How I Treat ETV in Pregnancy

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How I treat venous thromboembolism in pregnancy
Tracking no: BLD-2019-000963-CR1
Saskia Middeldorp (Amsterdam University Medical Centers, Netherlands) Wessel Ganzevoort (Amsterdam
University Medical Centers, Netherlands)
Abstract:
Of 1,000 pregnant women, one to two will experience venous thromboembolism (VTE) during pregnancy or the
postpartum period. Pulmonary embolism (PE) is a leading cause of maternal mortality and deep vein
thrombosis (DVT) leads to maternal morbidity and may diminish quality of life due to post-thrombotic
syndrome during the rest of a woman’s life. Despite this important burden, the evidence base for the
management of pregnancy-related VTE is weak. Recommendations from evidence-based guidelines are often
extrapolated from the non-pregnant population and thus weak or conditional. As a consequence, there is
wide variation of practice. In women with a suspicion of PE, the pregnancy-adapted YEARS algorithm is
safe and efficient, with 39% of women not needing computed tomographic pulmonary angiography (CTPA) to
rule out PE. Low-molecular-weight heparin (LMWH) in therapeutic doses is the treatment of choice during
pregnancy, and anticoagulation (LMWH or vitamin K antagonists [VKA] postpartum) should be continued
until 6 weeks after delivery with a minimum total duration of 3 months. Use of LMWH or vitamin K
antagonists does not preclude breastfeeding. Postpartum, direct oral anticoagulants (DOACs) are an
option if women do not breastfeed and long-term use is intended. Management of delivery, including the
type of analgesia, requires a multidisciplinary approach and depends on local preferences and patient-
specific conditions. Several options are possible and include waiting for spontaneous delivery with
temporary interruption of LMWH. Prophylaxis for the prevention of recurrent VTE in subsequent
pregnancies is indicated in most women with a history of VTE.
Conflict of interest: COI declared - see note
COI notes: Saskia Middeldorp is the principal investigator of the Highlow study, a randomized controlled
trial comparing low dose LMWH with intermediate dose LMWH in pregnant women with a history of VTE
(http://www.ClinicalTr ials.gov; NCT01828697). Saskia Middeldorp reports grants and fees paid to her
institution from GSK, BMS/Pfizer, Aspen, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Sanofi, and
Portola. Wessel Ganzevoort is the principal investigator of the DRIGITAT study, a randomized controlled
trial comparing diagnostic strategies in fetal growth restriction
(https://www.trialregister.nl/trial/6475) and reports an unrestricted grant from Roche Diagnostics paid
to his institution for in kind delivery of materials.
Preprint server: No;
Author contributions and disclosures: S.M. and W.G. wrote the paper.
Non-author contributions and disclosures: No;
Agreement to Share Publication-Related Data and Data Sharing Statement:
Clinical trial registration information (if any):

Accepted version.
How I treat venous thromboembolism in pregnancy
Saskia Middeldorp1 and Wessel Ganzevoort2
Corresponding author:
Saskia Middeldorp, s.middeldorp@amsterdamumc.nl
Amsterdam UMC, University of Amsterdam, 1 Department of Vascular Medicine, Amsterdam

