Indones J
112 Suparman Obstet Gynecol
Literature Review
Prevention and Treatment of Venous Thromboembolism in Pregnancy
Pencegahan dan Tatalaksana Tromboemboli Vena pada Kehamilan
Erna Suparman
Department of Obstetrics and Gynecology
Faculty of Medicine Sam Ratulangi University
Prof. Dr. R. D. Kandou General Hospital
Manado, North Celebes
Abstract Abstrak
Objective: To determine prevention and treatment of Tujuan: Mengetahui bagaimana pencegahan dan tatalak-
venous thromboembolism in pregnancy. sana tromboemboli vena pada kehamilan.
Methods: Literature Review. Metode: Kajian Pusataka.
Results: The diagnosis of TEV, both deep vein thrombosis Hasil: Diagnosis TEV, baik Deep vein thrombosis (DVT)
(DVT) and pulmonary embolism (PE) was clinical and dan pulmonary embolism (PE) berdasarkan klinis dan
confirmed by imaging. D-dimers commonly used in the dikonfirmasi dengan pencitraan. D-dimer yang biasa
non-pregnant population are less useful in pregnant digunakan pada populasi non-hamil kurang berguna pada
women. Prevention needs to be done by assessing the risk ibu hamil. Pencegahan perlu dilakukan dengan menilai risiko
of TEV in pregnant women and giving thrombophylaxis TEV pada ibu hamil dan memberikan trombofilaksis sesuai
according to risk. Treatment of TEV in pregnant women dengan risiko. Tatalaksana TEV pada ibu hamil terutama
mainly uses heparin, either unfractionated heparin (UFH) or menggunakan heparin, baik unfractionated heparin (UFH)
low molecular weight heparin (LMWH). maupun low molecular weight heparin (LMWH).
Conclusion: The ASH recommends the use of LMWH Kesimpulan: ASH merekomendasikan penggunaan LMWH
compared with UFH for the management of acute dibandingkan dengan UFH untuk pengelolaan VTE akut
VTE in pregnancy, in once-daily or divided doses. The pada kehamilan, dalam dosis sekali sehari atau terbagi.
recommended method of delivery for pregnant women Metode persalinan yang direkomendasikan untuk ibu hamil
receiving anticoagulant therapy should be planned delivery. yang menerima terapi antikoagulan harus direncanakan
persalinan.
Keywords: vein thromboemboli, deep vein thrombosis,
pulmonary embolism, pregnancy. Kata kunci: tromboemboli vena, deep vein thrombosis,
pulmonary embolism, kehamilan.
Received: September, 2021 Accepted: March, 2022 Published: April, 2022
INTRODUCTION In the period 2004-2014, the incidence of VTE
was around 5.7 cases per 10,000 deliveries. The
Venous thromboembolism (VTE), especially incidence of DVT itself decreased (5.3 to 4.4 cases
pulmonary thromboembolism which often per 10,000 deliveries) after the clinical community
originates from deep vein thrombosis (DVT), followed the guidelines and recommendations
is one of the most common causes of death in for thromboprophylaxis in pregnant women, but
pregnant women. Research in America with data the incidence of pulmonary thromboembolism
from 1998-2013 showed maternal mortality due tends to be the same.1 Approximately 15-24%
to pulmonary thromboembolism is 1.5 - 1.6 of cases of DVT will develop into pulmonary
deaths per 100,000 live births. The risk of death thromboembolism if left unchecked.2
from pulmonary thromboembolism is higher in Pregnant women have a risk of VTE 4 – 4.6 times
the postpartum period. A total of 8.8% of deaths compared to women of the same age who are not
in pregnancy were due to PTE in the postpartum pregnant. The risk of developing VTE increases
period compared to 6.7% at the time of delivery. with advancing gestational age, peaking at 1-3
Vol 10. No 2. April 2022 Prevention and Treatment of Venous 113
weeks postpartum. In the 3-month postpartum METHODS
period, the risk of VTE increased up to 60-fold
(OR 60.1; 95% CI). This risk is increased because The method in this research is to use literature
of vascular damage at the time of delivery.3 The review from various references.
