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470 Anticoagulation Therapy
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TABLE 19-14: Atrial Fibrillation and Other Cardiovascular
Diseases During Pregnancy
For high-risk conditions that would require anticoagulation outside of pregnancy, the following
options are reasonable (Class IIa; Level of Evidence C): LMWH twice daily throughout pregnancy,
with dose adjusted to achieve the LMWH manufacturer’s recommended peak anti-factor Xa
activity 4 hours after injection, or
•
Adjusted-dose UFH throughout pregnancy, administered subcutaneously every 12 hr in
doses adjusted to keep the mid-interval activated partial thromboplastin time at least twice
control or to maintain an anti-factor Xa heparin level of 0.35−0.70 units/mL, or
• UFH or LMWH (as above) until the 13th week, followed by substitution of a VKA until close
to delivery, when UFH or LMWH is resumed.
For a low-risk situation in which antiplatelet therapy would be the treatment recommendation
outside of pregnancy (Class IIb; Level of Evidence C):
UFH or LMWH, or no treatment may be considered during the first trimester of pregnancy
•
depending on the clinical situation.
hr: hours, LMWH: low molecular weight heparin, UFH: unfractionated heparin, VKA: vitamin K
antagonist
37
TREATMENT OF THROMBOSIS DURING
PREGNANCY
Diagnosis of VTE During Pregnancy
Early diagnosis of thrombosis during pregnancy is critical so that therapy can
be started and achieve favorable clinical outcomes for both the mother and
fetus. Figure 19-1 shows a suggested algorithm for the diagnosis of DVT
and PE that incorporates clinical features and diagnostic imaging.
• For VTE diagnosis:
Compression ultrasound is the test of choice
in women with suspected DVT but is less
accurate for isolated calf and iliac vein
thrombosis.
Magnetic resonance direct thrombus imaging
(MRDTI) is useful for diagnosis of iliac
vein thrombosis and causes no radiation
exposure.
Computed tomographic (CT scans) causes
low radiation exposure to the fetus but
exposes maternal breast tissue to radiation.
Ventilation/perfusion (V/Q) scans have a low
amount of radiation exposure.
PREGNANCY 471
Nondiagnostic
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Clinical Features Suggestive
of Deep-Vein Thrombosis
Begin lowmolecular-
weight heparin
D-Dimer test
Positive Negative
Suspicion of
iliac-vein
thrombosis
YesNo
MRDTI
Pulsed Doppler
study or computed
tomography
of iliac veins
Repeat compression
ultrasonography
Positive Positive
molecular-weight
Compression
ultrasonography
Clinical
followup
in 5–7 days
Restart low-
heparin
Clinical Features Suggestive
of Pulmonary Embolism
ultrasonography
PositiveNegative
Positive Negative
Continue low-
molecular-
weight heparin
other abnormality
Normalor Negative
Clinical
followup
Compression
Asthma or
Computed
tomographic
pulmonary
angiography
Continue low-
molecular-weight
heparin
Begin lowmolecular-
weight heparin
Chest
radiography
Computed tomographic
pulmonary angiography
or ventilation–perfusion
Normal
scanning
result or high
suspicion
Pulmonary angio-
graphy, serial
compression
ultrasonography,
MRDTI, or pulsed
Doppler study
FIGURE 19-1. Diagnosis of VTE During Pregnancy
MRDTI: magnetic resonance direct thrombus imaging
Source: Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl
J Med. 2008;359:2025-2033. Copyright © 2008, Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
Negative D-dimer is useful for ruling out DVT
in combination with a negative compression
ultrasound, but there may be false elevations
during pregnancy.
472 Anticoagulation Therapy
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Treatment of VTE During Pregnancy
2,33,36
Initiate treatment prior to objective confirmation if no contraindication to
anticoagulation.
•
First-line treatment of acute VTE in pregnant women is UFH or LMWH over other
options due to favorable safety profiles and ability to monitor dosing. Points to
consider when choosing between UFH or LMWH are discussed below.
Dosing and Monitoring of UFH
•
Adjusted dose IV UFH (IV bolus, with continuous infusion to maintain aPTT
within the therapeutic range or SC therapy adjusted to maintain the aPTT 6
hours after injection into the therapeutic aPTT range for at least 5 days) can
be considered in the initial treatment of PE and in situations in which delivery,
surgery, or thrombolysis (indicated for life-threatening or limb-threatening
thromboembolism) may be necessary.
•
If the woman is potentially unstable (large PE with hypoxia), presents with
extensive iliofemoral disease and extreme venous congestion, or has significant
renal impairment (e.g., a creatinine clearance of <30 mL/min), initial inpatient
intravenous (IV) adjusted-dose UFH should be considered.
