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## Complete Summary

#### GUIDELINE TITLE

Use of antithrombotic agents during pregnancy: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy.

#### BIBLIOGRAPHIC SOURCE(S)

Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents
during pregnancy: the Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl):627S-44S. \[119
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15383488)

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Ginsberg JS, Greer I, Hirsh
J. Use of antithrombotic agents during pregnancy. Chest 2001 Jan;119(1
Suppl):122S-131S.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [February 28, 2008, Heparin Sodium
    Injection](http://www.fda.gov/medwatch/safety/2008/safety08.htm#HeparinInj2):
    The U.S. Food and Drug Administration (FDA) informed the public that
    Baxter Healthcare Corporation has voluntarily recalled all of their
    multi-dose and single-use vials of heparin sodium for injection and
    their heparin lock flush solutions. Alternate heparin manufacturers
    are expected to be able to increase heparin production sufficiently
    to supply the U.S. market. There have been reports of serious
    adverse events including allergic or hypersensitivity-type
    reactions, with symptoms of oral swelling, nausea, vomiting,
    sweating, shortness of breath, and cases of severe hypotension.

-   [August 16, 2007, Coumadin
    (Warfarin)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Warfarin):
    Updates to the labeling for Coumadin to include pharmacogenomics
    information to explain that people\'s genetic makeup may influence
    how they respond to the drug.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

-   Pregnancy complications associated with thrombophilia (presence of
    antiphospholipid antibodies or hereditary thrombophilia)

-   Venous thromboembolism or pulmonary embolism during pregnancy

-   Venous thromboembolism associated with cesarean section

-   Systemic thromboembolism associated with mechanical heart valves
    during pregnancy

#### GUIDELINE CATEGORY

Management\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Emergency Medicine\
Family Practice\
Internal Medicine\
Obstetrics and Gynecology\
Pulmonary Medicine

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To provide evidence-based recommendations on the management of
thromboembolic complications during pregnancy

#### TARGET POPULATION

-   Pregnant women with or at risk of developing thromboembolic
    complications

-   Pregnant women with mechanical heart valves

-   Pregnant women with thrombophilia (antiphospholipid antibodies,
    factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia,
    protein S deficiency, protein C deficiency, antithrombin deficiency)

-   Pregnant women with a prior history of venous thromboembolism

-   Symptomatic pregnant women with clinical suspicion of deep vein
    thrombosis (DVT) or pulmonary embolism (PE)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Prevention, Management, and Treatment**

1.  Screening, as appropriate, for congenital thrombophilia and
    antiphospholipid antibodies (APLAs).

2.  Antithrombotic pharmacotherapy, including:

    -   Heparin; mini-dose unfractionated heparin (UFH); moderate-dose
        UFH; adjusted-dose UFH; prophylactic
        low-molecular-weight-heparin (LMWH; for example, dalteparin or
        enoxaparin); adjusted-dose LMWH (weight-adjusted, full-treatment
        doses of LMWH)

    -   Postpartum anticoagulant therapy (warfarin in combination with
        initial UFH or LMWH overlap)

    -   Aspirin therapy, such as antepartum aspirin; low-dose aspirin
        therapy in combination with anticoagulant therapy, as
        appropriate, during pregnancy

> **Note**: Aspirin therapy alone (rather than in combination with
> anticoagulant therapy) is considered but not recommended during
> pregnancy.

3.  Folic acid supplementation

4.  Surveillance of women with symptoms suspicious of deep vein
    thrombosis (DVT) or pulmonary embolism (PE), and of women who are at
    increased risk of venous thromboembolism (VTE) or thrombophilia

5.  Screening with noninvasive tests for DVT, such as compression
    ultrasound

6.  Laboratory testing and monitoring:

    -   Anti-factor Xa levels

    -   Activated partial thromboplastin time (aPTT)

7.  Patient education/counseling, such as pre-pregnancy counseling of
    risks associated with pregnancy in women receiving long-term
    anticoagulation therapy

#### MAJOR OUTCOMES CONSIDERED

Effectiveness and safety of antithrombotic therapy as evidenced by the
following:

-   Rates of fetal complications (e.g., spontaneous abortions, fetal
    hemorrhage, congenital fetal anomalies, fetal wastage) with maternal
    antithrombotic therapy

-   Rates of maternal complications including mortality, major bleeding
    episodes, venous thromboembolism (VTE), heparin-induced
    thrombocytopenia (HIT), and heparin-associated osteoporosis.

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Process of Searching for Evidence**

Defining the clinical question provided the framework for formulating
eligibility criteria that guided the search for relevant evidence. Prior
to searching for the evidence, methodological experts and librarians
reviewed each question to ensure that the librarians could derive a
comprehensive search strategy.

In specifying eligibility criteria, authors not only identified
patients, interventions, and outcomes, but also methodological criteria.
For most therapeutic studies, authors restricted eligibility to
randomized controlled trials (RCTs).

For many questions, RCTs did not provide sufficient data, and article
authors also included observational studies. This was also true when
randomized trials were not the most appropriate design to use for
addressing the research question. In particular, randomized trials are
not necessarily the best design to understand risk groups (e.g., the
baseline or expected risk of a given event for certain subpopulations).
Because there are no interventions examined in questions about
prognosis, one replaces interventions by the exposure, which is time.

