Use of Anticoagulants During Pregnancy and Postpartum

Use of anticoagulants during pregnancy and postpartum
http://www.uptodate.com/contents/use-of-anticoagulants-during-pregnan...
Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Author
Kenneth A Bauer, MD
Section Editors
Lawrence LK Leung, MD
Charles J Lockwood, MD, MHCM
Deputy Editors
Jennifer S Tirnauer, MD
Vanessa A Barss, MD, FACOG
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2015. | This topic last updated: Aug 14, 2015.
INTRODUCTION A subset of pregnant patients requires anticoagulation during pregnancy and/or in the
postpartum period, including women at high risk of deep vein thrombosis and women with prosthetic heart valves,
atrial fibrillation, cerebral venous sinus thrombosis, left ventricular dysfunction, and some women with fetal loss.
Use of anticoagulants during pregnancy is challenging due to the potential teratogenic effects and dosing
complexities of the various agents, and the management of anticoagulation around the time of labor. In addition,
women receiving chronic anticoagulation who are contemplating pregnancy need counseling regarding how to avoid
the potential teratogenic effects of warfarin.
This topic review describes our approach to the clinical issues of anticoagulant use in women during attempted
conception, pregnancy, and postpartum. Indications for anticoagulation during pregnancy are discussed in diseasespecific topic reviews:
(See "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)
(See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".)
(See "Inherited thrombophilias in pregnancy".)
(See "Pregnancy in women with sickle cell disease", section on 'VTE prophylaxis during hospitalization'.)
(See "Supraventricular arrhythmias during pregnancy", section on 'Anticoagulation'.)
The management of anticoagulants in women with mechanical heart valves during pregnancy and postpartum is
discussed separately. (See "Management of pregnant women with prosthetic heart valves".)
General issues related to anticoagulants are discussed separately. (See "Therapeutic use of unfractionated heparin
and low molecular weight heparin" and "Therapeutic use of warfarin and other vitamin K antagonists" and
"Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors".)
CHOICE OF ANTICOAGULANT
Overview of anticoagulant choice In contrast to anticoagulation of nonpregnant women, the choice of
anticoagulant during pregnancy needs to take into account fetal safety and maternal peripartum issues (eg,
unpredictable onset of labor, use of neuraxial anesthesia for management of labor pain).
Heparins Heparins are used for most pregnant women because they do not cross the placenta and do not
result in fetal anticoagulation.
Low molecular weight (LMW) heparins We recommend a LMW heparin rather than unfractionated
heparin for all but the final weeks of the pregnancy, because they are effective and easier to administer
than unfractionated heparin [1,2]. LMW heparins produce a more predictable anticoagulant response than
unfractionated heparin and do not require routine monitoring [3-5].
Unfractionated heparin Unfractionated heparin is a reasonable alternative to a LMW heparin when cost
or need for rapid reversal is important (eg, for delivery or perioperatively). Unfractionated heparin is
preferred over LMW heparin in patients with severe renal insufficiency (eg, creatinine clearance <30
mL/min) because LMW heparin clearance is almost exclusively renal, while elimination of unfractionated
heparin is renal and hepatic.
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Fondaparinux, argatroban, danaparoid There is less information on the fetal effects of fondaparinux,
argatroban, or danaparoid, but available evidence suggests that they are reasonable options for pregnant
women who require anticoagulation and cannot take any type of heparin (eg, due to heparin-induced
thrombocytopenia). (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on
'Terminology'.)
Avoidance of warfarin Warfarin is generally avoided during pregnancy because it crosses the placenta, is a
teratogen, and causes fetal anticoagulation throughout the pregnancy. Exposure during early pregnancy can
result in embryopathy, while exposure later in pregnancy can cause fetal bleeding, including intracranial
hemorrhage.
An exception is a woman considered to be at especially high risk for thrombosis or thromboembolism (eg, due
to a mechanical heart valve). In such patients, warfarin use during pregnancy is a potential option; the choice of
anticoagulant in this setting is based upon careful consideration of maternal and fetal risks in discussion with
the patient, as discussed in more detail separately. (See "Management of pregnant women with prosthetic heart
valves".)
Avoidance of direct oral anticoagulants The oral direct thrombin inhibitor dabigatran and oral direct factor
Xa inhibitors rivaroxaban, apixaban, and edoxaban are not used during pregnancy because of absence of
information on efficacy and fetal safety.
Women receiving chronic anticoagulation who are contemplating pregnancy need counseling regarding how to avoid
the teratogenic effects of oral anticoagulants. (See 'Women on warfarin' below and 'Women on direct thrombin
inhibitors or factor Xa inhibitors' below.)
LMW heparins A LMW heparin is the preferred anticoagulant for most pregnant women. This is largely because
available evidence has shown these agents to be effective and safe for the fetus (table 1). LMW heparins do not
cross the placenta and do not cause fetal anticoagulation [1,2].
A systematic review of studies of the use of LMW heparin for prevention or treatment of VTE in pregnancy concluded
that LMW heparin was both safe and effective (64 studies, 2777 pregnancies) [6]. Rates of venous and arterial
thrombosis were 0.8 and 0.5 percent, respectively, and rates of significant bleeding (2 percent), skin reactions (1.8
percent), and osteoporotic fractures (0.04 percent) were acceptably low. There were no maternal deaths and no
cases of heparin-induced thrombocytopenia.
Unfractionated heparin Unfractionated heparin is an acceptable and less expensive alternative to LMW heparin.
It may be more appropriate than LMW heparin during stages of the pregnancy when rapid temporal control of
anticoagulation is required (eg, near the time of delivery, if surgery is required). (See 'Switch to unfractionated
heparin' below.)
Unfractionated heparin is also preferred over LMW heparin in patients with severe renal insufficiency because LMW
heparin metabolism is exclusively renal, while metabolism of unfractionated heparin is renal and hepatic.
Unfractionated heparin does not cross the placenta, and available evidence has not indicated any harmful effects on
the fetus [7-9].
Alternatives to heparin Non-heparin anticoagulants are generally not used during pregnancy unless there is a
contraindication to heparins (eg, heparin-induced thrombocytopenia) or an inability to use injections.
Danaparoid Danaparoid is a low molecular weight heparinoid (heparan derivative) that is available in many
countries (eg, Canada, Japan, Europe, Australia) but not the United States. It does not cross the placenta. (See
"Therapeutic use of unfractionated heparin and low molecular weight heparin", section on 'Danaparoid'.)
High quality data regarding the use of danaparoid in pregnancy are lacking; this agent generally is reserved for
pregnant women with heparin-induced thrombocytopenia (HIT) during or immediately preceding pregnancy
[10-13]. (See 'HIT during or immediately preceding pregnancy' below.)
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Fondaparinux Fondaparinux is a synthetic polysaccharide based on the active moiety of heparin. Experience
with fondaparinux during pregnancy is extremely limited, and data regarding placental passage are mixed. As
an example, a series of 13 women treated with fondaparinux during 15 pregnancies reported uncomplicated
deliveries of healthy babies in 10 cases [14]. Of the remaining five pregnancies, three ended in miscarriage, one
had an elective termination due to fetal anomalies, and one was associated with recurrent VTE, possibly due to
underdosing. One of the adverse outcomes may have been related to a delay in delivery due to lack of
experience with fondaparinux management, which emphasizes the importance of having a clear delivery plan.
Another series reported the use of fondaparinux during 12 pregnancies in 10 women who had hypersensitivity
reactions to LMW heparin [15]. Outcomes were good; there was no major increased bleeding or fetal
abnormalities. The American College of Chest Physicians (ACCP) suggests limiting the use of fondaparinux
during pregnancy to women with severe reactions to heparin (eg, HIT) who are unable to receive danaparoid
[13]. (See "Therapeutic use of fondaparinux" and 'HIT during or immediately preceding pregnancy' below.)
Argatroban Argatroban is a parenteral direct thrombin inhibitor reserved for those with severe reactions to
heparins (eg, HIT) who cannot receive danaparoid or fondaparinux (eg, due to lack of availability or allergic
reactions) [16-18]. Argatroban requires continuous intravenous administration and is monitored by the activated
partial thromboplastin time (aPTT). (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa
inhibitors", section on 'Argatroban'.)
Anticoagulants that are generally avoided during pregnancy
Warfarin Warfarin is generally avoided in pregnant women, except in those considered especially high risk
(eg, due to a mechanical heart valve). (See "Management of pregnant women with prosthetic heart valves".)
Warfarin and other vitamin K antagonists freely cross the placenta and are teratogenic, with the highest risk
occurring with administration between weeks 6 and 12 of gestation; these agents can also cause fetal bleeding
at any stage of pregnancy [7,8,19,20].
Warfarin has also been reported to be associated with early miscarriage [21], although the incidence is
unknown, and it is unclear whether the increased rate of early miscarriages is due to the use of warfarin or to
the underlying conditions for which warfarin was administered. Warfarin has been used during the second
trimester of pregnancy when organogenesis has been mostly completed, but the risk of fetal bleeding is a
disadvantage compared with other agents. (See 'Warfarin teratogenicity' below and "Management of pregnant
women with prosthetic heart valves", section on 'Anticoagulation during pregnancy for mechanical heart
valves'.)
Oral direct thrombin inhibitors and factor Xa inhibitors Oral direct thrombin inhibitors (eg, dabigatran) and
factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) are not used during pregnancy due to increased
reproductive risks in animal studies and/or lack of clinical experience and safety and efficacy data [13].
WHEN TO START LMW HEPARIN
Switching from oral anticoagulants to LMW heparin Women receiving chronic oral anticoagulation who are
contemplating pregnancy need counseling regarding avoidance of the potential teratogenic effects of warfarin. (See
'Women on warfarin' below.)
Women receiving direct thrombin inhibitors (eg, dabigatran) or factor Xa inhibitors (eg, rivaroxaban, apixaban) should
plan to switch to low molecular weight (LMW) heparin when they become pregnant. (See 'Women on direct thrombin
inhibitors or factor Xa inhibitors' below.)
The management of anticoagulation around the time of conception is discussed below and in disease-specific topics.
(See 'Specific scenarios' below and "Management of pregnant women with prosthetic heart valves", section on
'Preconception evaluation and counseling' and "Supraventricular arrhythmias during pregnancy", section on
'Anticoagulation'.)
Initiating LMW heparin For women who are not receiving chronic anticoagulation but require anticoagulation
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during pregnancy (eg, for thromboprophylaxis), anticoagulation is initiated when pregnancy is established rather than
before conception. For these women, LMW heparin is generally started in the first trimester after pregnancy is
confirmed by a positive pregnancy test, as long as there is no vaginal bleeding.
ADMINISTRATION Low molecular weight (LMW) and unfractionated heparin are usually administered
subcutaneously, although unfractionated heparin can also be administered intravenously to achieve a more constant
level of anticoagulation or during times when rapid discontinuation is advantageous (eg, delivery, surgery). (See
'Switch to unfractionated heparin' below.)
Injections are usually well tolerated. Ice applied to the proposed injection site for 20 minutes prior to the injection can
help to minimize bruising, although this generally is not necessary.
Baseline laboratory testing We obtain a baseline platelet count in all patients to monitor for heparin-induced
thrombocytopenia. For patients on LMW heparin and unfractionated heparin, we assess the platelet count on day 3,
weekly during the first two weeks, and monthly thereafter. Platelet count should also be checked if thrombosis occurs
while on any form of heparin. (See 'Suspected heparin-induced thrombocytopenia' below.)
We also obtain a baseline serum creatinine level in all patients. Patients with diminished renal function may require
more intensive monitoring or use of unfractionated rather than LMW heparin. (See 'Choice of anticoagulant' above.)
Preservative-free vials The multi-dose vials of LMW and unfractionated heparin contain benzyl alcohol and/or
other preservatives; alcohols can have adverse fetal effects and are contraindicated in pregnancy. Prefilled, single
dose syringes are generally preservative-free. Confirmation of the absence of preservatives from the product label is
advised.
Dosing and laboratory monitoring Anticoagulants such as LMW heparin can be administered at different doses
depending upon the risk of thromboembolism and desired degree of anticoagulation (table 2). The appropriate dosing
level is discussed in topic reviews that describe the indications for anticoagulation. (See "Inherited thrombophilias in
pregnancy" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".)
We use the following terminology to describe heparin anticoagulation dosing:
Prophylactic dose anticoagulation refers to the use of low doses of anticoagulants, which aims to reduce the
risk of thromboembolism while minimizing bleeding complications.
Intermediate dose anticoagulation refers to the adjustment of prophylactic dose anticoagulation with weight gain
during pregnancy. (See 'Prophylactic and intermediate dose' below.)
Therapeutic dose anticoagulation refers to the use of anticoagulants at doses typically reserved for treatment of
thromboembolic disease. Therapeutic dosing is used when lower dosing is thought to be insufficient for
thromboembolism prophylaxis in some patients at very high risk of thromboembolism. Despite the
nomenclature, therapeutic dosing may be used prophylactically (ie, to prevent thromboembolism in the setting
of severe thrombophilias, mechanical heart valves and other high risk situations). For LMW heparin, therapeutic
dosing is based on weight and anti-factor Xa levels. For unfractionated heparin, therapeutic dosing is titrated to
keep the activated partial thromboplastin time in the therapeutic range (eg, 1.5 to 2.5 times baseline). (See
'Therapeutic dose' below.)
Dosing regimens for prophylactic and therapeutic LMW and unfractionated heparin are summarized in the table
(table 3) and below.
Dosing of heparins in pregnancy is altered because pregnancy-associated weight gain and metabolism affect the
pharmacokinetics of these agents. [22-26]. Higher doses are necessary compared with nonpregnant women due to
alterations in a variety of factors (eg, metabolism, plasma volume, renal clearance) [27-29]. In a study of LMW
heparin pharmacokinetics in 24 women at 12, 24, and 36 weeks of gestation and six weeks postpartum, peak
anti-factor Xa activity levels during pregnancy were lower than in nonpregnant (postpartum) women and occurred
later after injection (four versus two hours) [30].
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Prophylactic and intermediate dose

