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OBSTETRICS
Antithrombotic therapy and pregnancy: consensus report and
recommendations for prevention and treatment of venous
thromboembolism and adverse pregnancy outcomes
Adam J. Duhl, MD; Michael J. Paidas, MD; Serdar H. Ural, MD; Ware Branch, MD; Holly Casele, MD; Joan Cox-Gill, MD;
Sheri Lynn Hamersley, MD; Thomas M. Hyers, MD; Vern Katz, MD; Randall Kuhlmann, MD, PhD;
Edith A. Nutescu, PharmD; James A. Thorp, MD; James L. Zehnder, MD;
for the Pregnancy and Thrombosis Working Group

T he incidence of pregnancy-related
venous thromboembolism (VTE) is
difficult to measure. The common
Venous thromboembolism and adverse pregnancy outcomes are potential complica-
tions of pregnancy. Numerous studies have evaluated both the risk factors for and the
symptoms and signs are nonspecific— prevention and management of these outcomes in pregnant patients. This consensus
dyspnea, tachypnea, peripheral edema, group was convened to provide concise recommendations, based on the currently
and leg pain—and are often associated available literature, regarding the use of antithrombotic therapy in pregnant patients at
with advanced, normal pregnancy, risk for venous thromboembolic events and adverse pregnancy outcomes.
sometimes making the diagnosis diffi-
cult. Even when VTE is suspected, some Key words: pregnancy, thrombophilia, venous thromboembolism
practitioners are reluctant to use diag- Cite this article as: Duhl AJ, Paidas MJ, Ural SH, et al. Antithrombotic therapy and pregnancy:
nostic tests because of fears of radiation consensus report and recommendations for prevention and treatment of venous thromboembo-
exposure to the fetus. Consequently, the lism and adverse pregnancy outcome. Am J Obstet Gynecol 2007;197:457.e1-457.e21.
occurrence of VTE is probably underes-
timated in pregnant patients. Despite
these difficulties, the incidence of VTE in leading cause of maternal death in both who experience DVT during pregnancy
pregnancy is reported to be 4- to 6-fold the United Kingdom and North Amer- are also more likely to have poor preg-
higher than in age-matched nonpreg- ica, with death from PE occurring in 2 in nancy outcomes. Furthermore, the risk
nant women,1,2 and pulmonary embo- 100,000 deliveries in the United King- of VTE extends to the postpartum pe-
lism (PE) remains a frequent cause of dom4 and representing 11% of maternal riod, with 50% of VTE cases occurring
maternal mortality.2,3 Indeed, VTE is the deaths in the United States.5 Women postpartum.6
After a firm diagnosis of VTE has been
From the Department of Obstetrics and Gynecology, Mercy Hospital of Pittsburgh, made in the pregnant patient, the per-
Pittsburgh, PA (Dr Duhl); the Department of Obstetrics and Gynecology, Yale University ceived complications of antithrombotic
School of Medicine, New Haven, CT (Dr Paidas); the Department of Obstetrics and therapy sometimes delay or inhibit its im-
Gynecology, Penn State University, Hershey, PA (Dr Ural); the Department of Obstetrics plementation. A pregnant patient’s risk of
and Gynecology, University of Utah, Salt Lake City, UT (Dr Branch); the Department of having VTE develop is difficult to estimate
Obstetrics and Gynecology, San Diego Perinatal Center, San Diego, CA (Dr Casele); the and is dependent on numerous factors,
Comprehensive Center for Bleeding Disorders, Medical College of Wisconsin, Milwaukee,
some not readily identifiable by clinical
WI (Drs Cox-Gill and Kuhlmann); the Department of Obstetrics and Gynecology, Shady
Grove Adventist Hospital, Potomac, MD (Dr Hamersley); the Department of Pulmonary history or examination. As a result, identi-
Services, CARE Clinical Research, St Louis, MO (Dr Hyers); the Department of Obstetrics fying the patient who would benefit from
and Gynecology, Center for Genetic and Maternal-Fetal Medicine, Eugene, OR (Dr Katz); prophylaxis is difficult. A number of pub-
the Antithrombosis Services, University of Illinois College of Pharmacy, Chicago, IL (Ms lications have addressed these problems,
Nutescu); the Department of Obstetrics and Gynecology, Sacred Heart Women’s Hospital, and some guidelines for prevention and
Pensacola, FL (Dr Thorp); and the Department of Hematology/Clinical Oncology, Stanford treatment of VTE have been issued.7-10
University Medical Center, Stanford, CA (Dr Zehnder). However, these guidelines are incomplete
Received Dec. 6, 2006; revised March 23, 2007; accepted April 1, 2007. and are not always evidence based. The
Reprints not available from the authors. major reason for this deficiency is the rela-
Funding for the meetings and editorial assistance for the manuscript were provided by Aventis tive paucity of well-designed, properly
Pharmaceuticals, a member of the Sanofi-Aventis group. The working group, however, powered, randomized controlled trials in
maintained full and independent responsibility for content of the consensus document.
prevention and treatment of thromboem-
0002-9378/$32.00
bolism associated with pregnancy.
© 2007 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2007.04.022 To define current consensus on these is-
sues an expert meeting was organized by

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TABLE 1
Grading of evidence according to the US Preventive Services Task Force11
Grade of evidence
I Evidence obtained from at least 1 properly designed randomized controlled trial.
................................................................................................................................................................................................................................................................................................................................................................................
II-1 Evidence obtained from well-designed controlled trials without randomization.
................................................................................................................................................................................................................................................................................................................................................................................
II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center
or research group.
................................................................................................................................................................................................................................................................................................................................................................................
II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled
experiments also could be regarded as this type of evidence.
................................................................................................................................................................................................................................................................................................................................................................................
III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
................................................................................................................................................................................................................................................................................................................................................................................
Recommendation
................................................................................................................................................................................................................................................................................................................................................................................
A Recommendation is based on good and consistent scientific evidence.
................................................................................................................................................................................................................................................................................................................................................................................
B Recommendation is based on limited or inconsistent scientific evidence.
................................................................................................................................................................................................................................................................................................................................................................................
C Recommendation is based primarily on consensus and expert opinion.

Aventis Pharmaceuticals, a member of the P HARMACOLOGIC is minimally secreted into the breast milk
Sanofi-Aventis group. In subgroups, 6 top- M ANAGEMENT OF VTE IN and is therefore considered safe to use in
ics were discussed, including identification P REGNANCY breastfeeding mothers.7,16 Treatment
of the problem, risk assessment, options of Management of thrombosis in preg- guidelines recommend postpartum anti-
prevention and counseling for VTE, op- nancy remains a challenge. The antico- coagulation with warfarin for 4-6 weeks
tions of prevention and counseling for agulant drugs currently available for the with a target international normalized
poor obstetric history, practical manage- prevention and treatment of VTE in- ratio (INR) of 2.0-3.0 (with overlap with
ment of anticoagulation and pregnancy, clude warfarin, unfractionated heparin UFH or LMWH until the INR ⱖ2.0).7
and anticoagulation in labor, postpartum (UFH), low-molecular-weight heparins UFH has a short half-life and must be
and beyond. A round-table discussion of (LMWHs), factor-Xa inhibitors, and di- administered subcutaneously or via con-
all topics by all participants followed, from rect thrombin inhibitors. tinuous infusion.17 The current treat-
which an original outline resulted. Based Warfarin, a coumarin derivative, in- ment guidelines recommend subcutane-
on the outline, this report was drafted, re- teracts with many other medications. ous dosing of UFH every 12 hours; either
fined, and agreed on after multiple review as a low dose of 5000 U, to achieve target
Because of the physiologic changes asso-
rounds after the meeting was held. The anti-Xa between 0.1 and 0.3 U/mL
ciated with pregnancy as well as nausea
working group maintained full and inde- (moderate dosing), or to achieve target
and vomiting, it is difficult to attain sta-
pendent responsibility for content of the midinterval aPTT into the therapeutic
ble anticoagulation with this drug. Use of
consensus document. range (adjusted dosing).7 It requires fre-
the drug during the first trimester has
This report provides a concise update quent laboratory monitoring and dosage
been associated with spontaneous abor-
for practitioners in maternal and fetal adjustment. Although UFH can be re-
health. Recommendations for the use of tion and warfarin embryopathy, consist- versed by protamine sulfate, its use is
antithrombotic drugs in pregnancy are ing of mental retardation, optic atrophy, complicated by the potential for bleed-
given throughout the report. Recommen- microphthalmia, cataracts, ventral mid- ing complications (probably due to its
dation grades A to C and evidence levels I line dysplasia, nasal hypoplasia, stippled effect on factor IIa resulting in inhibition
to III are based on the US Preventive Ser- bones and epiphyses, and central ner- of prothrombin activity and an anticoag-
vices Task Force grading of evidence (Ta- vous system (CNS) abnormalities in ap- ulant effect). Although heparin-induced
ble 1).11 In brief, grade A recommenda- proximately 4-5% of exposed fetuses. thrombocytopenia (HIT) is infrequently
tions and level I evidence come from Frequencies of abnormalities up to 29% reported in pregnancy, it remains a con-
randomized controlled trials with clear re- have been reported in patients requir- cern, as up to 5% of individuals treated
sults; grade B recommendations and level ing warfarin for mechanical heart with standard heparin develop this com-
II evidence come from well-designed non- valves.12-14 Moreover, warfarin can plication, which is associated with a high
randomized studies with limited or incon- cause CNS abnormalities after exposure thrombosis risk. Long-term use of UFH
sistent evidence; and level III evidence and at any stage during pregnancy. Warfarin has been reported to cause osteoporosis,
grade C recommendations result from readily crosses the placenta and results in which is a concern in patients who re-
consensus opinions of respected experts fetal anticoagulation that is not readily quire treatment throughout their preg-
and authorities based on clinical experi- reversible, resulting in an increased risk nancy.17 UFH is classified by the Food
ence and descriptive studies. of intracranial hemorrhage.15 Warfarin and Drug Administration (FDA) as a