**Identifying the Evidence**

To identify the relevant evidence, a team of librarians at the
University at Buffalo conducted comprehensive literature searches. For
each question the authors provided, the librarians developed sensitive
(but not specific) search strategies, including all languages, and
conducted separate searches for systematic reviews, RCTs, and, if
applicable, observational studies. The librarians searched the Cochrane
Database of Systematic Reviews, the Database of Abstracts of Reviews of
Effectiveness and Cochrane Register of Controlled Trial, the ACP Journal
Club, MEDLINE, and Embase for studies published between 1966 and June
2002 in any language. To filter MEDLINE and Embase search results for
RCT evidence, the librarians used the search strategy developed by the
Cochrane Collaboration (full strategy available in Appendix online at:
<http://www.chestjournal.org/content/vol126/3_suppl_1>).

For observational studies, they restricted their searches to human
studies. Searches were not further restricted in terms of methodology.
While increasing the probability of identifying all published studies,
this sensitive approach resulted in large number of citations for many
of the defined clinical questions. Therefore, trained research
assistants screened the citation list developed from the search and
removed any apparently irrelevant citations. These irrelevant citations
included press news, editorials, narrative reviews, single case reports,
animal studies (any nonhuman studies), and letters to the editor.
Authors included data from abstracts of recent meetings if reporting was
transparent and all necessary data for the formulation of a
recommendation were available. The guideline developers did not
explicitly use Internet sources to search for research data.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

The rating scheme framework captures the trade-off between benefits and
risks (1 or 2) (and the methodological quality of the underlying
evidence (A, B, C+, or C). See \"Rating Scheme for the Strength of the
Recommendations.\"

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

**Summarizing Evidence**

The electronic searches also included searching for systematic reviews.
If authors were satisfied with a recent high-quality systematic review,
evidence from that review provided a foundation for the relevant
recommendation.

Pooled analyses from high-quality systematic reviews formed, wherever
possible, the evidence base of the recommendations. Pooling offers the
advantage of obtaining more precise estimates of treatment effects and
allows for a greater generalizability of results. However, pooling also
bears the risk of spurious generalization. In general, the summary
estimates of interest were the different types of outcomes conveying
benefit and downsides (i.e., risk, burden, and cost).

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Consensus Development Conference)

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The strength of any recommendation depends on the following two factors:
the trade-off between the benefits and the risks, burdens, and costs;
and the strength of the methodology that leads to the treatment effect.
The guideline developers grade the trade-off between benefits and risks
in the two categories: 1, in which the trade-off is clear enough that
most patients, despite differences in values, would make the same
choice; and 2, in which the trade-off is less clear, and individual
patients´ values will likely lead to different choices.

When randomized trials provide precise estimates suggesting large
treatment effects, and the risks and costs of therapy are small,
treatment for average patients with compatible values and preferences
can be confidently recommended.

If the balance between benefits and risks is in doubt, methodologically
rigorous studies providing **Grade A** evidence and recommendations may
still be weak (**Grade 2**). Uncertainty may come from less precise
estimates of benefit, harm, or costs, or from small effect sizes.

There is an independent impact of validity and consistency, and the
balance of positive and negative impacts of treatment on the strength of
recommendations. In situations in which there is doubt about the value
of the trade-off, any recommendation will be weaker, moving from **Grade
1** to **Grade 2**.

**Grade 1** recommendations can only be made when there is a relatively
clear picture of both the benefits and the risks, burdens, and costs,
and when the balance between the two clearly favors recommending or not
recommending the intervention for the typical patient with compatible
values and preferences. A number of factors can reduce the strength of a
recommendation, moving it from **Grade 1** to **Grade 2**. Uncertainty
about a recommendation to treat may be introduced if the following
conditions apply: (1) the target event that is trying to be prevented is
less important (confident recommendations are more likely to be made to
prevent death or stroke than asymptomatic deep vein thrombosis); (2) the
magnitude of risk reduction in the overall group is small; (3) the
probability of the target event is low in a particular subgroup of
patients; (4) the estimate of the treatment effect is imprecise, as
reflected in a wide confidence interval (CI) around the effect; (5)
there is substantial potential harm associated with therapy; or (6)
there is an expectation for a wide divergence in values even among
average or typical patients. Higher costs would also lead to weaker
recommendations to treat.

The more balanced the trade-off between benefits and risks, the greater
the influence of individual patient values in decision making. Virtually
all patients, if they understand the benefits and risks, will take
aspirin after experiencing a myocardial infarction (MI) or will comply
with prophylaxis to reduce the risk of thromboembolism after undergoing
hip replacement. Thus, one way of thinking about a **Grade 1**
recommendation is that variability in patient values is unlikely to
influence treatment choice in average or typical patients.

When the trade-off between benefits and risks is less clear, individual
patient values may influence treatment decisions even among patients
with average or typical preferences.