LMW heparin Prophylactic dose LMW heparin uses a fixed dose of anticoagulant (eg, dalteparin 5000
units subcutaneously every 24 hours; enoxaparin 40 mg subcutaneously every 24 hours) with adjustment for
extremes of body weight (table 3).
Due to concerns that standard prophylactic dose LMW heparin may not adequately prevent VTE in women at
intermediate risk, we often increase LMW heparin dosing as the pregnancy progresses and the patient's weight
increases, up to a maximum dose of enoxaparin 1 mg/kg once daily (ie, "intermediate dosing") (table 3). The
frequency of dose increases is individualized depending on the interval between office visits. This use of increased
dosing is based on findings from pharmacokinetic studies that suggested a greater dose requirement in most women
after 20 weeks of gestation [22]. Intermediate dosing provides a higher dose than standard prophylactic regimens of
LMW heparin, but with only a single daily injection, which is better tolerated than twice daily injections.
Support for our approach comes from a retrospective study that found a high incidence of VTE in high-risk pregnant
women who were treated with standard prophylactic dose LMW heparin [31]. This study included 34 women (44
pregnancies) at intermediate risk of VTE who received prophylactic dose LMW heparin for six weeks postpartum, and
57 women (82 pregnancies) at high risk of VTE who received both antepartum and postpartum prophylactic dose
LMW heparin. All VTE events occurred in the high-risk patients (postpartum VTE incidence 7.0 percent, 95% CI
2.916.7; antepartum incidence 1.8 percent, 95% CI 0.49.2). These results suggested that low-dose LMW heparin
prophylaxis may not be sufficient in high-risk patients.
Monitoring of prophylactic or intermediate dose LMW heparin is not required.
Unfractionated heparin Unfractionated heparin is given subcutaneously every 12 hours, with increasing
doses as the pregnancy progresses, from 5000 to 7500 units in the first trimester, to 7500 to 10,000 units in the
second trimester, to 10,000 units in the third trimester (reduce if the activated partial thromboplastin time [aPTT] is
elevated) [32,33]. Some clinicians use 5000 units subcutaneously every 12 hours throughout the pregnancy, but
studies have suggested that this dose is probably insufficient in some patients based on plasma heparin levels
[28,34-37].
Monitoring of prophylactic dose unfractionated heparin is generally not performed, although the aPTT can be
measured if there are concerns about bleeding or thrombosis.
Therapeutic dose
LMW heparin Therapeutic doses of LMW heparin based on body weight are usually administered every 12
hours by subcutaneous injection (table 3). Our preference is enoxaparin 1 mg/kg every 12 hours or dalteparin 100
units/kg every 12 hours; we do not employ once daily regimens (enoxaparin 1.5 mg/kg or dalteparin 200 units/kg
once daily) because we wish to avoid higher peak and lower trough levels.
We do not monitor laboratory values (eg, anti-factor Xa activity levels) in pregnant women treated with therapeutic
dose LMW heparin in routine clinical practice, although some experts do recommend such monitoring. If monitoring is
done, peak anti-factor Xa activity levels are tested four to six hours after dosing, with dose adjustment titrated to
achieve the manufacturer's recommended level (eg, 0.6 to 1.0 units/mL) [33]. Data supporting the need for laboratory
monitoring of therapeutic dose LMW heparin are sparse [30,38,39]. (See "Clinical use of coagulation tests", section
on 'Anti-factor Xa activity'.)
Unfractionated heparin Therapeutic dose unfractionated heparin is administered every 12 hours by
subcutaneous injection and titrated based on the aPTT. In some patients, the volume of medication in the injection
may become unacceptably high; this can be avoided by using more concentrated heparin solutions (eg, 20,000
units/mL). Heparin can be administered intravenously if the need for rapid discontinuation is likely (eg, imminent
labor, surgery).
Unfractionated heparin is monitored using the aPTT, measured six hours after injection. The dose should be adjusted
to maintain the aPTT at 1.5 to 2.5 times the mean of the control value or the patient's baseline aPTT value (table 4).
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We monitor the aPTT daily until the proper dose is achieved and every one to two weeks once it is in the therapeutic
range.
Intravenous heparin dosing and heparin dose monitoring in individuals with a baseline prolonged aPTT (eg, those
with antiphospholipid syndrome) are discussed separately. (See "Therapeutic use of unfractionated heparin and low
molecular weight heparin", section on 'Prolonged baseline aPTT'.)
PREVENTION OF THROMBOSIS AND BLEEDING Anticoagulants are administered to patients at increased risk
of thromboembolic disease, and this risk, although mitigated by therapy, persists and may increase during pregnancy.
Pregnant women should thus be aware of the signs and symptoms of thromboembolism (eg, leg swelling, pleuritic
chest pain, central nervous system symptoms) and have instructions to contact their clinician should these occur.
(See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis" and "Cerebrovascular
disorders complicating pregnancy".)
Concerns about excess bleeding in a patient receiving low molecular weight (LMW) or unfractionated heparin apply
only to the mother, since heparins do not cross the placenta. Patients should be educated about the signs and
symptoms of bleeding and instructed to contact their provider in the event of a bleed.
Other than appropriate dosing and monitoring, strategies to decrease the risk of bleeding include the following:
Convert from subcutaneous LMW heparin to unfractionated heparin prior to delivery, and from subcutaneous
unfractionated heparin to intravenous unfractionated heparin prior to anticipated delivery in those who require
more continuous anticoagulation. Discontinue heparin at the onset of labor. Maximum control of anticoagulation
can be achieved if the timing of delivery is planned (scheduled cesarean or induction of labor). (See 'Switch to
unfractionated heparin' below.)
If preterm labor develops in a patient receiving heparin, protamine sulfate has been used to reverse maternal
heparinization. However, it is best to avoid administration of protamine antepartum unless hemorrhage cannot
be controlled using routine supportive measures. (See "Therapeutic use of unfractionated heparin and low
molecular weight heparin", section on 'Reversal (protamine)' and "Therapeutic use of unfractionated heparin
and low molecular weight heparin", section on 'Bleeding'.)
Place or remove a neuraxial needle or catheter only after the patient is no longer anticoagulated. (See
'Neuraxial anesthesia' below.)
MANAGEMENT OF COMPLICATIONS
Treatment of bleeding on heparin Protamine sulfate can be used to rapidly reverse the effects of unfractionated
heparin in patients with serious or severe bleeding unrelated to pregnancy; patients at risk of severe bleeding
because of imminent vaginal or cesarean delivery; or patients at risk of serious or severe bleeding due to antepartum
complications (eg, placental abruption, placenta previa, expanding subchorionic hematoma). Repeated small doses
of protamine may be required because of ongoing absorption of heparin from subcutaneous tissue. (See
"Therapeutic use of unfractionated heparin and low molecular weight heparin", section on 'Reversal (protamine)'.)
Low molecular weight (LMW) heparin may not be completely reversed by protamine, but protamine may reduce
bleeding and should be used if bleeding is severe. (See "Therapeutic use of unfractionated heparin and low
molecular weight heparin", section on 'Reversal (protamine)'.)
Minor bleeding that is easily visible (eg, spotting) does not require pharmacologic reversal of anticoagulation. If
bleeding persists, one option is to withhold anticoagulation, if possible, until the bleeding stops and then resume the
anticoagulant. Such decisions depend on the degree and site of bleeding and the indication for anticoagulation, and
are made on a case-by-case basis by the hematologist and obstetrician.
Patients with bleeding who require VTE prophylaxis can be managed with mechanical means or vena cava filters if
needed; these interventions are discussed separately. (See "Prevention of venous thromboembolic disease in acutely
ill hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis' and "Deep vein thrombosis
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and pulmonary embolism in pregnancy: Treatment", section on 'Inferior vena cava filters'.)
