CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA category 1 credit hours can be earned in 2006. Instructions for how CME credits can be earned appear onthe last page of the Table of Contents.

Anticoagulants in PregnancyAndra H. James, MD, MPH,* David E. Abel, MD,†

and Leo R. Brancazio, MD‡*Assistant Professor, Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Duke

University Medical Center, Durham, North Carolina; †Director of Genetics and Staff Perinatologist,Northwest Perinatal Center, Portland, Oregon; and ‡Associate Clinical Professor, Division of Maternal–FetalMedicine, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina

Pregnancy is a hypercoagulable state that increases the risk of thromboembolic events. Theserisks may be further increased in the presence of an acquired or inherited thrombophilia. Throm-bophilias have been associated with both maternal and fetal complications. The use of anticoagu-lants during pregnancy may reduce the risk of maternal thromboses as well as the risk of adversepregnancy outcomes. The choice of an anticoagulant requires consideration of maternal risks,potential for teratogenicity, the underlying condition necessitating the treatment, and cost. Thisreview examines the options for anticoagulation, the clinical situations that may warrant suchtreatment, and factors to be considered at delivery and during the postpartum period.

Target Audience: Obstetricians & Gynecologists, Family PhysiciansLearning Objectives: After completion of this article, the reader should be able to describe the roles of

acquired and inherited thrombophilia in furthering the hypercoagulable state of pregnancy, identify thepotential consequences of using anticoagulants during pregnancy, and summarize the treatment optionswhen anticoagulation is required during pregnancy.

Pregnancy confers a fivefold risk of thrombosis (1).This predisposition results from the hypercoagulablestate of pregnancy, which has likely evolved to protectwomen from hemorrhage during miscarriage and child-birth. Among women with thrombophilia, an acquiredor inherited predisposition to thrombosis, the risk iseven higher, increased from a background risk of one totwo per 1000 (2) to as high as one in two (3–5). Not

only are women with thrombophilia at a higher risk ofthrombosis, they are more likely to experience placentalabruption, preeclampsia, fetal growth restriction, still-birth, and possibly recurrent miscarriage (6–8). Thegoal of anticoagulation is not only to prevent and treatmaternal thromboses, but to improve the outcome ofpregnancy. In women with a history of thrombosis andthrombophilia, anticoagulants have been shown to re-duce maternal morbidity and mortality (9). In womenwith the antiphospholipid syndrome (10), an acquiredthrombophilia, and recently in women with inheritedthrombophilia (11), anticoagulants have been shown toincrease the probability of a live birth. The purpose ofthis article is to review different anticoagulants and theiruse in pregnancy.

CHANGES IN COAGULATION DURINGNORMAL PREGNANCY

Rudolf Virchow, the 19th-century German pathol-ogist, is credited with describing the three factors that

The authors have disclosed that they have no financial relation-ships with or interests in any commercial companies pertaining tothis educational activity.

The author has disclosed that warfarin, unfractionated heparin,reviparin, tinzaparin, nadroparin, dalteparin, enoxaparin, danap-aroid, recombinant hirudin, fondaparinux, aspirin, dipyridamole,clopidogrel, ticlopidine, abciximab, streptokinase, alteplase, rete-plase and tenecteplase have not been approved by the U.S. Foodand Drug Administration for use in pregnancy.

Wolters Kluwer Health has identified and resolved all facultyconflicts of interest regarding this educational activity.

Reprint requests to: Andra H. James, MD, MPH, Division ofMaternal and Fetal Medicine, Box 3967, Duke University MedicalCenter, Durham, NC 27710. E-mail: andra.james@duke.edu.

CME REVIEWARTICLEVolume 61, Number 1OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright © 2005by Lippincott Williams & Wilkins 3

59

contribute to thrombosis: hypercoagulability, vascu-lar injury, and stasis (12). Venous stasis is increasedduring pregnancy. Contributing factors are the hor-monally induced increased venous capacitance ofpregnancy (13,14), impaired venous outflow causedby mechanical obstruction from the uterus (15), andpossibly decreased mobility (16–19). Venous stasisand vascular injury (15), however, appear to be lessimportant than hypercoagulability.

