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450 Anticoagulation Therapy
https://t.me/med1917
TABLE 19-1: Indications for Anticoagulation During Pregnancy
• Prevention of thrombosis during pregnancy
Prophylaxis against VTE
Prophylaxis against arterial thrombosis
Stroke prevention in patients with mechanical heart valves
Stroke prevention in atrial fibrillation
Treatment of thrombosis during pregnancy
•
Treatment of VTE during pregnancy
Treatment of arterial events during pregnancy
•
Prevention of pregnancy loss
VTE: venous thromboembolism
TABLE 19-2: Definitions for Grading Recommendations
ACCP Grade 1A: Strong recommendation, high-quality evidence
ACOG Level A: Based on good and consistent scientific evidence
AHA
ACCP: American College of Chest Physicians, ACOG: American College of Obstetrics and
Gynecology, AHA: American Heart Association, RCT: randomized controlled trial
Grade 1B: Strong recommendation, moderate-quality evidence
Grade 1C: Strong recommendation, low or very low-quality evidence
Grade 2A: Weak recommendation, high-quality evidence
Grade 2B: Weak recommendation, moderate-quality evidence
Grade 2C: Weak recommendation, low or very low-quality evidence
Level B: Based on limited or inconsistent scientific evidence
Level C: Based primarily on consensus and expert opinion
Size of treatment effect:
Class 1: Procedure/treatment should be performed/administered
Class IIa: It is reasonable to perform procedure/administer treatment
Class IIb: Procedure/treatment may be considered
Class III: No benefit or harmful
Estimate of certainty:
Level A: Multiple populations evaluated, multiple RCT or meta-analyses
Level B: Limited populations evaluated, single RCT or nonrandomized
studies
Level C: Very limited populations evaluated, only consensus opinion of
experts, case studies, or standard of care
10-12
Safety of Anticoagulants During Pregnancy
Use of anticoagulants in pregnancy must consider the safety to the fetus
(Table 19-3) and the mother (Table 19-4). Use of anticoagulants for breast-
feeding mothers must consider drug and metabolite transmission into breast
milk and safety to the infant (Table 19-5).
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TABLE 19-3: Safety to the Fetus
Drug Supporting Evidence
Apixaban •
Argatroban • Unknown if it crosses placenta.
In an ex vivo study using human placenta, apixaban was
shown to rapidly cross from the maternal to the fetal
circulation. Total apixaban concentrations in cord blood
in vivo are predicted at 35–90% of the maternal levels.
Apixaban may adversely affect fetal coagulation.
• Treatment of pregnant rats from implantation (gestation day
7) to weaning (lactation day 21) with apixaban at a dose
of 1,000 mg/kg (about 5 times the human exposure based
on unbound apixaban) did not result in death of offspring
or death of mother rats during labor in association with
uterine bleeding. However, increased incidence of maternal
bleeding, primarily during gestation, occurred at apixaban
doses of ≥25 mg/kg, corresponding to ≥1.3 x the human
exposure.
• ACCP: Recommends avoiding use (Grade 1C).
•
ISTH: Recommends avoiding use.
Limited case report data exist. In animal studies, there was
•
no evidence of impaired fertility or harm to the fetus in rats
given argatroban IV doses up to 27 mg/kg/day (0.3 times
the MRHD based on body surface area) and rabbits given
10.8 mg/kg/day (0.2 x the MRHD).
•
Clinicians should avoid use during pregnancy whenever
possible and reserve its use for those pregnant women
with HIT or a history of HIT who cannot receive danaparoid
(ACCP Grade 2C).
13-32
Aspirin •
Crosses placenta.
Due to reported teratogenic and other effects, use of aspirin
•
particularly in the third trimester.
• First trimester: Safety remains uncertain. There is no clear
evidence of harm to the fetus, and, if fetal anomalies
are caused by early aspirin exposure, they are very rare.
Clinicians should offer first-trimester patients aspirin if the
indication for aspirin is clear, and there is no satisfactory
alternative agent.
• Second and third trimester: Low-dose (50–150 mg/day)
aspirin therapy given to women at risk for preeclampsia
is safe for the mother and fetus. Aspirin is associated with
increased risk of intracranial hemorrhage in premature
infants when used in the last week of pregnancy.
(continued)
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TABLE 19-3: (Continued)
Drug Supporting Evidence
Bivalirudin •
Clopidogrel •
Dabigatran • Crosses the human placenta.
Danaparoid
Edoxaban • Unknown if it crosses placenta.
a
Unknown if it crosses placenta.
