Use of Anticoagulants During Pregnancy and Postpartum

Official reprint from UpToDatewww.uptodate.com ©2015 UpToDate

AuthorKenneth A Bauer, MD

Section EditorsLawrence LK Leung, MDCharles J Lockwood, MD, MHCM

Deputy EditorsJennifer S Tirnauer, MDVanessa A Barss, MD, FACOG

Use of anticoagulants during pregnancy and postpartum

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 disease-

specific topic reviews:

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).

®®

(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'.)●

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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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.

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.

●

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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Anticoagulants that are generally avoided during pregnancy

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

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'.)

●

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].

●


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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:

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].

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.)

●


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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

2.9–16.7; antepartum incidence 1.8 percent, 95% CI 0.4–9.2). 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:

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

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.)

●


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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):

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.

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

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).

●

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.


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underlying reason for anticoagulation.

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]:

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]:

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].

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".)

●

LMW heparin●

Unfractionated heparin●

Warfarin or other vitamin K antagonists●

Danaparoid●

Lepirudin (discontinued by the pharmaceutical company)●

Oral direct thrombin inhibitors (eg, dabigatran)●

Oral direct factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban)●

Fondaparinux●


9 of 26 9/3/2015 12:45 AM

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 12 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]:

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 calcium-

binding 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".)

th

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 12 week.

●th

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.

●


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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:

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

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.)

●


11 of 26 9/3/2015 12:45 AM

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:

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

American College of Chest Physicians (ACCP) [13]●

American College of Obstetricians and Gynecologists (ACOG) [61]●

European Society of Cardiology (ESC) [62]●

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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Elsaigh E, Thachil J, Nash MJ, et al. The use of fondaparinux in pregnancy. Br J Haematol 2015; 168:762.14.

Knol HM, Schultinge L, Erwich JJ, Meijer K. Fondaparinux as an alternative anticoagulant therapy duringpregnancy. J Thromb Haemost 2010; 8:1876.

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Tanimura K, Ebina Y, Sonoyama A, et al. Argatroban therapy for heparin-induced thrombocytopenia duringpregnancy in a woman with hereditary antithrombin deficiency. J Obstet Gynaecol Res 2012; 38:749.

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Ekbatani A, Asaro LR, Malinow AM. Anticoagulation with argatroban in a parturient with heparin-inducedthrombocytopenia. Int J Obstet Anesth 2010; 19:82.

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Young SK, Al-Mondhiry HA, Vaida SJ, et al. Successful use of argatroban during the third trimester ofpregnancy: case report and review of the literature. Pharmacotherapy 2008; 28:1531.

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Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependentcoagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity ofcoumarin derivatives. Am J Hum Genet 1987; 41:566.

20.

Schaefer C, Hannemann D, Meister R, et al. Vitamin K antagonists and pregnancy outcome. A multi-centreprospective study. Thromb Haemost 2006; 95:949.

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Hunt BJ, Doughty HA, Majumdar G, et al. Thromboprophylaxis with low molecular weight heparin (Fragmin) inhigh risk pregnancies. Thromb Haemost 1997; 77:39.

22.

Thomson AJ, Walker ID, Greer IA. Low-molecular-weight heparin for immediate management ofthromboembolic disease in pregnancy. Lancet 1998; 352:1904.

23.

Jacobsen AF, Qvigstad E, Sandset PM. Low molecular weight heparin (dalteparin) for the treatment of venousthromboembolism in pregnancy. BJOG 2003; 110:139.

24.

Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase inpregnancy to maintain therapeutic levels of anticoagulation. Am J Obstet Gynecol 2004; 191:1024.

25.

Norris LA, Bonnar J, Smith MP, et al. Low molecular weight heparin (tinzaparin) therapy for moderate riskthromboprophylaxis during pregnancy. A pharmacokinetic study. Thromb Haemost 2004; 92:791.

26.

Bremme K, Lind H, Blombäck M. The effect of prophylactic heparin treatment on enhanced thrombingeneration in pregnancy. Obstet Gynecol 1993; 81:78.