Normal pregnancy is accompanied by an in-crease in coagulation factors VII, VIII, X, and vonWillebrand factor and by a pronounced increase infibrinogen (20). Factors II, V, and IX are relativelyunchanged (20). Free protein S, the active, unboundform of protein S, a natural anticoagulant, is de-creased during pregnancy secondary to increased lev-els of its binding protein, the complement componentC4b (20). Plasminogen activator inhibitor type 1(PAI-1) levels are increased fivefold (20). All ofthese changes may contribute to the hypercoagulablestate of pregnancy.

The changes in the coagulation system begin withconception and do not return to baseline until morethan 8 weeks postpartum (20). In a metaanalysisexamining the incidence of deep vein thrombosis(DVT) in pregnancy, 22% of cases were found tooccur in the first trimester (21), and in one series, theproportion of DVT in the first trimester was found tobe as high as 44% (22). Compared with pregnancy,the risk of thrombosis is even higher after delivery(21,22). Over one third of pregnancy-related venousthromboembolism occurs postpartum (21,22).

INDICATIONS FOR ANTICOAGULATION

Despite the increased risk of thrombosis duringpregnancy and postpartum, most women do not re-quire anticoagulation. In most cases, the risks ofanticoagulation outweigh its benefits. The risk ofmaternal bleeding complications with heparin is re-ported to be as high as 2% (23). In addition tomaternal risks, anticoagulants may pose fetal risks,even with the use of agents that do not cross theplacenta. There is a fine balance between hemostaticand thrombotic interactions at the uteroplacental in-terface (24) and, in most women, this balance isachieved with the normal changes of pregnancy.

The exception is women with thrombophilia. In theantiphospholipid syndrome, an acquired thrombophilia,several studies have demonstrated that anticoagulationimproves the outcome of pregnancy (10). In inheritedthrombophilia, until very recently, only case reports andcase series demonstrated the role of anticoagulation in

improving the outcome of pregnancy, but a recent ran-domized trial (11) showed improved outcomes inwomen with inherited thrombophilia and a history of asingle fetal loss greater than 10 weeks gestation. Sixty-nine of 80 women who took 40 mg enoxaparin per dayhad a healthy live birth compared with 23 of 80 whotook a placebo (low-dose aspirin).

Although some experts would recommend throm-boprophylaxis for all pregnant women with inheritedthrombophilia, anticoagulation is not necessary ifthere is no personal history of thromboembolism orpoor pregnancy outcome (25). The exceptions, be-cause of their especially high risk of thrombosis, arewomen with antithrombin deficiency, homozygosityfor the factor V Leiden mutation or the prothrombingene G20210A mutation, or heterozygosity for bothmutations (compound heterozygosity) (26). Althoughthere are no large trials demonstrating the maternal orfetal benefits of anticoagulation in pregnancy, cur-rent indications include the conditions listed subse-quently. Full-dose (adjusted-dose) anticoagulation isrecommended (25,27) for women with:

• Current thrombosis;• A need for lifelong anticoagulation; and• Antiphospholipid syndrome with a history of

thrombosis.

Full dose (adjusted dose) or an intermediate ormoderate dose, as described in 1, is recommended(25,27) for women with:

• Antithrombin deficiency; and• Homozygosity for the factor V Leiden mutation,

the prothrombin gene G20210A mutation, orcompound heterozygosity for both mutations.

Thromboprophylaxis with low-dose anticoagula-tion is recommended (8,25) for women with ahistory of:

• Unprovoked thrombosis;• Antiphospholipid syndrome with a history of

poor pregnancy outcome as the only clinicalcriteria; and

• Thrombophilia and poor pregnancy outcome.

Close observation (assessment of signs and symp-toms of thrombosis at routine prenatal visits) is rec-ommended for women with a history of:

• Thrombosis in the setting of transient risk fac-tors (25); and

• Thrombophilia with no history of thrombosis.

60 Obstetrical and Gynecological Survey

UNIQUE ASPECTS OFANTICOAGULATION IN PREGNANCY

Anticoagulation in pregnancy requires consider-ation of both the mother and fetus. During preg-nancy, there is an increase in blood volume of 40% to50% (13) and an increase in the volume of distribu-tion. An increase in glomerular filtration (13) resultsin increased renal excretion. Additionally, there is inan increase in protein binding of heparin. Agents thatcross the placenta are potentially teratogenic. Be-cause 45% of pregnancies are unintended (28), manywomen do not realize they are pregnant during thecritical period for organogenesis, the fourth to eighthweek postconception (29).