Studies in rats receiving 1.6 x the recommended maximum
•
human dose and in rabbits at 3.2 x the MRHD showed no
evidence of harm to the fetus or impaired fertility.
•
Clinicians should avoid use during pregnancy whenever
possible and reserve its use for those pregnant women
with HIT or a history of HIT who cannot receive danaparoid
(ACCP Grade 2C).
Unknown if it crosses the placenta.
•
Animal studies in rats and rabbits demonstrated no evidence
of impaired fertility or fetotoxicity.
In rats given 2.6–6 x the MRHD of 300 mg/day, decreased
•
implantations occurred and treatment given after
implantation increased the number of dead offspring and
caused increased bleeding. Delayed or irregular ossification
of fetal skull bones and vertebrae occurred in some animal
studies.
•
ACCP: Recommends avoiding use (Grade 1C).
ISTH: Recommends avoiding use.
•
• Unknown if it crosses placenta.
Most case reports show successful pregnancy outcomes;
•
however, the quality of the evidence is low.
•
In Hokusai-VTE Investigators, 10 human cases of first trimester
exposure up to 6 weeks of use resulted in live births (4 fullterm, 2 pre-term), 1 first-trimester spontaneous abortion, and
3 cases of elective termination of pregnancy.
Rats experienced post-implantation loss, perhaps secondary
•
to maternal vaginal hemorrhage, at a dose of 300 mg/kg/day.
In rabbits, at maternally toxic doses, embryo-fetal toxicities
occurred at 600 mg/kg/day, as well as increased implantation
loss, increased spontaneous abortion, and decreased live
fetuses and fetal weight at doses ≥200 mg/kg/day (≥20 x the
human exposure). When rats were administered oral doses
up to 30 mg/kg/day (up to 3 x the human exposure based on
AUC) during the period of organogenesis through lactation
day 20, vaginal bleeding in pregnant rats and delayed
avoidance response in female offspring were seen.
• ACCP: Recommends avoiding use (Grade 1C).
• ISTH: Recommends avoiding use.
(continued)
TABLE 19-3: (Continued)
https://t.me/med1917
Drug Supporting Evidence
PREGNANCY 453
Fondaparinux •
LMWH (dalteparin,
enoxaparin, tinzaparin)
Prasugrel • Unknown if it crosses the placenta.
Rivaroxaban •
Unknown if it crosses placenta.
Results from 65 human cases reported no major bleeding,
•
and 1 case of recurrent VTE, likely due to inadequate
anticoagulation. Obstetric complications occurred in 18
cases, with spontaneous abortions in 13 cases, 1 case of
ectopic pregnancy, 1 case of preterm rupture of membranes,
1 case of early preeclampsia, and 2 cases of intrauterine fetal
growth retardation.
•
Animal studies conducted in rats and rabbits using doses
up to 10 mg/kg/day (32 and 65 x the MRHD based on body
surface area, respectively) revealed no evidence of impaired
fertility or fetal harm.
• Anti-factor Xa activity (at approximately 1/10 the
concentration of maternal plasma) has been found in
the umbilical cord plasma in newborns treated with
fondaparinux.
• Clinicians should avoid use during pregnancy whenever
possible and reserve its use for those pregnant women
with HIT or a history of HIT who cannot receive danaparoid
(ACCP Grade 2C).
Does not cross placenta.
•
• ACCP: Recommends LMWH over UFH (Grade 1B).
•
Reproductive and developmental studies in rats and rabbits
given doses up to 30 x the recommended human exposure
found no evidence of fetal harm.
Rivaroxaban crosses the placenta in animal studies.
•
Increased post-implantation loss has been seen in rabbits,
and pronounced maternal hemorrhagic complication in rats.
Increased fetal toxicity (increased resorptions, decreased
number of live fetuses, decreased fetal body weight)
occurred in rabbits given oral rivaroxaban doses of ≥10 mg/
kg or greater (approximately 4 x the MRHD of 20 mg/day)
during organogenesis. Decreased fetal body weight was
reported with rivaroxaban doses of 120 mg/kg (about 14
x the human exposure of unbound drug) administered to
pregnant rats.
• There are limited human case reports of 64 patients that
used rivaroxaban during the first trimester.
• ACCP: Recommends avoiding use (Grade 1C).
• ISTH: Recommends avoiding use.
Ticagrelor • Unknown if it crosses the placenta.
• In animal studies, structural abnormalities were reported
maternal ticagrelor doses 5–7 x the MRHD on an mg/m
Use during pregnancy is recommended only if the potential
benefit justifies the potential risk to the fetus.