**Grade 2** recommendations are those in which variation in patient
values or individual physician values will often mandate different
treatment choices, even among average or typical patients. An
alternative, but similar, interpretation is that a **Grade 2**
recommendation suggests that clinicians conduct detailed conversations
with patients to ensure that their ultimate recommendation is consistent
with the patient\'s values.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

  ------------------------------------------------------------------------------
  **Grade of         **Clarity of     **Methodological   **Implications**
  Recommendation**   Risk/Benefit**   Strength of        
                                      Supporting         
                                      Evidence**         
  ------------------ ---------------- ------------------ -----------------------
  **1A**             Clear            Randomized         Strong recommendation;
                                      controlled trials  can apply to most
                                      (RCTs) without     patients in most
                                      important          circumstances without
                                      limitations        reservation

  **1C+**            Clear            No RCTs, but       Strong recommendation;
                                      strong RCT results can apply to most
                                      can be             patients in most
                                      unequivocally      circumstances
                                      extrapolated, or   
                                      overwhelming       
                                      evidence from      
                                      observational      
                                      studies            

  **1B**             Clear            RCTs with          Strong recommendation;
                                      important          likely to apply to most
                                      limitations        patients
                                      (inconsistent      
                                      results,           
                                      methodological     
                                      flaws\*)           

  **1C**             Clear            Observational      Intermediate-strength
                                      studies            recommendation; may
                                                         change when stronger
                                                         evidence is available

  **2A**             Unclear          RCTs without       Intermediate-strength
                                      important          recommendation; best
                                      limitations        action may differ
                                                         depending on
                                                         circumstances or
                                                         patients\' or societal
                                                         values

  **2C+**            Unclear          No RCTs, but       Weak recommendation;
                                      strong RCT results best action may differ
                                      can be             depending on
                                      unequivocally      circumstances or
                                      extrapolated, or   patients\' or societal
                                      overwhelming       values
                                      evidence from      
                                      observational      
                                      studies            

  **2B**             Unclear          RCTs with          Weak recommendation;
                                      important          alternative approaches
                                      limitations        likely to be better for
                                      (inconsistent      some patients under
                                      results,           some circumstances
                                      methodological     
                                      flaws\*)           

  **2C**             Unclear          Observational      Very weak
                                      studies            recommendation; other
                                                         alternatives may be
                                                         equally reasonable
  ------------------------------------------------------------------------------

*\*These situations include RCTs with both lack of blinding and
subjective outcomes, where the risk of bias in measurement of outcomes
is high, or RCTs with large loss to follow-up.*

#### COST ANALYSIS

While conference participants agreed that recommendations should reflect
economic considerations, incorporating costs is fraught with difficult
challenges. For most recommendations, formal economic analyses are
unavailable. Even when analyses are available, they may be
methodologically weak or biased. Furthermore, costs differ radically
across jurisdictions, and even sometimes across hospitals within
jurisdictions.

Because of these challenges, the guideline developers consider economic
factors only when the costs of one therapeutic option over another are
substantially different within major jurisdictions in which clinicians
make use of our recommendations. As a result, in jurisdictions in which
resource constraints are severe, alternative allocations may serve the
health of the public far better than some of the interventions that are
designated as **Grade 1A**. This will likely be true for all less
industrialized countries and, with the increasing promotion of expensive
drugs with marginal benefits, may be increasingly true for wealthier
nations. Furthermore, recommendations change (either in direction or
with respect to grade) only when the guideline developers believe that
costs are high in relation to benefits. Instances in which costs have
influenced recommendations are labeled in the \"values and preferences\"
statements associated with the recommendation.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guideline authors formulated draft recommendations prior to the
conference that served as the foundation for authors to work together
and critique the recommendations. Drafts of all articles including draft
recommendations were available for review during the conference. A
representative of each article presented potentially controversial
issues in their recommendations at plenary meetings. Article authors met
to integrate feedback, to consider related recommendations in other
articles, and to revise their own guidelines accordingly. Authors
continued this process after the conference until they reached agreement
within their groups and with other author groups who had provided
critical feedback. Finally, the editors of this supplement harmonized
the articles and resolved remaining disagreements through facilitated
discussion.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The rating scheme is defined at the end of the \"Major Recommendations\"
field.

When describing the various regimens of unfractionated heparin (UFH) and
low-molecular-weight-heparin (LMWH), the guideline developers use the
following terminology:

-   *Mini-dose* UFH: UFH 5,000 U subcutaneous (SC) every 12 hours

-   *Moderate-dose* UFH: UFH SC every 12 hours in doses adjusted to
    target an anti-Xa level of 0.1 to 0.3 U/mL

-   *Adjusted-dose* UFH: UFH SC every 12 hours in doses adjusted to
    target a mid-interval activated partial thromboplastin time (aPTT)
    into the therapeutic range

-   *Prophylactic LMWH:* e.g., dalteparin 5,000 U SC every 24 hours, or
    enoxaparin 40 mg SC every 24 hours (although at extremes of body
    weight modification of dose may be required)

-   *Intermediate-dose LMWH*: e.g., dalteparin 5,000 U SC every 12
    hours, or enoxaparin 40 mg SC every 12 hours

-   *Adjusted-dose LMWH*: weight-adjusted, full-treatment doses of LMWH
    administered once or twice daily (e.g., dalteparin 200 U/kg, or
    tinzaparin 175 U/kg once daily, or dalteparin 100 U/kg every 12
    hours, or enoxaparin 1 mg/kg every 12 hours). As the half-life of
    LMWH is shorter in pregnancy, twice-daily dosing is preferable, at
    least in the initial treatment phase.

-   *Postpartum anticoagulants*: warfarin for 4 to 6 weeks with a target
    international normalized ratio (INR) of 2.0 to 3.0, with initial UFH
    or LMWH overlap until the INR is [\>]{.underline}2.0

-   In addition, the term *surveillance* refers to clinical vigilance
    and aggressive investigation of women with symptoms suspicious of
    deep vein thrombosis (DVT) or pulmonary embolism (PE).