Anticoagulants that have been used in pregnancyare discussed subsequently. Although these medica-tions, including heparin and aspirin, have not beenapproved for use in pregnancy by the U.S. Food andDrug Administration (FDA), they are neverthelesswidely used for the appropriate indications in preg-nancy. Their indications, routes of administration,pharmacokinetics, monitoring, placental transfer, andfetal effects are summarized in Table 2.

WARFARIN

Warfarin is a vitamin K antagonist. The coagulantactivity of factors II, VII, IX, and X requires avitamin K-dependent, posttranslational modification,the addition of a second carboxyl group, to theglutamate residues of the N-terminal regions ofthese proteins. During the process, the reduced formof vitamin K is converted to vitamin K epoxide.Warfarin interferes with the regeneration of the re-

duced form from the epoxide. Treatment with war-farin results in the production of coagulation factorswith reduced coagulant activity. Treatment with war-farin also interferes with the addition of a secondcarboxyl group to the natural anticoagulants, proteinC and protein S. For this reason, patients may ini-tially become hypercoagulable, but ultimately, theanticoagulant effect dominates (30).

Warfarin is generally contraindicated during preg-nancy. Taken during the critical period of organogene-sis, warfarin carries up to a 30% risk of congenitalanomalies (31–37). The reported risk of miscarriageranges from 14.6% to 56% (32,34,35,38). Placentaltransfer of warfarin later in pregnancy can result infetal bleeding (37,39) or stillbirth (32,34,35,38).Long-term neurologic damage has been reportedamong children exposed in utero (40). Consequently,warfarin is rarely prescribed in pregnancy. The ex-ceptional case is the patient at high risk of mortalityfrom thrombosis who may not be sufficiently antico-agulated with either heparin or low-molecular-weightheparin (25). Candidates for warfarin in pregnancyinclude women with mechanical heart valves (25).The current recommendation for the target interna-tional normalized ratio (INR) using adjusted-dosewarfarin in these cases is 2.0 to 3.0 (25).

HEPARIN

Unfractionated heparin (UFH) is a heterogeneousmixture of polysaccharide chains ranging in molec-ular weight from 3000 to 30,000 daltons. Both UFHand low-molecular-weight-heparin (LMWH) exerttheir anticoagulant activity by activating antithrom-

TABLE 1Protocols for thromboprophylaxis in pregnancy

Bates et al, 200425 Duke Protocol

Unfractionated heparinMinidose “low dose” 5000 U subcutaneously every 12 hrs 5000 U subcutaneously every 12 hrs �8 weeksModerate-dose “low dose” Every 12 hrs to target antifactor Xa

level of 0.1–0.3 U/mL7500 U subcutaneously every 12 hrs 8–28 weeks10,000 U subcutaneously every 12 hrs �28

weeksAdjusted-dose “full dose” Every 12 hrs to target midinterval

aPTT in therapeutic rangeEvery 8 or 12 hrs to target midinterval aPTT in

therapeutic rangeLow-molecular-weight heparin

Prophylactic dose “low dose” Enoxaparin 40 mg per dayDalteparin 5000 U per dayTinzaparin 4500 U per day

Enoxaparin 40 mg per day or 30 mg 2 times perday before 28 weeks then Enoxaparin 40 mg 2times per day after 28 weeks

Weight-adjusted dose “full dose” Enoxaparin 1 mg/kg 2 times per dayor 1.5 mg/kg per day

Dalteparin 100 U/kg every 12 hrs or200 U/kg every 24 hrs

Tinzaparin 175 mg U/kg per day

Enoxaparin 1 mg/kg 2 times per day with targetantifactor Xa levelof 0.5–1.0

Anticoagulants in Pregnancy Y CME Review Article 61

TAB

LE2

Ant

icoa

gula

nts

that

have

bee

nus

edin

pre

gnan

cy

Age

ntIn

dic

atio

nR

oute

ofA

dm

inis

trat

ion

Pha

rmac

okin

etic

s†M

onito

ring

Pla

cent

alTr

ansf

erFe

talE

ffec

ts

War

farin

*M

echa

nica

lhea

rtva

lves

25O

ral

Pea

kin

90m

in30

Hal

f-lif

eof

36–

42h30

Inte

rnat

iona

lno

rmal

ized

ratio

(INR

)