Dosing and Monitoring of LMWH
•
When hemodynamically stable, adjusted dose sub-Q LMWH is preferred over
adjusted dose UFH during pregnancy (ACCP Grade 1B), based on safety data
for both mother and the fetus.
Better bioavailability, longer plasma-half-life, more predictable
dose response, less monitoring, and improved safety profile with
respect to osteoporosis and thrombocytopenia compared to UFH
•
Alterations in volume of distribution
Elevated throughout pregnancy and declines postpartum
•
Alterations in renal clearance
More rapid during early pregnancy, decreases as pregnancy
progresses
•
Some clinicians prefer to use twice-daily LMWH during pregnancy because of
alterations in renal clearance. No comparative studies have been conducted.
33,44-48
33,38,45-49
Monitoring Strategies for LMWH in Pregnancy
•
Controversy exists about the need for monitoring LMWH with anti-factor Xa
levels during pregnancy. Currently acceptable strategies include the following:
Initial dosing based on weight with no further dose adjustment.
Dose adjustment guided by weight changes throughout pregnancy.
Manufacturer-recommended peak anti-factor Xa levels guide dose
•
Monthly monitoring throughout pregnancy is reasonable.
•
For therapeutic anticoagulation for VTE, peak anti-factor Xa levels measured 4
hours postdose to reach 0.6–1 unit/mL if a twice-daily regimen is used; slightly
adjustment.
PREGNANCY 473
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higher if a once-daily regimen is chosen.
•
Peak anti-factor Xa levels >1 unit/mL, or 12-hour trough levels >0.5 units/mL
may be targeted for patients with mechanical heart valves.
Duration of Therapy
•
Treatment of VTE should be continued throughout pregnancy (ACCP Grade 1B)
11,33,38
and continued until at least 6 weeks postpartum (for a minimum total duration
of 3 months) in comparison with shorter durations (ACCP Grade 2C).
PREVENTION OF PREGNANCY LOSS
TABLE 19-15: Recommendations for Prevention of Pregnancy
Complications in Women with Thrombophilia Based on Risk
Categories
Prevention of Pregnancy
Complications in Women
with Thrombophilia
Recurrent early pregnancy
loss (≥3 miscarriages before
10 weeks gestation)
History of pregnancy
complications
33,50,a
ACCP 2012 ACOG 2012
Recommend screening
for APLAs (Grade 1B)
Suggest not to
screen for inherited
thrombophilia
(Grade 2C)
Suggest not to
use antithrombotic
prophylaxis (Grade 2B)
From Bulletin #132
Testing for inherited thrombophilia
in women who have experienced
recurrent fetal loss, or placental
abruption is not recommended
because it is unclear if AC therapy
reduces recurrence (Level B)
APLA screening: 1 fetal loss or 3 or
more embryonic losses (Level B)
Insufficient evidence to either
screen for or treat women with
inherited thrombophilia and
obstetric histories that include
complications such as IUGR or
preeclampsia (Level B)
b
Testing for APLA in patient
with past VTE
Meet laboratory criteria for
APLA syndrome and meet the
clinical APLA criteria based
on ≥3 pregnancy losses
No recommendations Recommend testing for APLA in
AP: Prophylactic or
intermediate dose UFH
or prophylactic LMWH
with low-dose ASA,
75–100 mg/day, over no
treatment (Grade 1B)
women with a prior unexplained
VTE, a new VTE during pregnancy,
or in those with a history of VTE but
not tested previously (Level B)
In women with APLS and a history
of stillbirth or recurrent fetal loss
but no prior TE (Level B):
AP: Prophylactic doses of heparin
and low-dose aspirin
PP: Continue 6 weeks
(continued)
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TABLE 19-15: (Continued)
Prevention of Pregnancy
Complications in Women
with Thrombophilia
ACCP 2012 ACOG 2012
From Bulletin #132
b
Women with APLS who have
had a thrombotic event
a
Refer to Table 19-6 for corresponding dosing regimens.
b
Reaffirmed in 2017.
AC: anticoagulation, ACCP: American College of Chest Physicians, ACOG: American College
of Obstetrics and Gynecology, AP: antepartum, APLAs: antiphospholipid antibodies, APLS:
antiphospholipid antibody syndrome, ASA: aspirin, INR, international normalized ratio, IUGR:
intrauterine growth restriction, LMWH: low molecular weight heparin, PP: postpartum, TE:
thromboembolism, UFH: unfractionated heparin, VKA: vitamin K antagonist, VTE: venous
thromboembolism
Source:
Adapted from Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 Suppl):844S-886S.