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pregnancy category C drug. It does not other comparator regimens containing who require anticoagulation for mater-
cross the placenta and is considered safe UFH (intravenous [IV] UFH followed nal indications, and those who require
for the fetus when used during preg- by LMWH, IV UFH, followed by subcu- anticoagulation for the prevention of ad-
nancy. UFH is not secreted in breast milk taneous [SC] UFH and SC UFH). The verse pregnancy outcomes (APOs).
and can be used by nursing mothers.7 lower incidence of adverse events re- Pregnant women may have more than 1
LMWHs are administered subcutane- sulted in lower overall treatment costs indication for anticoagulation since the
ously either once or twice daily for the for the LMWH regimen.29 underlying medical illness may predis-
prevention or treatment of VTE. They Factor-Xa inhibitors are a relatively new pose to APOs that may be amenable to
have considerable theoretical benefits class of anticoagulants. Fondaparinux be- anticoagulant therapy.
over UFH, including better bioavailabil- came the first drug in this class to gain FDA
ity,18,19 longer plasma half-life (or higher approval for the prevention of VTE in ma-
anti-factor-Xa activity),20 more predict- jor orthopedic surgery and for the treat- Maternal thromboembolism
able pharmacokinetics and pharmaco- ment of acute VTE. Fondaparinux is la- 1.1 History of VTE. The risk of VTE in
dynamics,21 less potential to cause osteo- beled as a pregnancy category B drug. pregnancy ranges from 0.05% to 1.8%,
porosis,22 and lower incidence of HIT.23 Animal reproduction studies have demon- with a rate of recurrent VTE of 1.4-
LMWHs inhibit factor Xa more effec- strated no harm to the fetus or to fertility, 11.1%.46-48 Levels of coagulation activa-
tively than factor IIa to produce their an- although fondaparinux was found to be se- tion markers such as prothrombin frag-
tithrombotic effect.24 Many data are creted in breast milk in these studies.30 No ment 1.2 (PF1.2) and thrombin-
available supporting the use of LMWH adequate clinical data exist on the use of antithrombin complex (TAT) increase
over UFH for the treatment of acute VTE fondaparinux in pregnant women.30 with the progression of pregnancy to lev-
in nonpregnant patients,25 and monitor- Several direct thrombin inhibitors are els seen in patients with active thrombo-
ing anticoagulation intensity or dosage approved for clinical use in the United sis.49 Therefore, women in the later
adjustments are generally unnecessary States. Lepirudin, bivalirudin, and argatro- stages of pregnancy often require an in-
with LMWH in these populations. How- ban are labeled by the FDA as pregnancy crease in the dose of UFH to maintain
ever, pregnant patients can present an category B drugs.31-33 Animal studies have therapeutic levels of anticoagulation.50
exception to this rule because the phar- demonstrated no evidence of impaired fer- Brill-Edwards et al46 addressed the
macokinetics of LMWHs can change tility or harm to the fetus. However, animal safety of withholding heparin treatment
during pregnancy.7 The increased renal studies have shown that lepirudin can in 125 pregnant women with a history of
clearance and changes in maternal cross the placenta31 and argatroban has VTE occurring more than 3 months be-
weight over the course of pregnancy may been detected in breast milk.32 It is not fore the current pregnancy. An antepar-
necessitate higher and more frequent known, definitively, whether these drugs tum recurrence of VTE occurred in 2.4%
dosing than in the nonpregnant individ- are secreted in human breast milk. Cur- of these patients. No recurrences oc-
ual. LMWHs are cleared from the body rently there are no adequate clinical data curred in the 44 women without evi-
partially via a nonsaturable (renal) route on the use of direct thrombin inhibitors in dence of thrombophilia or with a tempo-
of elimination.26 Pregnancy is character- pregnant women. rary risk factor associated with the
ized by initial increase in glomerular previous episode, whereas 5.9% of 51 pa-
filtration rate with a subsequent decre- tients with thrombophilia or an idio-
ment at term. Protamine only reverses
R ISK A SSESSMENT pathic VTE had an antepartum recur-
The hemostasis changes in pregnancy
the anti-IIa activity of LMWH com- rence. A subsequent study by Pabinger et
that tend to create a prothrombotic mi-
pletely, whereas the anti-Xa activity is al51 also found that the risk of symptom-
lieu have been well documented.34-42
not fully neutralized (maximum reversal atic VTE recurrence was 3-fold higher
Pregnancy is associated with a 20-200%
⬃60%).26 LMWHs are classified by the during pregnancy, but that temporary
increase in levels of fibrinogen and fac-
FDA as a pregnancy category B drug. risk factors (such as trauma, surgery or
tors II, VII, VIII, X, and XII.43 Decreases
They do not cross the placenta and are immobilization) at the first event did not
occur in both the natural anticoagula-
safe for the fetus.7,27 LMWHs are not se- differentiate clearly between women at
tion system, such as decreases in protein
creted in breast milk and can therefore high risk or low risk of a pregnancy-as-
S levels,41 and in the fibrinolytic process,
be safely used by nursing mothers.7 The sociated VTE recurrence. These data
evidenced by increases in plasminogen-
safety profile of LMWHs has been fur- suggest that not all pregnant women
activator inhibitor 1 (PAI-1) and 2 (PAI-
ther confirmed in a recent systematic re- with a previous VTE need be treated with
2)44 and thrombin-activatable fibrinoly-
view encompassing 64 reports on 2777 prophylactic anticoagulants. They also
sis inhibitor (TAFI) levels.45
patients.28 Furthermore, a recent study indicate that the presence of thrombo-
confirmed that consistent administra- philia or previous idiopathic VTE is a
tion of LMWH during both the acute I DENTIFICATION OF P ATIENTS risk factor for VTE.
and long-term therapy for VTE during AT R ISK OF VTE 1.2 Inherited thrombophilic condi-
pregnancy was associated with lower Potential candidates for anticoagulation tions. Inherited thrombophilias are a
rates of adverse events compared with 3 in pregnancy can be classified as patients heterogeneous group of disorders in-

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TABLE 2
Thrombophilia and thromboembolism1
VT/VTE in pregnancy or
Inherited thrombophilia General incidence VT or VTE puerperium
AT deficiency (most thrombogenic) 0.02-0.17% 50% life chance of VTE 50% chance VTE in
1% in patients with VTE pregnancy
................................................................................................................................................................................................................................................................................................................................................................................
APCR or factor V Leiden* 3-7% of white women Incidence of 20-30% with VTE APCR found in 78% with VTE
Factor V Leiden in 46% with
VTE (predictive value
1:500)
................................................................................................................................................................................................................................................................................................................................................................................

Protein S or C deficiency 0.14-0.5% Found in 3.2% with VTE Protein S 0-6%
Protein C 3-10%
Postpartum:
Protein S 7-22%
Protein C 7-19%
................................................................................................................................................................................................................................................................................................................................................................................
Factor V Leiden and PGM G20210A Predictive value 4.6:100
Prevalence in VTE 9.3% vs 0
in control group
................................................................................................................................................................................................................................................................................................................................................................................
Hyperhomocysteinemia/homozygous MTHFR 8-10% of healthy population Increased risk NA
(C677T/A1298C)
................................................................................................................................................................................................................................................................................................................................................................................
APCR, activated protein C resistance; NA, not available; PGM, prothrombin gene mutation; VT, venous thrombosis.
* Includes causes other than factor V Leiden for resistance to APC.

Protein S levels decrease in pregnancy to below normal standard reference range.

cluding deficiencies of protein S, protein Other inherited thrombophilic muta- TAFI.45 There is a high incidence of in-
C, and antithrombin (AT). In 1994, an tions, including methylene tetrahydro- sulin-resistance syndrome (also known
association between a mutation in the folate reductase (MTHFR) C677T and as metabolic syndrome or syndrome X)
factor V gene and increased thrombotic A1298C (often associated with hyperho- in obese patients. A core feature of this
risk was first reported.52 This mutation is mocysteinemia) and PAI gene mutations syndrome is elevated plasma levels of
present in 5% of American white, 1% of 4G/4G, 4G/5G, and 5G/5G, have been PAI-1,71 the primary inhibitor of both
African American, and 5-9% of Euro- weakly associated with pregnancy com- tissue-type plasminogen activator
pean populations, but is rare in Asian plications.59-61 The MTHFR mutations (t-PA) and urokinase-type plasminogen
and African populations.53,54 The factor have been associated with neural tube activator (u-PA), which limits the fi-
V mutation is associated with resistance defects, and other malformations. brinolytic process.70 Low-dose aspirin
to activated protein C (APC) and is in- Data from several studies suggest that reduces plasma levels of PAI-1 in preg-
herited primarily in an autosomal-dom- abnormalities in the natural anticoagu- nant patients.72
inant fashion.54,55 Heterozygosity is lation system, such as AT deficiency, Data from several studies indicate
found in 20-40% of nonpregnant pa- APC resistance, and protein S or C defi- adverse outcomes associated with obe-
tients with thromboembolic disease, ciency, induce varying degrees of in- sity in pregnant women.73,74 The com-
whereas homozygosity confers a more creased risk for thrombosis in pregnancy bination of pregnancy and obesity
than 100-fold increased risk of thrombo- and the puerperium (Table 2).1,57,62-65 would logically be considered a com-
embolic disease.54 More recently, the Although heterozygous factor V Leiden pounded hypercoagulable and pro-
prothrombin gene mutation (pro- and prothrombin G20210A have lower thrombotic state. Sebire et al73 studied
thrombin G20210A) has been found to hazard ratios for thrombosis, they are by 287,213 singleton pregnancies. Com-
increase circulating prothrombin lev- far the most commonly noted mutations pared with women with normal body
els48 and hence the risk of both throm- associated with thrombosis and adverse mass index (BMI 20-24.9 kg/m2),
bosis50 and pregnancy complications.56 outcomes in pregnancy.49,66-68 obese women (BMI ⬎ 25 kg/m2) were
In women with a history of VTE during 1.3 Obesity. Obesity has been associ- significantly more likely to develop
pregnancy, prothrombin G20210A was ated with higher risk of atherothrom- gestational diabetes mellitus and pro-
found in 17% of patients compared with botic disease and VTE in the general teinuric preeclampsia, to have induced
1% of age-matched controls.57 Homozy- medical population.69 Multiple aspects labor, to undergo emergency cesarean
gosity for prothrombin G20210A is of obesity aggravate the prothrombotic delivery, and to experience postpartum
thought to confer an equivalent risk of risk in pregnancy. The fibrinolytic pro- hemorrhage, genital tract infection,
VTE to that of factor V Leiden cess is decreased, as manifest by in- urinary infection, wound infection,
homozygosity.58 creased levels of PAI-1, PAI-2,70 and birth weight greater than the 90th per-