Cardiovascular Sciences, and 2 Department of Obstetrics and Gynecology, Amsterdam
Reproduction & Development, Meibergdreef 9, Amsterdam, The Netherlands.
1
Abstract
Of 1,000 pregnant women, one to two will experience venous thromboembolism (VTE) during
pregnancy or the postpartum period. Pulmonary embolism (PE) is a leading cause of maternal
mortality and deep vein thrombosis (DVT) leads to maternal morbidity and may diminish quality
of life due to post-thrombotic syndrome during the rest of a woman’s life. Despite this important
burden, the evidence base for the management of pregnancy-related VTE is weak.
Recommendations from evidence-based guidelines are often extrapolated from the non-
pregnant population and thus weak or conditional. As a consequence, there is wide variation
of practice. In women with a suspicion of PE, the pregnancy-adapted YEARS algorithm is safe
and efficient, with 39% of women not needing computed tomographic pulmonary angiography
(CTPA) to rule out PE. Low-molecular-weight heparin (LMWH) in therapeutic doses is the
treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists
[VKA] postpartum) should be continued until 6 weeks after delivery with a minimum total
duration of 3 months. Use of LMWH or vitamin K antagonists does not preclude breastfeeding.
Postpartum, direct oral anticoagulants (DOACs) are an option if women do not breastfeed and
long-term use is intended. Management of delivery, including the type of analgesia, requires a
multidisciplinary approach and depends on local preferences and patient-specific conditions.
Several options are possible and include waiting for spontaneous delivery with temporary
interruption of LMWH. Prophylaxis for the prevention of recurrent VTE in subsequent
pregnancies is indicated in most women with a history of VTE.
2
Introduction
Women who experience venous thromboembolism (VTE) during pregnancy or the postpartum
period face a potentially life-threatening condition.1,2 VTE occurs in 1 to 2 of 1,000 pregnancies,
and the risk increases with age, mode of delivery, and presence of comorbid conditions. 3–5
Almost half of women with deep vein thrombosis (DVT) in pregnancy experience a reduced
quality of life as a result of post-thrombotic syndrome, because thrombosis in pregnant and
postpartum women predominantly affects the iliac or iliofemoral veins.6 Approximately two-
thirds of lower extremity DVTs occur antepartum, with an approximately equal distribution over
the trimesters.7,8 The epidemiology of pulmonary embolism (PE) appears to differ slightly from
DVT, with the majority of pregnancy-related episodes of PE occurring in the postpartum
period.3 Given the much longer duration of the antepartum period than the postpartum period,
the daily absolute risk of VTE is highest postpartum.
A challenge in dealing with VTE issues in pregnant and postpartum women is the absence of
high-quality evidence in this distinct population, although some progress has been and is being
made since the 2011 paper on this topic from one of the current authors (SM).9 In the absence
of evidence, it is impossible to identify optimal management and there is wide variation
between physicians, centers and countries. In this review, we will discuss how we treat
pregnancy-related VTE based on two patient histories from our clinical practice in an academic
hospital in The Netherlands.
3
Case 1
A 32-year-old 11-weeks pregnant woman presented to the emergency department in a
teaching hospital with a three-day history of left sided chest pain that increased with
inspiration, along with a one day history of shortness of breath. She had no other symptoms,
most notably no fever, hemoptysis or complaints of her legs. In the past month, she had been
admitted to hospital twice because of hyperemesis, and also had made a return trip to the
United States (i.e. two 8-hour flights) two weeks before presentation. She had not received
thrombosis prophylaxis. Her previous medical history was uneventful, except for an early
miscarriage three years earlier; her family history was negative for VTE. On physical
examination her body weight was 78 kg with a BMI of 23.8 kg/m2. She appeared somewhat
short of breath and in pain, with a respiratory rate of 22 excursions per minute, temperature
of 38.2 degrees Celsius, blood pressure of 115/70 mmHg, a regular pulse of 95 beats per
minute, transcutaneous oxygen saturation of 95% on room air, and no abnormalities on chest
examination. Her legs did not show signs of DVT. Laboratory results showed a normal
hemoglobin level (Hb 12.6 g/dL), mild leukocytosis (11.4 * 109/L) and a D-dimer level of
10,080 ng/mL. A chest radiograph was normal. Bilateral compression ultrasonography (CUS)
of the legs showed normal compressibility of the femoral and popliteal veins and no signs of
flow obstruction of the iliac veins on either side. Next, a CT pulmonary angiography (CTPA)
was performed that showed multiple central bilateral pulmonary emboli with a normal RV/LV
ratio (i.e. no signs of right ventricular dysfunction) and a small infarction in the left lung.
4
Case 2
A 27-year-old 32 weeks pregnant woman was transported to our emergency department
because of a unilateral car accident; she had hit the guard rail of the highway. At
presentation, she was unconscious, with pupil reactive on both sides, no pareses, and
multiple facial injuries. Her blood pressure was 128/77, pulse 115 beats per minute,
pregnant womb according to gestational age, with fetal movements observed by physical
examination. Additional trauma screening revealed multiple cerebral contusional foci,
intraparenchymal and subarachnoid hemorrhages, and fractures of the skull base, mastoid
and sphenoid bones with pneumencephaly. Obstetric ultrasound revealed a vital fetus,
without signs of placental hematoma or abruption. The present pregnancy had been
uneventful but for some edema to just above the ankle on the right side for about 2 months,
without swelling of her upper leg. Two weeks prior to the accident, a whole leg CUS
including visualization of the iliac vein had been normal. Because of the possibility that she
had lost consciousness prior to the accident, PE was considered. On bilateral compression
ultrasound, she was found to have a DVT of her left femoral vein, and no signs of iliac vein
obstruction; on the right side, no abnormalities were seen. A CT scan of the abdomen
confirmed the absence of iliac vein involvement and a CTPA confirmed the diagnosis of
bilateral PE with clear signs of right ventricular dysfunction, with a RV/LV ratio of more than
1 and flattening of the septum.
5
Diagnosis of VTE in pregnant patients
In pregnancy, specific aspects in the diagnosis of DVT and PE need to be considered. The
threshold of suspicion in pregnancy is low, as VTE is a major cause of maternal morbidity and
mortality. As a consequence of this, combined with the frequency of dyspnea and chest