**[Management of Women Receiving Long-Term Vitamin K Antagonist (VKA)
Therapy Who Are Considering Pregnancy]{.underline}**

1.  For women requiring long-term VKA therapy who are attempting
    pregnancy, the guideline developers suggest performing frequent
    pregnancy tests and substituting UFH or LMWH for warfarin when
    pregnancy is achieved (**Grade 2C**).

**[Treatment of Venous Thromboembolism (VTE) during
Pregnancy]{.underline}**

1.  In women with acute VTE, the guideline developers recommend either
    adjusted-dose LMWH throughout pregnancy or intravenous (IV) UFH
    (bolus followed by a continuous infusion to maintain the aPTT in the
    therapeutic range) for at least 5 days, followed by adjusted-dose
    UFH or LMWH for the remainder of the pregnancy. Anticoagulants
    should be administered for at least 6 weeks postpartum (**Grade
    1C+**).

2.  In women receiving adjusted-dose LMWH or UFH therapy, the guideline
    developers recommend discontinuing the heparin 24 hours prior to
    elective induction of labor (**Grade 1C**).

**[Prevention of VTE during Pregnancy]{.underline}**

**Prior VTE and Pregnancy**

1.  In patients with a single episode of VTE associated with a transient
    risk factor that is no longer present, the guideline developers
    recommend clinical surveillance and postpartum anticoagulants
    (**Grade 1C**). If the previous event is pregnancy or
    estrogen-related or there are additional risk factors (such as
    obesity), the guideline developers suggest antenatal anticoagulant
    prophylaxis (**Grade 2C**).

2.  In patients with a single idiopathic episode of VTE who are not
    receiving long-term anticoagulants, the guideline developers suggest
    prophylactic LMWH, or mini-dose UFH, or moderate-dose UFH, or
    clinical surveillance plus postpartum anticoagulants (**Grade 2C**).

3.  In patients with a single episode of VTE and thrombophilia
    (confirmed laboratory abnormality) or strong family history of
    thrombosis and not receiving long-term anticoagulants, the guideline
    developers suggest prophylactic or intermediate-dose LMWH, or
    mini-dose or moderate-dose UFH, plus postpartum anticoagulants
    (**Grade 2C**).

4.  In antithrombin-deficient women, compound heterozygotes for
    prothrombin G20210A and factor V Leiden and homozygotes for these
    conditions with a history of VTE, the guideline developers suggest
    intermediate-dose LMWH prophylaxis or moderate-dose UFH (**Grade
    2C**).

5.  In patients with multiple (two or more) episodes of VTE and/or women
    receiving long-term anticoagulants (e.g., single episode of
    VTE---either idiopathic or associated with thrombophilia) the
    guideline developers suggest adjusted-dose UFH or adjusted-dose LMWH
    followed by resumption of long-term anticoagulants postpartum
    (**Grade 2C**).

6.  In all women with previous DVT, antenatally and postpartum, the
    guideline developers suggest use of graduated elastic compression
    stockings (**Grade 2C**).

**Thrombophilia and VTE Associated with Pregnancy**

1.  In antithrombin-deficient women, compound heterozygotes for
    prothrombin G20210A and factor V Leiden, and homozygotes for these
    conditions with no prior VTE, the guideline developers suggest
    active prophylaxis (**Grade 2C**).

2.  In all other patients with no prior VTE and thrombophilia (confirmed
    laboratory abnormality), the guideline developers suggest
    surveillance or prophylactic LMWH or mini-dose UFH, plus postpartum
    anticoagulants (**Grade 2C**).

**[Thrombophilia and Pregnancy Complications]{.underline}**

1.  For women with recurrent pregnancy loss (three or more miscarriages)
    and women with prior severe or recurrent preeclampsia, abruptions,
    or otherwise unexplained intrauterine death, the guideline
    developers suggest screening for congenital thrombophilia and
    antiphospholipid antibodies (APLAs) (**Grade 2C**).

2.  For pregnant patients with APLAs and a history of multiple (two or
    more) early pregnancy losses or one or more late pregnancy losses,
    preeclampsia, intrauterine growth retardation (IUGR), or abruption,
    the guideline developers suggest administration of antepartum
    aspirin plus mini-dose or moderate-dose UFH or prophylactic LMWH
    (**Grade 2B**).

3.  For women who are homozygous for thermolabile variant (C677T) or
    MTHFR, the guideline developers suggest folic acid supplements prior
    to conception or, if already pregnant, as soon as possible, and
    throughout pregnancy (**Grade 2C**).

4.  For women with a congenital thrombophilic deficit and recurrent
    miscarriages, a second-trimester or later loss, severe or recurrent
    preeclampsia, or abruption, the guideline developers suggest
    low-dose aspirin therapy plus either mini-dose heparin or
    prophylactic LMWH therapy (**Grade 2C**). The guideline developers
    also suggest that postpartum anticoagulants be administered to these
    women (**Grade 2C**).

5.  Patients with APLAs and a history of venous thrombosis are usually
    receiving long-term oral anticoagulation therapy because of the high
    risk of recurrence. During pregnancy, the guideline developers
    recommend adjusted-dose LMWH or UFH therapy plus low-dose aspirin
    and resumption of long-term oral anticoagulation therapy postpartum
    (**Grade 1C**).

