dur

ing

preg

nanc

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port

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on

seve

n pr

espe

cifi e

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es

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Yes

Incl

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o

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unf

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min

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t.

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3© 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 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

.

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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.

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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

.

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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)

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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

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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)

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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

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

 © 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from

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11© 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 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

)

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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

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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).

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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

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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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17© 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

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

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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

)

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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)

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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)

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23© 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

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

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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)

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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

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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)

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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)

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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)

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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

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)

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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

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33© 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)

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

)

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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

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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

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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

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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

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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

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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

)

 © 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from

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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

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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)

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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)

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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)

 © 2012 American College of Chest Physicians at Metrohealth Medical Center on February 16, 2012chestjournal.chestpubs.orgDownloaded from

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44© 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—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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45© 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

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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46© 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

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)

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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

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48© 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

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.

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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

.

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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.

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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.

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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)

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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

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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

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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)

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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

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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

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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

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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

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60© 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

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

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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

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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

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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

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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

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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

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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

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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

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68© 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

, 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

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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

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form

atio

ns,

n/N

(%)

Fet

al a

nd/o

r N

eona

tal

Hem

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age,

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N (%

)

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l Pr

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ly

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nanc

y L

oss,

n/

N (%

)

Lat

e Pr

egna

ncy

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s,

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(%)

Neo

nata

l Dea

th

Egy

pt,

Has

soun

a an

d A

llam

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9

892

wom

en1,

231

preg

nanc

ies

Stud

ies

publ

ishe

d

betw

een

Janu

ary

2000

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ptem

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2009

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lvin

g pr

egna

nt

wom

en

with

m

echa

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l he

art v

alve

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ved

defi n

ed

antic

oagu

lant

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gim

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e ty

pe

Cag

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d

ball:

134

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lting

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c: 3

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1

Und

efi n

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56Va

lve

posi

tion

M

itral

: 671

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ortic

: 141

M

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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

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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)

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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

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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 .

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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,

Practice GuidelinesAmerican College of Chest Physicians Evidence-Based ClinicalAntithrombotic Therapy and Prevention of Thrombosis, 9th ed: VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy :

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