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TABLE 3
Clinical risk factors for VTE (ORs with CIs)
Lindqvist et al37 Danilenko-Dixon et al77 Anderson and Spencer78
(N ⴝ 603) (N ⴝ 90) (N ⴝ 1231)
Moderate-risk factors
.......................................................................................................................................................................................................................................................................................................................................................................
Age ⱖ 35 y 1.3 (1-1.7) 2.0 (age ⬎ 40 y)
.......................................................................................................................................................................................................................................................................................................................................................................
Parity
..............................................................................................................................................................................................................................................................................................................................................................
2 1.5 (1.1-1.9) 1.1 (0.9-1.4)
..............................................................................................................................................................................................................................................................................................................................................................
ⱖ3 2.4 (1.8-3.1)
.......................................................................................................................................................................................................................................................................................................................................................................
Smoking 1.4 (1.1-1.9) 2.5 (1.3-4.7)
.......................................................................................................................................................................................................................................................................................................................................................................
Multiple gestation 1.8 (1.1-3.0) 7 (0.4-135.5)
.......................................................................................................................................................................................................................................................................................................................................................................
Preeclampsia 2.9 (2.1-3.9) 1 (0.14-7.1)
.......................................................................................................................................................................................................................................................................................................................................................................
Varicose veins 2.4 (1.04-5.4) 4.5
.......................................................................................................................................................................................................................................................................................................................................................................
Obesity 1.5 (0.7-3.2) ⬍2
.......................................................................................................................................................................................................................................................................................................................................................................
Cesarean section 3.6 (3.0-4.3)
.......................................................................................................................................................................................................................................................................................................................................................................
Obstetric hemorrhage 9 (1.1-71.0)
................................................................................................................................................................................................................................................................................................................................................................................
High-risk factors
.......................................................................................................................................................................................................................................................................................................................................................................
Spinal cord injury ⬎ 10
.......................................................................................................................................................................................................................................................................................................................................................................
Major abdominal surgery ⱖ 30 min ⬎ 10

centile, and intrauterine death. This 2. Moderate risk: Patients undergo- prolonged immobilization, which is
population of patients may benefit ing a minor procedure with general known to be a risk factor for VTE in
from screening for common thrombo- anesthesia for more than 30 min- the absence of pregnancy. Therefore,
philic mutations such as factor V Lei- utes and are 40-60 years old or have prolonged bed rest under these con-
den, prothrombin G20210A, MTHFR additional risk factors. Patients ditions may also place pregnant
C677T/A1298C, as well as functional younger than 40 years with no ad- women at a higher risk of VTE. Fur-
protein S and C, and AT deficiency, al- ditional risk factors and undergo- thermore, other moderate risk factors
though few data currently exist as to ing major surgery. should also be considered including
the benefit of screening in obese pa- 3. High risk: Patients older than 40 age older than 35 years, smoking, mul-
tients. Further studies are necessary to years or with additional risk factors tiple gestation, and preeclampsia, as
determine whether this population undergoing major surgery. Pa- outlined in Table 3.37,77,78
should be screened. The risk-benefit tients undergoing minor surgery 2. Adverse pregnancy outcomes.
ratio of prescribing heparin or low- who are older than 60 years or have After excluding congenital birth defects
dose aspirin to high-risk obese patients additional risk factors. and idiopathic preterm delivery, severe
who have not had a VTE requires fur- preeclampsia at 36 weeks or less, intra-
ther investigation. 1.5 Family history. As many throm- uterine growth retardation (IUGR), fetal
1.4. Surgery. Pregnancy adds an ad- bophilic states are inherited, patients loss at 20 weeks’ gestation or more, and
ditional hypercoagulable state to the with a family history of VTE may be at abruption account for three-quarters of
thrombotic risks associated with surgery. increased risk for VTE. The risk is further all cases of fetal mortality and/or mor-
In general the risk of fatal PE is 0.2-0.9% increased in the presence of thrombo- bidity, with a prevalence of approxi-
in patients undergoing elective sur- philic conditions. Specifically, the risk is mately 8% (Table 4).79
gery.75 Risk factors include advanced increased approximately 8-fold for AT Numerous studies examining the as-
age, a history of VTE, obesity, heart fail- deficiency, 7-fold for protein C defi- sociation between inherited thrombo-
ure, paralysis, or thrombophilia.75 Surgi- ciency, and doubled for factor V Leiden philias and adverse reproductive out-
cal risk has been classified into the fol- mutation.76 comes have been performed. However,
lowing 3 categories:75 1.6. Other risk factors. Bed rest is of- there are no clear conclusions to be
ten recommended to pregnant women drawn from these studies, as some show
1. Low risk: Patients under the age of with threatened preterm labor, pre- a positive relationship between throm-
40 years, no additional risk factors, eclampsia, and/or signs of uteroplacental bophilias and adverse outcomes,
and undergoing minor procedure. insufficiency. However, this involves whereas others show no association.

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TABLE 4
Prevalence and risk of recurrence of APO without thrombophilia
Previous pregnancy Prevalence of pregnancy Pregnancy complication in Fetal death with pregnancy
complication complication (%) subsequent pregnancy (%) complication (%)
Fetal loss after or at 20 wks 0.5 8.5 8.5
................................................................................................................................................................................................................................................................................................................................................................................
Severe preeclampsia 2 26 13.5
................................................................................................................................................................................................................................................................................................................................................................................
HELLP 1 4 13.5
................................................................................................................................................................................................................................................................................................................................................................................
Eclampsia 0.5 3 13.5
................................................................................................................................................................................................................................................................................................................................................................................
Abruption 0.8 5 26
................................................................................................................................................................................................................................................................................................................................................................................
IUGR ⱕ 5th percentile 5.3 16 20
................................................................................................................................................................................................................................................................................................................................................................................
One or more 8 61-85 —
................................................................................................................................................................................................................................................................................................................................................................................
Reprinted from Paidas et al79 with permission from Elsevier.

Some of the most widely quoted studies noted between IUGR and prothrombin There is more evidence suggesting that
demonstrating a positive association are G20210A (OR 5.7, 95% CI, 1.2-27) and loss of the conceptus in the fetal period
flawed by the small number of patients or protein S deficiency (OR 10.2, 95% CI, (loss of the fetus documented to have been
the use of composite outcomes.56,80 Sys- 1.1-91).82 alive at or beyond 10 weeks’ gestation) is
tematic reviews have evaluated the associ- It is difficult to determine the rela- associated with thrombophilias,100,102-104
ation between factor V Leiden or the pro- tionship between thrombophilias and though negative studies also exist.105 Most
thrombin gene mutation G20210A and abruptio placentae. This is due to the case-control and cohort studies suggest a
IUGR.81-83 Both mutations confer an in- presence of confounding variables, such 2- to 4-fold increase in the rate of throm-
creased risk of giving birth to a growth-re- as chronic hypertension,96,97 and be- bophilias among women with a history of
stricted infant (factor V Leiden: odds ratio cause it is often observed in the setting of fetal death, especially in those with more
[OR] 2.7, 95% CI 1.3-5.5; prothrombin other APOs, such as preeclampsia, than 1 episode.100,102,106-108 In contrast,
G20210A mutation: OR 2.5, 95% CI 1.3- IUGR, and fetal death. For example, 29% many studies of the general obstetric pop-
5.5), but the association may be driven by of patients with abruption had a protein ulation have found a weaker association
small studies of poor quality that demon- S deficiency compared with 0.2-2% in between thrombophilia and recurrent
strated extreme associations.81 the general population.97 Systematic re- pregnancy loss.109-111 Uteroplacental
Several studies, most of which were views do suggest an association between thrombosis is a common feature in preg-
case controlled, have examined the rela- factor V Leiden and abruptio placentae, nancies with unexplained late fetal loss102
tion between heterozygous factor V Lei- but this is based on few studies with con- and could theoretically be reduced by hep-
den and severe preeclampsia.56,80,83-93 founding factors and low numbers of arin thromboprophylaxis, which may help
Factor V Leiden was identified in be- patients.82,83 to prevent a recurrence by decreasing vas-
tween 5% and 26% of patients with se- Studies of the possible relationship cular injury and thrombin generation and
vere preeclampsia, eclampsia, or HELLP between thrombophilia and pregnancy further reducing thrombosis in the utero-
syndrome (hemolysis, elevated liver en- loss are plagued by differences in the def- placental circulation.
zymes, low platelets).56,84-87,93-95 In a initions used for miscarriage and fetal Protein Z levels at the 20th percentile
systematic review of 18 preeclampsia death, the methods used to select pa- (1.30 ␮g/mL) are also associated with an
studies,82 a positive association between tients, and the lack of appropriate, eth- increased risk of APO (OR 4.25, 95% CI
factor V Leiden and preeclampsia or nicity-matched controls. Most research 1.54-11.76, sensitivity 93%, specificity
eclampsia (OR 1.6, 95% CI, 1.2-2.1) was suggests that thrombophilias (AT defi- 32%).112 In the same group of patients,
found. ciency, protein C or S deficiency, factor V protein S levels were significantly lower in
In the largest study published to date Leiden, prothrombin G20210A, and the the second and third trimesters in patients
involving women whose infants had most common MTHFR mutation) are with APO compared with patients with
IUGR (defined as ⬍ 10th percentile), the not associated with loss of the conceptus normal pregnancy outcome (34.4 ⫾
prevalence of factor V Leiden was 4.5% or recurrent miscarriage before 10 11.8% vs 38.9 ⫾ 10.3% and 27.5 ⫾ 8.4% vs
and of prothrombin G20210A was weeks’ gestation (preembryonic or em- 31.2 ⫾ 7.4%, respectively, for the second
2.5%.59 Prevalence rates ranging from bryonic losses).98,99 At the same time, and third trimesters; P ⬍ .05 for both),
5% to 35% for factor V Leiden, 2.5% to other investigators have reported that suggesting that decreased protein S and Z
15% for prothrombin G20210A, and 1% untreated women with recurrent mis- levels are additional risk factors for APO.
to 23% for protein S deficiency have also carriage and factor V Leiden have partic- To further clarify the prothrombotic ele-
been reported. In a systematic review of 3 ularly poor subsequent pregnancy ments involved, Laude et al113 studied
studies, significant associations were outcomes.100,101 women with a history of recurrent preg-

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FIGURE
Figure risk assessment and prevention of VTE and APOs in pregnant patients
Thrombophilia screening for patients with:
a history of VTE; history of unexplained fetal loss
Risk assessment ≥ 20 weeks, severe preeclampsia/HELLP, severe
IUGR, or family history of thrombosis

Low risk Moderate risk High risk Highest risk


• Transient risk factors • History of APO: severe • History of idiopathic VTE • History of antiphospholipid
• Family history of VTE preeclampsia, IUGR < 5th outside of pregnancy without antibody syndrome
• History of APO: severe percentile, fetal loss at ≥ 20 identifiable risk factors • Active arterial and/or venous
preeclampsia, IUGR < 5th weeks • History of VTE with thromboembolism
percentile, fetal loss at ≥ 20 • History of VTE with transient thrombophilia (factor V Leiden, • Known antithrombin deficiency
weeks risk factors including prothrombin G20210A, • Homozygotes or compound
pregnancy functional protein C/S heterozygotes for factor V Leiden
• Thrombophilia with family deficiency or antithrombin) or prothrombin mutations
history of VTE • History of antiphospholipid
antibody syndrome (criteria
met by recurrent pregnancy
Prevention of VTE loss only) Prevention of VTE/APO
• Possible intrapartum • Therapeutic anticoagulation
antithrombotic compression mandatory during pregnancy and for
Prevention of VTE
boots ≥ 6 weeks during postpartum
• Postpartum enoxaparin 40 • Enoxaparin 1 mg/kg BID or dalteparin
mg SC QD, 30 mg BID* or 200 U/kg QD
dalteparin 5,000 U SC QD Prevention of VTE/APO ‡
• Weekly peak and trough monitoring of
Prevention of APO • Antepartum enoxaparin 40 mg anti-Xa levels, adjusting dose to keep
• Antepartum enoxaparin 40 SC QD, 30 mg BID* or peak anti-Xa at 0.8−1.0 IU/mL and
mg SC QD or dalteparin dalteparin 5,000 U SC QD trough anti-Xa at ≥ 0.5 IU/mL†
5,000 U SC QD May require BID dosing • Postpartum anticoagulation: target
• Assessing anti-Xa levels each INR 2.5-3.5 for 4-6 weeks with initial
trimester is an option overlap of UFH or LMWH until INR
• Postpartum treatment in ≥ 2.5
patients with a history of VTE

Monitoring guidelines for patients treated with LMWH or UFH


1. Anti-factor Xa assay: target peak range (3-4 hours after dosing) is 0.2-0.4 IU/mL for prophylaxis and 0.5-1.0 for treatment (upper range for treatment 0.8-1.0 IU/mL).
Target trough range (12 hours after dosing) 0.1-0.3 IU/mL for prophylaxis and 0.2-0.4 IU/mL (> 0.5 IU/mL if highest risk) for treatment.
2. Heparin-induced thrombocytopenia: check platelet counts at start of treatment with heparin, then weekly for 3 weeks.
3. During in-hospital treatment for VTE, fetal surveillance is recommended.
Treatment recommendations based on empiric evidence from the consensus panel

*The choice of enoxaparin dose should be tailored according to the individual patient as these doses have not been compared in this setting.