6.  Patients with APLAs and no prior VTE or pregnancy loss should be
    considered to have an increased risk for the development of venous
    thrombosis and, perhaps, pregnancy loss. The guideline developers
    suggest one of the following approaches for these women:
    surveillance, mini-dose heparin, prophylactic LMWH, and/or low-dose
    aspirin, 75 to 162 mg daily (**all Grade 2C**).

**[Prophylaxis in Patients with Mechanical Heart Valves]{.underline}**

In women with prosthetic heart valves, the guideline developers
recommend:

1.  Adjusted-dose, twice-daily LMWH throughout pregnancy in doses
    adjusted either to keep a 4-hour postinjection anti-Xa heparin level
    at approximately 1.0 to 1.2 U/mL (preferable) or according to weight
    (**Grade 1C**), or

2.  Aggressive adjusted-dose UFH throughout pregnancy: i.e.,
    administered SC every 12 hours in doses adjusted to keep the
    mid-interval aPTT at least twice control or to attain an anti-Xa
    heparin level of 0.35 to 0.70 U/mL (**Grade 1C**), or

3.  UFH or LMWH (as above) until the thirteenth week, change to warfarin
    until the middle of the third trimester, and then restart UFH or
    LMWH (**Grade 1C**).

> *Remark*: Long-term anticoagulants should be resumed postpartum with
> all regimens.

4.  In women with prosthetic heart valves at high risk, the guideline
    developers suggest the addition of low-dose aspirin, 75 to 162
    mg/day (**Grade 2C**).

**[Definitions]{.underline}**

  ------------------------------------------------------------------------------
  **Grade of         **Clarity of     **Methodological   **Implications**
  Recommendation**   Risk/Benefit**   Strength of        
                                      Supporting         
                                      Evidence**         
  ------------------ ---------------- ------------------ -----------------------
  **1A**             Clear            Randomized         Strong recommendation;
                                      controlled trials  can apply to most
                                      (RCTs) without     patients in most
                                      important          circumstances without
                                      limitations        reservation

  **1C+**            Clear            No RCTs, but       Strong recommendation;
                                      strong RCT results can apply to most
                                      can be             patients in most
                                      unequivocally      circumstances
                                      extrapolated, or   
                                      overwhelming       
                                      evidence from      
                                      observational      
                                      studies            

  **1B**             Clear            RCTs with          Strong recommendation;
                                      important          likely to apply to most
                                      limitations        patients
                                      (inconsistent      
                                      results,           
                                      methodological     
                                      flaws\*)           

  **1C**             Clear            Observational      Intermediate-strength
                                      studies            recommendation; may
                                                         change when stronger
                                                         evidence is available

  **2A**             Unclear          RCTs without       Intermediate-strength
                                      important          recommendation; best
                                      limitations        action may differ
                                                         depending on
                                                         circumstances or
                                                         patients\' or societal
                                                         values

  **2C+**            Unclear          No RCTs, but       Weak recommendation;
                                      strong RCT results best action may differ
                                      can be             depending on
                                      unequivocally      circumstances or
                                      extrapolated, or   patients\' or societal
                                      overwhelming       values
                                      evidence from      
                                      observational      
                                      studies            

  **2B**             Unclear          RCTs with          Weak recommendation;
                                      important          alternative approaches
                                      limitations        likely to be better for
                                      (inconsistent      some patients under
                                      results,           some circumstances
                                      methodological     
                                      flaws\*)           

  **2C**             Unclear          Observational      Very weak
                                      studies            recommendation; other
                                                         alternatives may be
                                                         equally reasonable
  ------------------------------------------------------------------------------

*\*These situations include RCTs with both lack of blinding and
subjective outcomes, where the risk of bias in measurement of outcomes
is high, or RCTs with large loss to follow-up.*

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for each
recommendation (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   The appropriate use of antithrombotic agents during pregnancy can
    help prevent and treat venous thromboembolism or systemic embolism,
    while decreasing the risk and rate of negative maternal and fetal
    health outcomes.

-   Low-molecular-weight heparins (LMWHs) have potential advantages over
    unfractionated heparin (UFH) during pregnancy because they cause
    less heparin-induced thrombocytopenia (HIT), have a longer plasma
    half-life and a more predictable dose response than UFH, with the
    potential for once-daily administration, and are likely associated
    with a lower risk of heparin-induced osteoporosis.

-   Heparin and LMWHs are not secreted into breast milk and can be
    safely administered to nursing mothers.

#### POTENTIAL HARMS

**General**

-   Prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism
    (PE) is problematic because it involves long-term parenteral
    unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).
    Both are expensive, inconvenient, painful to administer, and are
    associated with risks for bleeding, osteoporosis, and
    heparin-induced thrombocytopenia (HIT), although these complications
    , particularly HIT, are very uncommon with LMWH.

-   Allergic skin reactions to both LMWH and UFH can occur. These take
    the form of itchy, erythematous infiltrated plaques, which may
    resolve when preparations are switched, although cross-reactivity
    can occur. As HIT can present with isolated skin manifestations,
    this entity should be excluded when skin lesions develop.

**Fetal Complications of Anticoagulants during Pregnancy**

-   There are two potential fetal complications of maternal
    anticoagulant therapy: teratogenicity and bleeding. Neither UFH nor
    LMWH cross the placenta; therefore, these agents do not have the
    potential to cause fetal bleeding or teratogenicity, although
    bleeding at the uteroplacental junction is possible.