Suspected heparin-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) is an adverse reaction
to heparin in which an antibody to platelets is induced by the drug. Unlike other drug-induced thrombocytopenias, the
HIT antibody causes platelet activation that can result in life-threatening arterial and venous thrombosis. (See
"Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and 'HIT during or immediately preceding
pregnancy' below.)
HIT can occur in any patient receiving any amount of heparin; however, the incidence in pregnant women is very low.
This was illustrated in a meta-analysis of 2777 pregnancies during which LMW heparin was administered; no
instances of HIT were reported [6]. LMW heparin appears less likely to precipitate HIT compared with unfractionated
heparin in some populations (eg, surgical patients); this has not been studied in pregnancy [3].
Any patient who develops thrombocytopenia while receiving heparin should have a clinical evaluation for HIT that
includes platelet count and assessment for thrombosis and/or skin changes. Those with a high clinical suspicion for
HIT should have immediate discontinuation of heparin, institution of an alternative anticoagulant, and laboratory
testing for HIT. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on
'Evaluation' and 'HIT during or immediately preceding pregnancy' below.)
Of note, a modest decrease in platelet count is expected during pregnancy and should not prompt laboratory testing
for HIT. (See "Thrombocytopenia in pregnancy", section on 'Gestational thrombocytopenia'.)
In addition to evaluation for HIT, pregnant patients with a drop in platelet count that is greater than expected should
be evaluated for other potential causes of thrombocytopenia besides HIT. (See "Thrombocytopenia in pregnancy".)
Bone loss Prolonged use of unfractionated heparin (ie, more than a few weeks) is associated with decreases in
bone mineral density (BMD). Women taking unfractionated heparin for more than a few weeks should have adequate
intake of calcium and vitamin D, and regular weight bearing exercise (eg, walking) should be encouraged. (See
"Prevention of osteoporosis", section on 'Minimizing bone loss'.)
It is unclear whether bone loss may be reduced or prevented by using LMW heparin instead of unfractionated
heparin. A study that randomly assigned 44 pregnant women to receive either dalteparin (target anti-Xa greater than
0.20 international units/mL three hours after injection) or unfractionated heparin (mean dose 17,250 units/day) found
that mean BMD in the lumbosacral spine was significantly lower with unfractionated heparin at one week to three
years postpartum; those who received LMW heparin had similar BMD to postpartum women who were not exposed
to any form of heparin [40]. Other studies have found no difference in the effect of LMW versus unfractionated
heparin on BMD [41]. (See "Drugs that affect bone metabolism", section on 'Anticoagulants'.)
LABOR AND DELIVERY Anticoagulation during labor should be avoided except in the highest risk settings (eg,
reduced cardiopulmonary reserve and recent pulmonary embolus).
Switch to unfractionated heparin With limited exceptions (eg, for patients with mechanical heart valves), most
obstetricians prefer that therapeutic dose low molecular weight (LMW) heparin be replaced with unfractionated
heparin at 36 to 37 weeks of gestation, or earlier in the event of threatened preterm birth. In contrast, patients with
mechanical valves are generally switched to unfractionated heparin later, as discussed separately. (See
"Management of pregnant women with prosthetic heart valves", section on 'Delivery'.)
Switching to unfractionated heparin increases the patient's likelihood of being able to receive neuraxial anesthesia
and may decrease the risk of bleeding associated with delivery. Subcutaneous unfractionated heparin is discontinued
for most patients when spontaneous labor begins, or 24 hours before planned induction of labor or cesarean delivery
[33]. We do not administer a reversal agent (eg, protamine) unless there is excessive or unexpected bleeding due to
the anticoagulant.
Some patients have a strong need for ongoing anticoagulation (eg, atrial fibrillation with thrombus, pulmonary
embolism within a few weeks prior to delivery), and a period of 24 or 36 hours without anticoagulation may be
undesirable. Details of management in these settings are presented separately. (See "Management of pregnant
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women with prosthetic heart valves", section on 'Delivery' and "Deep vein thrombosis and pulmonary embolism in
pregnancy: Treatment", section on 'Labor and delivery'.)
Women who are anticoagulated with heparin until the onset of labor and deliver vaginally generally do not have
greater blood loss than non-anticoagulated women. However, cesarean delivery in patients on heparin may be
accompanied by increased wound complications or greater blood loss than would otherwise be anticipated in a
woman not receiving an anticoagulant [42-44].
Neuraxial anesthesia A catheter for neuraxial anesthesia should not be inserted if a patient is anticoagulated,
due to the risk of spinal or epidural hematoma. Therefore, anticoagulation is discontinued before labor so women can
receive neuraxial anesthesia, which is performed for >95 percent of cesarean deliveries and >60 percent of women
undergoing labor and vaginal delivery in the United States [45]. Examples of the interval between anticoagulant
discontinuation and placement of a neuraxial catheter include the following (table 5):
Prophylactic dose LMW heparin After at least 12 hours have elapsed since the last dose.
Intermediate and therapeutic dose LMW heparin After at least 24 hours have elapsed since the last dose.
Prophylactic and therapeutic dose unfractionated heparin Once the activated partial thromboplastin time
(aPTT) has normalized following discontinuation (timing depends on dose, typically within six hours for
prophylactic doses and 12 hours with therapeutic doses).
Further details, and timing of anticoagulant resumption after catheter removal, are discussed in detail separately.
(See "Neuraxial (spinal, epidural) anesthesia in the patient receiving anticoagulant or antiplatelet medication".)
POSTPARTUM AND BREASTFEEDING
Resuming or initiating anticoagulation postpartum Anticoagulation is reinstituted following delivery in most
patients who were receiving an anticoagulant during pregnancy; a possible exception is patients who received
anticoagulation to prevent miscarriage or fetal loss.
For women with acute venous thromboembolism (VTE) who are still in the active treatment period (ie, first three
months) or who have other indications requiring continuous anticoagulation (eg, high-risk thrombophilia),
concurrent unfractionated heparin or low molecular weight (LMW) heparin at therapeutic doses should be
administered along with warfarin for a minimum of five days and an additional one to two days after an
appropriate International Normalized Ratio (INR) has been obtained.
The unfractionated heparin or LMW heparin can be resumed four to six hours after vaginal delivery or 6 to 12
hours after cesarean delivery, unless there was significant bleeding.
Resumption of anticoagulation for women with mechanical heart valves is discussed separately. (See
"Management of pregnant women with prosthetic heart valves", section on 'Postpartum'.)
Additional patients who were not receiving anticoagulation during pregnancy may initiate it postpartum for VTE
prevention (eg, some women with thrombophilia due to inherited defects or prior VTE who did not receive
anticoagulation during pregnancy). These indications are discussed separately. (See "Inherited thrombophilias
in pregnancy", section on 'Prevention of VTE' and "Deep vein thrombosis and pulmonary embolism in
pregnancy: Prevention".)
We initiate prophylactic doses of unfractionated heparin or LMW heparin 6 to 12 hours after vaginal delivery and
12 to 24 hours after cesarean delivery. If oral anticoagulation is chosen for continued postpartum
thromboprophylaxis, warfarin can be started immediately after delivery; unfractionated or LMW heparin can be
discontinued when a therapeutic INR has been obtained in women who are not at very high risk for thrombotic
complications.
Prophylactic anticoagulation for women who undergo cesarean delivery is discussed separately. (See "Cesarean
delivery: Preoperative issues", section on 'Thromboembolism prophylaxis'.)
Duration of postpartum anticoagulation The duration of postpartum anticoagulation depends upon the
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underlying reason for anticoagulation.