The dose of enoxaparin may be increased to maintain peak level at the top end of the desired range.

Aspirin and heparin are recommended in patients with antiphospholipid antibodies.
Duhl. Antithrombotic therapy and pregnancy. AJOG 2007.

nancy loss or late fetal demise (⬎ 10th tive use, trauma, obesity, cancer, or under- or a family history of thrombosis. Evidence
week) and their levels of circulating proco- lying medical conditions, may benefit in favor of this practice is limited but accu-
agulant thrombin-generating micropar- from being screened for thrombophilia mulating at present. The prospective ran-
ticles. Of the patients, 59% in the early (Figure). Screening patients with a first domized trial by Gris et al114 firmly sug-
pregnancy-loss group (⬍ 10 weeks) and VTE for thrombophilias is currently the gests a potential treatment benefit in
48% in the late fetal-demise group had in- subject of considerable study and debate. screening women with otherwise unex-
creased levels of microparticles. The Though encouraged by some clinicians, plained fetal death for factor V Leiden,
women were not pregnant at the time of routine testing for thrombophilias may be prothrombin G20210A, and functional
the assessment and these findings would of limited clinical value. In contrast, pa- protein S deficiency.
indicate an ongoing preexisting pro- tients presenting with recurrent thrombo- The basic tests for thrombophilia
thrombotic state that may be further en- sis or with thrombosis in the setting of a screening include functional protein C,
hanced during pregnancy. strong family history of VTE may be can- functional protein S, antithrombin III
didates for thrombophilia testing. (AT-III) (functional assay), APC resis-
S CREENING FOR Some obstetricians have recommended tance (or factor V Leiden [polymerase
T HROMBOPHILIA thrombophilia screening in women with chain reaction]), and prothrombin
Patients with a history of thrombosis, unexplained fetal loss at 20 weeks’ gesta- G20210A [polymerase chain reaction]).
whether it is of idiopathic origin or associ- tion or longer, severe preeclampsia or Other screening for acquired thrombo-
ated with pregnancy, with oral contracep- HELLP, severe IUGR (⬍ 5th percentile), philic conditions can include testing for

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TABLE 5
Heparin administration to prevent APO
Author N Drug Patients studied Outcome
Riyazi et al133 26 Nadroparin ⫹ ASA 80 mg Thrombophilia plus prior preeclampsia or Treatment associated with lower rates of
IUGR preeclampsia/IUGR compared with
historical control
................................................................................................................................................................................................................................................................................................................................................................................
134
Brenner et al 50 Enoxaparin Thrombophilia plus recurrent fetal loss Treatment associated with higher live birth
rate compared with historical control
(75% vs 20%)
................................................................................................................................................................................................................................................................................................................................................................................
135
Ogueh et al 24 UFH Thrombophilia plus IUGR or abruption No improvement compared with historical
control.
................................................................................................................................................................................................................................................................................................................................................................................
Kupferminc et al 136
33 Enoxaparin ⫹ ASA 100 Thrombophilia plus preeclampsia or IUGR Higher birth weight and gestational age at
mg delivery compared with previous
untreated complicated pregnancies.
................................................................................................................................................................................................................................................................................................................................................................................
137
Grandone et al 25 UFH or enoxaparin Thrombophilia plus APO/ Treatment was associated with lower rates
of APO in treated (10%) vs nontreated
(93%) patients.
................................................................................................................................................................................................................................................................................................................................................................................
138
Brenner 183 Enoxaparin Thrombophilia plus recurrent fetal loss Treatment was associated with increased
rate of live birth, and decreased rate of
preeclampsia and abruption compared
with historical control.
................................................................................................................................................................................................................................................................................................................................................................................
Paidas et al 139
41 Enoxaparin, dalteparin, or Thrombophilia plus APO ⬃80% risk reduction in APO compared
UFH with untreated pregnancies.
................................................................................................................................................................................................................................................................................................................................................................................
114
Gris et al 160 Enoxaparin or aspirin Thrombophilia plus unexplained fetal loss Enoxaparin was associated with higher live
birth rates (86%) compared with aspirin
(29%).

anticardiolipin antibodies immuno- tion or longer, severe preeclampsia/ Typically, patients at highest risk are
globulin G (IgG) and IgM, and lupus an- HELLP at less than 34 weeks’ gestation, on coumarin before pregnancy and ide-
ticoagulant. However, not all of these an- severe IUGR, or a family history of ally should be converted to LMWH be-
tibodies need to be drawn. A platelet thrombosis may benefit from thrombo- fore conception or as soon as the patient
count can be used to screen for throm- philia screening.114 The basic screening presents for care. Previous guidelines
bocytosis and related disorders. Further tests include factor V Leiden mutation, have recommended that target peak an-
supplemental screening may consist of prothrombin G20210A mutation, func- ti-Xa levels (measured 4 hours after a
homocysteine, other factor V mutations, tional protein C and S deficiencies, AT- subcutaneous dose) should be 1.0-1.2
thrombomodulin gene variants, protein III deficiency, lupus anticoagulant, ho- IU/mL.5 Therapeutic anticoagulation
Z levels, PAI-1 activity levels, PAI-1 mocysteine level, and anticardiolipin should be considered in high-risk
4G/5G polymorphisms, MTHFR, ho- antibodies.79 (Level IIIC) women during pregnancy but using pro-
mocysteine PAI-1 polymorphisms, and phylactic dosing and less frequent mon-
factor evaluation (VII, VIII, IX, XI). itoring than in the highest-risk group.
Currently, the costs of routine thrombo- R ISK A SSESSMENT AND The prophylactic and therapeutic doses
philia screening for all patients are prohib- A NTITHROMBOTIC for the most commonly used LMWHs
itive. Clearly, more evidence-based data R ECOMMENDATIONS D URING are illustrated in Table 5.24 Because of the
from prospective randomized trials evalu- P REGNANCY altered pharmacokinetics of heparin me-
ating the use of anticoagulation for the pre- Patients can be classified according to tabolism in pregnancy,18,115-117 dosage
vention of APOs are needed before these their risk for VTE, their risk of an APO, adjustment may be necessary to achieve
costs can be justified. or both. Antithrombotic recommenda- desired adequate peak or trough anti-Xa
tions are based on an assessment of an levels and thus monitoring for therapeu-
C ONSENSUS P ANEL individual patient’s level of risk, and are tic anticoagulation is suggested. Dosing
R ECOMMENDATIONS outlined in the Figure. It should be em- adjustment is also needed to achieve ad-
FOR T HROMBOPHILIA phasized that the risk categories and equate levels in obese patients. If UFH is
S CREENING treatment regimens are based on level II used for therapeutic anticoagulation,
● Patients with a history of thrombosis, and III studies and/or extrapolated from higher doses and 3 times daily dosing are
unexplained fetal loss at 20 weeks’ gesta- level I nonpregnant studies. usually required to maintain adequate

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TABLE 6
Prophylactic and therapeutic doses for the most commonly used LMWHs
Proprietary name, Anti-factor-Xa/IIa Prophylactic dosage Therapeutic dosage
LMWH manufacturer activity for VTE for VTE
Enoxaparin sodium Lovenox, Sanofi-Aventis 2.7/1 40 mg (4000 IU) QD 1 mg (100 IU)/kg BID
................................................................................................................................................................................................................................................................................................................................................................................
Dalteparin sodium Fragmin, Pfizer Corporation 2.1/1 2500-5000 IU QD or 2500 IU BID 100 IU/kg BID
................................................................................................................................................................................................................................................................................................................................................................................
Nadroparin calcium Fraxiparin, GlaxoSmithKline 3.2/1 3075 IU QD 170 IU/kg QD or BID
................................................................................................................................................................................................................................................................................................................................................................................
Tinzaparin sodium Innohep, LEO Pharma 1.9/1 2500-4500 IU QD 175 IU/kg QD
................................................................................................................................................................................................................................................................................................................................................................................
Ardeparin sodium Normiflo, Wyeth-Ayerst 2.0/1 100 IU/kg per day BID NA
................................................................................................................................................................................................................................................................................................................................................................................
Reviparin sodium Clivarin, Knoll AG 3.5/1 1432-3436 IU antifactor Xa QD 142 IU/kg BID
................................................................................................................................................................................................................................................................................................................................................................................
NA, data not available.
Adapted from Laurent et al24 with permission from Wolters Kluwer Health.