-   In contrast, coumarin derivatives cross the placenta and have the
    potential to cause both bleeding in the fetus and teratogenicity.
    Coumarin derivatives can cause an embryopathy, consisting of nasal
    hypoplasia and/or stippled epiphyses, after in utero exposure to
    vitamin K antagonists (VKAs) during the first trimester of
    pregnancy, and central nervous system (CNS) abnormalities after
    exposure to such drugs during any trimester.

-   In addition, VKAs cause an anticoagulant effect in the fetus, which
    is a concern, particularly at the time of delivery, when the
    combination of anticoagulant effect and trauma of delivery can lead
    to bleeding in the neonate.

**Maternal Complications of Anticoagulant Therapy during Pregnancy**

-   In a cohort study, the rate of major bleeding in pregnant patients
    treated with UFH therapy was 2%, which is consistent with the
    reported rates of bleeding associated with heparin therapy in
    nonpregnant patients and with warfarin therapy when used for the
    treatment of DVT. In addition, adjusted-dose subcutaneous (SC) UFH
    can cause a persistent anticoagulant effect at the time of delivery,
    which can complicate its use prior to labor. In a small study, an
    anticoagulant effect persisted for up to 28 hours after the last
    injection of adjusted-dose SC UFH, resulting in deliveries that were
    complicated by a prolonged activated partial thromboplastin time
    (aPTT).

-   Bleeding complications appear to be very uncommon with low molecular
    weight heparin.

*HIT*

-   Approximately 3% of nonpregnant patients receiving UFH acquire
    immune, IgG-mediated thrombocytopenia, which is frequently
    complicated by extension of preexisting VTE or new arterial
    thrombosis.

*Heparin-Induced Osteoporosis*

-   Long-term heparin therapy has been reported to cause osteoporosis in
    both laboratory animals and humans.

*Safety of Aspirin during Pregnancy*

-   Potential complications of aspirin during pregnancy include birth
    defects and bleeding in the neonate and in the mother. Both a
    meta-analysis and a large randomized trial that enrolled \>9,000
    patients reported that low-dose (60 to 150 mg/day) aspirin therapy
    administered during the second and third trimesters of pregnancy in
    women at risk for pregnancy-induced hypertension or intrauterine
    growth retardation (IUGR) was safe for the mother and fetus. Thus,
    based on current evidence, low-dose aspirin (\<150 mg/day) during
    the second and third trimester appears to be safe. The safety of
    higher doses of aspirin and/or aspirin ingestion during the first
    trimester remains uncertain.

**Subgroups Most Likely to be Harmed**

Pregnant women with prosthetic heart valves

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   Coumarins are contraindicated in pregnancy in North America due to
    fetal concerns.

-   European experts have recommended warfarin therapy throughout
    pregnancy in view of the reports of bad maternal outcomes with
    heparin and their impression that the risk of embryopathy with
    coumarin derivatives has been overstated. Although this latter
    approach is reasonable, it is fraught with medicolegal concerns,
    because the package insert states that warfarin is contraindicated
    during pregnancy. The guideline developers believe that warfarin
    should be avoided between 6 weeks and 12 weeks of gestation (to
    avoid embryopathy) and close to term (to avoid delivery of an
    anticoagulated fetus). Although the risks associated with warfarin
    during the remainder of pregnancy have been considered smaller, the
    recent association with neurodevelopment problems with mid-pregnancy
    exposure must also be considered.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

**Interpreting the Recommendations**

Clinicians, third-party payers, institutional review committees, or the
courts should not construe these guidelines in any way as absolute
dictates. In general, anything other than a **Grade 1A** recommendation
indicates that the article authors acknowledge that other
interpretations of the evidence, and other clinical policies, may be
reasonable and appropriate. Even **Grade 1A** recommendations will not
apply to all circumstances and all patients. For instance, the guideline
developers have been conservative in their considerations of cost and
have seldom downgraded recommendations from **Grade 1** to **Grade 2**
on the basis of expense. As a result, in jurisdictions in which resource
constraints are severe, alternative allocations may serve the health of
the public far better than some of the interventions that are designated
as **Grade 1A**. This will likely be true for all less industrialized
countries and, with the increasing promotion of expensive drugs with
marginal benefits, may be increasingly true for wealthier nations.

Similarly, following **Grade 1A** recommendations will at times not
serve the best interests of patients with atypical values or preferences
or of those whose risks differ markedly from those of the usual patient.
For instance, consider patients who find anticoagulant therapy extremely
aversive, either because it interferes with their lifestyle (e.g.,
prevents participation in contact sports) or because of the need for
monitoring. Clinicians may reasonably conclude that following some
**Grade 1A** recommendations for anticoagulation therapy for either
group of patients will be a mistake. The same may be true for patients
with particular comorbidities (e.g., a recent gastrointestinal bleed or
a balance disorder with repeated falls) or other special circumstances
(e.g., very advanced age) that put them at unusual risk.

The guideline developers trust that these observations convey their
acknowledgment that no recommendations or clinical practice guidelines
can take into account the often compelling and unique features of
individual clinical circumstances. No clinician, and no body charged
with evaluating a clinician\'s actions, should attempt to apply our
recommendations in a rote or blanket fashion.