Yes

Mis

carr

iage

—14

.6–5

6%32

–35,

38,1

08

Stil

lbirt

h—5–

33%

32,3

4,35

,38

Con

geni

tal

anom

alie

s—0

–30%

31–3

7

Feta

lor

neon

atal

intr

acra

nial

hem

orrh

age—

2%37

,39

Ad

vers

ene

urol

ogic

outc

ome—

14%

40

Low

IQ—

4%40

Unf

ract

iona

ted

hep

arin

*Tr

eatm

ent

orp

rop

hyla

xis25

Intr

aven

ous

orsu

b-

cuta

neou

sP

eak

in2

hd

urin

gp

regn

ancy

94

Act

ivat

edp

artia

lth

rom

bop

last

intim

e(a

PTT

)94

Non

e42–

44N

oin

crea

sein

adve

rse

feta

lou

tcom

ein

100

pre

gnan

-ci

es23

Low

-mol

ecul

ar-w

eigh

the

par

ins*

Trea

tmen

tor

pro

phy

laxi

s25

Sub

cuta

neou

sE

noxa

par

in:

pea

kin

3–4

hd

urin

gp

regn

ancy

95

Ant

ifact

orX

ale

vels

Non

e43,4

4,50

,51

No

incr

ease

inad

vers

efe

tal

outc

ome11

1

Dal

tep

arin

:p

eak

in4

hd

urin

gp

regn

ancy

109

Hal

f-lif

e4

–5h

dur

ing

pre

gnan

cy11

0

No

incr

ease

inad

vers

efe

tal

outc

ome

amon

g62

4p

reg-

nanc

ies

with

enox

apar

inex

pos

ure52

Dan

apar

oid

*H

epar

inal

lerg

y56–5

8,11

2or

HIT

54,5

6,59

–61

Sub

cuta

neou

sP

eak

bet

wee

n2–

5h

Hal

f-lif

e2.

34h53

Ant

ifact

orX

ale

vels

53

Low

pla

cent

alp

erm

eab

ility

54

No

evid

ence

ofan

tifac

tor

Xa

activ

ityin

plac

enta

lbl

ood55

No

adve

rse

feta

lout

com

ere

por

ted

inp

ublis

hed

case

rep

orts

53

Not

avai

lab

lein

the

Uni

ted

Sta

tes

Rec

omb

inan

thi

rud

in*

Hep

arin

alle

rgy62

orH

IT54

,63

Intr

aven

ous

orsu

b-

cuta

neou

sP

eak

in1–

2h

afte

rsu

bcu

tane

ous

adm

inis

trat

ion11

3

Hal

f-lif

e1–

3h

afte

rin

trav

enou

sad

min

istr

atio

n114,

115

Act

ivat

edp

artia

lth

rom

bop

last

intim

e(a

PTT

)

Low

plac

enta

ltra

nsfe

rin

dogs

64

�2%

ofm

ater

nall

evel

sde

-te

cted

inpl

asm

aof

feta

lra

bbits

55

No

adve

rse

feta

lout

com

ein

2of

2ca

ses62

,63

Fond

apar

inux

*H

epar

inal

lerg

y67,1

16

orH

IT11

6

Sub

cuta

neou

sP

eak

in2

h117

Hal

f-lif

e17

hin

heal

thy,

youn

gvo

l-un

teer

s117

Not

req

uire

d11

8N

otr

ansf

erin

invi

tro

pla

cen-

talm

odel

65,6

6

10%

ofm

ater

nall

evel

sd

e-te

cted

inum

bili

calc

ord

blo

od67

No

adve

rse

feta

lout

com

ein

5of

5ca

ses67

Low

-dos

eas

piri

n*S

upp

lem

enta

lthe

rap

yin

wom

enw

ithm

echa

ni-

calh

eart

valv

es71

orw

omen

with

the

antip

hosp

holip

idsy

ndro

me10

Ora

lP

eak

in30

–40

min

68

Hal

f-lif

eis

15–2

0m

in,

but

the

pla

tele

tin

hib

itory

effe

ctla

sts

for

the

lifes

pan

ofth

ep

late

lets

(10

day

s);

50%

ofp

late

let

func

tion

retu

rns

in5–

6d

ays68

Pla

tele

tfu

nctio

nan

alys

is11

9

Yes

No

adve

rse

feta

lout

com

ein

met

aana

lyse

sof

larg

e,ra

n-d

omiz

edtr

ials

69,1

20

(Con

tinue

s)