anticoagulation peak levels to rise the ac- available in clinical laboratories. Most lab- such as cesarean delivery, bed rest, or the
tivated partial thromboplastin time oratories that offer this test have it set up postpartem period, creates a very differ-
(aPTT) to 2-2.5 times normal.118 for 1 of the LMWHs (eg, enoxaparin, ent approach to thromboprophylaxis
Women at moderate risk may be offered which has a recommended therapeutic compared with the nonpregnant state.
prophylactic doses of LMWH (Figure), range of 0.5-1.0 anti-Xa units/mL and a Dosages and monitoring guidelines for
with 2500-5000 IU dalteparin twice daily prophylactic range of 0.2-0.4 IU/mL). As nonpregnant women cannot be extrapo-
(BID), 40 mg enoxaparin once daily (QD), the various LMWHs have different factor lated accurately to pregnant women. All
or 30 mg enoxaparin BID. Although the Xa/IIa activity (Table 5),24 the test must be protocols and regimens of thrombopro-
relative efficacy of these 2 enoxaparin calibrated for the drug in question. For ex- phylaxis in pregnancy entail extensive
doses has not been studied, and the use of ample, a factor Xa assay set up for enox- patient and clinician interaction. Modi-
40 mg enoxaparin QD is common prac- aparin should not be used interchangeably fications during pregnancy are common,
tice, members of the consensus panel have for another LMWH or anti-Xa drug, as it and treatment plans need to be individ-
divided opinions for the choice of dose, may give erroneous readings. ualized with informed consent between
based on the pharmacokinetic properties patients and their physicians.
of LMWH in pregnancy.7 Until studies P REVENTION AND C OUNSELING
comparing the 2 regimens are published, FOR VTE
clinicians should choose the most appro- Current recommendations for throm- H OW TO M ANAGE P ATIENTS
priate regimen for their patient and her boprophylaxis during pregnancy are W ITHOUT P RIOR VTE OR
clinical situation. Some investigators aim based largely on case series and extrapo- T HROMBOPHILIA
to achieve peak anti-Xa levels (3-4 hours lation from studies of nonpregnant pa- Thromboprophylaxis in pregnancy is ac-
after dosing) ranging from 0.2-0.4 IU/mL tients. Because of the incidence of recur- complished primarily with self-adminis-
but, in general, monitoring is not necessary rent VTE being low, studies need to be tered subcutaneous UFH or LMWH.
for these patients. Women at low risk may extremely large to obtain sufficient However, because thromboprophylaxis
not need antepartum prophylaxis, but power to demonstrate the efficacy of any carries a risk of bleeding, HIT, and osteo-
some authors recommend postpartum strategy and thus far, such a randomized porosis when given for prolonged peri-
prophylaxis ranging from 3 days to 6 prospective trial in pregnancy has not ods, its use may only be justified or cost
weeks, particularly in obese women and been done. In the nonobstetric litera- effective in selected pregnant women.
women with cesarean birth.24,43 ture, thromboprophylaxis is prescribed Nevertheless, pregnant women with 1
to protect patients during short periods high-risk factor or multiple (⬎ 3) mod-
M ONITORING OF P ATIENTS ON covering specific vulnerable events such erate-risk factors for VTE (Table
LMWH OR F ACTOR -X A as orthopedic surgery. In pregnancy, 3)37,77,78 are considered for thrombo-
I NHIBITORS thromboprophylaxis is given for pro- prophylaxis in the United Kingdom119
Where monitoring is indicated, an anti-Xa longed periods because pregnancy and (Table 6),119 although more data are re-
assay must be used because the aPTT is in- the puerperium is a hypercoagulable quired before this approach can be ac-
sensitive to LMWHs and Xa inhibi- state lasting approximately 308 days cepted in the United States. The Confi-
tors.26,29 Most commonly, anti-Xa-activ- from conception until 6 weeks after de- dential Enquiries into Maternal Deaths
ity assays involve setting up a standard livery. Maintaining a constant level of in the United Kingdom revealed that,
curve using the drug in question and mea- anticoagulation, with changing renal when maternal death occurred due to
suring drug activity using a chromogenic clearance, increasing weight, and super- VTE, 1 or more of these risk factors was
substrate, but this test is not routinely imposed periods of even higher risk, present in 80% of the women.120

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1. Thromboprophylaxis during ce- ion of the Working Group mechanical with UFH or LMWH administered ante-
sarean delivery. Thromboprophylaxis thromboprophylaxis may be considered natally and during the 6 weeks postpar-
during cesarean delivery is not widely and perhaps recommended in patients tum may be an appropriate option for
used in the United States. Expert pan- with multiple risk factors. some patients. Patients should also be
els8,75 have published recommendations encouraged to regain mobility after
for thromboprophylaxis in pregnancy C ONSENSUS P ANEL childbirth, but in individuals in whom
but they do not specifically address ce- R ECOMMENDATIONS FOR this is not possible, compression stock-
sarean delivery. In 1995, the Royal Col- M ANAGING P ATIENTS W ITHOUT ings could be worn.
lege of Obstetricians and Gynaecologists P RIOR VTE OR 3. How to manage patients with a his-
(RCOG) published recommendations T HROMBOPHILIA tory of 2 or more VTEs. Few data are
for thromboprophylaxis during cesarean available to suggest that, if a person has
delivery (Table 6),119 but only one fifth ● Thromboprophylaxis use in all preg- had 2 or more episodes of idiopathic
of physicians in the United Kingdom nant patients without prior VTE or VTE, she will be at increased risk of VTE
were found to be following them. As a thrombophilia may only be justified or during pregnancy. Theoretically, this
consequence, the RCOG now recom- cost effective in selected pregnant pa- group of patients may have an even
mends that all women undergoing cesar- tients.121 (Level IIIC) higher risk of VTE compared with pa-
ean delivery should receive heparin ● There are insufficient data to recom- tients with no history and so may already
thromboprophylaxis.120 mend routine pharmacologic prophy- receive lifelong anticoagulation. If not,
Currently, only 4 prospective random- laxis in patients undergoing cesarean then antenatal and postpartum prophy-
ized trials of thromboprophylaxis during delivery.121 (Level II-2B) lactic anticoagulation with UFH or
cesarean delivery have been published, and ● Intermittent pneumatic compression LMWH124,125 and patient counseling
none are of adequate size to determine may be considered in patients under- should be mandatory in these patients.
whether thromboprophylaxis for routine going cesarean delivery with multiple However, the patient must be informed
cesarean delivery is warranted.121 Simi- VTE risk factors.123 (Level IIIC) of the limited amount of data available to
larly, the effectiveness of nonpharmaco- support the use of anticoagulants in this
logic mechanisms of thromboprophylaxis, H OW TO M ANAGE P ATIENTS setting.
such as venous compression stockings and W ITH A H ISTORY OF VTE 4. How to manage patients with prior
pneumatic compression boots, have not 1. Provoked VTE or temporary risk fac- VTE and thrombophilia. Most experts
been studied in pregnant patients. Al- tors. It is unclear whether women with a agree that the management of pregnant
though there are compelling data from history of provoked VTE or temporary women with prior VTE and an acquired
both meta-analyses and several placebo- risk factors, such as a bone fracture or a or inherited thrombophilia requires
controlled, double-blind randomized tri- prolonged period of immobility, are at some sort of thromboprophylaxis in the
als demonstrating that there is no signifi- increased risk of VTE during pregnancy. antepartum and postpartum peri-
cant increase in major bleeding from They may be at lower risk than women ods.43,126-128 Although not prospectively
thromboprophylactic regimens of UFH or with a history of idiopathic VTE but at evaluated in a clinical trial, the intensity
LMWHs, there is a significant increase in higher risk than patients with no history of thromboprophylaxis should reflect
minor bleeding (66%) and impaired sur- of any VTE.52 However, as a conse- the relative risk conferred by having that
gical hemostasis observed with these quence of this theoretical increased risk thrombophilia. Most authors recom-
drugs.122 Not only is there a lack of data over the general obstetric population, it mend full anticoagulation using aspirin
regarding the efficacy of thromboprophy- is reasonable to counsel the patient ac- and heparin in women with a prior VTE
laxis in pregnancy and the potential for cordingly. At present, the need for either and antiphospholipid syndrome. In
increased morbidity, but concern about antepartum or postpartum thrombo- women with low-risk thrombophilias,
increased costs associated with thrombo- prophylaxis is unsettled, and clinicians such as hyperhomocysteinemia or factor
prophylaxis during cesarean delivery also are forced to manage cases on an individ- V Leiden/prothrombin G202010A het-
contributes to the lack of prophylaxis. ual basis. erozygosity, prophylactic doses of UFH
Until a prospective randomized trial of ad- 2. Idiopathic VTE. Few data are avail- or LMWH are probably sufficient. In
equate sample size is conducted that ad- able on the management of pregnant pregnant women with high-risk throm-
dresses this question, routine pharmaco- women who have a history of idiopathic bophilias, such as AT-III deficiency, ho-
logic thromboprophylaxis during cesarean VTE prior to the current pregnancy. mozygotes for either factor V Leiden or
delivery with UFH or LMWH cannot be These patients are likely to be at higher the G20210A mutation, or compound
recommended. However, such a trial is risk of VTE compared with individuals heterozygotes for factor V Leiden and
unlikely given the low VTE incidence rates without a history.46 One of the difficul- prothrombin G20210A mutations, ad-
and cost concerns. Because intermittent ties faced by physicians in counseling justed-dose UFH or LMWH to achieve a
pneumatic compression may be as effec- such patients lies in weighing the risks of target aPTT (2-2.5 control) or anti-Xa
tive as UFH or LMWH, and does not in- treatment with the risk of developing a level (0.5-1.0) should be recommended.
troduce risk to the patient,123 in the opin- thrombus. Prophylactic anticoagulation These relative risks and the recom-

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mended intensity of prophylaxis are


summarized in Table 7.56,129,130 TABLE 7
Relative risk of recurrent VTE in pregnancy56,129,130
C ONSENSUS P ANEL Disorder Risk of VTE Prophylaxis intensity
R ECOMMENDATIONS FOR Factor V Leiden heterozygote 3- to 9-fold Low-dose prophylaxis
..............................................................................................................................................................................................................................................
M ANAGING P ATIENTS W ITH Factor V Leiden homozygote 49- to 80-fold Adjusted-dose therapy
..............................................................................................................................................................................................................................................
P RIOR VTE Prothrombin G20210A heterozygote 2- to 9-fold Low-dose prophylaxis
..............................................................................................................................................................................................................................................
● In patients with a history of idiopathic Prothrombin G20210A homozygote 16-fold Adjusted-dose therapy
..............................................................................................................................................................................................................................................
VTE, prophylaxis with LMWH or Antithrombin III deficiency 25- to 50-fold Adjusted-dose therapy
UFH may be considered antepartum ..............................................................................................................................................................................................................................................
Protein C deficiency 3- to 15-fold Low-dose prophylaxis
and for 6 weeks postpartum.46 (Level ..............................................................................................................................................................................................................................................