discomfort even in healthy pregnancies, the numbers needed to test to find a confirmed
diagnosis is markedly higher than in the nonpregnant population. Few studies have addressed
the utility of an empirical clinical probability assessment or a pregnancy-specific clinical
decision rule, with or without the use of D-dimer levels.10,11 D-dimer levels increase during
pregnancy and are often above the regular threshold of 500 ng/mL thus triggering further
imaging for VTE diagnosis.12 Imaging of the lungs for PE expose both the pregnant woman
and her fetus to radiation. Radiation exposure of the fetus is lowest for CTPA, whereas
exposure to the proliferating breast tissue of the woman may be lower with V/Q scanning.13–15
This is the reason why V/Q scanning is still the first test ordered in many North American
centers as is suggested in the ASH 2018 guideline.15 In the guideline it is clearly pointed out
that both techniques have their own risks and benefits.15 However, V/Q scanning is not widely
available and it is likely that pregnancy adapted CTPA techniques are able to reduce the
amount of maternal radiation without compromising sensitivity. In 2018 and 2019, two well-
sized multicenter prospective outcome studies in pregnant women with suspected PE have
been published that provide an evidence-based approach to this diagnostic challenge.16–18 In
the first study, 395 women with suspected PE from 11 centers in France and Switzerland were
included.16 PE was excluded in women with a low or intermediate pretest clinical probability
based on the revised Geneva score and a D-dimer level lower than 500 ng/mL. Women with a
high pretest clinical probability or a D-dimer of 500 ng/mL or higher underwent bilateral CUS
of the legs, followed by CTPA (or V/Q scan in case of nondiagnostic CTPA) if no DVT was
found. The prevalence of VTE was 7.1%: one-quarter of these diagnoses were proximal DVT
found on ultrasound, whereas the remainder had a positive CTPA result. The strategy proved
to be safe with a rate of symptomatic VTE at 3 month follow-up of 0.0% (95% CI, 0.0% to 1.0%)
among untreated women. CTPA could be avoided in 12% based on a D-dimer of less than 500
6
ng/mL combined with a low or intermediate clinical probability. In the second study, 498
pregnant women from 18 centers in France, Ireland and the Netherlands were managed with
the pregnancy-adapted YEARS algorithm (Figure).17 PE was excluded with a D-dimer lower
than 500 ng/mL in women with at least one YEARS item (clinical signs of deep-vein
thrombosis, hemoptysis, and PE as the most likely diagnosis), or lower than 1000 ng/mL in
women with no YEARS items. Adaptation of the YEARS algorithm for pregnant women
involved CUS, but for women with symptoms of DVT only; if the results were positive CTPA
was not performed. The prevalence of VTE was 4%: one-fifth of these diagnoses were proximal
DVTs found on ultrasound, whereas the others had a positive CTPA. The strategy proved to
be safe with a rate of symptomatic VTE of 0.21% (95% CI 0.04 to 1.20). The upper limit of the
95% confidence interval meets the 1.82% cut-off proposed by the International Society on
Thrombosis and Haemostasis (ISTH) for confirming the safety of VTE diagnostic strategies.19
CTPA could be avoided in 39% of the pregnant women. The proportions of women who were
managed without CTPA were 65% in the first trimester, 46% in the second trimester, and 32%
in the third trimester. Based on the above, we consider the pregnancy-adapted YEARS
algorithm safe and efficient, and it is the diagnostic strategy we practice in our hospital in
women with a suspicion of PE during pregnancy. Of note, in both management studies the
proportion of protocol deviations was high, indicating the challenge of using these strategies
in this population. Our case, which occurred prior to publication of abovementioned
management studies, underwent a bilateral CUS despite the absence of leg symptoms.
Our second case had had atypical leg symptoms two weeks prior to the diagnosis of PE. At
that time, a formal pregnancy-adapted clinical probability assessment was not performed, but
the likelihood based on clinical judgment was considered low, and DVT was considered ruled
out after a negative whole leg compression ultrasound with visualization of the iliac vein. Also
for DVT, a pregnancy-adapted clinical prediction rule has been developed and retrospectively
validated. In our patient, the LEFt rule (symptoms in the left leg (“L”), calf circumference
difference equal or greater than 2 centimetres (“E” for edema) and a first trimester presentation
(“Ft”)) would have been 0, indicating a low clinical probability.10,20 Prospective validation of a
7
sequential diagnostic strategy based on the assessment of clinical probability with the LEFt
rule, D-dimer measurement and complete CUS in pregnant women with suspected DVT is
ongoing (ClinicalTrials.gov NCT01708239). The ASH 2018 guideline suggests to perform
serial ultrasound in women with an initial negative ultrasound, but in a prospective cohort study
of 221 pregnant women assessing this strategy, all 16 DVTs were diagnosed at the first
ultrasound.15,21 In another prospective study using a single whole leg compression ultrasound
to exclude DVT the incidence of VTE during 3-months follow-up was low (1.1%, 95%CI 0.3-
4.0%), although the upper limit of the 95%CI does not exclude a potentially unacceptable
failure rate .22 At present we do not recommend using the LEFt rule but use a single whole leg
ultrasound with visualization of the iliac vein in women with suspected DVT.
It is important to stress that in case of leg symptoms that suggest a pelvic vein thrombosis
(mainly a swollen upper leg or pain in the buttock) and if there is uncertainty about the
adequacy of ultrasonographic visualization of the iliac vein, MRI may be considered as an
additional test, although this technique is not validated for DVT. We will never be able to tell
for sure whether our second case had had DVT in her right leg that was not diagnosed,
although we still deem that unlikely.
Case 1 – continued
Our patient was treated with LMWH (tinzaparin 14,000 IU once-daily, based on body weight
at the time of diagnosis) and admitted to the obstetric ward for 5 days for pain relief with
tramadol and acetaminophen. After hospital discharge, she continued with the same dose of
LMWH, to which she adhered and tolerated well apart from some mild bruising around the
injection sites. She had adequate peak anti-Xa-levels throughout pregnancy, and normal
platelet counts. Her chest pain had subsided in a few weeks, but she remained somewhat
short of breath throughout pregnancy. At a gestational age of 30 weeks, we performed a
CTPA as she felt increasingly breathless and was tachycardic, without another clear
explanation such as anemia. The CTPA showed complete resolution of the pulmonary emboli
and lung infarction. 8