62 Obstetrical and Gynecological Survey

bin. The active portion of the heparin molecule is aunique five-unit long, saccharide sequence that in-duces a conformational change in antithrombin andaccelerates its interaction with activated factor X(factor Xa), resulting in the inactivation of factor Xa.Thrombin is also inactivated by heparin, but throm-bin’s inactivation requires saccharide sequences thatare 18 units long. Whereas most of the chains of UFHcontain these 18 unit-long sequences, fewer than halfof the chains of LMWH are of sufficient length.Consequently, UFH has activity against both factorXa and thrombin, whereas LMWH has relativelylittle activity against thrombin (41).

Heparins, UFH or LMWH, are the preferred agentsfor anticoagulation in pregnancy (25). The main ad-vantage of heparins over other anticoagulants is thatthere is no transplacental passage (42–44). Disadvan-tages of UFH include the necessity of parenteraladministration, a 2% risk of major bleeding (23),osteoporosis with a 17% to 36% reduction in bonedensity (45,46), a 2% risk of vertebral fracture (47),and a risk of heparin-induced thrombocytopenia(HIT) (25).

There are two types of thrombocytopenia afterheparin administration. One is a benign, self-limitingcondition, noted in 10% to 20% of patients andtypically seen 1 to 4 days after initiation of therapy.There are no thromboembolic or hemorrhagic se-quelae; the platelet count usually remains above100,000 and returns to normal despite continued ad-ministration of heparin (48). The other, HIT, whichresults from the formation of IgG antibodies againsta complex of heparin with platelet factor 4, is sus-pected when the platelet count falls below 100,000,or to 50% of the baseline level, 5 to 15 days after theinitiation of therapy (48). The antibody complexesmay bind to endothelium resulting in life- or limb-threatening thromboses (48). Although the risk of HITis low in pregnancy, and may be lower than in non-pregnant patients (49), the actual risk is unknown (25).

LOW-MOLECULAR-WEIGHT HEPARINS

LMWHs are fragments of unfractionated heparin pro-duced by an enzymatic or chemical depolymerizationprocess that yield chains with a mean molecular weightof approximately 5000 daltons. Compared with UFH,LMWHs have relatively greater activity against fac-tor Xa and are less likely to bind to plasma proteins,endothelial cells, and macrophages. This reduction inbinding increases the bioavailability, half-life, andanticoagulant activity of LMWH relative to UFH (41).TA

BLE

2(C

ontin

ued

)

Age

ntIn

dic

atio

nR

oute

ofA

dm

inis

trat

ion

Pha

rmac

okin

etic

s†M

onito

ring

Pla

cent

alTr

ansf

erFe

talE

ffec

ts

Oth

eran

tipla

tele

tag

ents

*H

isto

ryof

myo

card

ial

infa

rctio

nor

risk

fac-

tors

for

arte

rialt

hrom

-b

osis

Sup

ple

men

talt

hera

py

inw

omen

with

mec

hani

-ca

lhea

rtva

lves

Ora

lD

ipyr

idam

ole:

half-

life

of10

h68

Clo

pid

ogre

l:p

eak

in2

h;ha

lf-lif

e48

h;st

ead

yst

ate

(50

–60

%of

pla

tele

tin

hib

ition

)af

ter

4–7

day

s;68

Ticl

opid

ine:

pea

kp

late

let

inhi

biti

onaf

ter

3–4

day

s121

Ab

cixi

mab

:p

eak

with

inm

inut

es;78

half-

life

30m

inaf

ter

intr

aven

ous

inje

ctio

n68

Pla

tele

tfu

nctio

nan

alys

is12

2–12

5

No

dat

afo

rd

ipyr

idam

ole,

clop

idog

rel,

ticlo

pid

ine.