Women receiving anticoagulation for VTE prophylaxis during pregnancy should continue to receive
anticoagulation for at least six weeks postpartum, due to the continued high risk of VTE in the early postpartum
period. (See "Inherited thrombophilias in pregnancy" and "Deep vein thrombosis and pulmonary embolism in
pregnancy: Prevention", section on 'Duration'.)
The duration of anticoagulation for women who have had a VTE during pregnancy is discussed separately. (See
"Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)
Breastfeeding Many anticoagulants can be used during breastfeeding because they do not accumulate in breast
milk. The 2012 American College of Chest Physicians (ACCP) guidelines recommend continuation of the following
anticoagulants during breastfeeding [13]:
LMW heparin
Unfractionated heparin
Warfarin or other vitamin K antagonists
Danaparoid
Lepirudin (discontinued by the pharmaceutical company)
Continuation of low-dose aspirin for vascular indications is also suggested [13].
In contrast to the agents listed above, we do not use the following during breastfeeding, consistent with the 2012
ACCP guidelines [12]:
Oral direct thrombin inhibitors (eg, dabigatran)
Oral direct factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban)
Fondaparinux
If anticoagulation is required during breastfeeding, another agent should be selected.
Birth control in women with increased VTE risk Contraceptive options in women with inherited thrombophilias
are discussed separately. (See "Contraceptive counseling for women with inherited thrombophilias".)
SPECIFIC SCENARIOS
HIT during or immediately preceding pregnancy A prior episode of heparin-induced thrombocytopenia (HIT)
that has been adequately treated is not an indication for anticoagulation during pregnancy. However, if a pregnant
patient with a history of HIT requires anticoagulation for another reason, or if a patient develops HIT immediately prior
to or during pregnancy, an anticoagulant other than heparin should be used. All sources of heparin (including heparin
flushes) should be avoided.
The 2012 American College of Chest Physicians (ACCP) guidelines recommend danaparoid as the preferred
alternative to heparin for pregnant patients; this agent is not available in the United States [13]. For patients who
cannot receive danaparoid, argatroban or fondaparinux can be used. We generally use fondaparinux because of the
ease of administration during pregnancy. Other aspects of the management of HIT are discussed separately. (See
"Management of heparin-induced thrombocytopenia".)
The use of danaparoid, outside of the US, in women with HIT is supported by review of outcomes of 91 pregnancies
in 83 women with HIT who were treated with danaparoid; some of the patients also had antiphospholipid syndrome
[46]. Maternal adverse events included two post-cesarean deaths in the setting of placenta previa and placental
abruption (one from pulmonary embolus and one from bleeding in which the patient refused transfusion); three major
bleeds; three thromboembolic events; and 10 rashes. There were seven early miscarriages, one therapeutic
termination, and one neonatal death associated with a lupus anticoagulant and placental infarction [47]. Of note, HIT
is associated with a high baseline mortality, even with treatment. The live birth rate in this review was 90 percent,
which compares favorably with women treated with aspirin or heparin during pregnancy [46].
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We screen for HIT in pregnant patients receiving unfractionated or low molecular weight (LMW) heparin by checking
platelet counts before initiating heparin therapy and periodically thereafter. (See 'Suspected heparin-induced
thrombocytopenia' above.)
Thromboembolism during pregnancy If a new thromboembolic event is suspected during pregnancy, this
should be evaluated immediately. Diagnosis and management of venous thromboembolism (VTE) during pregnancy
is discussed separately. (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis" and
"Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)
Cesarean delivery Cesarean delivery increases the risk of VTE, especially when performed emergently.
Prevention of VTE in women undergoing cesarean delivery is reviewed separately. (See "Cesarean delivery:
Preoperative issues", section on 'Thromboembolism prophylaxis'.)
Women on warfarin Warfarin and other vitamin K antagonists cross the placenta; these agents can be
teratogenic and can cause fetal bleeding, including hemorrhagic fetal death. Thus, warfarin use is generally avoided
during pregnancy, or, rarely, restricted to the second and early third trimester. For women at exceptionally high
thromboembolic risk (eg, women with mechanical heart valves) the benefits and risks (including fetal risks) of
warfarin use are weighed during each phase of pregnancy (eg, first trimester versus later trimesters) and an
alternative anticoagulant is used as delivery approaches, as discussed in detail separately. (See "Management of
pregnant women with prosthetic heart valves".)
Warfarin-associated bleeding The management of excessive anticoagulation and/or bleeding in a pregnant
woman on warfarin depends on the original indication for warfarin therapy, the degree and site of bleeding, and the
International Normalized Ratio (INR). Thus, management decisions are made on a case-by-case basis in
consultation with the hematologist and other specialists (eg, cardiologist, neurologist, obstetrician). Available agents
for reversal (eg, fresh frozen plasma [FFP], unactivated prothrombin complex concentrates [PCCs]) and their use in
specific situations are discussed separately (See "Management of warfarin-associated bleeding or supratherapeutic
INR" and "Reversal of anticoagulation in warfarin-associated intracerebral hemorrhage".)
In the setting of preterm labor and/or unplanned delivery in a woman on warfarin, it is important to remember that the
fetus is anticoagulated. (See 'Delivery' below.)
Warfarin teratogenicity Warfarin is a teratogen. The precise incidence of warfarin embryopathy is unknown,
with different series reporting widely ranging incidences; the best overall estimate of the risk is less than 10 percent.
The teratogenic effect appears to be dose-related rather than correlating with maternal INR; doses less than 5
mg/day appear to provide the highest margin of safety [48,49].
The risk of teratogenicity is greatest for fetuses exposed to warfarin between the sixth and 12th weeks of gestation
[34], but toxicity before or after this period is still possible [50-53]. As an example, the following findings were noted in
report of 72 pregnancies in women with prosthetic cardiac valves who were treated with warfarin [19]:
Virtually no embryopathic events occurred in the 23 pregnancies in which warfarin was discontinued by the sixth
week of gestation and not restarted until after the 12th week.
Warfarin embryopathy occurred in 25 percent of the 12 pregnancies in which warfarin was not stopped until
after the seventh week.
Embryopathy occurred in 30 percent of the 37 pregnancies in which warfarin was continued throughout the
entire pregnancy.
The most common developmental abnormalities affect bone and cartilage; these simulate chondromalacia punctata,
with stippled epiphyses and nasal and limb hypoplasia [34]. The mechanism of this type of warfarin teratogenicity has
not been established, but may be related to the drug's interference with the post-translational modification of calciumbinding proteins that are important for the normal growth and development of bony structures [20]. (See "Vitamin K
and the synthesis and function of gamma carboxyglutamic acid".)
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Less well-documented are reports of central nervous system abnormalities (eg, optic atrophy, microcephaly, mental
retardation, spasticity, and hypotonia) associated with warfarin use at any stage during pregnancy [7,54-57]. This
complication may be related to fetal anticoagulation leading to cerebral hemorrhage.
Attempted conception/first trimester Women taking warfarin prior to conception should have a clear plan to
switch to another anticoagulant (eg, LMW heparin) during attempted conception or upon becoming pregnant, in order
to avoid teratogenic effects of the drug during the first trimester.
The optimal timing for changing to LMW heparin is unclear, and it is necessary to balance the importance of avoiding
warfarin during early pregnancy/organogenesis with the inconvenience of using LMW heparin for an undefined period
until conception occurs. The two major options are to change to LMW heparin during attempted conception, or to wait
until pregnancy is confirmed before changing from warfarin to LMW heparin, as long as the switch can be made
before six weeks of pregnancy (ie, 14 days after the missed first day of expected menses).
The 2012 ACCP guidelines have made a weak suggestion in favor of performing frequent pregnancy tests and
substituting treatment with LMW heparin as soon as pregnancy is achieved, rather than changing to LMW heparin
while attempting pregnancy [13]. (See 'Society guidelines' below.)
We believe that this is a reasonable option for a woman who meets all of the following criteria:
She has regular monthly menstrual cycles.
She agrees to have a blood pregnancy test within the first seven days of the missed first day of expected
menses. This can be facilitated by having a standing order at a laboratory or giving her laboratory requisitions in
advance.
She can be switched to a LMW heparin preparation promptly if the pregnancy test is positive, and will have a
second blood pregnancy test if the first test is negative and menses have not begun within 10 days of the
missed first day of expected menses. This can be facilitated by having a prescription for LMW heparin readily
available or filled in advance.
She understands the increased risk and types of embryopathy if she continues to take her long-term vitamin K
antagonist during or after the sixth week of pregnancy (ie, 14 days after the missed first day of expected
menses). (See 'Warfarin teratogenicity' above.)
Women who do not meet all of the above criteria; those who prefer to minimize the possible increased risk of early
miscarriage associated with warfarin therapy; and those who place less value on avoiding risks, inconveniences, and
costs of LMW heparin of uncertain duration should be switched to LMW heparin during attempted conception. An
exception is a woman with a mechanical heart valve, for whom warfarin generally is continued during attempted
conception, as discussed separately. (See "Management of pregnant women with prosthetic heart valves", section on
'Anticoagulation for mechanical valves'.)
If a woman becomes pregnant while taking warfarin, LMW heparin should be substituted as soon as possible. Prompt
obstetric consultation should be obtained to establish the gestational age of the fetus and to provide appropriate
counseling regarding any potential teratogenic risk to the fetus.
Delivery The risk of fetal hemorrhage related to warfarin use is thought to be greatest during and immediately
after delivery [19,48,56-60]. If warfarin is used during pregnancy, it should be discontinued after 34 to 36 weeks of
gestation, and an alternative anticoagulant substituted if appropriate. (See 'Switch to unfractionated heparin' above.)
If preterm delivery occurs in a patient receiving warfarin, cesarean delivery should be considered to reduce the risk of
fetal bleeding [34]. Vitamin K and fresh frozen plasma should be administered to the neonate if preterm delivery
occurs in a patient receiving warfarin.
The immaturity of fetal enzyme systems and the relatively low concentration of vitamin K-dependent clotting factors
render the fetus more sensitive than the mother to the anticoagulant effects of warfarin [7,54,55]. Importantly, fetal
levels of coagulation factors do not correlate with maternal levels, and infusion of fresh frozen plasma into the mother
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does not reliably reverse fetal anticoagulation.