2
(continued)
at
basis.
454 Anticoagulation Therapy
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TABLE 19-3: (Continued)
Drug Supporting Evidence
UFH •
Warfarin • Crosses placenta. Use is contraindicated in pregnancy
a
Not available in the U.S. market at this time.
ACCP: American College of Chest Physicians, CNS: central nervous system, HIT: heparin-induced
thrombocytopenia, ISTH: International Society of Thrombosis and Haemostasis, LMWH: low
molecular weight heparin, MRHD: maximum recommended human dose, UFH: unfractionated
heparin, VTE: venous thromboembolism, x: times
Does not cross placenta.
except in women with mechanical heart valves and high
risk for TE. Doses >5 mg daily may be at higher risk of
complications than lower doses.
Any time: There is a risk of fetal hemorrhage, particularly
•
when given close to time of delivery.
•
Weeks 6–12 of pregnancy: Nasal hypoplasia, stippled
epiphyses, respiratory deficiency, CNS abnormalities have
been reported.
• 2nd and 3rd trimesters: CNS toxicities include mental
retardation, optic atrophy, spasticity, and seizures. Fetal
death, neonatal hemorrhage, and increased risk of maternal
hemorrhage have been reported.
• Multidose vials of unfractionated heparin (UFH)
and low molecular weight heparin (LMWH)
contain benzyl alcohol, which has been reported
to cause cases of fetal gasping syndrome in
neonates. Use of preservative-free vials or singledose syringes is advised.
•
International Society of Thrombosis and
Haemostasis (ISTH) recommends against the use
of DOACs in pregnancy and switching to LMWH
if an unintentional pregnancy occurs. However,
at this time, inadvertent exposure is not in itself
medical grounds for termination of pregnancy.
Women who do decide to continue with pregnancy
while on a DOAC are recommended to have early
obstetric review and fetal monitoring.
16
• ISTH recommends clinicians collect data on
the course and outcomes after DOAC exposure
and report findings to the manufacturers and
PREGNANCY 455
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regulatory authorities, as well as to the ISTH
registry: https://www.isth.org/news/308993/
Participate-Registry-of-Pregnancy-inPatients-Exposed-to-DOACs.htm to ensure
consistency of data collection.
16
TABLE 19-4: Maternal Safety
Adverse Effect Supporting Evidence
Bleeding •
Bone • Prolonged UFH use during pregnancy may reduce bone mineral
HIT • Documented HIT in pregnancy is rare, at <0.01% of women, and this
Skin • Skin rashes can be seen in up to 2% of pregnant women receiving
Reported risk of major bleeding with therapeutic anticoagulants is
comparable in pregnant and nonpregnant women.
PPH (blood loss >500 mL within 24 hr of delivery) is seen in up to
•
5% of women receiving anticoagulant therapy; the frequency of this
complication is dependent on a number of factors such as maternal
age, parity, and mode of delivery. The rate of PPH does not appear to
be appreciably higher in women receiving antepartum LMWH therapy
than in other women when these are taken into account.
Injection-site bruising is common throughout pregnancy and can vary
•
by location and injection technique.
density and lead to the development of symptomatic vertebral
fractures in up to 2% of women.
Less bone loss is seen with LMWH.
Supplemental calcium may be recommended for some.
incidence is lower with LMWH than with UFH.
In the setting of serologically confirmed HIT in pregnancy, substitute
•
UFH or LMWH for a DTI.
LMWH and are usually managed with a change in brand. If there is skin
necrosis around the injection sites, HIT-associated skin necrosis should
be excluded.
1,2,33-35
DTI: direct thrombin inhibitor, HIT: heparin-induced thrombocytopenia, hr: hours, LMWH: low
molecular weight heparin, PPH: postpartum hemorrhage, UFH: unfractionated heparin
456 Anticoagulation Therapy
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TABLE 19-5: Safety of Anticoagulants During Lactation
Anticoagulant Potential Risks During Breastfeeding
Apixaban • Recommend PI information, which indicates that is unknown if apixaban
Argatroban • Rat studies have shown the presence in breast milk.
Aspirin • There is increased association between salicylates and Reye’s syndrome.
is excreted in human milk.
It is recommended to discontinue nursing or discontinue apixaban in the
•
nursing mother, considering the importance of therapy to the mother.
Micromedex Lactation Rating: Infant risk cannot be ruled out.
•
•
ISTH: Breastfeeding women should avoid use.
AC Forum: It should not be used while breastfeeding.
•
•
Micromedex Lactation Rating: Infant risk cannot be ruled out.