27.

Dahlman TC, Hellgren MS, Blombäck M. Thrombosis prophylaxis in pregnancy with use of subcutaneousheparin adjusted by monitoring heparin concentration in plasma. Am J Obstet Gynecol 1989; 161:420.

28.

Chunilal SD, Young E, Johnston MA, et al. The APTT response of pregnant plasma to unfractionated heparin.Thromb Haemost 2002; 87:92.

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Sephton V, Farquharson RG, Topping J, et al. A longitudinal study of maternal dose response to low molecularweight heparin in pregnancy. Obstet Gynecol 2003; 101:1307.

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Roeters van Lennep JE, Meijer E, Klumper FJ, et al. Prophylaxis with low-dose low-molecular-weight heparinduring pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9:473.

31.

Barbour LA, Smith JM, Marlar RA. Heparin levels to guide thromboembolism prophylaxis during pregnancy. AmJ Obstet Gynecol 1995; 173:1869.

32.

James A, Committee on Practice Bulletins—Obstetrics. Practice bulletin no. 123: thromboembolism inpregnancy. Obstet Gynecol 2011; 118:718.

33.

Barbour LA. Current concepts of anticoagulant therapy in pregnancy. Obstet Gynecol Clin North Am 1997;24:499.

34.

Bates SM, Ginsberg JS. How we manage venous thromboembolism during pregnancy. Blood 2002; 100:3470.35.

Friedrich E, Hameed AB. Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation inpregnancy. J Perinatol 2010; 30:253.

36.

Brancazio LR, Roperti KA, Stierer R, Laifer SA. Pharmacokinetics and pharmacodynamics of subcutaneousheparin during the early third trimester of pregnancy. Am J Obstet Gynecol 1995; 173:1240.

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Gyamfi C, Cohen R, Desancho MT, Gaddipati S. Prophylactic dosing adjustment in pregnancy based upon38.


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measurements of anti-factor Xa levels. J Matern Fetal Neonatal Med 2005; 18:329.

Fox NS, Laughon SK, Bender SD, et al. Anti-factor Xa plasma levels in pregnant women receiving lowmolecular weight heparin thromboprophylaxis. Obstet Gynecol 2008; 112:884.

39.

Pettilä V, Leinonen P, Markkola A, et al. Postpartum bone mineral density in women treated forthromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost 2002; 87:182.

40.

Backos M, Rai R, Thomas E, et al. Bone density changes in pregnant women treated with heparin: aprospective, longitudinal study. Hum Reprod 1999; 14:2876.

41.

Limmer JS, Grotegut CA, Thames E, et al. Postpartum wound and bleeding complications in women whoreceived peripartum anticoagulation. Thromb Res 2013; 132:e19.

42.

Knol HM, Schultinge L, Veeger NJ, et al. The risk of postpartum hemorrhage in women using high dose oflow-molecular-weight heparins during pregnancy. Thromb Res 2012; 130:334.

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Snijder CA, Cornette JM, Hop WC, et al. Thrombophylaxis and bleeding complications after cesarean section.Acta Obstet Gynecol Scand 2012; 91:560.

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Osterman MJ, Martin JA. Epidural and spinal anesthesia use during labor: 27-state reporting area, 2008. NatlVital Stat Rep 2011; 59:1.

45.

Magnani HN. An analysis of clinical outcomes of 91 pregnancies in 83 women treated with danaparoid(Orgaran). Thromb Res 2010; 125:297.

46.

van Besien K, Hoffman R, Golichowski A. Pregnancy associated with lupus anticoagulant and heparin inducedthrombocytopenia: management with a low molecular weight heparinoid. Thromb Res 1991; 62:23.

47.

Cotrufo M, De Feo M, De Santo LS, et al. Risk of warfarin during pregnancy with mechanical valve prostheses.Obstet Gynecol 2002; 99:35.

48.