Women on direct thrombin inhibitors or factor Xa inhibitors Direct thrombin inhibitors and factor Xa inhibitors
are not used during pregnancy. A woman taking one of these agents who plans to become pregnant should be
monitored very closely as described for women taking warfarin. (See 'Attempted conception/first trimester' above.)
If a woman taking one of these agents becomes pregnant, she should switch immediately to LMW heparin.
SOCIETY GUIDELINES Guidelines for the use of anticoagulants have been published by the following societies:
American College of Chest Physicians (ACCP) [13]
American College of Obstetricians and Gynecologists (ACOG) [61]
European Society of Cardiology (ESC) [62]
Our practices are largely consistent with these guidelines, with the acknowledgement that most of the data on which
recommendations are based are not from randomized trials.
SUMMARY AND RECOMMENDATIONS
For most patients who require anticoagulation during pregnancy (with the exception of patients with mechanical
heart valves), heparins are safer than other anticoagulants. For such patients, we recommend low molecular
weight (LMW) heparin rather than unfractionated heparin for all but the final weeks of the pregnancy (Grade
1B). This is based on the ease of administration of LMW heparin compared with unfractionated heparin.
Unfractionated heparin is a reasonable alternative when cost or need for rapid reversal is important, and it is the
preferred agent for patients with severe renal insufficiency (eg, creatinine clearance 30 mL/min) and for all
patients in preparation for labor and delivery. (See 'Choice of anticoagulant' above.)
The choice of anticoagulant in pregnant women with mechanical heart valves is discussed separately. (See
"Management of pregnant women with prosthetic heart valves".)
LMW heparin can be administered at different doses depending upon the risk of thromboembolism and desired
degree of anticoagulation (table 2). The general terms "therapeutic dose" and "prophylactic dose" are used to
convey the intensity of anticoagulation and vary depending upon the agent used (table 3). It is important to use
preservative-free preparations. We obtain a baseline creatinine level and platelet count prior to initiating LMW or
unfractionated heparin, and monitor platelet counts during heparin administration. (See 'Administration' above.)
Choice of the appropriate dosing level is discussed in separate topic reviews on indications for anticoagulation:
Inherited thrombophilia (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE'.)
Prior venous thromboembolism (See "Deep vein thrombosis and pulmonary embolism in pregnancy:
Prevention", section on 'Indications'.)
Bleeding is a risk with any anticoagulant. Management of bleeding depends on the degree and site of bleeding,
and the original indication for anticoagulation, and decisions regarding discontinuation and reversal of
anticoagulants are made on a case-by-case basis in consultation with a hematologist and other specialists.
(See 'Prevention of thrombosis and bleeding' above and 'Treatment of bleeding on heparin' above.)
Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin; the incidence of HIT during
pregnancy is very low. We monitor for HIT by assessing the patient's platelet count periodically during LMW or
unfractionated heparin administration. Patients with suspected HIT should have an immediate assessment of
clinical parameters (eg, platelet count, presence of thrombosis or skin changes); for those considered to a high
likelihood of HIT, an alternate anticoagulant should be substituted and laboratory testing for HIT should be
obtained. (See 'Suspected heparin-induced thrombocytopenia' above and 'HIT during or immediately preceding
pregnancy' above.)
Anticoagulation during labor should be avoided; most obstetricians replace therapeutic dose LMW heparin with
unfractionated heparin at 36 to 37 weeks of gestation to reduce the risk of bleeding associated with delivery. An
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exception is women with mechanical heart valves, for whom the switch to unfractionated heparin generally is
made later. (See 'Switch to unfractionated heparin' above.)
A catheter for neuraxial anesthesia cannot be inserted if a patient is anticoagulated. The length of time without
anticoagulation prior to neuraxial anesthesia depends upon the agent and dose used. (See 'Neuraxial
anesthesia' above.)
Anticoagulation is reinstituted following delivery in most patients who were receiving an anticoagulant during
pregnancy; additional patients may initiate anticoagulation postpartum for venous thromboembolism (VTE)
prophylaxis. Unfractionated or LMW heparin can be resumed at prophylactic doses as early as four to six hours
after vaginal delivery and 6 to 12 hours after cesarean delivery unless there was significant bleeding, although
for most patients we wait 6 to 12 hours after vaginal delivery and 12 to 24 hours after cesarean. Many
anticoagulants (eg, heparins, warfarin) can be used during breastfeeding because they do not accumulate in
breast milk. (See 'Postpartum and breastfeeding' above.)
Women receiving chronic anticoagulation who are contemplating pregnancy need counseling regarding
avoidance of the potential teratogenic effects of oral anticoagulants (eg, warfarin). Warfarin, oral direct thrombin
inhibitors, and factor Xa inhibitors should not be continued during the first trimester, and a switch should be
made to LMW heparin either before attempted conception or immediately upon confirmation of pregnancy. (See
'Women on warfarin' above and 'Women on direct thrombin inhibitors or factor Xa inhibitors' above and 'When to
start LMW heparin' above.)
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14. Elsaigh E, Thachil J, Nash MJ, et al. The use of fondaparinux in pregnancy. Br J Haematol 2015; 168:762.
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pregnancy. J Thromb Haemost 2010; 8:1876.
16. Tanimura K, Ebina Y, Sonoyama A, et al. Argatroban therapy for heparin-induced thrombocytopenia during
pregnancy in a woman with hereditary antithrombin deficiency. J Obstet Gynaecol Res 2012; 38:749.
17. Ekbatani A, Asaro LR, Malinow AM. Anticoagulation with argatroban in a parturient with heparin-induced
thrombocytopenia. Int J Obstet Anesth 2010; 19:82.
18. Young SK, Al-Mondhiry HA, Vaida SJ, et al. Successful use of argatroban during the third trimester of
pregnancy: case report and review of the literature. Pharmacotherapy 2008; 28:1531.
19. Iturbe-Alessio I, Fonseca MC, Mutchinik O, et al. Risks of anticoagulant therapy in pregnant women with
artificial heart valves. N Engl J Med 1986; 315:1390.
20. Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependent
coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of
coumarin derivatives. Am J Hum Genet 1987; 41:566.
21. Schaefer C, Hannemann D, Meister R, et al. Vitamin K antagonists and pregnancy outcome. A multi-centre
prospective study. Thromb Haemost 2006; 95:949.
22. Hunt BJ, Doughty HA, Majumdar G, et al. Thromboprophylaxis with low molecular weight heparin (Fragmin) in
high risk pregnancies. Thromb Haemost 1997; 77:39.
23. Thomson AJ, Walker ID, Greer IA. Low-molecular-weight heparin for immediate management of
thromboembolic disease in pregnancy. Lancet 1998; 352:1904.
24. Jacobsen AF, Qvigstad E, Sandset PM. Low molecular weight heparin (dalteparin) for the treatment of venous
thromboembolism in pregnancy. BJOG 2003; 110:139.
25. Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in
pregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004; 191:1024.
26. Norris LA, Bonnar J, Smith MP, et al. Low molecular weight heparin (tinzaparin) therapy for moderate risk
thromboprophylaxis during pregnancy. A pharmacokinetic study. Thromb Haemost 2004; 92:791.
27. Bremme K, Lind H, Blombck M. The effect of prophylactic heparin treatment on enhanced thrombin
generation in pregnancy. Obstet Gynecol 1993; 81:78.
28. Dahlman TC, Hellgren MS, Blombck M. Thrombosis prophylaxis in pregnancy with use of subcutaneous
heparin adjusted by monitoring heparin concentration in plasma. Am J Obstet Gynecol 1989; 161:420.
29. Chunilal SD, Young E, Johnston MA, et al. The APTT response of pregnant plasma to unfractionated heparin.
Thromb Haemost 2002; 87:92.
30. Sephton V, Farquharson RG, Topping J, et al. A longitudinal study of maternal dose response to low molecular
weight heparin in pregnancy. Obstet Gynecol 2003; 101:1307.
31. Roeters van Lennep JE, Meijer E, Klumper FJ, et al. Prophylaxis with low-dose low-molecular-weight heparin
during pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9:473.
32. Barbour LA, Smith JM, Marlar RA. Heparin levels to guide thromboembolism prophylaxis during pregnancy. Am
J Obstet Gynecol 1995; 173:1869.
33. James A, Committee on Practice BulletinsObstetrics. Practice bulletin no. 123: thromboembolism in
pregnancy. Obstet Gynecol 2011; 118:718.
34. Barbour LA. Current concepts of anticoagulant therapy in pregnancy. Obstet Gynecol Clin North Am 1997;
24:499.
35. Bates SM, Ginsberg JS. How we manage venous thromboembolism during pregnancy. Blood 2002; 100:3470.
36. Friedrich E, Hameed AB. Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation in
pregnancy. J Perinatol 2010; 30:253.
37. Brancazio LR, Roperti KA, Stierer R, Laifer SA. Pharmacokinetics and pharmacodynamics of subcutaneous
heparin during the early third trimester of pregnancy. Am J Obstet Gynecol 1995; 173:1240.
38. Gyamfi C, Cohen R, Desancho MT, Gaddipati S. Prophylactic dosing adjustment in pregnancy based upon
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measurements of anti-factor Xa levels. J Matern Fetal Neonatal Med 2005; 18:329.