risk then decreases and is the same as the risk in
the nonpregnant state at 12 weeks postpartum.1 RESULTS
Risk factors that increase the incidence of VTE in
the nonpregnant population also increase the PATHOGENESIS OF THROMBOEMBOLISM
risk of VTE in pregnant women, such as old age, IN PREGNANCY
anemia, obesity, smoking, and other factors.3
The most important factor in the incidence of Pregnancy and the postpartum period are
VTE in pregnant women is a previous history of prothrombotic conditions characterized by an
VTE. The incidence of VTE in pregnant women increase in the three components of Virchow's
with a history of VTE and who were not given triad, namely venous stasis, endothelial damage,
thromboprophylaxis was found to be very high, and hypercoagulation. Venous stasis in the
around 1000 cases per 10,000 pregnant women lower extremities occurs in pregnancy due to
(10%). The second important factor in VTE in progesterone-induced venous-vasodilation and
pregnant women is hereditary thrombophilia. compression of the large veins by the gravid
The risk of VTE in pregnant women with uterus. Although blood volume and venous
thrombophilia is much higher than in pregnant return are increased, the linear velocity of the
women in general (OR 15.4, 95% CI).3 History of lower extremity veins is reduced because of
cardiovascular disease is the third highest risk increased venous capacity. This venous stasis
factor with an incidence of 100-200 cases per lasts up to about 6 weeks postpartum.5
10,000 pregnant women. Preeclampsia, one of Endothelial damage that occurs during labor
the most common complications of pregnancy, on the uteroplacental surface may increase the
also increases the risk of VTE. The study of Kane risk of VTE in the postpartum period. The use
et al. showed that preeclampsia increased the of assistive devices such as forceps, vacuum, or
risk of VTE in the postpartum period by 1.6 times, surgery can exacerbate these risks. The increased
but not in the prenatal/antepartum period.4 blood volume in pregnancy may also cause shear
Another risk factor that significantly increases stress on the blood vessels.6
the risk of VTE in pregnant women is a cesarean Pregnancy is a hypercoagulable condition
section, but this risk was found to decrease characterized by an increase in pro coagulation
with thromboprophylaxis according to recent factors such as factors V, VII, VIII, IX, X, XII, and
guidelines.3 von Willebrand factor. This condition is also
The increased risk of VTE in pregnant women, accompanied by reduced anticoagulation factors,
especially those accompanied by other risk namely protein S. Fibrinolysis is also reduced due
factors and the high morbidity and mortality of to increased activity of plasminogen activator
VTE, requires early diagnosis, prevention, and inhibitor types I and II, and reduced activity of
appropriate management. The purpose of this tissue plasminogen activator.6 These changes are
review is to discuss the diagnosis, prevention, and physiological to prepare for blood clotting during
management of thromboembolism in pregnancy. labor, which is characterized by an increase in
Table 1. Risk factors for venous thromboembolism in
D-dimer and prothrombin fragments.
pregnancy 1,3,4
DIAGNOSIS OF VTE IN PREGNANCY
Risk Factors
Previous VTE history Deep vein thrombosis (DVT)
Hereditary hemophilia The most common complaint in more than 80%
History of cardiovascular disease of pregnant women with DVT is pain and swelling
Post-partum in the extremities. However, this complaint is also
Pre-eclampsia often complained by pregnant women without
Elderly
DVT. A unilateral calf circumference difference
Anemia
Obesity
of more than 2 cm is a sign suggestive of lower
Smoking extremity DVT. In the guidelines of the American
College of Obstetricians and Gynecologists
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114 Suparman Obstet Gynecol
(ACOG), the initial investigation recommended Investigations such as blood gas analysis
in patients presenting with suspected DVT (BGA) are neither sensitive nor specific for the
is compression ultrasonography (CUS). diagnosis of PE. Patients with PE usually develop
Thromboembolism in pregnant patients is usually a respiratory alkalosis, similar to that found in
found in the iliofemoral or ileal, in contrast to the normal pregnancy. Normal PO2 and PCO2 levels
general population, which is usually found in the are often found in patients with PE, so normal
distal. BGA levels cannot rule out PE.10 Examination of
When CUS results are negative or doubtful and D-dimer, such as in DVT is difficult to do because