Some available data have suggested that low intermittent doses can be
•
used safely in breastfeeding.
•
AAP Rating: It is associated with significant effects on some nursing
infants and should be given to nursing mothers with caution.
WHO: Avoid breastfeeding.
•
•
Micromedex Lactation Rating: Infant risk cannot be ruled out.
ACCP: For lactating women using low-dose aspirin for vascular
•
indications who wish to breastfeed, suggest continuing this medication
(Grade 2C).
• AHA: In the presence of a low-risk situation in which antiplatelet therapy
would be the treatment recommendation outside of pregnancy, lowdose aspirin use may be considered (Class IIb; Level of Evidence C).
a
13,16,33,36-39
Bivalirudin •
Clopidogrel • Available data are limited; weigh the potential risks and benefits before
Dabigatran • It is not known whether dabigatran is excreted in human milk. Until
Dalteparin • Small amounts have been found in breast milk.
Unknown whether bivalirudin is excreted into human breast milk.
•
Until more data are available, use caution when considering the use of
bivalirudin in lactating women.
Micromedex Lactation Rating: Infant risk cannot be ruled out.
•
prescribing.
• Animal data in rats showed that it enters breast milk.
• Micromedex Lactation Rating: Infant risk cannot be ruled out.
further data are available, exercise caution when administering
dabigatran to a nursing mother.
• Micromedex Lactation Rating: Infant risk cannot be ruled out.
• ISTH: Breastfeeding women should avoid use.
• AC Forum: It should not be used while breastfeeding.
• Micromedex Lactation Rating: Infant risk cannot be ruled out.
• ACCP: Recommends Grade 1B for breastfeeding.
• ACOG: It may be used in women who breastfeed (Level B).
• AHA: It is reasonable to use (Class IIa; Level of Evidence C).
• AC Forum: It is safe for the breastfed infant.
(continued)
TABLE 19-5: (Continued)
https://t.me/med1917
Anticoagulant Potential Risks During Breastfeeding
Danaparoid
Edoxaban • Edoxaban was found in the milk of lactating rats.
Enoxaparin • It is unlikely that it passes into breast milk.
b
• It is unknown if it passes into breast milk, and the safety cannot be
established.
Limited reports suggest that little to no danaparoid appears in the breast
•
milk, and infant gastric secretions would likely inactivate any amounts
that were passed since danaparoid is not absorbed orally.
• ACCP: Recommends Grade 1B for breastfeeding.
Micromedex Lactation Rating: Infant risk cannot be ruled out.
•
•
Because potential harm to a nursing infant exists, either edoxaban
or breastfeeding should be discontinued, considering the need for
treatment of the mother.
• Micromedex Lactation Rating: Infant risk cannot be ruled out.
•
ISTH: Breastfeeding women should avoid use.
AC Forum: It should not be used while breastfeeding.
•
•
Micromedex Lactation Rating: Infant risk cannot be ruled out.
ACCP: Recommends Grade 1B for breastfeeding.
•
•
ACOG: It may be used in women who breastfeed (Level B).
AHA: It is reasonable to use (Class IIa; Level of Evidence C).
•
• AC Forum: It is safe for the breastfed infant.
a
PREGNANCY 457
Fondaparinux • Animal data showed that it was detected in milk of lactating rats.
•
Micromedex Lactation Rating: Infant risk cannot be ruled out.
ACCP: Alternative anticoagulants are recommended other than
•
fondaparinux (Grade 2C).
Prasugrel • Available data are limited; weigh the potential risks and benefits before
Rivaroxaban • Animal studies indicate it is secreted into milk.
prescribing.
• Animal data in rats showed that its metabolites entered breast milk.
• Micromedex Lactation Rating: Infant risk cannot be ruled out.
• A human case report shows that rivaroxaban passes into human breast
milk, with the ratio of milk to plasma reported at 0.4. No conclusions can
be drawn regarding the safety of rivaroxaban in nursing mothers and
their breastfed infants.
• Due to the potential of serious adverse reactions in breastfeeding
infants, a decision should be made whether to discontinue rivaroxaban
use or to discontinue nursing during therapy, taking into account the
importance of the drug to the mother.
• Micromedex Lactation Rating: Infant risk cannot be ruled out.
• ISTH: Breastfeeding women should avoid use.
• AC Forum: It should not be used while breastfeeding.
(continued)
458 Anticoagulation Therapy
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TABLE 19-5: (Continued)
Anticoagulant Potential Risks During Breastfeeding
Ticagrelor • Ticagrelor is excreted in the milk of lactating rats.