Vitale N, De Feo M, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant womenwith mechanical heart valves. J Am Coll Cardiol 1999; 33:1637.

49.

Stevenson RE, Burton OM, Ferlauto GJ, Taylor HA. Hazards of oral anticoagulants during pregnancy. JAMA1980; 243:1549.

50.

Chong MK, Harvey D, de Swiet M. Follow-up study of children whose mothers were treated with warfarin duringpregnancy. Br J Obstet Gynaecol 1984; 91:1070.

51.

Whitfield MF. Chondrodysplasia punctata after warfarin in early pregnancy. Case report and summary of theliterature. Arch Dis Child 1980; 55:139.

52.

Zakzouk MS. The congenital warfarin syndrome. J Laryngol Otol 1986; 100:215.53.

Beeley L. Adverse effects of drugs in the first trimester of pregnancy. Clin Obstet Gynaecol 1986; 13:177.54.

Beeley L. Adverse effects of drugs in later pregnancy. Clin Obstet Gynaecol 1986; 13:197.55.

Ginsberg JS, Chan WS, Bates SM, Kaatz S. Anticoagulation of pregnant women with mechanical heart valves.Arch Intern Med 2003; 163:694.

56.

Ginsberg JS, Hirsh J, Turner DC, et al. Risks to the fetus of anticoagulant therapy during pregnancy. ThrombHaemost 1989; 61:197.

57.

Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to preventthromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol1996; 27:1698.

58.

Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve prostheses. Br Heart J 1994; 71:196.59.

Wong V, Cheng CH, Chan KC. Fetal and neonatal outcome of exposure to anticoagulants during pregnancy.Am J Med Genet 1993; 45:17.

60.

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European Society of Gynecology (ESG), Association for European Paediatric Cardiology (AEPC), GermanSociety for Gender Medicine (DGesGM), et al. ESC Guidelines on the management of cardiovascular diseasesduring pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of theEuropean Society of Cardiology (ESC). Eur Heart J 2011; 32:3147.

62.


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Topic 1342 Version 26.0


16 of 26 9/3/2015 12:45 AM

GRAPHICS

Drug ratings in pregnancy (US Food and Drug Administration)

Category Interpretation

A Controlled human studies show no risk

Controlled studies in pregnant women fail to demonstrate a risk to the fetus in thefirst trimester with no evidence of risk in later trimesters. The possibility of fetalharm appears remote.

B No evidence of risk in studies

Either animal reproduction studies have not demonstrated a fetal risk but there areno controlled studies in pregnant women, or animal-reproduction studies haveshown an adverse effect (other than a decrease in fertility) that was not confirmed incontrolled studies in women in the first trimester and there is no evidence of a risk inlater trimesters.

C Risk cannot be ruled out

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

D Positive evidence of risk

There is positive evidence of human fetal risk, but the benefits from use in pregnantwomen may be acceptable despite the risk (eg, if the drug is needed in alife-threatening situation or for a serious disease for which safer drugs cannot beused or are ineffective).

X Contraindicated in pregnancy

Studies in animals or human beings have demonstrated fetal abnormalities or thereis evidence of fetal risk based on human experience, or both, and the risk of the useof the drug in pregnant women clearly outweighs any possible benefit. The drug iscontraindicated in women who are or may become pregnant.

In 2015, the US Food and Drug Administration (FDA) began overseeing the phase-out of pregnancyrisk categories (A, B, C, D, and X) from prescription drug labeling and began requiring informationfrom available human and animal studies of (1) known or potential maternal or fetal adversereactions, and (2) dose adjustments needed during pregnancy and the postpartum period. Additionalinformation is available at the FDA website: Pregnancy and Lactation Labeling Final Rule.

Reproduced with permission from: Lexicomp Online. Copyright © 1978-2015 Lexicomp, Inc. All RightsReserved.