**Limitations of Guideline Development Methods**

The limitations of these guidelines include the possibility that some
authors followed this methodology more closely than others, although the
development process was centralized and supervised by the editors.
Second, it is possible that the guideline developers missed relevant
studies despite the comprehensive searching process. Third, the
guideline developers did not centralize the methodological evaluation of
all studies to facilitate uniformity in the validity assessments of the
research incorporated into these guidelines. Fourth, if high-quality
meta-analyses were unavailable, the guideline developers did not
statistically pool primary study results using meta-analysis. Finally,
sparse data on patient preferences and values, resources, and other
costs represent additional limitations that are inherent to most
guideline development methods.

**Pregnant Patients with Mechanical Heart Valves**

There are still insufficient grounds to make definitive recommendations
about optimal antithrombotic therapy in pregnant patients with
mechanical heart valves because properly designed studies have not been
performed. Substantial concern remains about the fetal safety of
warfarin, the efficacy of subcutaneous (SC) heparin and of
low-molecular-weight heparin (LMWH) in preventing thromboembolic
complications, and the risks of maternal bleed with various regimens.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

**Guideline Implementation Strategies**

A full review of implementation strategies for practice guidelines is
provided in the companion document titled \"Antithrombotic and
Antithrombolytic Therapy: From Evidence to Application.\" The review
suggests that there are few implementation strategies that are of
unequivocal, consistent benefit, and that are clearly and consistently
worth resource investment. The following is a summary of the
recommendations (see \"Major Recommendations\" for a definition of the
recommendation grades).

To encourage uptake of guidelines, the guideline developers recommend
that appreciable resources be devoted to distribution of educational
material (**Grade 2B**).

They also suggest that:

-   Few resources be devoted to educational meetings (**Grade 2B**)

-   Few resources be devoted to educational outreach visits (**Grade
    2A**)

-   Appreciable resources be devoted to computer reminders (**Grade
    2A**)

-   Appreciable resources be devoted to patient-mediated interventions
    to encourage uptake of the guidelines (**Grade 2B**)

-   Few resources be devoted to audit and feedback (**Grade 2B**)

#### IMPLEMENTATION TOOLS

Patient Resources\
Personal Digital Assistant (PDA) Downloads\
Quick Reference Guides/Physician Guides\
Resources\
Slide Presentation\
Tool Kits

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Patient-centeredness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents
during pregnancy: the Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004 Sep;126(3 Suppl):627S-44S. \[119
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15383488)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2001 Jan (revised 2004 Sep)

#### GUIDELINE DEVELOPER(S)

American College of Chest Physicians - Medical Specialty Society

#### SOURCE(S) OF FUNDING

Funding was provided through an unrestricted educational grant by
AstraZeneca LP, Aventis Pharmaceuticals, GlaxoSmithKline, Bristol-Myer
Squibb/Sanofi-Synthelabo Partnership, and Organon Sanofi-Synthelabo LLC.

#### GUIDELINE COMMITTEE

American College of Chest Physicians Consensus Panel on Antithrombotic
and Thrombolytic Therapy

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Primary Authors*: Jeffrey S. Ginsberg, MD, FRCPC (Chair); Shannon M.
Bates, MDCM, FRCPC; Ian A. Greer, MD, FRCP (Glas Edin London), FRCOG;
Jack Hirsh, MD, FCCP

*Committee Co-Chairs*: Jack Hirsh, MD, FCCP (Chair); Gregory W. Albers,
MD; Gordon H. Guyatt, MD, MSc; Holger J. Schünemann, MD, MSc, PhD, FCCP

*Participants*: Giancarlo Agnelli, MD; Amin Al-Ahmad, MD; Pierre
Amarenco, MD; Jack E. Ansell, MD; Shannon M. Bates, MD; Richard C.
Becker, MD; Peter B. Berger, MD; David Bergqvist, MD, PhD, FRCS; Rebecca
J. Beyth, MD, MSc; Stewart Brower, MLIS; Harry R. Buller, MD; Henry I.
Bussey, PharmD, FCCP; Christopher P. Cannon, MD, FACC; Elizabeth A.
Chalmers, MB, ChB, MD, MRCP(UK). FRCPath; Anthony K.C. Chan, MD; G.
Patrick Clagett, MD; Barry Coller, MD; Clifford W. Colwell, MD; Deborah
Cook, MD, MSc; James E. Dalen, MD, MPH, FCCP; J. Donald Easton, MD;
Michael Ezekowitz, MD; Garret A. Fitzgerald, MD; William H. Geerts, MD,
FCCP; Jeffrey S. Ginsberg, MD, FCCP; Alan S. Go, MD; Shaun D. Goodman,
MD, FACC; Ian A. Greer, MD, FRCP, FRCOG; Andreas Greinacher, MD; Jeremy
Grimshaw, MD, PhD; Cindy Grines, MD; Jonathan L. Halperin, MD; Robert A.
Harrington, MD; John Heffner, MD, MPH; John A. Heit, MD; Judith S.
Hochman, MD, FACC; Dieter Horstkotte, MD, FESC; Russell D. Hull, MBBS,
MSc, FCCP; Elaine Hylek, MD; Thomas M. Hyers, MD, FCCP; Mark R. Jackson,
MD; Alan Jacobson, MD; Roman Jaeschke, MD, MSc; Ajay Kakkar BSc, PhD;
Clive Kearon, MD, PhD, FCCP; Matthew Kraay; Michael R. Lassen, MD; Mark
N. Levine, MD, MSc; Alessandro Liberati, MD; Gregory YH Lip, MD, FESC,
FACC; Warren J. Manning, MD; M. Patricia Massicotte, MD, MSc, FRCPC,
MSc; Thomas W. Meade, MD; Venu Menon, MD, FACC; Alan D. Michelson, MD;
Nancy Miller, RN; Paul Monagle, MBBS, MSc, MD, FRACP, FRCPA, FCCP;
Heather Munger, MLS; Christopher M. O´Connor, MD; Martin O´Donnell, MD;
E. Magnus Ohman, MD, FCCP; Carlo Patrono, MD; Stephen G. Pauker, MD;
Graham F. Pineo, MD; Leon Poller, MD; Jeffrey J. Popma, MD; Martin H.
Prins, MD; Robert Raschke, MD, MS; Gary Raskob, PhD; Joel G. Ray, MD,
MSc; Gerald Roth, MD; Ralph L. Sacco, MD; Deeb N. Salem, MD, FCCP; Meyer
M. Samama, MD; Andrew Schafer; Sam Schulman, MD, PhD; Daniel Singer, MD;
Michael Sobel, MD; Paul D. Stein, MD, FCCP; Marco Tangelder, MD; Victor
F. Tapson, MD, FCCP; Philip Teal, MD; Raymond Verhaeghe, MD; David A.
Vorchheimer, MD; Theodore E. Warkentin, MD; Jeffrey Weitz, MD; Robert G.
Wilcox, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Dr. Bates has no conflicts of interest to disclose.