Case 2 - continued
Our patient probably had collapsed which led to her car accident, due to massive central
pulmonary emboli with signs of right ventricular dysfunction. At presentation, she was
tachycardic but her blood pressure was adequate. Clearly, she had an absolute
contraindication for both thrombolysis or therapeutic dose anticoagulation because of the
neurotrauma. In the hours after admission her cardiorespiratory status deteriorated, and
after careful multidisciplinary consideration it was decided to perform a combined
procedure under general anesthesia: the interventional radiologist placed an inferior vena
cava (IVC) filter through the right femoral vein below the renal veins, the obstetrician
delivered the baby through a cesarean section and after delivery the radiologist performed
thrombosuction of the pulmonary arteries with a single bolus infusion of 5000 IU of
unfractionated heparin. She was then treated with prophylactic dose LMWH (nadroparin
2850 IE) for 6 weeks, until the intracerebral blood was fully resorbed. Unfortunately,
attempts to retrieve the filter were not successful.
9
Treatment of VTE in pregnant patients
Low-molecular-weight heparin (LMWH) is the drug of choice in pregnant women, as it does
not cross the placenta and does not have teratogenic effects.15 Table 1 lists the safety of
several anticoagulants that are used to treat VTE during pregnancy or breastfeeding.
Optimal use of therapeutic doses of LMWH in pregnant women is generally extrapolated from
the nonpregnant population. For the initial treatment of acute VTE in pregnancy, there is no
evidence base to choose a twice-daily regimen over a once-daily regimen of therapeutic dose
LMWH.15 It is unclear whether the pre-pregnancy weight or the actual body weight should be
used to determine the appropriate dose of LMWH, and we use the actual body weight at time
of diagnosis. Although there is no evidence that anti-Xa level monitoring and subsequent dose
adjustments improve clinical outcomes, there is no evidence to demonstrate that it is harmful
either.15 In our institution we have the test available and in women with acute VTE we monitor
anti-factor Xa levels four hours after injection and target to an anti-Xa level of 0.8 to 1.6 with a
once-daily regimen at 6 to 8- week intervals. A practical advice is to instruct women to inject
themselves in the morning, in order to meet the four-hour post-injection time point of blood
withdrawal.
The maternal safety issue of any anticoagulant is the risk of bleeding. The risk of anticoagulant-
associated bleeding is thought to be low,23 as most bleeding in pregnant woman has a primary
obstetric origin. A systematic review and meta-analysis that included 18 observational studies
describing 981 pregnant patients using therapeutic dose anticoagulation treatment (LMWH or
UFH) for treatment of acute VTE, reported an antepartum incidence of hemorrhagic
complications was 3.28% (95% CI 2.10–4.72).24
LMWH leads to local bruising and skin reactions in up to 25% of pregnant patients, which are
mainly type IV delayed hypersensitivity reactions at the injection site of subcutaneously
administered LMWH.25,26 Type I allergy is rare and should always be considered, but if no
symptoms or signs are present, we pragmatically switch to another LMWH.25,27 If all registered
10
LMWHs lead to skin problems, danaparoid sodium or fondaparinux can be considered. A rare
but serious maternal complication of heparins is heparin-induced thrombocytopenia (HIT). The
incidence of HIT in pregnant patients very low (<0.1%), but some case reports have been
published.28 Although the ASH 2018 guideline on HIT suggests against platelet monitoring in
patients at very low risk,29 this is a conditional recommendation and in our institution we monitor
platelets at baseline and between 4 and 12 days post-initiation of therapy, at a time that is most
practical for the patient if she is treated outside the hospital; and at infrequent intervals (6 to 8
weeks, coinciding with anti-Xa levels and obstetric follow-up visits) thereafter. Although long-
term unfractionated heparin use has been associated with symptomatic osteoporosis in up to
2% of patients,30 contemporary studies with LMWH showed that this is not an issue.31
Other anticoagulants and their use in pregnancy are either less preferred or contraindicated
(Table 1). Unfractionated heparin can be administered both intravenously and subcutaneously
and has a similar safety profile with regard to fetal safety, but needs activated partial
thromboplastin time (aPTT) monitoring and is associated with a higher risk of HIT.32 It is often
considered for women in whom rapid reversal of the anticoagulant effect may be needed.
However, these presumed benefits are offset by difficulty in maintaining therapeutic aPTT
results, with the obvious risk of extending thrombosis as a result of under-treatment in a woman
with acute VTE, and over-anticoagulation in a woman in whom this option is chosen because
of an increased risk of bleeding.33 In such patients, we choose a twice-daily LMWH regimen
based on actual body weight over intravenous unfractionated heparin, with the theoretical
rationale that peak anti-Xa levels are somewhat lower (at a similar area under the curve) than
with a once-daily regimen,34 and that in case of a bleeding emergency, LMWH can still be
partially neutralized by protamine sulfate.
Danaparoid also doesn’t cross the placenta and can be used if LMWH is not an option, for
instance in the rare case of HIT.35 Fondaparinux crosses the placenta to some extent and
experience in human pregnancies, particularly during the first trimester, is limited.15,36,37
Nevertheless we have used fondaparinux in a few women who were suspected of having type
11
I allergy to LMWH during pregnancy. LMWH, danaparoid and fondaparinux can be safely used
in women who breastfeed.15
As vitamin K antagonists (VKA) cross the placenta and may cause coumadin embryopathy
and long-term effects, we avoid the use of these agents throughout the entire pregnancy for
the treatment and prevention of VTE.15,38,39 VKA can be used during breastfeeding.15
Direct oral anticoagulants, i.e. direct thrombin inhibitors and factor Xa inhibitors are
contraindicated in pregnancy and during breast feeding.15 There is limited human safety
evidence in the literature and there appears to be animal toxicity according to the
manufacturer’s summary of product characteristics.40,41 If a woman inadvertently becomes
pregnant while using a DOAC, we advise to switch to LMWH immediately.42 DOAC use is not
regarded as medical grounds for the termination of a pregnancy. 43 Physicians are
recommended to report all DOAC exposure during pregnancy to the ISTH registry.44
Systemic thrombolysis should be considered in pregnant patients with PE who are
hemodynamically unstable, as this is associated with high maternal and fetal mortality. In a
literature review 23 cases on the use of systemic thrombolysis in pregnancy for massive PE
were identified.45 There were no maternal deaths, and bleeding complications were reported
in 39% of the cases. Bleeding was classified as major in 22% of women, 9% of the fetuses
died and 39% of pregnancies resulted in pre-term delivery. Of course, the findings may not be
accurate as a consequence of publication bias. However, the key message is that thrombolysis
should not be withheld in pregnant women with life-threatening hemodynamic instability and
PE in whom risks to the fetus and risk of severe bleeding in the mother must be accepted in
view of her life-threatening condition.15 Whether catheter-directed thrombolysis for severe PE
is associated with a lower risk of bleeding than systematic thrombolysis is unknown, even in
the nonpregnant population.46 Therefore, in our patient we chose to perform catheter-directed
thrombosuction without addition of thrombolytic agents. We generally avoid placement of an
IVC filter in pregnant patients, because experience during pregnancy is limited and filter
migration and inferior caval vein perforation have been described.47 This may be overturned in
