Received: 7 February 2024

- -Revised: 10 May 2024

https://doi.org/10.1016/j.rpth.2024.102446

ILLUSTRATED REVIEW
Accepted: 14 May 2024

Venous thromboembolism in pregnancy and postpartum: an

illustrated review

Annabel K. Frank1 | Bethany Samuelson Bannow2

1
Division of Hematology/Oncology,
Department of Medicine, University of Abstract
California, San Francisco, California, USA
The topic of this review is venous thromboembolism (VTE) during pregnancy and
2
Hemostasis and Thrombosis Center,
postpartum. The following topics will be addressed: epidemiology and pathophysiology
Oregon Health & Science University,
Portland, Oregon, USA of VTE in pregnancy and postpartum, diagnostic considerations for VTE in pregnancy,
indications for prophylactic and therapeutic anticoagulation in pregnancy and post-
Correspondence
Bethany T. Samuelson Bannow, Hemostasis partum, choice of anticoagulation in pregnancy and breastfeeding, anticoagulation
and Thrombosis Center, Oregon Health &
management during labor and delivery, and anticoagulation considerations for assisted
Science University, 3181 SW Sam Jackson
Park Rd, OC14HO, Portland, OR 97239, reproductive technology.
USA.
Email: [email protected]

Handling Editor: Michelle Sholzberg

-
© 2024 The Author(s). Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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VTE Risk Factors in Pregnancy and Postpartum

Prior VTE –
unprovoked or
Systemic lupus provoked (surgery
or estrogen-
erythematosus
related)
and
antiphospholipid
syndrome Heart disease
(valvular,
cardiomyopathy,
other)

Family history of Assisted

VTE (first degree reproductive
relative) technology

Obesity
May-Thurner:
Right iliac
artery Gestational
compresses diabetes
left iliac vein
or other
anatomic
anomalies
Labor & Delivery Risk Factors
- Preeclampsia and eclampsia
Sickle cell
- Preterm labor
disease8
- Placenta previa
- Placental abruption

Grand multipara (≥5 prior - Caesarean section

pregnancies) or first
pregnancy at ≥35 years of - Postpartum hemorrhage
age
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Suspected PE in Pregnancy: Diagnostic Approach

Clinical Prediction Tool

Pregnancy-Adapted Geneva Score

Keep in mind:
How is this helpful?
1. Age ≥ 40 (+1) While this scoring system
HR increases in
pregnancy (normal
2. Surgery (under general anesthesia) or lower limb has not been validated as
physiology!) fracture in past month (+2) a method to determine
3. Prior VTE (+3) who needs a CT scan, it
4. Unilateral lower limb pain (+3) provides a pre-test
5. Hemoptysis (+2) probability that clinicians
6. Pain on lower limb palpation or unilateral edema (+4) may find useful in
7. HR > 100 bpm (+5) conjunction with clinical
gestalt and the YEARS
Prevalence PE diagnostic algorithm.
0-1 points: 2.3%
2-6 points: 11.6%
≥ 7 points 61.5%

Diagnostic Algorithm

Pregnancy-Adapted YEARS Algorithm

DVT missed in 0.21%

(1/477) PE SUSPECTED

No missed PEs

Order D-dimer
Lower extremity &
ultrasound Assess YEARS Criteria
DVT 1. Signs DVT
suspected 2. Hemoptysis
3. PE most likely dx
+ -

Anticoagulation

≥ 1 YEARS criteria present & D-dimer < 500 ng/ml ≥ 1 YEARS criteria present & D-dimer ≥ 500 ng/ml
OR OR
No YEARS criteria present & D-dimer <1000 ng/ml No YEARS criteria present & D-dimer ≥1000 ng/ml

PE ruled out CT Pulmonary Angiography

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Anticoagulant Safety in Pregnancy

Medication Considerations
Do not cross placenta; extensive observational
Heparins
safety data

Does not cross placenta and considered safe (can

Danaparoid
be used for heparin-induced thrombocytopenia)

Crosses placenta minimally; likely safe (limited

Fondaparinux
data)
Crosses placenta, teratogenic; highest risk 6-12
weeks gestation and dose >5mg/daily, though
Warfarin
toxicity outside this period and at lower doses
reported
Crosses placenta; unknown risk and safety
DOACs
concerns exist from limited human data

LMWH Safety Specifics

Bleeding
↑ risk bleeding peripartum including postpartum hemorrhage (PPH)
LMWH relative risk PPH: ~1.5; absolute risk of PPH varies by setting and
mode of delivery; baseline risk of severe PPH in the US is 0.03%

Skin reactions
Minor reactions are common, serious reactions rare
Switching LMWH agents can help

Osteoporosis
Negligible risk if used exclusively for pregnancy. A study of LMWH in
pregnancy found NO impact on bone mineral density
In contrast, unfractionated heparin (UFH) has a greater impact on bone
density loss, but this is primarily with long-term use

Heparin-induced thrombocytopenia (HIT)

