Keywords
venous thromboembolism - pregnancy - risk assessment
Introduction
Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism
(PE). Despite improvements in care pathways for pregnant people, VTE is still a leading
cause of death in pregnancy and in the postpartum period.[1] During 2014 to 2016, VTE was listed as the leading cause of direct maternal death
(defined as death from a cause arising directly from pregnancy) in the United Kingdom
and Ireland, at 1.39 (95% confidence interval [CI]: 0.95–1.96) per 100,000 pregnancies.[2] A maternal death due to PE has tragic and wide-reaching consequences for the mother's
family, friends, and society. VTE can also result in lifelong physical and psychological
impairment.[3]
VTE risk increases during pregnancy and reaches a peak in the early postpartum period.
The pooled incidence rate of VTE in a systematic review restricted to studies in which
VTE cases were validated was reported to be 118 (95% CI: 101–137) per 100,000 person-years
during the antepartum period and 424 (95% CI: 238–755) per 100,000 person-years during
the postpartum period.[4] Superficial venous thrombosis (SVT) is also common during pregnancy and postpartum
and, while it is a manifestation of VTE, is also a strong risk factor for pregnancy-associated
DVT. A nationwide cohort study including data from Danish registries was published
recently.[5] Among 1,276,046 deliveries, 710 diagnoses of lower extremity SVT were reported during
pregnancy and up to 12 weeks postpartum (0.6 per 1,000 person-years [95% CI: 0.5–0.6]).
Among 211 people with and without antepartum SVT, 22 (10.4%) and 25 (11.8%), respectively,
were diagnosed with DVT (hazard ratio [HR]: 83.3 [95% CI: 46.3–149.7]).
What causes this pregnancy-related increase in VTE risk? Reported underlying mechanisms
include pelvic venous compression by the pregnant uterus, hormone- and uterus-related
venous stasis, compression of the left iliac vein by the right iliac artery, and changes
in procoagulant and anticoagulant pathways along with fibrinolytic mechanisms.[6]
[7]
[8]
[9] For example, plasma endogenous thrombin potential (a marker of prothrombotic potential)
and plasminogen activator inhibitor-1 levels (markers of fibrinolytic activity) are
significantly higher in pregnant people than in nonpregnant controls.[8]
[9] In pregnancy, platelets also undergo morphological changes and platelet activation
is increased.[10] When they are activated, platelets release many signaling factors, known as the
platelet releasate,[11] which plays crucial roles in wound healing, hemostasis, and inflammation.[12] Intriguingly, maternal platelet releasate contents differ in pregnant people compared
with nonpregnant people. In a recent Irish study, 18 healthy pregnant and 13 nonpregnant
platelet releasate were analyzed using comparative label-free quantitative proteomic
profiling and the differences were characterized.[13] Sixty-nine PR proteins were differentially released, and it was possible to discriminate
pregnant and nonpregnant people in the case of 11 PR proteins. It remains to be determined
whether this change in platelet releasate contents contributes to pregnancy-associated
VTE risk.
In this review, we provide an update on the recent evidence of known VTE risk factors
in pregnancy, the frequency of these risk factors, and evidence-based prevention of
VTE in people with prior VTE, anchoring to recently published randomized controlled
trial (RCT) data. We outline knowledge gaps and current approaches to VTE prevention
in the postpartum period, including ongoing pilot trials. Finally, we review recently
published registry data on the incidence and prognosis of superficial vein thrombosis
during pregnancy and the postpartum period.
VTE Risk Factors in Pregnancy
VTE Risk Factors in Pregnancy
The higher pregnancy-associated VTE baseline risk can be increased by additional characteristics
that can preexist or present during pregnancy or in the peripartum period.[6]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21] This is why it is so crucial to carry out a VTE risk assessment at various time
points in pregnancy, repeating this risk assessment postpartum or if risk factors
change.[22] Risk factors can relate to personal characteristics (age, body mass index [BMI],
smoking), previous medical history (history of VTE, inflammatory disease), or current
pregnancy (preeclampsia, preterm delivery, mode of delivery). They can be classified
according to their strength of association with VTE: very strong (e.g., personal history
of VTE), strong (e.g., emergency cesarean delivery, morbid obesity), and weak (e.g.,
age ≥35 years). Literature pertaining to the strength of risk factors, in terms of
their odds ratios (ORs) for VTE, has been summarized by the authors in detail in previous
reviews.[6]
[23]
[24]
How Frequently and When Do Pregnancy-Associated VTE Risk Factors Occur?
How Frequently and When Do Pregnancy-Associated VTE Risk Factors Occur?