Asm

alla

mou

ntof

abci

xim

abw

asd

etec

ted

onth

efe

tal

sid

eof

anin

vitr

op

lace

n-ta

lmod

el78

No

adve

rse

feta

lout

com

ew

ithd

i-p

yrid

amol

ein

num

erou

sca

ses

No

adve

rse

feta

lout

com

ew

ithcl

o-p

idog

reli

n2

of2

case

s74,7

5

No

adve

rse

feta

lout

com

ew

ithtic

lop

idin

ein

2of

2ca

ses75

–77

No

adve

rse

feta

lout

com

ew

ithab

-ci

xim

abin

one

case

77

Thro

mb

olyt

ics*

Life

-or

limb

-thr

eate

ning

thro

mb

oem

bol

ism

Intr

aven

ous

Str

epto

kina

se:

half-

life

18–2

3m

in12

6

Alte

pla

se:

half-

life

3–8

min

126

Ret

epla

se:

half-

life

15–1

8m

in12

6

Tene

ctep

lase

:ha

lf-lif

e18

–20

min

126

Non

eN

oFe

tall

oss—

5.8%

91

Hem

orrh

age—

8.1%

91

Mat

erna

lmor

talit

y—1.

2%91

Rep

orts

ofsu

bch

orio

nic

hem

ato-

mas

,89ab

rup

tiop

lace

ntae

84

*Not

app

rove

dfo

rus

ed

urin

gp

regn

ancy

by

the

U.S

.Fe

der

alFo

odan

dD

rug

Ad

min

istr

atio

n.†D

ata

not

spec

ific

top

regn

ancy

unle

ssst

ated

.H

ITin

dic

ates

hep

arin

-ind

uced

thro

mb

ocyt

open

ia.

Anticoagulants in Pregnancy Y CME Review Article 63

There are no large comparative studies in preg-nancy, but in nonpregnant patients, LMWHs havebeen associated with fewer side effects than UFH(25). Although parenteral administration is still re-quired, potential advantages of LMWHs over unfrac-tionated heparin are less bleeding, less bone loss, amore predictable response, a lower risk of HIT, anda longer half-life (25). Like UFH, there is no trans-placental passage (43,44,50,51). The primary disad-vantages of the LMWHs are their cost and longerhalf-life. The latter may increase the risk of bleedingduring the intrapartum period.

The LMWH that has been studied the most isenoxaparin. A Medline search of LMWHs and preg-nancy revealed five articles about reviparin, nineabout tinzaparin, 14 about nadroparin, 37 aboutdalteparin, and 61 about enoxaparin. Both UFH andLMWHs are considered safe in pregnancy (23,52).

DANAPAROID

Danaparoid is a low-molecular-weight heparinoidconsisting of the glycosaminoglycans heparin sul-fate, dermatan sulfate, and chondroitin sulfate (53).Like UFH and LMWH, danaparoid catalyzes theantithrombin-mediated inactivation of factor Xa (53).It is administered intravenously and has low placen-tal permeability (54). No evidence of antifactor Xaactivity has been found in the placental blood ofwomen taking danaparoid (55). It has been consid-ered the drug of choice for cases of heparin allergy(56–58) or HIT in pregnancy (54,56,59–61). In pub-lished cases, no adverse fetal outcomes have been re-ported. Unfortunately, danaparoid is no longer availablein the United States.

RECOMBINANT HIRUDIN

Recombinant hirudin, a direct thrombin inhibitor,is the recombinant version of the medicinal leechprotein. It is administered intravenously or subcuta-neously. There are two published cases of its use inpregnancy, one for heparin allergy (62) and the otherfor HIT (63), neither with adverse fetal outcomes.Placental transfer in humans is not documented, butthere is low transfer in dogs (64) and rabbits (lessthan 2% of maternal levels) (55).

FONDAPARINUX

Fondaparinux, a selective inhibitor of factor Xa, isa pentasaccharide that mimics the active site of hep-

arin that binds to antithrombin. Fondaparinux is ad-ministered subcutaneously. In an in vitro model,there was no placental transfer (65,66), but 10% ofmaternal levels have been detected in umbilical cordblood (67). In the United States, because danaparoidis unavailable, fondaparinux may be the preferredalternative to heparins in the case of heparin allergyor HIT in pregnancy.

ASPIRIN

Aspirin is an antiplatelet drug. Platelets process pros-taglandin H2 (PGH2) to produce thromboxane, whichinduces platelet aggregation and vasoconstriction. As-pirin permanently inactivates cyclooxygenase, the en-zyme necessary for the conversion of arachidonic acidto PGH2, the first step in the process (68).