IIIC) Protein S deficiency 2-fold Low-dose prophylaxis


..............................................................................................................................................................................................................................................
● In patients with a history of 2 or more Hyperhomocysteinemia 2.5- to 4-fold Low-dose prophylaxis
..............................................................................................................................................................................................................................................
VTE episodes, antenatal and postpar- Antiphospholipid antibodies 5.3-fold Adjusted-dose therapy
tum prophylaxis with LMWH and ..............................................................................................................................................................................................................................................
Compound heterozygote of Factor V Leiden 150-fold Adjusted-dose therapy
UFH should be used.124,125 (Level and Prothrombin G20210A
IIIC)
● Patients with a history of VTE and
thrombophilia should receive prophy-
laxis with LMWH or UFH. Prophy- history, asymptomatic pregnant patients C ONSENSUS P ANEL
laxis intensity should be tailored to the with AT-III deficiency or those who are R ECOMMENDATIONS FOR
risk conferred by the thrombo- homozygotes or compound heterozy- M ANAGING P ATIENTS W ITH N O
philia (Table 756,129,130).43,126-128 gotes for the factor V Leiden or pro- P RIOR VTE OR APO B UT W ITH
(Level II-3C) thrombin G20210A mutations are at T HROMBOPHILIA
● Patients with a history of VTE on pre- very high risk for maternal thromboem-
gestational full anticoagulation should bolic disorders and require UFH or ● There is insufficient evidence to rec-
be maintained on full anticoagulation LMWH throughout pregnancy.43 With ommend anticoagulant drug treat-
during pregnancy. (Level IIIC) the exception of the above, there does ment during pregnancy in asymptom-
not appear to be any justification for an- atic women with no prior VTE or
H OW TO M ANAGE P ATIENTS tenatal treatment with UFH or LMWH APO. Some such patients will have ad-
W ITH N O P RIOR VTE OR in asymptomatic patients incidentally ditional risk factors that may lead the
A DVERSE P REGNANCY found to have an inherited thrombo- clinician to treat.132 (Level IIIC)
O UTCOMES B UT W ITH philia and no history of prior VTE or ● Asymptomatic women with AT defi-
T HROMBOPHILIA characteristic adverse pregnancy out- ciency or who are homozygotes or
Retrospective data have been used to comes.7,43,124 Short-term thrombopro- compound heterozygotes for the fac-
suggest that previously asymptomatic phylaxis with UFH or LMWH might be
tor V Leiden and prothrombin
women with an inherited thrombophilia considered in pregnant women with
G20210A mutations require thera-
are at increased risk of VTE and a poten- thrombophilia and no history of VTE or
peutic UFH or LMWH throughout
tially poor obstetric outcome.131 How- adverse pregnancy outcomes when other
pregnancy.43 Asymptomatic patients
ever, the only prospective study involv- risk factors are also present, such as mul-
incidentally found to have other in-
ing previously asymptomatic women tiple family members with VTE or med-
herited thrombophilia and no prior
who tested positive for factor V Leiden ical complications known to be associ-
ated with VTE. VTE or APO do not require UFH or
revealed no higher rates of VTE, pre-
Current guidelines are based on rec- LMWH.5,43,124 (Level II-2B)
eclampsia, or fetal death in comparison
ommendations by the American College ● For patients being treated with LMWH,
with those women who tested negative
for this mutation.132 Also, it is likely that of Chest Physicians (ACCP) and are if an antifactor-Xa level is evaluated, the
the level of risk varies according to the grade 1C (equivalent to level II-2 in these target peak range (drawn 3-4 hours after
type of thrombophilia and the presence guidelines), derived mainly from obser- subcutaneous administration) is 0.2-0.4
or absence of other risk factors, such as vational studies that are likely to be re- IU/mL in prophylactic settings and 0.5-
immobilization, obesity, or smoking. To vised in the future as well-controlled ob- 1.0 IU/mL in the therapeutic setting.
avoid overtreatment, risk-assessment stetric studies become available.7 Table Trough levels (12 hours after dosing)
categories (Figure) are used to identify 756,129,130 and the Figure illustrate risk should be between 0.1-0.3 IU/mL in a
patients who warrant either prophylactic categories for patients with a thrombo- prophylactic setting and 0.2-0.4 IU/mL
or therapeutic treatment with antico- philia and the recommended treatments in a therapeutic setting.24,124,124,130
agulants. Regardless of their antecedent and dosages.56,129,130 (Level II-2B)

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● Platelet counts should be drawn for all ications, as estrogen decreases levels of tients, only 1 case of HIT was
patients using heparin therapy.130 homocysteine. reported.27,143
(Level IIIC) There are limited data available in- Paradoxically, more than half of the
● One possible regimen is drawing be- vestigating the use of anticoagulation patients with asymptomatic HIT expe-
fore initiation of heparin therapy and in women with a history of APOs, with rience a thrombotic event in the fol-
every week for 3 weeks.130 the existing studies comprising small lowing 30 days.142 Patients should
● Fitted compression stockings, cal- numbers of patients, various indica- therefore be treated with an alternative
cium, and vitamin D supplementation tions and dosages of heparin therapy, anticoagulant such as the synthetic
may be of benefit.43 (Level IIIC) and including other medications (Ta- pentasaccharide fondaparinux, which
ble 8114,133-139). Hence, we are cur- selectively inhibits Factor Xa. If the pa-
rently unable to draw adequate conclu- tient has no evidence of active throm-
H OW TO M ANAGE P REGNANT sions about the efficacy and safety of
W OMEN W ITHOUT bosis, prophylactic fondaparinux so-
LMWH in these patients, although dium (2.5 mg QD) is recommended,
T HROMBOPHILIA OR VTE B UT most authorities will offer LMWH
W ITH O THER R ISK F ACTORS whereas those with an active thrombo-
therapy to women with thrombophilia sis should be given therapeutic levels of
Pregnant women who have received ovu-
and multiple pregnancy losses. In the drug (5 mg for body weight ⬍ 50
lation-induction drugs to achieve preg-
2003, a Cochrane review found that kg, 7.5 mg for body weight 50-100 kg or
nancy have supraphysiologic levels of es-
there were no completed trials to de- 10 mg for body weight ⬎ 100 kg).30
trogen throughout the first and early
termine the effects of heparin on preg- Fondaparinux does not cross the pla-
second trimester and are possibly at higher
nancy outcomes for women with centa and is considered a class B
risk of VTE. Other factors associated with
thrombophilia.140 In a more recent medication but is not FDA approved
VTE include ovarian hyperstimulation
Cochrane review evaluating the use of
syndrome, hyperemesis gravidarum, de- for use in pregnancy.30,144 Postpartum,
anticoagulation for the treatment of
hydration, prolonged bed rest, nephrotic fondaparinux should be used for the
recurrent pregnancy loss (⬎ 2 spontane-
syndrome, and surgery. Temporary use of first several days until warfarin therapy
ous losses or 1 intrauterine fetal demise)
intermittent compression devices, and/or has raised the INR to 1.5-2.0.
in women without antiphospholipid
UFH or LMWH prophylaxis might be Some women can develop a severe al-
syndrome but including inherited
considered, especially in the presence of lergic reaction to heparin, which can ini-
thrombophilias, only 2 randomized
obesity, surgery, or prolonged bed rest. tially present with large red plaques but
studies were identified, and they con-
Later in pregnancy, women placed on pro- can progress to areas of massive skin ne-
cluded that the evidence for using aspirin
longed bed rest for premature labor, espe- crosis. In gravid women with a severe
or heparin in this setting is too limited to
cially if obese, may be at heightened risk for heparin allergy, heparin should be dis-
make recommendations.141
VTE, and prophylactic measures should be continued and alternative therapy be-
considered. There are currently no data on gun, in a similar manner to women who
the use of prophylactic heparin in this have HIT develop.145,146 Alternatively,
population.
P RACTICAL M ANAGEMENT OF
A NTICOAGULATION AND many experts believe a mild local allergy
P REGNANCY : HIT AND can be managed without immediate
H OW TO M ANAGE P ATIENTS H EPARIN A LLERGY discontinuation.
W ITH A P OOR O BSTETRIC HIT may affect up to 3% of patients ex- In these cases, consulting a hematolo-
H ISTORY posed to heparin.23 Type I thrombocyto- gist is essential for the patients’ overall
Counseling for women with a poor ob- penia occurs within a few days of heparin care.
stetric history is based on the type of exposure, is self-limited, and benign.
thrombophilia identified. Type II is an autoimmune, immuno-
Ultimately, the risks and benefits of globulin-mediated syndrome associated C ONSENSUS P ANEL
treatment should be discussed with the with venous and arterial thrombosis and R ECOMMENDATIONS FOR THE
patient so that she can make an in- may occur from 5 days to 3 weeks after E VALUATION OF HIT
formed decision. Patients with a his- starting treatment. Because type I is ini-
tory of thrombophilia, whether inher- tially difficult to differentiate from type ● Platelet counts should be checked at
ited or acquired, should be counseled II, any drop in platelet count below the start of treatment with UFH, then
regarding the inherent risks associated 150,000, or drop of 50% from baseline, weekly for the next 3 weeks.130 (Level
with estrogen therapy (ie, with oral should signal the clinician to stop hepa- II-3A)
contraceptives or hormone replace- rin therapy. Importantly, this includes ● Any patient who shows a decrease in
ment therapy and selective estrogen re- heparin flushes of iv lines. Fortunately, platelets (⬍ 100,000) should have treat-
ceptor modulator-class medications). HIT is extremely rare in pregnancy142 ment discontinued.7 (Level II-3A)
Women with mild hyperhomocys- and very rare in patients treated with ● Consulting a hematologist is essential
teinemia may use estrogen-based med- LMWH. In fact, in more than 1100 pa- for the patients’ overall care. (Level IIIC)

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P RACTICAL M ANAGEMENT OF birth is planned, obstetric problems may clearance and plasma volume during
A NTICOAGULATION AND unexpectedly necessitate early delivery. pregnancy. Some panel members believe
P REGNANCY : T HROMBOLYTICS that in pregnant women with a large
There are no conclusive data to direct the VTE, a starting dose of 1.2 mg/kg enox-
D IAGNOSIS OF VTE
use of either thrombolysis or surgical aparin BID is necessary to achieve thera-
The suspicion of VTE based on clinical
embolectomy for the treatment of mas- peutic anti-Xa levels. The choice of
history and physical examination should
sive thromboembolism in pregnant and enoxaparin regimen should therefore be
be established by diagnostic studies in-
nonpregnant patients. Anecdotal experi- tailored to each patient’s clinical situa-
cluding at least 1 of the following: Dopp-
ence and several published cases suggest tion. There is considerable evidence that
ler ultrasound, venography, lung
that the use of thrombolytic drugs dur- pregnancy may require higher doses to
ventilation/perfusion scanning, spiral
ing pregnancy may be safe and effective achieve similar anti-Xa levels compared
computed tomography, pulmonary
and might be considered when at risk of with nonpregnant women.115,117 If
venography, and magnetic resonance
maternal death or chronic venous insuf- readily available, initial therapy should
angiography. A highly confident diagno-
ficiency, especially in the first or early include a peak anti-Xa level that is drawn
sis of VTE during pregnancy should be
second trimester of pregnancy. Dissolu- 3-4 hours postinjection after the third
established because both diagnosis and
tion of massive and/or life-threatening dose.117,166,167 Trough levels approxi-
treatment have significant immediate
thromboembolism during pregnancy mately 1 hour or less before the subse-
and remote ramifications; empiric ther-
has been reported.147-162 The use of quent dose should be kept at or above 0.4
apy with a questionable diagnosis is
thrombolytic drugs during pregnancy is IU/mL.
highly discouraged. Patients with a con-
investigational with very limited safety The use of temporary venocaval filters
firmed diagnosis of VTE are usually hos-
data. The reports demonstrate the po- should be considered in pregnant pa-
pitalized for initiation of treatment. If
tients when the thrombus is extensive
tential for nearly immediate resolution there is any evidence of, or significant
(extending into the upper femoral, illeal,
of massive blood clots using either place- risk for, cardiopulmonary compromise,
or vena caval system) or the patient is at
ment of a catheter within the clot allow- admission to a critical care unit should
particularly high risk for PE, such as
ing a local pulsed spray of a thrombolytic be considered. Fetal surveillance, includ-
those who have failed previous treat-
drug or with systemic therapy. Catheter- ing ultrasound and/or fetal heart rate
ment or women with a history of PE.
directed thrombolysis is a promising in- monitoring, if appropriate, should be
Graduated compression stockings can be
vestigational technique that could be obtained daily.
used, and patients should be encouraged
considered during pregnancy in severe
to ambulate as soon as possible after
cases when the acute or chronic risk of
M ANAGEMENT OF VTE starting treatment. Acute therapy should
thromboembolism outweighs the po-
Before implementing anticoagulation continue in the hospital for 3-7 days de-
tential risk of pregnancy loss.
therapy, a thrombophilia panel should pending on the extent of VTE and the
be obtained including factor V Leiden patient’s clinical status. Calcium and vi-
mutation, prothrombin G20210A muta- tamin D supplementation should be
T REATMENT OF VTE IN tion, protein C and S deficiencies, AT-III started and continued for the duration of
P REGNANCY deficiency, lupus anticoagulant, homo- treatment with LMWH or UFH. Patients
The management of therapeutic antico- cysteine level, and anticardiolipin anti- may also need a stool softener to avoid
agulation during pregnancy must be un- bodies. LMWH therapy may be initiated constipation. Patients should be in-
dertaken with extraordinary care and an immediately or after 5-10 days of treat- structed on self-injection and home use
in-depth understanding of maternal and ment with UFH. The largest volume of of LMWH. Subcutaneous injection ports
fetal physiology and the effects of the clinical experience with LMWH in preg- are available for patients who have a sig-
therapy on both mother and fetus. Ther- nancy is with enoxaparin and daltepa- nificant fear of self-injection, although it
apeutic considerations in pregnant rin.24,125,143,163-165 At least 1 small ran- is not known how or if they affect the
women are quite different from non- domized, controlled trial (level I data) in absorption of LMWH. These ports
pregnant patients. More importantly, pregnancy concluded that treatment should be changed weekly.
knowledge of the effects of treatment on with LMWH was safe and effective, and
the fetus before, during, and after birth is was associated with fewer bleeding com-
critical. It is also important that care pro- plications than UFH.165 M ONITORING P ATIENTS
viders are intimately familiar with com- Minimum starting therapeutic doses With the initial hospital therapy, peak
mon obstetric problems, including pre- of LMWH in pregnancy should be: anti-Xa levels should be kept well within
mature labor or rupture of membranes, enoxaparin 1 mg/kg sc BID or dalteparin the therapeutic range for the hospital’s
diabetes, and preeclampsia. It is not in- 100 IU/kg sc BID. As the patient is hos- laboratory. The lower therapeutic range
tuitive to nonobstetric care providers pitalized with a documented VTE, for anti-Xa level is 0.5-0.6 IU/mL and the
that time of birth is often unpredictable. slightly higher starting doses may be ini- upper limit is 0.8-1.0 IU/mL (Figure).
Even if an elective induction or cesarean tiated because of the enhanced renal For particularly high-risk patients or for