AP: Prophylactic- or
intermediate-dose
LMWH rather than
clinical vigilance or
routine care (Grade 2C)
PP: Prophylactic or
intermediate-dose
LMWH or VKA INR 2–3
for 6 weeks over no
prophylaxis (Grade 2B
Most experts recommend
prophylactic anticoagulation with
heparin throughout pregnancy and
6 weeks postpartum (Level C)
USE OF ANTICOAGULANTS DURING LABOR
AND DELIVERY
TABLE 19-16: Anticoagulants During Labor and Delivery
Treatment doses of sub-Q
UFH
1,2,33,38,51,52
51,52
Prolonged aPTT can be seen more than 24 hr after the last
every 12-hr dose; consider induction of labor with planned
discontinuation of heparin prior to delivery; aPTT monitoring and/
or administration of protamine sulfate around the time of delivery
may be necessary.
• Protamine has been reported to cause neonatal respiratory
depression.
• Neuraxial anesthesia should not be used in anticoagulated
women.
Treatment doses of
LMWH
Consider induction of labor, with discontinuation of LMWH 24–36
hr prior to elective induction of labor or cesarean section.
• If induction of labor is not planned, caution patients to
withhold further LMWH doses at the onset of regular
contractions.
• Neuraxial anesthesia should not be used in anticoagulated
women (i.e., within 24 hr of last dose of treatment-dose
LMWH).
(continued)
TABLE 19-16: (Continued)
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Prophylactic doses of
UFH or LMWH
Stop treatment 12–24 hr before induction or cesarean delivery.
•
Wait at least 10–12 hr after the last dose of prophylactic
dose LMWH before placement of epidural catheter or spinal
anesthesia.
Prophylactic doses of UFH 5,000 units sub-Q every 12 hr
•
have no contraindications to neuraxial anesthesia; safety and
recommendations with higher doses of UFH are uncertain; a
delay of 12 hr may be warranted in this situation.
PREGNANCY 475
Converting from LMWH
to IV UFH prior to delivery
New VTE In patients with new VTE within 4 weeks of delivery, consider
Postpartum
anticoagulants
Postpartum
anticoagulants in patients
receiving epidural
catheters
aPTT: activated partial thromboplastin time, DOAC: direct-acting oral anticoagulant, hr:
hours, INR: international normalized ratio, IV: intravenous, IVC: inferior vena cava, LMWH: low
molecular weight heparin, sub-Q: subcutaneous, UFH: unfractionated heparin, VTE: venous
thromboembolism
Wait 10–11 hr after the last dose of LMWH before initiating IV UFH.
hospital admission with planned induction of therapy with IV UFH,
and/or placement of temporary IVC filter.
May be started 12–24 hr after delivery as long as there are no
bleeding concerns; consider IV UFH in women at high risk of
bleeding, with LMWH reasonable for most women.
•
Restart warfarin when hemostasis has occurred, bridging with
UFH or LMWH until INR therapeutic.
Caution with the use of DOACs postpartum due to limited
•
data and risk of treatment failure during this time.
For patients receiving twice daily LMWH: Administer the first
dose no sooner than 24 hr postoperatively, and with adequate
hemostasis in place; remove indwelling catheters prior to the
initiation of LMWH; for patients with continuous technique, the
epidural may be kept in place overnight but must be removed
before the first dose of LMWH; delay the first dose of LMWH for at
least 2 hr after catheter removal.
For patients receiving once daily LMWH: Administer the first dose
6–8 hr postoperatively; the second dose should occur no sooner
than 24 hr after the first; indwelling catheters may be maintained;
the removal of the catheter should occur no sooner than 10–12
hr after the last LMWH dose; further dosing should occur at least
2 hr after catheter removal; no additional hemostasis-altering
medications should be given due to additive effects.
• For patients who have undergone a miscarriage,
withholding anticoagulation until 12–24 hours
after a dilation and curettage has been performed
may be necessary to help minimize risk of
postpartum hemorrhage.
476 Anticoagulation Therapy
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SUMMARY
Anticoagulation in pregnancy remains a challenging area, with pregnant and
postpartum women carrying a higher risk of thrombosis than the nonpregnant
patient. Clinicians need to consider anticoagulant safety and efficacy for
the mother, effects on the fetus, safety during breastfeeding, and optimal
management around labor and delivery. Controversies remain about how
to manage patients with mechanical heart valves, how and when to monitor
laboratory data, and how to manage patients using DOACs.
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