Aspirin is safe in low doses of 81 mg per day.Large, randomized trials have demonstrated no in-creased risk of miscarriage, congenital anomalies,placental abruption, fetal hemorrhage, or neonatalbleeding (69,70). Although its safety makes it anattractive choice for anticoagulation, 81 mg per dayis insufficient in most cases in which thrombopro-phylaxis is required. In women with either mechan-ical heart valves or the antiphospholipid syndrome,low-dose aspirin may be used in combination withheparins (10,71).

In one study, aspirin alone was shown to comparefavorably with aspirin plus LMWH in the treatmentof women with the antiphospholipid syndrome andno history of thrombosis. The live birth rate was 72%versus 78%, which was not a statistically significantdifference (72). Low-dose aspirin alone may be anacceptable alternative for the woman who has lupus,the lupus anticoagulant, or moderate to high levels ofanticardiolipin antibodies, but no history of throm-bosis or poor pregnancy outcome. In cases of lowlevels of anticardiolipin antibodies, because low lev-els are of questionable significance, no anticoagula-tion is required (73).

OTHER ANTIPLATELET AGENTS

Other antiplatelet agents have been used for throm-boprophylaxis in women with a history of myocardialinfarction, in women with risk factors for arterial throm-bosis and, for supplemental therapy, in women withmechanical heart valves. There are no data for placentaltransfer of dipyridamole, an agent that inhibits plateletsby increasing intraplatelet cyclic AMP, but there arenumerous cases of its use in pregnancy with no adversefetal outcomes reported. There are also no data on

64 Obstetrical and Gynecological Survey

placental transfer of clopidogrel and ticlopidine, whichselectively inhibit ADP-induced platelet aggregation,but there are two cases of the use of clopidogrel (74,75)and two cases of the use of ticlopidine (75,76) with noadverse fetal outcomes. The use of abciximab, whichblocks the platelet glycoprotein IIb/IIIa receptor thatallows platelet aggregation (68), has been reported inthe treatment of one patient with an acute myocardialinfarction during pregnancy with no adverse fetaloutcome (77). A small amount of abciximab wasfound on the fetal side of an in vitro placentalmodel (78).

THROMBOLYSIS

Thrombolysis is indicated for life- or limb-threaten-ing thromboembolism. There are recent reports of itsuse in pregnancy to treat pulmonary embolism (79–83),coronary artery thrombosis (84), massive deep veinthrombosis (81,85,86), cerebral vein thrombosis(87,88), and mechanical valve thrombosis (89,90).Thrombolytic agents such as urokinase, streptokinase,and recombinant tissue plasminogen activator do notcross the placenta (91), but can potentially jeopardizethe fetus if bleeding occurs in the retroplacental space(89) or results in maternal hypovolemia (91). The riskof fetal loss has been estimated to be 5.8% (91) and therisk of maternal mortality to be 1.2% (91).

INITIATING ANTICOAGULATION

Women on lifelong anticoagulation may be con-verted from warfarin to LMWH before pregnancy oras soon as possible after conception. The problemwith conversion before pregnancy is the inconve-nience and discomfort of the parenteral administra-tion of heparins and the risks associated with theirlong-term use. The problem with conversion afterconception is that the half-life of warfarin is 36 to 42hours (30), and it may remain in the maternal circu-lation for several days, increasing the risk of miscar-riage and congenital anomalies.

Women who are not on lifelong anticoagulation,but are candidates for thromboprophylaxis in preg-nancy, should start soon after conception. An excep-tion is women who undergo ovulation induction.Because ovulation induction has been shown to in-crease the risk of thrombosis (92), anticoagulationshould begin when ovulation induction is initiated.

The recommendations for thromboprophylaxis dur-ing pregnancy from the 7th American College of ChestPhysicians Conference on Antithrombotic and Throm-bolytic Therapy (25), as well as the protocol from

Duke University Medical Center, are included inTable 1. The Duke protocol reflects the increasingrequirements for both heparin and LMWH as preg-nancy progresses (93–96).

HEPARIN-INDUCEDTHROMBOCYTOPENIA

Because of the possibility of HIT, the platelet countshould be monitored for the first 2 weeks after start-ing heparin (97). Although platelet counts usuallydrop 10% in pregnancy (98) and thrombocytopeniaaffects up to 10% of all pregnancies (98), HIT is arare but potentially serious complication that must beconsidered in women who develop thrombocytope-nia after starting heparin. HIT is diagnosed when theplatelet count drops by 50% or more after exposureto heparin (usually within 5–10 days) and antiplateletfactor 4 antibodies are detected (99). In women inwhom HIT develops, besides immediate discontinu-ation of heparin or LMWH, the use of an alternativeanticoagulant is required.