Hep
Exceedingly rare
Ex
LMWH carries substantially lower risk of HIT compared to UFH
LM
Absolute risk: ~0.2% versus 2.6%
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Indications for Anticoagulation

A) Indications for Prophylactic Anticoagulation

1. History of estrogen-provoked VTE

2. Inherited thrombophilia (Conditional – See table)
3. Other high-risk individuals (See Note)

Thrombophilia Antepartum Postpartum

History of estrogen-provoked VTE; homozygous

YES YES
FVL; compound heterozygous FVL/PGM
Family history of VTE + homozygous PGM or
YES YES
antithrombin deficiency
Family history of VTE + protein C or S deficiency, or
No YES
homozygous PGM without family history
History of VTE with non-hormonal transient risk
factor (trauma, surgery), not on anticoagulation at No YES
baseline
Any other inherited “thrombophilia” (heterozygous
No No
FVL, heterozygous PGM, other)
Abbreviations: FVL – Factor V Leiden; PGM – Prothrombin Gene Mutation
Recommendations from American Society of Hematology 2018

Note:
Recurrent Miscarriage: prophylactic AC has NOT shown benefit for
individuals w/ inherited thrombophilia & recurrent miscarriage (ALIFE trial)
Antiphospholipid Antibodies: prophylactic AC & aspirin may benefit
pregnant patients who have antiphospholipid antibodies w/ history of recurrent
pregnancy loss, even without prior thrombosis

B) Indications for Therapeutic Anticoagulation

1. NEW VTE in pregnancy or postpartum

Æ Duration of therapy 3-6 months
Æ Minimum 6 weeks postpartum
2. CONTINUATION of therapy in patient on long-term
anticoagulation (including most patients taking
reduced-dose DOAC therapy)
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Prophylactic Anticoagulation

When to start prophylactic AC?

- First positive pregnancy test, or
- Ultrasound-confirmed pregnancy; no later than 8 weeks
When to stop prophylactic AC?
- 6 weeks postpartum is standard, consider extending in high-risk patients
Which medication? LMWH (Consider UFH in renal dysfunction)

What dose of prophylactic AC?

- Low-dose, based on *Highlow* trial
- Consider weight-adjusted intermediate dose for patients with a concerning
history (hemodynamically significant PE, limb-threatening DVT) as there was a
non-significant trend toward increased postpartum PE in low-dose arm

1110 pregnant women with history of 555 assigned to weight-adjusted

VTE randomly assigned intermediate dose LMWH
81% related to pregnancy,
postpartum, or hormone-associated;
others: minor or major transient risk 555 assigned to fixed low-dose
factor, unprovoked LMWH

Median follow-up: 247 days

Highlow Efficacy and Safety Outcomes

10.0%
Intermediate-dose (n=555)
Low-dose (n=555)
8.0%

6.0%

4.0%

2.0%

0.0%
Antepartum VTE Postpartum VTE Major Bleeding Minor Bleeding

LMWH Dosing. Low-dose options for thromboprophylaxis, based on *Highlow*

Nadroparin Enoxaparin Dalteparin Tinzaparin

<100 kg 2850 IU 4000 IU (40 mg) 5000 IU 3500 IU
≥100 kg 3800 IU 6000 IU (60 mg) 7500 IU 4500 IU
All doses are administered once daily. IU=international unit.
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Future Directions

High quality research is urgently needed for pregnant and postpartum

populations at risk for VTE and with a new diagnosis of VTE.
Most recommendations are conditional with low certaintyy in evidence.

Select topics warranting additional study:

1. Role of prophylactic anticoagulation
oagula for patients with sickle cell disease in
pregnancy and postpartum m
2. Safety and efficacy of once
c vers
ce versus
e su twice daily dosing for therapeutic LMWH
3. Role of anti-Xa monitoring
ng
4. Management of anticoagulant therapy around the time of delivery (planned
l t th
induction; timing of neuraxial anesthesia))
5. Safety of DOACS in pregnancy and breastfeeding

Current Ongoing Clinical Trials as of December 2023

Trial Design
Aspirin vs LMWH for postpartum VTE Single center pilot, randomized
prevention (LEAP) controlled trial assessing postpartum
prophylactic anticoagulation with 3
Clinicaltrials.gov ID: NCT05058924 weeks of LMWH followed by 3 weeks
of aspirin compared to standard of care
of prophylactic LMWH for 6 weeks

Postpartum aspirin to reduce VTE in A randomized trial of aspirin versus

selected high-risk patients (Pilot placebo for postpartum women at
PARTUM) modest risk of VTE (examples:
heterozygous factor V Leiden,
Clinicaltrials.gov ID: NCT04153760 immobilization, cesarean delivery and
obesity, and others).

Assessing Women's Preferences for This study is conducting interviews

Postpartum Thromboprophylaxis: the using the “standard-gamble” technique
PREFER-PostPartum (PREFER-PP) to determine threshold of risk of
postpartum venous thromboembolism
Clinicaltrials.gov ID: NCT05318547 at which women prefer the use of short-
term postpartum thromboprophylaxis
with LMWH over no treatment.
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