12
exceptional circumstances, as in our second case in whom it was anticipated that the absolute
contraindication for therapeutic anticoagulation would persist for weeks.
Our patient went into spontaneous labour, at a gestational age of 39+2 weeks, and delivered
a healthy daughter 21 hours after the last injection of LMWH. Estimated blood loss was 200
mL, and LMWH was re-started 12 hours after delivery at full-dose.
Management of delivery in women with VTE
Several options for delivery in women using anticoagulants are possible, and depend strongly
on local preferences and experience, which result from the perception of risks and benefits of
either the wait-for-spontaneous-delivery approach or the planned-delivery approach. The ASH
2018 guideline panel suggests cessation of LMWH with spontaneous onset of labor in pregnant
women receiving prophylactic-dose LMWH and planned delivery with prior discontinuation of
anticoagulant therapy in pregnant women receiving therapeutic-dose LMWH.15 Of note, this
conditional recommendation is based on very low certainty in evidence about effects, and
hence raised substantial discussion amongst the panel members; the pros and cons are
discussed in detail in the guideline. The one panelist who advocated to allow spontaneous
labor with therapeutic-dose LMWH “even with the potential for limiting access to neuraxial
analgesia and anesthesia and potentially increasing the risk of major bleeding” is author (SM)
of the present How I treat paper. In our institution this wait-for-spontaneous-delivery approach
is the default choice with all dosages. We pragmatically base this on the fact that advantages
and disadvantages of both approaches are limited and we primarily follow the golden rule of
‘in dubio abstine’ (when in doubt, abstain). The potential disadvantages of unplanned
spontaneous delivery are the increased risk of bleeding and limiting accessibility to neuraxial
analgesia. With regard to the potential increase in major postpartum bleeding, data are very
conflicting and of low quality.43 In a systematic review, rates of bleeding in the postpartum
period could be retrieved for 13 studies including 725 pregnancies.24 Bleeding events occurred
13
in 38.8% of patients; major bleeding (≥1000 mL) occurred in 1.9% (95% CI 0.80-3.60), clinically
relevant non-major bleeding (≥500 mL-1000 mL) in 5.7%, and the remainder were minor
bleeds (< 500 mL). In our own retrospective cohort study among 95 women on therapeutic
dose LMWH, the incidence of postpartum hemorrhage defined as>500 mL blood loss was 18%
which was similar to the rate of 22% in 524 women not using anticoagulants.48 Given that the
reported incidence of postpartum bleeding without anticoagulant use ranges from 4 to 22% of
all pregnancies,49–51 we suspect that pregnancy-related bleeding in women using
anticoagulants is generally underreported. To complicate things even further, there is no
homogeneous definition of PPH, and for anticoagulant-related bleeding events in pregnancy
and the postpartum period commonly used classification criteria may not suffice. Therefore,
recently a proposal for classification of severity of such bleeding events was made by an
international multidisciplinary group of clinical investigators and clinicians, and published also
on behalf of the ISTH subcommittee for control of anticoagulation.52
With regard to accessibility to neuraxial analgesia and anesthesia, the choices of required
intervals to allow neuraxial analgesia or anesthesia are very conservative: a time interval of 12
hours for prophylactic dose LMWH and 24 hours for higher dose LMWH, and strictly adhered
to. Alternative forms of pain relief during spontaneous labor are also available as a less
effective but secondary option such as patient-controlled analgesia with remifentanil, although
we acknowledge the need to pay attention to the potential for neonatal respiratory depression
as a disadvantage to this method.53 For an emergency cesarean section the only alternative is
general anesthesia. The actual accessibility to neuraxial analgesia in women using LMWH
appears reassuring. Preliminary results on 587 women who participated in the thrombosis
prophylaxis Highlow study (NCT 01828697) showed that the proportions of patients using
LMWH during pregnancy that had a time interval that was too short to be able to receive
neuraxial anesthesia were 2.4% in patients on prophylactic dose LMWH and 5.1% of patients
using higher dose LMWH.54 If there is no obstetric indication for an induced delivery, we instruct
women to not inject LMWH as soon as labor starts with either contractions or rupture of the
membranes. Active management of the third stage of labor remains necessary to minimize the
14
risks of obstetric hemorrhage and is standard practice.
The data on the potential disadvantages of planned delivery are conflicting. Observational data
have found consistent associations between induction of delivery and increased interventions
including cesarean section.55,56 These results are probably largely driven by indication bias. In
the past decade data of randomized trials for various indications have provided evidence to
suggest that if there is a good indication for induced delivery the increased cesarean section
rate is not observed or it can sometimes even be protective.57,58 The crucial question thus is
whether the assumed benefits of planned delivery in this setting are such a good clinical
indication. These trials also did not investigate other subtler outcomes that are changed by
medical interventions, including the potential programming effects of late relative preterm birth,
where even in the term period subtle effects on school performance were found,59 and patient
experiences.
In women at very high risk for extension or recurrent VTE (arbitrarily within a month prior to
expected delivery), we consider the risks of a prolonged period without anticoagulation to be
higher and therefore we schedule a planned delivery, so that the duration of time without
anticoagulation can be minimized. Those at the highest risk of recurrence (proximal DVT or
PE within two weeks prior to delivery) can be switched to therapeutic intravenous
unfractionated heparin, which is then discontinued 4 hours prior to the expected time of delivery
or the use of neuraxial anesthesia.
Our patient went into spontaneous labour, at a gestational age of 39+2 weeks, and delivered
a healthy daughter 21 hours after the last injection of LMWH. Estimated blood loss was 200
mL, and LMWH was re-started 12 hours after delivery at full-dose until 6 weeks postpartum.
15
After the unsuccessful filter retrieval, therapeutic dose LMWH was switched to full dose
DOAC. The presentation of the PE, together with the filter being present permanently as
well as the patient’s preference, led to the shared decision to continue some form of
anticoagulation and we switched to a low dose DOAC for secondary VTE prevention 4.5
months after the PE. She did not develop symptoms of post-thrombotic syndrome nor did
she have residual pulmonary symptoms. She gradually recovered from her neurological
trauma and now, 3 years later, she is back to her old functional level and working. Also her
daughter is doing very well.
Postpartum duration of anticoagulant treatment
Anticoagulation should be restarted after delivery, as soon as possible, but depending on the
amount of estimated vaginal blood loss and the type of delivery. Generally, restarting
therapeutic dose anticoagulation 12 to 24 hours after delivery is feasible, but this period should
be longer if hemostasis is not adequate. If the anticipated interval is longer than 24 hours due
to bleeding, a prophylactic dose 24 hours after delivery should be considered. In most women
in whom the intention is to stop anticoagulation 6 weeks after delivery, continuation with
therapeutic dose LMWH until 6 weeks postpartum (or until discontinuation if VTE occurred in
late pregnancy) is the most practical option. In women who will continue anticoagulation