Graphic 50021 Version 23.0


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ACOG recommended thromboprophylaxis for pregnancies complicatedby inherited thrombophilias*

Clinical scenarioAntepartummanagement

Postpartummanagement

Lower-risk thrombophiliawithout previous VTE

Surveillance withoutanticoagulation therapy

Postpartum anticoagulationtherapy for patients withadditional risks factors

Low-risk thrombophila with afamily history (first-degreerelative) of VTE


Postpartum anticoagulationtherapy or intermediate-doseLMWH/UFH

Low-risk thrombophilia with asingle previous episode of VTE -not receiving long-termanticoagulation therapy

Prophylactic orintermediate-dose LMWH/UFHor surveillance withoutanticoagulation therapy

Postpartum anticoagulationtherapy or intermediate-doseLMWH/UFH

High-risk thrombophiliawithout previous VTE

Surveillance withoutanticoagulation therapy, orprophylactic LMWH or UFH

Postpartum anticoagulationtherapy

High-risk thrombophilia with asingle previous episode of VTEor an affected first-degreerelative - not receivinglong-term anticoagulationtherapy

Prophylactic, intermediate-dose,or adjusted-dose LMWH/UFHregimen

Postpartum anticoagulationtherapy, or intermediate oradjusted-dose LMWH/UFH forsix weeks (therapy level shouldbe at least as high asantepartum treatment)

No thrombophilia with previoussingle episode of VTE associatedwith transient risk factor that isno longer present - excludespregnancy- or estrogen-relatedrisk factor



No thrombophilia with previoussingle episode of VTE associatedwith transient risk factor thatwas pregnancy- or estrogen-related

Prophylactic-dose LMWH orUFH


No thrombophilia with previoussingle episode of VTE without anassociated risk factor(idiopathic) - not receivinglong-term anticoagulationtherapy

Prophylactic-dose LMWH orUFH


Thrombophilia or nothrombophilia with two or moreepisodes of VTE - not receivinglong-term anticoagulationtherapy

Prophylactic or therapeutic-doseLMWH

OR

Prophylactic or therapeutic-doseUFH


OR

Therapeutic-dose LMWH/UFH forsix weeks

¶

∆

◊

¶

§

§

¥

¥

¥


18 of 26 9/3/2015 12:45 AM

Thrombophilia or nothrombophilia with two or moreepisodes of VTE - Receivinglong-term anticoagulationtherapy

Therapeutic-dose LMWH or UFH Resumption of long-termanticoagulation 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 VTEand management of antiphospholipid syndrome are addressed elsewhere.¶ Low-risk thrombophilia: factor V Leiden heterozygous; prothrombin G20210A heterozygous; protein C orprotein S deficiency.∆ First-degree relative with a history of a thrombotic episode before age 50 years, or other majorthrombotic risk factors (eg, obesity, prolonged immobility).◊ Intermediate dosing is variably defined in the literature. The American College of Chest Physicians hasdefined it as a pregnancy LMWH regimen of enoxaparin 40 mg or dalteparin 5000 units given every 12hours. In UpToDate, intermediate dosing refers to prophylactic LMWH dosing that is increased as thepregnancy progresses and the patient's weight increases, up to a maximum dose of enoxaparin 1 mg/kgonce daily.§ High-risk thrombophilia: antithrombin deficiency; double heterozygous for prothrombin G20210A mutationand 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. ObstetGynecol 2013; 122:706. DOI: 10.1097/01.AOG.0000433981.36184.4e. Copyright © 2013 American Collegeof Obstetricians and Gynecologists. Unauthorized reproduction of this material is prohibited.