39. Fox NS, Laughon SK, Bender SD, et al. Anti-factor Xa plasma levels in pregnant women receiving low
molecular weight heparin thromboprophylaxis. Obstet Gynecol 2008; 112:884.
40. Pettil V, Leinonen P, Markkola A, et al. Postpartum bone mineral density in women treated for
thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost 2002; 87:182.
41. Backos M, Rai R, Thomas E, et al. Bone density changes in pregnant women treated with heparin: a
prospective, longitudinal study. Hum Reprod 1999; 14:2876.
42. Limmer JS, Grotegut CA, Thames E, et al. Postpartum wound and bleeding complications in women who
received peripartum anticoagulation. Thromb Res 2013; 132:e19.
43. Knol HM, Schultinge L, Veeger NJ, et al. The risk of postpartum hemorrhage in women using high dose of
low-molecular-weight heparins during pregnancy. Thromb Res 2012; 130:334.
44. Snijder CA, Cornette JM, Hop WC, et al. Thrombophylaxis and bleeding complications after cesarean section.
Acta Obstet Gynecol Scand 2012; 91:560.
45. Osterman MJ, Martin JA. Epidural and spinal anesthesia use during labor: 27-state reporting area, 2008. Natl
Vital Stat Rep 2011; 59:1.
46. Magnani HN. An analysis of clinical outcomes of 91 pregnancies in 83 women treated with danaparoid
(Orgaran). Thromb Res 2010; 125:297.
47. van Besien K, Hoffman R, Golichowski A. Pregnancy associated with lupus anticoagulant and heparin induced
thrombocytopenia: management with a low molecular weight heparinoid. Thromb Res 1991; 62:23.
48. Cotrufo M, De Feo M, De Santo LS, et al. Risk of warfarin during pregnancy with mechanical valve prostheses.
Obstet Gynecol 2002; 99:35.
49. Vitale N, De Feo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women
with mechanical heart valves. J Am Coll Cardiol 1999; 33:1637.
50. Stevenson RE, Burton OM, Ferlauto GJ, Taylor HA. Hazards of oral anticoagulants during pregnancy. JAMA
1980; 243:1549.
51. Chong MK, Harvey D, de Swiet M. Follow-up study of children whose mothers were treated with warfarin during
pregnancy. Br J Obstet Gynaecol 1984; 91:1070.
52. Whitfield MF. Chondrodysplasia punctata after warfarin in early pregnancy. Case report and summary of the
literature. Arch Dis Child 1980; 55:139.
53. Zakzouk MS. The congenital warfarin syndrome. J Laryngol Otol 1986; 100:215.
54. Beeley L. Adverse effects of drugs in the first trimester of pregnancy. Clin Obstet Gynaecol 1986; 13:177.
55. Beeley L. Adverse effects of drugs in later pregnancy. Clin Obstet Gynaecol 1986; 13:197.
56. Ginsberg JS, Chan WS, Bates SM, Kaatz S. Anticoagulation of pregnant women with mechanical heart valves.
Arch Intern Med 2003; 163:694.
57. Ginsberg JS, Hirsh J, Turner DC, et al. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb
Haemost 1989; 61:197.
58. Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent
thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol
1996; 27:1698.
59. Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve prostheses. Br Heart J 1994; 71:196.
60. Wong V, Cheng CH, Chan KC. Fetal and neonatal outcome of exposure to anticoagulants during pregnancy.
Am J Med Genet 1993; 45:17.
61. American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics. ACOG
Practice Bulletin No. 111: Inherited thrombophilias in pregnancy. Obstet Gynecol 2010; 115:877.
62. European Society of Gynecology (ESG), Association for European Paediatric Cardiology (AEPC), German
Society for Gender Medicine (DGesGM), et al. ESC Guidelines on the management of cardiovascular diseases
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European Society of Cardiology (ESC). Eur Heart J 2011; 32:3147.
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Topic 1342 Version 26.0
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GRAPHICS
Drug ratings in pregnancy (US Food and Drug Administration)
Category
A
Interpretation
Controlled human studies show no risk
Controlled studies in pregnant women fail to demonstrate a risk to the fetus in the
first trimester with no evidence of risk in later trimesters. The possibility of fetal
harm appears remote.
No evidence of risk in studies