indefinitely and who plan to breastfeed their baby, we first restart LMWH, and initiate the first
loading dose of VKA at least one day later. LMWH can be discontinued after at least three
days of VKA and as soon as the INR is above 2.0. It is important to reassure women that they
can breastfeed during use of either LMWH or VKA; particularly non-lipophilic types such as
acenocoumarol and warfarin (Table 1).15,60,61 Alternatively, if women do not plan to breastfeed,
LMWH can be replaced by a DOAC. We treat women with therapeutic dose LMWH until 6
weeks postpartum and with a minimum duration of 3 months. If the pregnancy-related VTE
was the first episode, we advise to discontinue anticoagulation after 3 months total duration or
16
after 6 weeks postpartum. In the recent ESC 2019 pulmonary embolism guidelines, pregnancy
is considered a minor transient risk factor leading to an intermediate (3 to 8% per year) risk of
recurrence after discontinuation of anticoagulants and a recommendation to consider
extending anticoagulation in women with a pregnancy-related VTE.46
Two years later, she consulted us because she wanted to become pregnant again. As she had
a history of pregnancy-related VTE, we advised antepartum and postpartum prophylaxis with
LMWH. She was enrolled into the Highlow study, (NCT01828697), an international,
multicenter, randomized controlled trial, comparing low-dose with intermediate dose LWMH for
the prevention of pregnancy-related recurrent VTE, and she was treated with the intermediate
dose. There were no major issues during this pregnancy and she delivered a healthy girl. She
continued LMWH prophylaxis until 6 weeks after delivery.
Prevention of recurrent VTE in a next pregnancy
After pregnancy-related VTE the risk of recurrence during subsequent pregnancies is 6% to
10% if no prophylaxis is given.62–64 The risk of recurrence is influenced by the factors present
during the first VTE, as is the case for nonpregnant patients. Women who have had a single
episode of VTE that was associated with a transient non-hormonal risk factor are at low risk
of recurrence during pregnancy.62,63,65 For these patients, the burden of subcutaneous
injections, side effects and risk of peripartum bleeding may not outweigh the high number
needed to treat during pregnancy, and only postpartum thromboprophylaxis for 6 weeks is
recommended.15 In all other pregnant women with a history of VTE, i.e. unprovoked VTE or
VTE provoked in the presence of minor or hormonal risk factors or recurrent VTE, both ante-
and postpartum prophylaxis is suggested.15 Given that the increased risk of VTE is more or
less similar across trimesters, we initiate LMWH prophylaxis as soon as a pregnancy test is
positive and to do so, we prescribe a starting dose of LMWH preconceptionally. The optimal
dose of LMWH for prevention of pregnancy-related recurrent VTE is unknown. Retrospective
17
cohort studies suggest high recurrence rates ranging from 2.5 to 8% of VTE despite
thromboprophylaxis,63,64,66–69 but data are conflicting.70,71 A Cochrane review concluded that
there is insufficient evidence on which to base recommendations for thromboprophylaxis
during pregnancy and the early postnatal period, with the small number of differences
detected in this review being largely derived from trials that were not of high methodological
quality.72 Whereas the American College of Chest Physicians (ACCP) 2012 guideline
suggested use of either low prophylactic or intermediate (half of therapeutic) dose with no
preference for one dose over the other,73 the 2018 American Society of Hematology VTE
suggests against an intermediate dose antepartum, and has no preference of a prophylactic
or intermediate dose postpartum.15 The Highlow study (NCT01828697), an international,
multicenter, randomized controlled trial, comparing low-dose with intermediate dose LWMH
for the prevention of pregnancy-related recurrent VTE, is ongoing and will provide valuable
information.74 To date, over 950 patients have been recruited and results are expected in
2021/2022.
Women who use anticoagulants outside of pregnancy should - if on DOAC - be switched to
VKA preconceptionally.42 As soon as the pregnancy test is positive, the VKA should be
switched to therapeutic dosed LMWH and the effect of VKA can be reversed by oral vitamin K
supplements.42
Finally, it is very important that treating physicians counsel all young women with an episode
VTE about future pregnancy, as well as other women-specific issues, which we call the
5P’s: period, pill, prognosis, pregnancy, and post-thrombotic syndrome.75
Conclusions
The management of pregnancy-related VTE is based on extrapolation from the non-pregnant
population and clinical trial data for the optimal treatment are scarce. LMWH in therapeutic
doses is the treatment of choice during pregnancy, and anticoagulation should be continued
until 6 weeks after delivery with a minimum total duration of 3 months. Whether dosing should
be based on weight or anti-Xa levels is unknown, and practices differ between centers. There
18
is limited experience with thrombolysis and IVC filter use in pregnant women, but in some
cases these interventions must be considered. Management of delivery requires a
multidisciplinary approach. With some limitations neuraxial analgesia is possible and
spontaneous vaginal delivery is the preferred option in obstetric patients who need therapeutic
anticoagulation. Prevention of recurrent VTE in subsequent pregnancies is indicated in most
women with a history of VTE, and results from a large randomized trial investigating the optimal
dose are expected in the coming years.
Authorship
S.M. and W.G. have both written the manuscript.
Disclosures
Saskia Middeldorp is the principal investigator of the Highlow study, a randomized controlled
trial comparing low‐dose LMWH with intermediate‐dose LMWH in pregnant women with a
history of VTE (http://www.ClinicalTrials.gov; NCT01828697). Saskia Middeldorp reports
grants and fees paid to her institution from GSK, BMS/Pfizer, Aspen, Daiichi Sankyo, Bayer,
Boehringer Ingelheim, Sanofi, and Portola.
Wessel Ganzevoort is the principal investigator of the DRIGITAT study, a randomized
controlled trial comparing diagnostic strategies in fetal growth restriction
(https://www.trialregister.nl/trial/6475) and reports an unrestricted grant from Roche
Diagnostics paid to his institution for in kind delivery of materials.
Acknowledgement
We kindly acknowledge Dr K.P. van Lienden for his involvement with case 2 and critical
review of the manuscript.
19
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27
Table 1. Summary table of safety of anticoagulant use in pregnancy and during breastfeeding15
Anticoagulant Safe during pregnancy Safe during Evidence based summary
breastfeeding
Heparins Yes Yes Does not cross the placenta; extensive safety data from observational
studies
Vitamin K antagonists No Yes Crosses the placenta, may cause coumadin embryopathy (if used between
6th and 12th week), fetal bleeding and neurodevelopmental deficits
Direct oral No No Crosses the placenta, reproductive effects unknown
anticoagulants
Danaparoid Yes Yes Does not cross the placenta
Fondaparinux Probably yes Yes Crosses the placenta to some extent; limited data suggest it is safe for the
fetus
28
Table 2: How I treat pregnancy-related VTE, and a summary of alternatives*
Our approach in most patients Our alternatives (not exhaustive)
Diagnosis of suspected DVT Single whole leg compression ultrasound If clinical suspicion is high, repeat CUS after
(CUS) with visualization of the iliac vein 3-7 days
Diagnosis of suspected PE Pregnancy-adapted YEARS algorithm (see YEARS algorithm with bilateral CUS of the
Figure) legs also if no signs of DVT
Initial treatment of VTE in pregnancy Therapeutic dose LMWH in a once-daily Temporary vena cava filter only in women
regimen, based on actual body weight and with an absolute contraindication for
peak antiXa levels 4 hours after injection anticoagulation.
(instruct women to inject LMWH in the
morning).
Infrequent monitoring of platelets and anti-Xa