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Use of heparins during pregnancy

Heparin Dose level Dosage

LMW heparin Prophylactic* Enoxaparin 40 mg SC once daily

Dalteparin 5000 units SC once daily

Intermediate Enoxaparin 40 mg SC once daily, increase as pregnancyprogresses to 1 mg/kg once daily

Dalteparin 5000 units once daily, increase as pregnancyprogresses to 100 units/kg once daily

Therapeutic Enoxaparin 1 mg/kg every 12 hours

Dalteparin 100 units/kg every 12 hours

Unfractionatedheparin

Prophylactic 5000 units SC twice daily

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 timescontrol 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 riskand for treatment of venous thromboembolism. This dosing table should not be used in women withprosthetic heart valves. Refer to the UpToDate topic on anticoagulant use in pregnancy for details ofadministration and monitoring. Refer to UpToDate topics on specific pregnant patient populations forother dosing recommendations (eg, prosthetic heart valve, atrial fibrillation, treatment of deep veinthrombosis 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 tableon 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 IItitration based upon the activated partial thromboplastin time

IV infusion

aPTTRate change,

mL/hour*Dose change,units/24-hour

Additional action

≤45 +6 +5760 Repeated aPTT in 4 to6 hours

46 to 54 +3 +2880 Repeated aPTT in 4 to6 hours

55 to 85 0 0 None

86 to 110 –3 –2880 Stop heparin sodiumtreatment for 1 hour;repeated aPTT 4 to 6hours after restartingheparin treatment

>110 –6 –5760 Stop heparin treatmentfor 1 hour; repeatedaPTT 4 to 6 hours afterrestarting heparintreatment

NOTE: This table reflects the original aPTT ranges, bolus sizes, and suggested changes in infusionrate that were present at the time this study was performed. The therapeutic ranges (ie, relationshipbetween the aPTT and anti-factor Xa activity), initial and subsequent bolus sizes, and sizes of theinfusion rate changes, as well as dosing differences depending on the disorder under treatment (eg,venous thromboembolism, stroke, acute coronary syndrome) should be established separately foreach 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 oncedaily, unless subtherapeutic.

Redrawn from: Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy inpatients with venous thrombosis. Arch Intern Med 1992; 152:1589.


¶

∆


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Timing of neuraxial anesthesia during antithrombotic therapy

AnticoagulantInterval from last

dose toplacement/removal

Interval fromplacement/removal

to next doseNotes

Warfarin 4 to 5 days, verify INR<1.5; no monitoringneeded for single dosewithin 24 hours ofplacement

Continue regularneurologicevaluation until 24hours afterremoval. If dosedwith catheter inplace, check INRdaily and removewhen INR <1.5; ifINR 1.5-3.0,remove catheterwith caution,monitor neurologicstatus until INRstabilized; if INR>3, hold/reducewarfarin dose. Useof antihemostaticmedications that donot influence INRmay increase riskof bleedingcomplications.

Heparin(unfractionated)

When heparin givenfor >4 days, checkplatelets (risk ofHIT) prior toinsertion orremoval

Therapeutic dosing(IV)

2 to 4 hours, check fornormal aPTT

1 hour Bloody/difficult needleplacement mayincrease bleeding riskwith subsequent IVheparin; use withcaution

Prophylactic dosing(SC)

Delaying heparin injectionuntil after placement mayreduce risk

1 hour No contraindication totwice daily 5000units; safety of higheror more frequentdosage is notestablished

Low molecular weightheparin (LMWH)

Anti-Xa level is notpredictive of therisk of bleeding. Donot use withantoplatelet or oral


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anticoagulantmedications as thisincreases risk ofspinal hematoma.

Therapeutic dosing(SC) (enoxaparin 1mg/kg every 12hours; enoxaparin1.5 mg/kg daily;dalteparin 100-120U/kg every 12hours; dalteparin200 U/kg daily;nadroparin 86 U/kgevery 12 hours;nadroparin 171 U/kgdaily; tinzaparin 175U/kg daily)

>24 hours 6 to 8 hours (placement), >4hours (removal), delay 24hours after traumaticplacement; twice-dailydosing, first dose >24 hourspostop; once-daily dosingfirst dose 6 to 8 hourspostop, second dose 24 hourslater

Do not usetherapeutic dosingwith catheter in place

Prophylactic dosing(SC) (enoxaparin 30mg every 12 hours;enoxaparin 40 mgdaily; dalteparin2500-5000 U daily;nadroparin 2850 Udaily; nadroparin 38U/kg daily;tinzaparin 50-75U/kg daily;tinzaparin 3500 Udaily)