PERIPARTUM MANAGEMENT

As a result of the longer half-life of LMWH, con-version to UFH should be considered at 36 to 37weeks gestation or sooner if an earlier delivery isanticipated (ie, multiple gestation, preterm labor,oligohydramnios, fetal growth restriction, or pre-eclampsia are present). Although epidural and spinalhematomas are rare complications of LMWH (100),if LMWH has been administered within 12 to 24hours, anesthesia personnel may be reluctant to pro-vide regional anesthesia. Conversion to the shorter-acting UFH, which clears within 5 hours afteradministration (94), provides the patient with theoption of a regional anesthetic.

Depending on the risk of thrombosis, UFH may beheld for 6 to 24 hours before anticipated delivery.Protamine sulfate, a reversing agent, is rarely necessary.

Although the use of pneumatic compression de-vices for the prevention of peripartum thrombosis hasnot been studied, extrapolation from perioperativedata (101) would suggest benefit. The devices maybe placed in labor after epidural administration orbefore cesarean delivery.

POSTPARTUM MANAGEMENT

The pneumatic compression devices should be leftin place until the patient is ambulatory and untilanticoagulation is restarted. To minimize bleeding

Anticoagulants in Pregnancy Y CME Review Article 65

complications, reinitiation of anticoagulation shouldbe postponed until 12 hours after vaginal delivery, 12hours after epidural catheter removal, or 24 hoursafter cesarean delivery. Unless a woman prefers toremain on UFH or LMWH, she may be bridged towarfarin (continued on UFH or LMWH until a ther-apeutic INR is achieved) and continued on warfarinfor 6 weeks postpartum. Women who had a throm-botic event during pregnancy should be continued onanticoagulation for at least 3 to 6 months. Women onlifelong anticoagulation should be continued on war-farin indefinitely. Although warfarin is contraindi-cated during pregnancy, it is not contraindicatedduring breast feeding. In a study of the transfer ofwarfarin into breast milk, less than 25 ng warfarinwas detected per milliliter (102). The AmericanAcademy of Pediatrics Committee on Drugs supportsbreast feeding for women who take warfarin (103).

CONTRACEPTION

Although contraindicated for the woman who willdiscontinue anticoagulation after the postpartum pe-riod, combined oral contraceptives are acceptable forthe woman who will be on lifelong anticoagulation.For the woman who will not remain on anticoagula-tion, progestin-only contraceptives are probably ac-ceptable. Although progestins may alter the levels ofvarious coagulation factors (104,105) among progestin-only contraceptive users, only a nonsignificant in-crease in the risk of venous thromboembolism hasbeen reported (106). Copper intrauterine devices mayincrease the risk of heavy menstrual bleeding, but thelevonorgestrel intrauterine system reduces menstrualblood flow (107) and may be a good contraceptivechoice for a woman on anticoagulation.

SUMMARY

Pregnancy increases the risk of thrombosis, a riskthat is compounded by the presence of thrombo-philia. Despite the increased risk of thrombosis inpregnancy, anticoagulants are not routinely indicated,because the risks usually outweigh the benefits. Theexception is women on lifelong anticoagulation or cer-tain women with a history of thrombosis or thrombo-philia. In women with thrombophilia, new evidencesuggests that anticoagulants not only decrease therisk of thrombosis, but may reduce the risk of poorpregnancy outcome. Warfarin, although used rou-tinely outside of pregnancy, is potentially harmful tothe fetus and is rarely indicated. Aspirin, in lowdoses, is used primarily as supplemental therapy.

Heparins are the anticoagulants of choice in preg-nancy. LMWH offers the advantages of fewer sideeffects and a longer half-life than UFH. The longerhalf-life, however, may preclude regional anesthesiaso conversion to the shorter-acting UFH should beconsidered in the late third trimester. Becausethe risk of thrombosis is higher immediately afterdelivery, women receiving anticoagulants duringpregnancy should be continued on them postpartum.Although relatively safe, UFH and LMWH are notwithout risks. The clinician must be aware of thepossible side effects and complications of therapy tomanage anticoagulants safely in pregnancy.

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