iliac vein thrombosis is suspected (swelling of the there is no normal value of D-dimer in pregnant
whole leg with or without back, waist, or buttocks women.11
pain), the next investigation recommended is According to ACOG guidelines, ventilation-
iliac vein Doppler ultrasonography, venography, perfusion scanning (V/Q scanning) and computed
or magnetic resonance imaging (MRI). Empirical tomographic pulmonary angiography (CTPA)
anticoagulation may also be given in some cases. examinations can be performed in pregnant
When the results are negative and there is no women with suspected PE. Clinical practice
suspicion of iliac vein thrombosis, re-examination guidelines from the American Thoracic Society
can be performed on day 3 and day 7.7 recommend a chest X-ray in all pregnant patients
The D-dimer examination is less useful in ruling with suspected PE without DVT symptoms. If the
out VTE in pregnant women because normal photo is abnormal, it is recommended to continue
pregnancy is accompanied by a progressive with CTPA examination, while the normal photo
increase in D-dimer, so it is not recommended.7 is followed by V/Q scanning.12
The use of a scoring system such as the Wells
score needs to be interpreted with caution as this PREVENTION OF THROMBOEMBOLISM
score was not validated for the pregnant maternal IN PREGNANCY
population.8 The use of clinical prediction LEFt
(Left leg, Edema [calf diameter difference 2cm], Not all pregnant or postpartum women
First trimester) can help in predicting DVT in require thromboprophylaxis. ACOG recommends
pregnant women. In a study of 194 pregnant assessing VTE risk factors for all pregnant women
women, DVT was not found in patients with a before or in early pregnancy.7 One tool that can
score of 0. However, this system should not be be used to assess this risk is to use the modified
used as the sole means of excluding DVT. This Padua or Caprini scoring system for the pregnant
tool also still needs further validation.9 woman population. ACOG also recommends the
assessment of thrombophilia in pregnant women
Pulmonary Embolism / PE with a previous history of VTE.13
PE symptoms such as dyspnea, palpitations,
chest pain that is aggravated by movement Thrombophylaxis in Cesarean Section
are often found in pregnant women with non- In cesarean delivery, ACOG and the American
thrombotic causes, such as gastroesophageal College of Chest Physician (ACCP) recommend
reflux or discomfort due to an enlarged uterus. using pneumatic compression devices and early
This causes the diagnosis of PE in pregnant women mobilization for all pregnant women who are not
to be difficult.8 In addition, scoring systems such receiving pharmacological thromboprophylaxis.13
as Wells or Geneva are not validated for pregnant In pregnant women at high risk of VTE,
patients. Clinicians need to consider the diagnosis the recommendations are not clear. ACOG
of PE in pregnant women who present with these recommends a combination of pneumatic
symptoms given the high mortality. Symptoms compression and low molecular weight heparin
that can be found in PE include palpitations, (LMWH).7 ACCP recommends combination
anxiety, pleuritic chest pain, cyanosis, and thromboprophylaxis for patients with a score
cough with or without hemoptoe. On physical of 5 or more. In pregnancy, this score is usually
examination, usually found tachypnea, crackles, found in patients with a history of VTE or a family
decreased breath sounds, and tachycardia. In history or with thrombophilia.13
some cases, signs of right ventricular failure can
also be found, such as a split-second heart sound, Antepartum and Postpartum Thrombophylaxis
jugular venous distension, parasternal removal, Pharmacological thromboprophylaxis can be
and hepatomegaly.2 given to pregnant women with a high risk of
Vol 10. No 2. April 2022 Prevention and Treatment of Venous 115
VTE. The recommendations from ACOG 2018 consider the advantages of preventing VTE and
regarding pregnant women who are indicated the disadvantages of fetal complications and
for pharmacological thromboprophylaxis can bleeding.7
be seen in Table 2. These recommendations
Table 2. Pharmacological thromboprophylaxis recommendations in pregnancy and the puerperium 7
Clinical Scenario Antepartum Postpartum Management
Management
No history of VTE or Supervision, without Postpartum prophylactic
thrombophilia pharmacological therapy anticoagulation monitoring or
therapy may be considered if the
patient has multiple risk factors
for VTE*
VTE diagnosed during pregnancy LMWH/UFH therapeutic dose LMWH/UFH therapeutic dose at
least 6 weeks postpartum. The
duration of administration may be
longer. Oral anticoagulants may
be considered.