Either animal reproduction studies have not demonstrated a fetal risk but there are
no controlled studies in pregnant women, or animal-reproduction studies have
shown an adverse effect (other than a decrease in fertility) that was not confirmed in
controlled studies in women in the first trimester and there is no evidence of a risk in
later trimesters.
Risk cannot be ruled out

Either studies in animals have revealed adverse effects on the fetus (teratogenic or
embryocidal effects or other) and there are no controlled studies in women, or
studies in women and animals are not available. Drugs should be given only if the
potential benefits justify the potential risk to the fetus.
Positive evidence of risk

There is positive evidence of human fetal risk, but the benefits from use in pregnant
women may be acceptable despite the risk (eg, if the drug is needed in a
life-threatening situation or for a serious disease for which safer drugs cannot be
used or are ineffective).
Contraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal abnormalities or there
is evidence of fetal risk based on human experience, or both, and the risk of the use
of the drug in pregnant women clearly outweighs any possible benefit. The drug is
contraindicated in women who are or may become pregnant.
In 2015, the US Food and Drug Administration (FDA) began overseeing the phase-out of pregnancy
risk categories (A, B, C, D, and X) from prescription drug labeling and began requiring information
from available human and animal studies of (1) known or potential maternal or fetal adverse
reactions, and (2) dose adjustments needed during pregnancy and the postpartum period. Additional
information is available at the FDA website: Pregnancy and Lactation Labeling Final Rule.
Reproduced with permission from: Lexicomp Online. Copyright 1978-2015 Lexicomp, Inc. All Rights
Reserved.
Graphic 50021 Version 23.0
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ACOG recommended thromboprophylaxis for pregnancies complicated

by inherited thrombophilias*
Clinical scenario
Antepartum
Postpartum
management
management
Lower-risk thrombophilia
Surveillance without
Postpartum anticoagulation
without previous VTE
anticoagulation therapy
therapy for patients with
Low-risk thrombophila with a
family history (first-degree
relative) of VTE
additional risks factors
therapy or intermediate-dose
LMWH/UFH
Low-risk thrombophilia with a
Prophylactic or
single previous episode of VTE -
intermediate-dose LMWH/UFH
therapy or intermediate-dose
not receiving long-term
or surveillance without
LMWH/UFH
High-risk thrombophilia
without previous VTE
anticoagulation therapy, or
prophylactic LMWH or UFH
therapy
High-risk thrombophilia with a
Prophylactic, intermediate-dose,
single previous episode of VTE
or adjusted-dose LMWH/UFH
therapy, or intermediate or
or an affected first-degree
regimen
adjusted-dose LMWH/UFH for
relative - not receiving
six weeks (therapy level should
long-term anticoagulation
be at least as high as
therapy
antepartum treatment)
No thrombophilia with previous
single episode of VTE associated
therapy
Prophylactic-dose LMWH or
with transient risk factor that is

no longer present - excludes
pregnancy- or estrogen-related
risk factor
single episode of VTE associated
UFH
therapy
with transient risk factor that

was pregnancy- or estrogenrelated
single episode of VTE without an
Prophylactic-dose LMWH or
UFH
therapy
Thrombophilia or no
Prophylactic or therapeutic-dose
thrombophilia with two or more

episodes of VTE - not receiving
LMWH
therapy
OR
OR
Prophylactic or therapeutic-dose
Therapeutic-dose LMWH/UFH for
UFH
six weeks
associated risk factor

(idiopathic) - not receiving
therapy
therapy
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Thrombophilia or no
thrombophilia with two or more
Therapeutic-dose LMWH or UFH
Resumption of long-term
episodes of VTE - Receiving

therapy
LMWH: low molecular weight heparin; UFH: unfractionated heparin; VTE: venous thromboembolism.
* Postpartum treatment levels should be greater or equal to antepartum treatment. Treatment of acute VTE
and management of antiphospholipid syndrome are addressed elsewhere.
Low-risk thrombophilia: factor V Leiden heterozygous; prothrombin G20210A heterozygous; protein C or
protein S deficiency.
First-degree relative with a history of a thrombotic episode before age 50 years, or other major
thrombotic risk factors (eg, obesity, prolonged immobility).
Intermediate dosing is variably defined in the literature. The American College of Chest Physicians has
defined it as a pregnancy LMWH regimen of enoxaparin 40 mg or dalteparin 5000 units given every 12
hours. In UpToDate, intermediate dosing refers to prophylactic LMWH dosing that is increased as the
pregnancy progresses and the patient's weight increases, up to a maximum dose of enoxaparin 1 mg/kg
once daily.
High-risk thrombophilia: antithrombin deficiency; double heterozygous for prothrombin G20210A mutation
and factor V Leiden; factor V Leiden homozygous or prothrombin G20210A mutation homozygous.
Surveillance without anticoagulation therapy is supported as an alternative approach by some experts.
Reproduced with permission from: ACOG Practice Bulletin #138. Thromboembolism in pregnancy. Obstet
Gynecol 2013; 122:706. DOI: 10.1097/01.AOG.0000433981.36184.4e. Copyright 2013 American College
of Obstetricians and Gynecologists. Unauthorized reproduction of this material is prohibited.
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Use of heparins during pregnancy

Heparin
LMW heparin
Dose level
Prophylactic*
Dosage
Enoxaparin 40 mg SC once daily
Dalteparin 5000 units SC once daily
Intermediate
Enoxaparin 40 mg SC once daily, increase as pregnancy

progresses to 1 mg/kg once daily
Dalteparin 5000 units once daily, increase as pregnancy
progresses to 100 units/kg once daily
Therapeutic
Enoxaparin 1 mg/kg every 12 hours

Dalteparin 100 units/kg every 12 hours
Unfractionated
Prophylactic
5000 units SC twice daily
heparin
Intermediate
First trimester: 5000 to 7500 units every 12 hours