It is unknown whether ticagrelor or its active metabolites are excreted
•
in human milk. The manufacturer recommends discontinuing nursing or
discontinuing ticagrelor, considering the importance of the drug to the
mother.
•
Micromedex Lactation Rating: Infant risk cannot be ruled out.
Tinzaparin • Very low levels have been detected in rat breast milk.
Micromedex Lactation Rating: Infant risk cannot be ruled out.
•
•
ACCP: Recommends Grade 1B for breastfeeding.
ACOG: It may be used in women who breastfeed (Level B)
•
•
AHA: It is reasonable to use (Class IIa; Level of Evidence C).
AC Forum: It is safe for the breastfed infant.
•
UFH • Not secreted in breast milk and is considered safe for nursing mothers.
•
Micromedex Lactation Rating: Infant risk is minimal.
• AAP Rating: Maternal medication is usually compatible with
breastfeeding.
ACCP: Recommends Grade 1A for breastfeeding.
•
•
ACOG: It may be used in women who breastfeed (Level B).
WHO: It is compatible with breastfeeding.
•
•
AHA: It is reasonable to use (Class IIa; Level of Evidence C).
AC Forum: It is safe for the breastfed infant.
•
a
Warfarin • Not secreted in breast milk and is considered safe for nursing mothers.
a
Refer to Table 19-2 for definitions on levels of recommendations.
b
Not available in the U.S. market at this time.
AAP: American Academy of Pediatrics, ACCP: American College of Chest Physicians, AC Forum:
guidance document endorsed by the Anticoagulation Forum Board of Directors, AHA: American
Heart Association, ISTH: International Society of Thrombosis and Haemostasis, WHO: World
Health Organization
Preconception Planning
Evaluation of a woman who may require anticoagulation during pregnancy
should occur before conception, ideally, or at least early in pregnancy.
•
Patients with a high risk of maternal mortality due to thrombosis (e.g., mechanical heart valves, chronic thromboembolic pulmonary hypertension, history of
•
AAP Rating: Maternal medication usually compatible with breastfeeding.
ACCP: Recommends Grade 1A for breastfeeding.
•
•
WHO: It is compatible with breastfeeding.
• Micromedex: Infant risk is minimal.
• ACOG: It may be used in women who breastfeed (Level B).
• AHA: It is reasonable to use (Class IIa; Level of Evidence C).
• AC Forum: It is safe for the breastfed infant.
1,2,40
PREGNANCY 459
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recurrent thrombosis while fully anticoagulated, history of myocardial infarction)
may be advised against pregnancy.
•
Patients already on anticoagulation prior to pregnancy will likely need to
33,38,40
continue; counsel them preconception regarding the need to switch from a
vitamin K antagonist (VKA) or DOAC to LMWH.
•
ACCP: For women requiring long-term VKAs who are attempting pregnancy and
16,41
are candidates for LMWH substitution, performing frequent pregnancy tests and
substituting LMWH for VKAs when pregnancy is achieved—rather than switching
to LMWH while attempting pregnancy—is suggested (Grade 2C).
•
ISTH: Recommends all women of childbearing potential should receive
33
documented counseling before starting DOACs, with emphasis on avoiding
pregnancy; if pregnancy is desired, switch to an alternative anticoagulant
preconceptually (VKA then switch to LMWH as soon as pregnant and before 6
weeks gestation, or LMWH).
16
UFH and LMWH Regimens and Associated Doses as
Defined by ACCP and ACOG
The ACCP’s and ACOG’s definitions to describe UFH and LMWH regimens
and associated doses differ slightly and are listed in Table 19-6.
PREVENTION OF THROMBOSIS DURING
PREGNANCY
Pregnancy as a Risk Factor for VTE
•
Hypercoagulability
Coagulation is not fully corrected until at least 6 weeks postpartum.
Some retrospective data show that the risk for stroke, myocardial
1,2,42,43
infarction (MI), and VTE is elevated out to 12 weeks postpartum.
True diagnosis of deficiencies (protein C, S, antithrombin) should
wait until at least 6 weeks postpartum and off VKAs for at least 2
weeks.
•
Venous stasis
>30% reduction in flow by 15 weeks; >60% reduction by 36 weeks.
90% of DVTs in left leg due to compression of left iliac vein by the
right iliac artery where they cross.
•
Vascular damage
Trauma to pelvic veins during delivery.
Pelvic vein thromboses, rare outside of pregnancy or pelvic surgery,
account for approximately 10% of DVT during pregnancy and the
postpartum period.
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