NOVEMBER 2007 American Journal of Obstetrics & Gynecology 457.e13


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those with a large and significant throm- nancy will be managed by a “team” This has also been demonstrated in a re-
bosis and/or embolus in pregnancy, approach. This team includes the obste- cent prospectively studied cohort of pa-
trough levels (drawn 12 hours after the trician, hematologist, pulmonologist, tients receiving enoxaparin at prophy-
dose) might be considered in the initial anesthesiologist, and cardiologist as re- lactic and full anticoagulation doses.175
treatment to achieve 24 hours of contin- quired. The patient should also be coun- Patients with a recent history of VTE
uous therapeutic anti-Xa levels (usually seled that vaginal delivery is preferable to who have been managed with UFH or
⬎ 0.5 IU/mL for highest-risk patients, cesarean delivery, with cesarean delivery LMWH at full anticoagulation may be
depending on the laboratory). Reaching reserved for the usual maternal and fetal managed during labor as defined above
a therapeutic trough level may require indications. Patients on full anticoagula- or switched to prophylactic dosing of
increasing the dose so that peak anti-Xa tion with warfarin are generally transi- LMWH during the labor and delivery
levels exceed the upper therapeutic limit, tioned to either LMWH or UFH at 32-36 process.7,169 However, the anesthetic op-
or increasing the frequency of adminis- weeks’ gestation at full anticoagulation.7 tions are limited. In a cesarean delivery,
tration to 3 times daily. Peak anti-Xa lev- Before delivery or induction, it has been endotracheal intubation with central in-
els in the range of 1.0-2.0 IU/mL have recommended that IV UFH, due to a duction of anesthesia is indicated if de-
been reported without bleeding compli- shorter half-life, be implemented to livery takes place within 12 hours of tak-
cations in nonpregnant patients,168 and achieve an aPTT level 1.5-2.0 times the ing a prophylactic dose of LMWH.
anecdotal experience suggests that they patient’s baseline or to attain a heparin Patients who have had a deep vein
are well tolerated in pregnancy. Moni- level of 3-7 U/mL.7,169 Treatment with thrombosis within the last 3 months and
toring of anti-Xa levels in pregnant UFH is stopped during labor169,170 and is are fully anticoagulated with UFH or
women with acute VTE would be espe- discontinued 3-6 hours before elective LMWH can be switched to prophylactic
cially important in patients with im- cesarean delivery.170 Both of these ap- LMWH or UFH at 36 weeks’ gestation.
paired renal or hepatic function, ex- proaches enable the patient to have an- Treatment with LMWH or UFH can be
tremes of weight (⬍ 50 kg or ⬎ 100 kg) esthetic and delivery options. The Amer- withheld during labor.24,169,172 Patients
or in the presence of other risk factors for ican Society of Anesthesiologists (ASA) who receive prophylactic doses of UFH
bleeding, such as thrombocytopenia, re- allows for the use of regional analgesia/ or LMWH can stop treatment 12-24
cent surgery, or severe preeclampsia. anesthesia 12 hours after a prophylactic hours before induction or elective cesar-
Monitoring for HIT should be carried dose and 24 hours after a therapeutic ean delivery.169,176 Patients receiving full
out in all patients after starting treatment dose of LMWH. There are considerable anticoagulation with LMWH should
with UFH or LMWH (Figure). Fecal oc- benefits for continuing prophylactic or have the LMWH withheld for 24 hours
cult-blood tests should be performed pe- therapeutic LMWH up until onset of la- before induction of labor or cesarean
riodically for patients on therapeutic bor and/or rupture of membranes. If the delivery.7
doses of these drugs. After discharge patient labors before the ASA time lim-
from hospital, therapeutic LMWH its, then aggressive use of an IV narcotic
should be continued throughout preg- provides safe and satisfactory analgesia, S PECIAL C ONSIDERATIONS
nancy and the postpartum.7,24 and general anesthesia may be used for During labor and delivery, including
cesarean delivery if necessary. Another cesarean delivery, pneumatic compres-
C ONSENSUS P ANEL alternative is to schedule induction of la- sion devices for the lower extremities
R ECOMMENDATIONS FOR bor with discontinuation of the LMWH have been recommended. Stronger evi-
T REATMENT OF VTE to achieve the ASA guidelines. However, dence supporting their use using data
it should be emphasized that induction from the nonpregnant surgical popula-
● Treatment should be initiated immedi- of labor in a patient with an unfavorable tion has been extrapolated to cesarean
ately on diagnosis of VTE with either cervix may increase the risk of cesarean deliveries.119
LMWH or UFH for 5-10 days, followed delivery, which should be avoided if at all Antithrombin (AT) is normally present
by LMWH.7,12-28,30-33 (Level II-1A) possible because of the risk of VTE or in human plasma at 12.5 mg/dL and is the
● LMWH may be preferable to UFH in major hemorrhage.171 Full anticoagula- major inhibitor of thrombin, in addition
these patients.18-24 (Level IB) tion with LMWH can be maintained to inhibiting other activated clotting fac-
during the labor and delivery process tors such as XII, IX, XI, and X. Patients
A NTICOAGULATION IN with the appropriately counseled patient who are AT-deficient are thought to be
P ATIENTS D URING L ABOR and with the correct clinical indications highly “hypercoagulable” individuals dur-
AND D ELIVERY , AND (ie, recent VTE, mitral stenosis with ing the antepartum, intrapartum, and
THE P OSTPARTUM atrial fibrillation).169,172 Data from sev- postpartum periods.7,130,177-181 These pa-
Patients receiving full anticoagulation eral small studies have demonstrated no tients should receive AT concentrate in ad-
with UFH, LMWH, or warfarin should increased risk of major bleeding with dition to adjusted-dose anticoagulation if
be counseled about the risks and benefits surgical procedures, operative vaginal they experience an acute arterial or
of anticoagulation, both maternal and delivery, and cesarean delivery in pa- VTE.130,180,182,183 Recovery may vary, and
fetal, and understand that their preg- tients treated with LMWHs.27,170-174 in addition to baseline levels, an AT level