Second trimester: 7500 to 10,000 units every 12 hours
Third trimester: 10,000 units every 12 hours
Therapeutic
Dose every 12 hours to keep aPTT at 1.5 to 2.5 times

control or patient's baseline six hours after dose
Doses apply to pregnant women receiving heparin for venous thromboembolism prophylaxis.
Therapeutic dose level refers to doses used both for prophylaxis in individuals at especially high risk
and for treatment of venous thromboembolism. This dosing table should not be used in women with
prosthetic heart valves. Refer to the UpToDate topic on anticoagulant use in pregnancy for details of
administration and monitoring. Refer to UpToDate topics on specific pregnant patient populations for
other dosing recommendations (eg, prosthetic heart valve, atrial fibrillation, treatment of deep vein
thrombosis or pulmonary embolism).
LMW: low molecular weight; SC: subcutaneously; aPTT: activated partial thromboplastin time.
* Prophylactic dosing may require modifications for extremes of body weight; refer to the UpToDate table
on LMW heparin dosing in obesity for details.
Our "intermediate" dose level differs from that used in society guidelines (eg, ACCP, ACOG).
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Example of a non-weight-based intravenous heparin protocol: Part II

titration based upon the activated partial thromboplastin time
IV infusion
aPTT
45
+6
Rate change,
Dose change,
mL/hour*
units/24-hour
+5760
Additional action
Repeated aPTT in 4 to
6 hours
46 to 54
+3
+2880
Repeated aPTT in 4 to
6 hours
55 to 85
None
86 to 110
2880
Stop heparin sodium

treatment for 1 hour;
repeated aPTT 4 to 6
hours after restarting
heparin treatment
>110
5760
Stop heparin treatment

for 1 hour; repeated
aPTT 4 to 6 hours after
restarting heparin
treatment
NOTE: This table reflects the original aPTT ranges, bolus sizes, and suggested changes in infusion
rate that were present at the time this study was performed. The therapeutic ranges (ie, relationship
between the aPTT and anti-factor Xa activity), initial and subsequent bolus sizes, and sizes of the
infusion rate changes, as well as dosing differences depending on the disorder under treatment (eg,
venous thromboembolism, stroke, acute coronary syndrome) should be established separately for
each institution.
aPTT: activated partial thromboplastin time; IV: intravenous.
* Heparin sodium concentration, 20,000 units in 500 mL = 40 units/mL.
With the use of Actin-FS thromboplastin reagent (Dade, Mississauga, Ontario).
During the first 24 hours, repeated aPTT in 4 to 6 hours. Thereafter, the aPTT will be determined once
daily, unless subtherapeutic.
Redrawn from: Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in
patients with venous thrombosis. Arch Intern Med 1992; 152:1589.
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Timing of neuraxial anesthesia during antithrombotic therapy
Anticoagulant
Warfarin
Interval from last

dose to
Interval from
placement/removal
placement/removal
to next dose
Notes
4 to 5 days, verify INR
Continue regular
<1.5; no monitoring
neurologic
needed for single dose
evaluation until 24
within 24 hours of
hours after
placement
removal. If dosed
with catheter in
place, check INR
daily and remove
when INR <1.5; if
INR 1.5-3.0,
remove catheter
with caution,
monitor neurologic
status until INR
stabilized; if INR
>3, hold/reduce
warfarin dose. Use
of antihemostatic
medications that do
not influence INR
may increase risk
of bleeding
complications.
Heparin
When heparin given
(unfractionated)
for >4 days, check

platelets (risk of
HIT) prior to
insertion or
removal
Therapeutic dosing
(IV)
2 to 4 hours, check for

normal aPTT
1 hour
Bloody/difficult needle
placement may
increase bleeding risk
with subsequent IV
heparin; use with
caution
Prophylactic dosing
Delaying heparin injection
(SC)
until after placement may

reduce risk
1 hour
No contraindication to
twice daily 5000
units; safety of higher
or more frequent
dosage is not
established
Low molecular weight
Anti-Xa level is not
heparin (LMWH)
predictive of the
risk of bleeding. Do
not use with
antoplatelet or oral
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anticoagulant
medications as this
increases risk of
spinal hematoma.
Therapeutic dosing
6 to 8 hours (placement), >4
Do not use
(SC) (enoxaparin 1
mg/kg every 12
>24 hours
hours (removal), delay 24
therapeutic dosing
with catheter in place
hours; enoxaparin
1.5 mg/kg daily;
placement; twice-daily
dalteparin 100-120
U/kg every 12
postop; once-daily dosing
hours; dalteparin
200 U/kg daily;
postop, second dose 24 hours
hours after traumatic

dosing, first dose >24 hours
first dose 6 to 8 hours
later
nadroparin 86 U/kg
every 12 hours;
nadroparin 171 U/kg
daily; tinzaparin 175
U/kg daily)
Prophylactic dosing
(SC) (enoxaparin 30
10 to 12 hours
6 to 8 hours (placement), >4
Do not use twice-daily
hours (removal), delay 24
dosing with catheter
mg every 12 hours;
enoxaparin 40 mg
hours after traumatic
in place, due to
placement; twice-daily
increased risk of
daily; dalteparin
2500-5000 U daily;
dosing, first dose >24 hours
spinal hematoma
nadroparin 2850 U
daily; nadroparin 38
first dose 6 to 8 hours

postop, second dose 24 hours
U/kg daily;
tinzaparin 50-75
later
postop; once-daily dosing,
U/kg daily;
tinzaparin 3500 U
daily)
Fondaparinux
36 to 42 hours (European
6 to 8 hours; avoid use
Do not use with
guidelines)
after traumatic neuraxial
catheter in place.
placement
(European
guidelines allow
epidural catheter
with prophylactic
dosing.) Limited
clinical experience.
Factor Xa inhibitors
(European
guidelines)
Antithrombotic
effect monitored
with PT, aPTT,
Heptest
Rivaroxaban
22 to 26 hours
4 to 6 hours
AHA recommends 3
to 5 days after last
dose; wait 24 hours
to redose
Apixaban
Thrombin inhibitors
26 to 30 hours
Avoid neuraxial techniques
4 to 6 hours
aPTT or thrombin
time
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Dabigatran
AHA recommends 5
days after last dose
(7 days for renal
failure); wait 4 hours
to redose
Argatroban
Hirudin derivatives
(desirudin,
bivalirudin)
Antiplatelet
Bleeding time does
medication
not predict
hemostatic
problems
P2Y12 receptor
blockers
Clopidogrel
7 days
After catheter removal
Prasugrel
7 to 10 days
6 hours after catheter

removal
Ticlodipine
14 days
After catheter removal
Ticagrelor
5 days
6 hours after catheter
European guidelines
European guidelines
removal
GP IIb/IIIa inhibitors
Contraindicated for 4
weeks after surgery;
monitor neurologic status
if given after neuraxial
technique
Tirofiban
4 to 8 hours
Eptifibatide
4 to 8 hours
Abciximab
24 to 48 hours
Aspirin
May continue dosage
May continue dosage
Affects platelet
function for the life
of the platelet.
Avoid neuraxial
techniques on
aspirin if early
postoperative use
of other
antihemostatic
drugs (including
heparin) is
anticipated.
NSAIDs (nonsteroidal
May continue dosage
May continue dosage
Effect on platelet
antiinflammatory
function normalizes
drugs)
within 3 days.
Avoid neuraxial
techniques on
NSAIDs if early
postoperative use
of other
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antihemostatic
drugs (including
heparin) is
anticipated. COX-2
inhibitors
(celecoxib) have
minimal effect on
platelet function.
Herbal medications
May continue dosage
May continue dosage
(garlic, ginkgo,
ginseng)
Concurrent use
with other
antihemostatic
drugs may increase
bleeding risk
INR: international normalized ration; PT: prothrombin time; aPTT: activated partial thromboplastin time;
HIT: heparin-induced thrombocytopenia; IV: intravenous; SC: subcutaneous; AHA: American Heart
Association.
Data from:
1. Horlocker TT, Wedel DJ, Rowlingon JC, et al. Regional anesthesia in the patient receiving
antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine
Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 2010; 35:64.
2. Gogarten W, Vandermuelen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents:
recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol 2010; 27:999.
3. Wysokinski WE, McBane RD. Periprocedural bridging management of anticoagulation. Circulation
2012; 126:486.
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Disclosures
Disclosures: Kenneth A Bauer, MD Consultant/Advisory Boards: Janssen Pharmaceuticals [Anticoagulation (Rivaroxaban)]; Daiichi Sankyo
[Anticoagulation (Edoxaban)]; Portola Pharmaceuticals [Anticoagulation reversal, anticoagulation (Andexanet, betrixaban)]; Instrumentation
Laboratory [Coagulation instruments/reagents (ACL TOP instruments and reagents)]. Lawrence LK Leung, MD Nothing to disclose. Charles J
Lockwood, MD, MHCM Consultant/Advisory Boards: Celula [Aneuploidy screening (Prenatal and cancer DNA screening tests in
development)]. Jennifer S Tirnauer, MD Nothing to disclose. Vanessa A Barss, MD, FACOG Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
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