History of one episode of VTE Supervision, without Postpartum prophylactic
precipitated by causes other than pharmacological therapy anticoagulation monitoring or
estrogen or pregnancy (surgery, therapy may be considered if the
trauma, immobilization), without patient has multiple risk factors
thrombophilia for VTE*
History of one unprovoked LMWH/UFH moderate LMWH/UFH prophylactic dose,
VTE episode, including prophylactic dose or therapeutic moderate dose, or therapeutic
pregnancy-related or hormonal dose dose for 6 weeks postpartum
contraceptives
Low-risk thrombophilia** with no Supervision, without Postpartum prophylactic
history of VTE pharmacological therapy anticoagulation monitoring or
therapy may be considered if the
patient has multiple risk factors
for VTE*
Low-risk thrombophilia with a Surveillance or prophylactic Postpartum prophylactic
nuclear family history of VTE LMWH/UHF anticoagulation therapy or
moderate dose LMWH/UFH
High-risk thrombophilia*** no Prophylactic or moderate dose Postpartum prophylactic
history of VTE LMWH/UFH anticoagulation therapy or
moderate dose LMWH/UFH
High-risk thrombophilia with a LMWH/UFH prophylactic dose, Prophylactic postpartum
history of one episode of VTE/ moderate dose, or therapeutic anticoagulation therapy or
nuclear family history dose moderate/therapeutic doses of
LMWH/UFH for 6 weeks (level
of therapy should be similar to
antepartum management)
History of two or more VTE Moderate/therapeutic dose Postpartum anticoagulation
episodes LMWH/UFH therapy with moderate/
therapeutic doses of LMWH/
UFH for 6 weeks (level of therapy
should be similar to antepartum
management)
History of two or more VTE LMWH/UFH therapeutic dose Continue long-term anticoagulant
episodes – being on long-term therapy.
anticoagulant medication
Indones J
116 Suparman Obstet Gynecol
*Obesity, prolonged immobilization, cesarean delivery, the consensus of the Society for Obstetric
family history of VTE Anesthesia and Perinatology recommends
** Low-risk thrombophilia: Factor V Leiden heterozygous;
heterozygous G20210A prothrombin gene mutation; protein
delaying reinitiation for at least 24 hours or
C or protein S deficiency; antiphospholipid antibodies. using IV UFH if earlier initiation is desired.16 In
*** High-risk thrombophilia: Homozygous Factor V Leiden; patients requiring anticoagulation for longer
homozygous G20210A prothrombin gene mutation; than 6 weeks, bridging to warfarin or direct oral
Heterozygous Factor V Leiden plus heterozygous G20210A
anticoagulation (if not breastfeeding) may be
prothrombin gene mutation; antithrombin deficiency.
considered. The initial dose of warfarin is 5 mg
MANAGEMENT OF THROMBOEMBOLISM once daily, with subsequent doses determined by
IN PREGNANCY the international normalized ratio (INR).7
Initial VTE management in pregnant women Thrombolysis / Thrombectomy
depends on the degree of suspicion of PE. In Thrombolytic agents are known to have side
cases with a strong suspicion of PE, empiric effects, namely severe maternal bleeding, so
anticoagulation is given until there is no evidence they are only given to life-threatening acute PE.
of VTE. In patients with suspected PE but who have Thrombectomy can be performed to save lives if
contraindications to anticoagulation, a diagnostic other attempts fail. Thrombectomy is a procedure
evaluation is preceded by administration of in which an intravenous catheter is inserted to
therapy without anticoagulation (eg inferior vena reach the thrombus, then placing a thrombolytic
cava filter) after VTE is confirmed. agent around the thrombus in the hope that the
When anticoagulation is indicated, the thrombus will lysis. In a literature review, Catheter
recommended initiation of anticoagulation Directed Thrombolysis (CDT) had a lower risk of
by both ACCP and ACOG is subcutaneous bleeding but the possibility of systemic spread of
therapeutic dose LMWH.7,14 LMWH is preferable the thrombolytic agent was possible.17
to intravenous (IV) Unfractionated Heparin (UFH)
because it has a better efficacy and safety profile. ANTICOAGULANT REGIMEN IN PREGNANCY
These findings were obtained by extrapolating a
meta-analysis from 22 randomized clinical trials The use of anticoagulants in pregnant women
with the general (nonpregnant) population. The is different from the general population. The
use of subcutaneous LMWH has a lower mortality benefits and risks need to be considered for
rate, lower recurrent thrombosis, and lower heavy both the fetus and the mother. Heparin is the
bleeding compared to IV UFH.15 In patients with recommended anticoagulant in pregnancy.