10 to 12 hours 6 to 8 hours (placement), >4hours (removal), delay 24hours after traumaticplacement; twice-dailydosing, first dose >24 hourspostop; once-daily dosing,first dose 6 to 8 hourspostop, second dose 24 hourslater

Do not use twice-dailydosing with catheterin place, due toincreased risk ofspinal hematoma

Fondaparinux 36 to 42 hours (Europeanguidelines)

6 to 8 hours; avoid useafter traumatic neuraxialplacement

Do not use withcatheter in place.(Europeanguidelines allowepidural catheterwith prophylacticdosing.) Limitedclinical experience.

Factor Xa inhibitors (Europeanguidelines)Antithromboticeffect monitoredwith PT, aPTT,Heptest

Rivaroxaban 22 to 26 hours 4 to 6 hours AHA recommends 3to 5 days after lastdose; wait 24 hoursto redose

Apixaban 26 to 30 hours 4 to 6 hours

Thrombin inhibitors Avoid neuraxial techniques aPTT or thrombintime


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Dabigatran AHA recommends 5days after last dose(7 days for renalfailure); wait 4 hoursto redose

Argatroban

Hirudin derivatives(desirudin,bivalirudin)

Antiplateletmedication

Bleeding time doesnot predicthemostaticproblems

P2Y12 receptorblockers

Clopidogrel 7 days After catheter removal

Prasugrel 7 to 10 days 6 hours after catheterremoval

European guidelines

Ticlodipine 14 days After catheter removal

Ticagrelor 5 days 6 hours after catheterremoval

European guidelines

GP IIb/IIIa inhibitors Contraindicated for 4weeks after surgery;monitor neurologic statusif given after neuraxialtechnique

Tirofiban 4 to 8 hours

Eptifibatide 4 to 8 hours

Abciximab 24 to 48 hours

Aspirin May continue dosage May continue dosage Affects plateletfunction for the lifeof the platelet.Avoid neuraxialtechniques onaspirin if earlypostoperative useof otherantihemostaticdrugs (includingheparin) isanticipated.

NSAIDs (nonsteroidalantiinflammatorydrugs)

May continue dosage May continue dosage Effect on plateletfunction normalizeswithin 3 days.Avoid neuraxialtechniques onNSAIDs if earlypostoperative useof other


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antihemostaticdrugs (includingheparin) isanticipated. COX-2inhibitors(celecoxib) haveminimal effect onplatelet function.

Herbal medications(garlic, ginkgo,ginseng)

May continue dosage May continue dosage Concurrent usewith otherantihemostaticdrugs may increasebleeding risk

INR: international normalized ration; PT: prothrombin time; aPTT: activated partial thromboplastin time;HIT: heparin-induced thrombocytopenia; IV: intravenous; SC: subcutaneous; AHA: American HeartAssociation.

Data from:Horlocker TT, Wedel DJ, Rowlingon JC, et al. Regional anesthesia in the patient receivingantithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain MedicineEvidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 2010; 35:64.

1.

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.

2.

Wysokinski WE, McBane RD. Periprocedural bridging management of anticoagulation. Circulation2012; 126:486.

3.



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Disclosures: Kenneth A Bauer, MD Consultant/Advisory Boards: Janssen Pharmaceuticals [Anticoagulation (Rivaroxaban)]; Daiichi Sankyo[Anticoagulation (Edoxaban)]; Portola Pharmaceuticals [Anticoagulation reversal, anticoagulation (Andexanet, betrixaban)]; InstrumentationLaboratory [Coagulation instruments/reagents (ACL TOP instruments and reagents)]. Lawrence LK Leung, MD Nothing to disclose. Charles JLockwood, MD, MHCM Consultant/Advisory Boards: Celula [Aneuploidy screening (Prenatal and cancer DNA screening tests indevelopment)]. 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 amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures


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Use of Anticoagulants During Pregnancy and Postpartum