levels (every 6 to 8 weeks, combined with
obstetric follow-up)
Management of delivery If no obstetric indication for a planned Planned delivery in women with recent VTE
delivery, wait for spontaneous delivery. (4 weeks prior to expected delivery); consider
switching LMWH to twice-daily regimen of
Counsel women about possibly not being therapeutic dose LMWH
able to receive neuraxial analgesia but
alternative methods instead if necessary. Unfractionated heparin i.v. with APTT
monitoring in women with acute VTE (i.e. in
As soon as spontaneous labor starts, no recent 2 weeks) who have to deliver. Stop
LMWH injections. Active management of third unfractionated heparin 4 hours prior to
stage of labor. delivery. Neuraxial anesthesia is possible.
29
Postpartum management Restart LMWH 12 to 24 hours after delivery, Start VKA 24 to 48 hours after restarting
depending on amount of blood loss and LMWH if hemostasis is adequate and
adequate hemostasis. Continue LMWH for measure INR 3 days after starting VKA. Stop
the rest of the anticoagulation period LMWH if INR is above 2.0
Breastfeeding is not contraindicated with DOACs are an option if not breastfeeding

LWMH or VKA. and long-term treatment is intended
Duration of anticoagulation until 6 weeks

postpartum, or longer to guarantee a
minimum total duration of 3 months if VTE
occurred in late pregnancy.
Prevention of recurrent VTE in pregnancy In women with unprovoked or hormone-