PE or situations requiring immediate delivery, The pharmacokinetics of heparin will change
surgery, or thrombolysis, IV UFH is preferred in pregnancy as the total blood volume and
because it has a shorter half-life and can be glomerular filtration rate increase. This causes
discontinued protamine when necessary. Oral heparin to have a lower half-life and peak
anticoagulants are avoided in pregnancy because plasma concentration, so larger doses are
of the unknown safety profile. The use of warfarin required. The therapeutic dose of heparin was
is avoided because it is teratogenic, especially in adjusted according to the activated partial
the first trimester.7 thromboplastin time (aPTT), while the LMWH
In patients who are about to give birth, the was adjusted according to the mother's weight.
administration of LMWH should be discontinued At prophylactic doses or moderate doses, the
at least 12 hours before induction. Discontinuation dose given is specific according to the type of
for 24 hours is recommended for the use of drug given. The American Society of Hematology
therapeutic doses. In the use of heparin 7500 U (ASH) recommends the use of LMWH over the
SC twice daily or more, discontinuation should use of UFH in the management of acute VTE,
be carried out for 12 hours with an evaluation of with the LMWH dose being once or divided
coagulation status. This discontinuation is done into twice-daily doses.18 For pregnant women
to avoid spinal hematoma in the administration receiving anticoagulant therapy, the ASH
of neuraxial anesthesia.7 recommends scheduled delivery, with stopping
After delivery, the heparin regimen should be anticoagulation a few days before delivery.18
restarted after 12 hours of cesarean section or Management of acute VTE in the anticoagulant
6 hours after vaginal delivery, unless significant regimen taken from the ACOG practical bulletin
bleeding occurs. For LMWH administration, can be seen in Table 3.7
Vol 10. No 2. April 2022 Prevention and Treatment of Venous 117
Table 3. Anticoagulant regimen 7
Anticoagulant regimen Dose
Prophylactic LMWH Enoxaparin, 40 mg SC once daily
Dalteparin, 5,000 U SC once daily
Tinzaparin, 4,500 U SC once daily
Nadroparin, 2850 U SC once daily
LMWH moderate dose Enoxaparin, 40 mg SC every 12 hours
Dalteparin, 5,000 U SC every 12 hours
LMWH therapeutic dose Enoxaparin, 1 mg/kg every 12 hours
Dalteparin, 200 U/kg once daily
Tinzaparin, 175 U/kg once daily
Dalteparin, 100U/kg every 12 hours
Anti-Xa targets in a therapeutic range of 0.6-1.0U/ml 4 hours after
injection at twice-daily doses; dose increase may be required for
daily dosing.
Prophylactic UFH UFH 5,000-7,000 U SC every 12 hours in the first trimester
UFH 7,500-10,000 U SC every 12 hours in the second trimester
UFH 10,000 U SC every 12 hours in the third trimester, unless the
aPTT is elevated
UFH therapeutic dose UFH 10,000 U or more SC every 12 hours with dose adjusted to
aPTT in the therapeutic range (1.5-2.5x control) 6 hours after
injection
Postpartum anticoagulation Prophylactic, moderate, or therapeutic doses of LMWH for 6-8
weeks as indicated. Oral anticoagulation may be considered
according to the duration of therapy, lactation, and patient
preferences
CONCLUSIONS AND SUGGESTIONS
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E, Greer IA. A population-based study of venous
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pregnancy. Further assessment of thrombophilia 5. Devis P, Knuttinen MG. Deep venous thrombosis in
pregnancy: incidence, pathogenesis and endovascular
needs to be carried out in pregnant women with management. Cardiovasc Diagn Ther. 2017;7(Suppl
a previous history of VTE. Thromboprophylaxis 3):S309–19.
with heparin is indicated in patients at high 6. Dado CD, Levinson AT, Bourjeily G. Pregnancy and
risk of VTE, eg those with a history of high-risk Pulmonary Embolism. Clin Chest Med. 2018;39(3):525–
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7. American College of Obstetricians and Gynecologists’
ASH recommends the use of LMWH compared Committee on Practice Bulletins—Obstetrics. ACOG
with UFH for the management of acute VTE in Practice Bulletin No. 196: Thromboembolism in
pregnancy, in once-daily or divided doses. The Pregnancy. Obstet Gynecol. 2018;132(1):e1–17.
recommended method of delivery for pregnant 8. Chan W-S. Diagnosis of venous thromboembolism in
pregnancy. Thromb Res. 2018;163:221–8.
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be planned delivery. Ramsay T, et al. Predicting deep venous thrombosis
in pregnancy: out in “LEFt” field? Ann Intern Med.
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