Dr. Greer has received honoraria for his participation on advisory
boards and/or as a speaker at educational events from Aventis.

Dr. Hirsh has received research funding from AstraZeneca and has
received honararia for his participation on advisory boards and/or as a
speaker at educational events from AstraZeneca, Aventis Pharma,
Sanofi-Synthelabo-Organon, Bristol-Myers Squibb, GlaxoSmithKline and
Asahi.

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Ginsberg JS, Greer I, Hirsh
J. Use of antithrombotic agents during pregnancy. Chest 2001 Jan;119(1
Suppl):122S-131S.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [Chest - The Cardiopulmonary and
Critical Care
Journal](http://www.chestjournal.org/content/vol126/3_suppl/).

Print copies: Available from the American College of Chest Physicians,
Products and Registration Division, 3300 Dundee Road, Northbrook IL
60062-2348.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   The Seventh ACCP Conference on Antithrombotic and Thrombolytic
    Therapy. Evidence-based guidelines. Northbrook, IL: ACCP, 2004 Sep.

-   Methodology for guideline development for the Seventh American
    College of Chest Physicians Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Applying the grades of recommendation for antithrombotic and
    thrombolytic therapy: The Seventh ACCP Conference on Antithrombotic
    and Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Hemorrhagic complications of anticoagulant treatment: The Seventh
    ACCP Conference on Antithrombotic and Thrombolytic Therapy.
    Northbrook, IL: ACCP, 2004 Sep.

-   Antithrombotic and thrombolytic therapy: from evidence to
    application: The Seventh ACCP Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

-   Platelet-active drugs: the relationships among dose, effectiveness,
    and side effects: The Seventh ACCP Conference on Antithrombotic and
    Thrombolytic Therapy. Northbrook, IL: ACCP, 2004 Sep.

Electronic copies: Available from the [Chest - The Cardiopulmonary and
Critical Care Journal Web
site](http://www.chestjournal.org/content/vol126/3_suppl/).

Print copies: Available from the American College of Chest Physicians
(ACCP), Products and Registration Division, 3300 Dundee Road, Northbrook
IL 60062-2348.

The following is also available:

-   Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy:
    Evidence-based guidelines; quick reference guide. Northbrook, IL:
    ACCP, 2004 Sep. Personal Digital Assistant (PDA) download available
    at [ACCP Web site](http://accp.apprisor.com/dlselect.cfm).

Additional implementation tools are also available:

-   Clinical resource: antithrombotic and thrombolytic therapy.
    Northbrook, IL. ACCP, 2004. Ordering information: Available from the
    [ACCP Web
    site](http://www.chestnet.org/education/guidelines/products.php).

#### PATIENT RESOURCES

The following is available:

-   A patient\'s guide to antithrombotic and thrombolytic therapy. In:
    Clinical resource: antithrombotic and thrombolytic therapy.
    Northbrook (IL): American College of Chest Physicians (ACCP). 2004.

Ordering information is available from the [ACCP Web
site](http://www.chestnet.org/education/guidelines/products.php).

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This summary was completed by ECRI on July 12, 2001. The information was
verified by the guideline developer on October 2001. This NGC summary
was updated by ECRI on December 9, 2004. The updated information was
verified by the guideline developer on January 12, 2005. This summary
was updated by ECRI on March 6, 2007 following the U.S. Food and Drug
Administration (FDA) advisory on Coumadin (warfarin sodium). This
summary was updated by ECRI Institute on June 22, 2007 following the
U.S. Food and Drug Administration (FDA) advisory on heparin sodium
injection. This summary was updated by ECRI Institute on September 7,
2007 following the revised U.S. Food and Drug Administration (FDA)
advisory on Coumadin (warfarin). This summary was updated by ECRI
Institute on March 14, 2008 following the updated FDA advisory on
heparin sodium injection.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

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under the auspices of medical specialty societies, relevant professional
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Guidelines represented on the NGC Web site are submitted by guideline
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Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
concerning the content or clinical efficacy or effectiveness of the
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Readers with questions regarding guideline content are directed to
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Date Modified: 11/3/2008