related first episode of VTE, who do not use
anticoagulants outside pregnancy,
antepartum and postpartum LMWH
prophylaxis – include in Highlow study
In women with a first episode of VTE related

to a major provoking risk factor and without
concomitant hormonal risk factor, postpartum
LMWH prophylaxis only
In women who use long-term anticoagulation

(DOAC) for VTE outside pregnancy, switch to
VKA preconceptionally, and to LMWH with
vitamin K suppletion as soon as pregnancy
test is positive.
* For justification, please see full text.
30
Figure. Pregnancy-adapted YEARS algorithm for diagnosis of PE in pregnant women17,18
31

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How I treat venous thromboembolism in pregnancy

Saskia Middeldorp, s.middeldorp@amsterdamumc.nl

Amsterdam UMC, University of Amsterdam, 1 Department of Vascular Medicine, Amsterdam

treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists

multidisciplinary approach and depends on local preferences and patient-specific conditions.

interruption of LMWH. Prophylaxis for the prevention of recurrent VTE in subsequent

pregnancies is indicated in most women with a history of VTE.

period face a potentially life-threatening condition.1,2 VTE occurs in 1 to 2 of 1,000 pregnancies,

quality of life as a result of post-thrombotic syndrome, because thrombosis in pregnant and

DVT, with the majority of pregnancy-related episodes of PE occurring in the postpartum

the daily absolute risk of VTE is highest postpartum.

of evidence, it is impossible to identify optimal management and there is wide variation

hospital in The Netherlands.

A 32-year-old 11-weeks pregnant woman presented to the emergency department in a

A 27-year-old 32 weeks pregnant woman was transported to our emergency department

examination. Additional trauma screening revealed multiple cerebral contusional foci,

1 and flattening of the septum.

the utility of an empirical clinical probability assessment or a pregnancy-specific clinical

been published that provide an evidence-based approach to this diagnostic challenge.16–18 In

in this population. Our case, which occurred prior to publication of abovementioned

ongoing (ClinicalTrials.gov NCT01708239). The ASH 2018 guideline suggests to perform

adequacy of ultrasonographic visualization of the iliac vein, MRI may be considered as an

although we still deem that unlikely.

short of breath throughout pregnancy. At a gestational age of 30 weeks, we performed a

and lung infarction. 8

contraindication for both thrombolysis or therapeutic dose anticoagulation because of the

after careful multidisciplinary consideration it was decided to perform a combined

thrombosuction of the pulmonary arteries with a single bolus infusion of 5000 IU of

attempts to retrieve the filter were not successful.

Low-molecular-weight heparin (LMWH) is the drug of choice in pregnant women, as it does

adjustments improve clinical outcomes, there is no evidence to demonstrate that it is harmful

once-daily regimen at 6 to 8- week intervals. A practical advice is to instruct women to inject

UFH) for treatment of acute VTE, reported an antepartum incidence of hemorrhagic

complications was 3.28% (95% CI 2.10–4.72).24

mainly type IV delayed hypersensitivity reactions at the injection site of subcutaneously

but serious maternal complication of heparins is heparin-induced thrombocytopenia (HIT). The

of an increased risk of bleeding.33 In such patients, we choose a twice-daily LMWH regimen

partially neutralized by protamine sulfate.

experience in human pregnancies, particularly during the first trimester, is limited.15,36,37

in women who breastfeed.15

manufacturer’s summary of product characteristics.40,41 If a woman inadvertently becomes

regarded as medical grounds for the termination of a pregnancy. 43 Physicians are

Systemic thrombolysis should be considered in pregnant patients with PE who are

view of her life-threatening condition.15 Whether catheter-directed thrombolysis for severe PE

the nonpregnant population.46 Therefore, in our patient we chose to perform catheter-directed

thrombosuction without addition of thrombolytic agents. We generally avoid placement of an

contraindication for therapeutic anticoagulation would persist for weeks.

mL, and LMWH was re-started 12 hours after delivery at full-dose.

Management of delivery in women with VTE

either the wait-for-spontaneous-delivery approach or the planned-delivery approach. The ASH

anticoagulant therapy in pregnant women receiving therapeutic-dose LMWH.15 Of note, this

all pregnancies,49–51 we suspect that pregnancy-related bleeding in women using

anticoagulants is generally underreported. To complicate things even further, there is no

homogeneous definition of PPH, and for anticoagulant-related bleeding events in pregnancy

on behalf of the ISTH subcommittee for control of anticoagulation.52

expected delivery), we consider the risks of a prolonged period without anticoagulation to be

PE within two weeks prior to delivery) can be switched to therapeutic intravenous