457.e14 American Journal of Obstetrics & Gynecology NOVEMBER 2007


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should be measured 20-30 minutes after doses for loading and maintenance, as quired in AT-deficient patients, patients
infusion of the first dose of AT-III.178 It is well as dosing intervals, should be indi- with a history of arterial thrombosis,
generally recommended that, after the ini- vidualized for each patient, their clinical patients with 2 or more episodes of VTE,
tial dose of AT-III, AT levels be evaluated condition, response to therapy, and the and in women with antiphospholipid
every 12 hours after administration and AT-III level.177 syndrome.7,185 If full anticoagulation
before the next dose of AT-III to maintain with LMWH is desired (ie, for patients
levels greater than 80%.177,184 After some with homozygous prothrombin
surgical procedures, hemorrhages, acute P OSTPARTUM M ANAGEMENT G20210A), treatment with LMWH is
arterial, or venous thrombosis, and during Patients who require full anticoagulation generally continued for 6-8 weeks post-
IV heparin administration, the half-life of during the antenatal period will gener- partum and then stopped.7,8,169 Warfa-
AT-III has been reported to be short- ally require full anticoagulation during rin may also be used in this scenario.7,169
ened.177 During these scenarios the AT lev- the postpartum period. Patients treated When LMWH is given once daily, the
els should be monitored more frequently previously with warfarin can be given first peak antifactor-Xa level is obtained
and replacement be administered as neces- this drug after delivery because it is safe 3-4 hours after the third dose.7,172,185,186
sary.177 In obstetric patients in whom an to use while breast feeding.7,185 Patients Peak levels considered to be acceptable
infusion is indicated for hereditary defi- who require warfarin therapy are gener- for prophylaxis are 0.2-0.4 IU/mL. Peak
ciency to control a thrombotic episode or ally treated with LMWH or IV UFH and levels considered acceptable for full anti-
to prevent thrombosis, AT levels should be are then transitioned to warfarin.7,185 It coagulation are 0.5-1.0 IU/mL.
returned to normal and maintained at this is safe to resume UFH/LMWH therapy Patients who receive prophylactic
level for 2-8 days.177 Concurrent adminis- within 12 hours of delivery. A period of doses of LMWH or UFH for past or re-
tration of an anticoagulant should be at least 3-5 days in which the patient is cent VTE should continue this dosing
based on medical judgment. Involving a fully anticoagulated with UFH or regimen for 6-8 weeks postpartum.7,169
hematologist experienced in AT-III defi- LMWH and fully anticoagulated with Patients with thrombophilia without ev-
ciency is essential for the patients’ overall warfarin (INR 2-3) is often needed be- idence of past or recent VTE who are
care. fore treatment with UFH or LMWH can managed with prophylactic UFH or
be stopped.185 At least 2 therapeutic LMWH can receive the same dose 6-8
C ONSENSUS P ANEL INRs should be confirmed before stop- weeks postpartum.7,24,125,187 However,
R ECOMMENDATIONS FOR ping UFH or LMWH therapy. Failure to this approach is controversial and fur-
M EASURING A NTITHROMBIN perform the transition therapy or over- ther clinical investigation is necessary as
L EVELS aggressively increasing the warfarin dose some physicians believe that these pa-
because of a low INR can result in mater- tients can be followed expectantly during
● Evaluate AT levels before infusion and
nal complications, such as bleeding from the postpartum period.7,178 Most au-
20 minutes after infusion (peak).177
the involuting placental site, and, start- thors agree that patients without a his-
(Level IIIC)
ing warfarin therapy without concomi- tory of VTE but with thrombophilia, or
● Evaluate AT levels after 12 hours and
tant LMWH or UFH may lead to para- with recurrent pregnancy loss with
then preceding the next infusion
doxical coumadin skin necrosis.185 The thrombophilia, who undergo a cesarean
(trough).177,184 (Level IIIC)
initial dose of warfarin should not exceed delivery should receive postoperative/
● Obtain subsequent AT levels before
5 mg or the dose taken before pregnancy, postpartum treatment with prophylactic
and 20 minutes after each infusion un-
whichever is less.185 Only physicians ex- UFH or LMWH for 6 weeks.7,18,125,169
til predictable peak and troughs have
perienced in anticoagulation should per- Opinions vary in similar groups of
been achieved (ranging from 80% to
form the transition therapy. women who undergo vaginal delivery.
120%).177,184 (Level IIIC)
Patients who receive full anticoagula-
● Maintain plasma levels between 80%
tion with UFH or LMWH during the an-
and 120% with the administration of
tenatal period should be weighed before R EGIONAL A NESTHETIC
AT-III at doses of 60% of the initial
starting treatment in the postpartum be- C ONSIDERATIONS
loading dose given every 24 hours.
cause their body weight may have There have been reports in the literature
Subsequent doses should be adjusted
changed significantly and they may re- of hematoma formation in the epidural
based on AT levels.177,184 (Level
quire a lower dose of UFH or LMWH. In space in nonpregnant patients treated
IIIC)
patients in whom warfarin therapy is ap- with LMWH. The majority of these pa-
● Involving a hematologist experienced
propriate, transitioning can be carried tients were elderly individuals who were
in AT-III deficiency is essential for the
out as described previously. If full anti- also treated with nonsteroidal anti-in-
patients’ overall care. (Level IIIC)
coagulation is needed because of a recent flammatory drugs, which impair platelet
The above recommendations for dos- episode of VTE, treatment with warfarin aggregation and subsequently affect
ing and establishing the maintenance is often recommended for 3-6 months platelet function. It has been accepted
dosage should be interpreted as general postpartum.7,178,185 Life-long anticoag- along with our anesthetic colleagues that
guidelines for therapy only. The exact ulation with warfarin is generally re- the following guidelines be followed

NOVEMBER 2007 American Journal of Obstetrics & Gynecology 457.e15


Review Obstetrics www.AJOG.org

when LMWH are used during based on bleeding and physical exam- casional thrombotic events, occurring as
pregnancy. ination.172,174,176,188 (Level II-1A) a result of IgG antibodies crossing the
Epidural catheter and spinal anesthe- ● If necessary, induce labor at term (39 placenta, have been reported in infants
sia should be delayed for 10-12 hours weeks) secondary to past obstetric his- of mothers with antiphospholipid anti-
after the last dose of LMWH in patients tory and the patient’s desire for re- bodies.194 These findings suggest that in-
receiving prophylactic doses of gional anesthesia. Counsel the patient herited thrombophilia in the infant con-
LMWH.176 In patients receiving full- in advance that regional anesthesia tributes to, but is not the sole cause of,
dose anticoagulation, catheter place- may not be an option if labor starts thrombotic complications; the question
ment or spinal anesthesia should not be earlier. Be aware that induction can of whether fetal thrombophilia is a risk
performed for a minimum of 24 hours prolong labor (independent of risk factor for poor pregnancy outcomes is
after the last dose of LMWH.176 Prophy- factor for VTE) and can increase the controversial. Several large studies of
lactic doses of LMWH should be with- risk for cesarean delivery (risk factor pregnancy outcomes associated with
held for 12 hours before induction of la- for VTE and for hemorrhage when an- maternal thrombophilia have reported
bor or cesarean section, and full dosing ticoagulation is necessary in the post- conflicting results regarding pregnancy
should be withheld for 24 hours before partum period). (Level IIIC) outcomes and there have been no long-
induction or cesarean delivery.172,176 Pa- ● Use endotracheal intubation with cen- term follow-up studies of the infants
tients on LMWH should receive the next tral induction of anesthesia in patients from such pregnancies.56,58,80,82,84-95
dose of LMWH (full anticoagulation) requiring cesarean delivery who re- On the basis of the evidence that
10-12 hours after removal of the epi- ceived doses of LMWH before 12 thrombosis is a significant factor in poor
dural/spinal catheter.176 Two studies in- hours (prophylactic) or before 24 pregnancy outcomes, clinical trials have
volving more than 80 patients showed no hours (therapeutic). (Level IIIC) been performed by using prophylaxis
complications when using the estab- with UFH and LMWH or full anticoag-
lished recommendations of not placing ulation during pregnancy in women
the epidural catheter until 12-24 hours P EDIATRIC /N EONATAL with previous APO.114,138,139 However,
after the last dose and not giving the next C ONSIDERATIONS no long-term follow-up of the infants
dose of LMWH until 10-12 hours after Understanding the pathophysiology of was reported in these studies. The use of
the removal of the epidural or spinal poor pregnancy outcomes and of treat- UFH or LMWH instead of warfarin is
catheter.174,188 Furthermore, no compli- ments designed to prevent maternal risk clearly advantageous for the fetus, be-
cations were reported following this ap- will benefit the fetus; however, there is cause warfarin anticoagulation during
proach in a prospectively evaluated co- minimal information regarding long- pregnancy is associated with an in-
hort of 180 patients managed with term fetal outcomes. Several lines of ev- creased risk of warfarin-induced embry-
LMWH.172 However, the sample sizes of idence suggest a role for thrombophilia opathy and an increased risk of fetal
these studies may be insufficient to draw and thrombosis in pregnancies associ- intracranial hemorrhage.12-15 It is un-
firm conclusions on the rare risk of epi- ated with IUGR, fetal loss, placental ab- known whether paternal inheritance of
dural or spinal hematoma. With UFH, ruption, and preeclampsia.56,80,82,97-111 thrombophilia in the infant contributes
the timing of insertion and removal of Fetal thrombotic vasculopathy has been to poor pregnancy outcomes, although a
the epidural catheter, as well as timing of observed both in the placentas of such large Canadian study suggested that this
cesarean delivery and the heparin dose, pregnancies and in neonates with neona- is not a significant risk factor.59 Most in-
should be adjusted to avoid epidural an- tal encephalopathy.189 A small case series vestigators agree that infants born to
esthesia during peak heparin concentra- has suggested an association between thrombophilic mothers or fathers may
tions to reduce the risk of epidural placental infarcts and neonatal throm- benefit from screening for the parental
hematoma.36 bosis.190 Further evidence of thrombotic defect in order to guide future prophy-
cause has been suggested by elevated lactic measures to prevent thrombosis in
thrombin generation in vivo, measured the child. However, it should be noted
C ONSENSUS P ANEL by TATs, in women with pregnancies af- that there are significant ramifications of
R ECOMMENDATIONS FOR fected by IUGR or preeclampsia com- screening in terms of unwarranted med-
R EGIONAL A NESTHESIA pared with women with normal preg- ical interventions and insurance cover-
nancies.191 Although the prevalence of age. The option of screening should be
● Withhold treatment with LMWH thrombophilic conditions is greater in discussed with the parents. To augment
(prophylactic or full dosing) for 12 or infants with thrombosis compared with effective counseling of future pregnan-
24 hours, respectively, before induc- the normal population, thrombosis is cies and perinatal outcomes, a patholo-
tion of labor or elective cesarean deliv- rare in neonates with thrombophilia gist should examine the placenta and
ery, respectively.172,174,176,188 (Level who do not have additional risk factors umbilical cord in at-risk pregnancies.
II-1A) (such as central venous catheters, cardiac Furthermore, evaluation and prompt
● Start LWMH therapy 10-12 hours af- disease, septicemia, dehydration, poly- treatment of additional risk factors, such
ter removing the epidural catheter, cythemia, a diabetic mother).192,193 Oc- as asphyxia, polycythemia, dehydration,

457.e16 American Journal of Obstetrics & Gynecology NOVEMBER 2007


www.AJOG.org Obstetrics Review

septicemia, and cardiac disease, may be who are at risk of VTE or APOs. We have 11. Methods and background. US Preventive
warranted. In addition, affected infants provided step-by-step recommenda- Services Task Force. Agency for Healthcare Re-
search and Quality. Rockville, MD. May 2004.
who require central venous catheters tions for pregnant women with a variety Available at: http://www.ahrq.gov/clinic/
should be considered for prophylactic of indications for thromboprophylaxis uspstmeth.htm. Accessed on June 4, 2007.
anticoagulation with low-dose UFH. and treatment. However, these guide- 12. Weg JG. Venous thromboembolism in
lines are based largely on level II and III pregnancy. Semin Reprod Crit Care Med
evidence, or have been extrapolated 1998;19:231-41.
C ONSENSUS P ANEL 13. Zakzouk MS. The congenital warfarin syn-
R ECOMMENDATIONS FOR from the nonpregnant population. We
drome. J Laryngol Otol 1986;100:215-9.
M ANAGEMENT OF I NFANTS IN hope that, in the future, the prognosis for 14. Wong V, Cheng CH, Chan KC. Fetal and
A T -R ISK P REGNANCIES these women will be improved by the ac- neonatal outcome of exposure to anticoagu-
quisition of data from large-scale, pro- lants during pregnancy. Am J Med Genet
● Maternal anticoagulation with warfa- spective, randomized studies. f 1993;45:17-21.
rin prior to delivery of the infant 15. Meschengieser SS, Fondevila CG, Santar-
should be avoided where possible.12-14 elli MT, Lazzari MA. Anticoagulation in pregnant
(Level II-3A) ACKNOWLEDGMENTS women with mechanical heart valve prosthe-
We would like to acknowledge Dan Bridges for ses. Heart 1999;82:23-6.
● Although not supported by the Na- 16. Orme ML, Lewis PJ, de Swiet M, et al. May
tional Society of Genetic Counselors, providing editorial support in the preparation of
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