The relationship between VTE risk variables and the risk of pregnancy-associated VTE
varies; however, we now know that, certainly when assessed in the postpartum period,
these risk factors are multiple and common ([Table 1]).[25] According to a recently published cross-sectional study of prospectively collected
data from 21,019 sequential postpartum VTE risk assessments completed over a 3-year
period in the Rotunda Hospital, Dublin, Ireland, the most frequent VTE risk factors
related to maternal characteristics and delivery characteristics included overweight
status and obesity (36%), age ≥ 35 years (35%), and cesarean delivery (32%).[25] In total, 78% of people had at least one VTE risk factor, and 40% of them had several
risk factors (two or more). The crucial necessity of doing a VTE risk assessment after
delivery is shown by the fact that in 19% of people, all VTE risk factors occurred
during delivery or in the postpartum period (and were not present prior to this peripartum
time).[25]
Table 1
Prevalence of postpartum VTE risk factors among people delivering an infant >24 weeks'
gestation and undergoing VTE risk assessment between January 2015 and December 2017
in a single center
|
VTE risk factor (RF)
|
No. of people (N = 21,019)
|
% with RF (95% CI)
|
|
Overweight or obesity
|
7,536
|
36 (35–37)
|
|
Overweight (BMI 25.1–29.9)
|
4,391
|
21 (20–21)
|
|
Obese class I and II (BMI 30–39.9)
|
2,837
|
14 (13–14)
|
|
Obese class III (BMI >40)
|
308
|
1.5 (1.3–1.6)
|
|
Age ≥35 y
|
7,302
|
35 (34–35)
|
|
Operative vaginal delivery
|
3,751
|
18 (17–18)
|
|
Emergency cesarean delivery
|
3,578
|
17 (17–18)
|
|
Planned cesarean delivery
|
3,139
|
15 (15–15)
|
|
Parity ≥3
|
1,482
|
7.1 (6.7–7.4)
|
|
Smoker
|
1,376
|
6.6 (6.2–6.9)
|
|
Preterm delivery (<37 wk of gestation)
|
1,366
|
6.5 (6.2–6.8)
|
|
PPH > 1,000 mL or blood transfusion
|
748
|
3.6 (3.3–3.8)
|
|
High-risk family history of VTE
|
406
|
1.9 (1.8–2.1)
|
|
Prolonged labor
|
401
|
1.9 (1.7–2.1)
|
|
Multiple pregnancy
|
346
|
1.7 (1.5–1.8)
|
|
IUGR
|
341
|
1.6 (1.5–1.8)
|
|
Severe medical comorbidity
|
328
|
1.6 (1.4–1.7)
|
|
Gross varicose veins
|
314
|
1.5 (1.3–1.7)
|
|
Preeclampsia
|
314
|
1.5 (1.3–1.7)
|
|
MROP
|
274
|
1.3 (1.2–1.5)
|
|
Immobility
|
205
|
1.0 (0.9–1.1)
|
|
Previous VTE
|
114
|
0.5 (0.5–0.7)
|
|
Stillbirth
|
100
|
0.5 (0.4–0.6)
|
|
Systemic infection
|
92
|
0.5 (0.4–0.5)
|
|
Thrombophilia
|
81
|
0.4 (0.3–0.5)
|
Abbreviations: BMI, body mass index; IUGR, intrauterine growth restriction; MROP,
manual removal of the placenta; PPH, postpartum hemorrhage; VTE, venous thromboembolism.
Source: O'Shaughnessy et al.[25]
Thrombophilia
People with hereditary and acquired thrombophilia are more likely to experience pregnancy-associated
VTE than people without these disorders, especially if they also have a family history
of VTE.[26]
[27]
[28]
[29] The reported increase in pregnancy-associated VTE risk varies significantly between
studies and by thrombophilia type. The acceptable threshold for starting thromboprophylaxis
during pregnancy, according to experts from the American Society of Hematology's (ASH)
guidelines panel, is approximately 2%.[26] In some thrombophilias, the absolute risk of VTE during pregnancy does not appear
to cross this threshold, while it does in others. For instance, in a pooled analysis
of published cohort studies including thrombophilic women with a family history of
VTE reported in the 2018 ASH guideline, an absolute risk of 0.5% (95% CI: 0.06–1.21%)
was estimated.[26] This is not surprising, given the results of a more general case control study including
437 first-degree relatives of 112 symptomatic heterozygous factor V Leiden (FVL) mutation
carriers (and 30 relatives of 6 homozygous FVL carriers) reported annual VTE incidences
of 0.45% (95% CI: 0.28–0.61%) in FVL mutation–positive relatives of propositi who
were heterozygous FVL carriers and 0.10% (CI: 0.02–0.19%) in those who did not have
the mutation (relative risk [RR]: 4.2 [CI: 1.8–9.9]).[30] Notably, 30% of VTE events were associated with pregnancy or use of oral contraceptives.
Prior Venous Thromboembolism
Prior Venous Thromboembolism
VTE is much more likely to occur in pregnant people with a personal history of VTE[16]
[31] than in those without a history of VTE. The reported absolute risk in the absence
of thromboprophylaxis is estimated at 2 to 6% in the antepartum[32]
[33]
[34] and 6 to 8% in the postpartum period,[31]
[33]
[34] and it appears to be highest for people with an unprovoked or a hormone-related
VTE in these cases. In comparison to people who had an unprovoked or nonhormonal transient
risk factor–provoked event, people with a history of a VTE event in the presence of
oral hormonal contraceptive use or pregnancy experienced a higher VTE recurrence rate
during pregnancy (although this finding did not reach statistical significance).[33]
[34] In addition, a sizable retrospective cohort study found that people with pregnancy-associated
VTE had a greater risk of recurrence during a future pregnancy than people with unprovoked
VTE (4.5 vs. 2.7%; RR: 1.7; 95% CI: 1.0–2.8).[35] However, among people whose past incident was triggered by a significant transitory
nonhormonal VTE risk factor, the chance of VTE recurrence during pregnancy was predicted
to be 1.0% (95% CI: 1.9–5.7%).[7]
Interaction of VTE Risk Factors during Pregnancy and in the Postpartum Period
Interaction of VTE Risk Factors during Pregnancy and in the Postpartum Period
Although the frequency and risk of individual VTE risk factors has been characterized
in multiple observational studies, an important knowledge gap still exists surrounding
the duration of the increased risk and the interaction of VTE risk factors with each
other, which requires a high statistical power and thus very large sample sizes.
The possibility that individual risk factors impact the risk of postpartum VTE for
different durations would have clinical implications, but this has not been investigated
thoroughly. One large United Kingdom retrospective cohort has suggested that people
who are obese, with preeclampsia, infection, or those with cesarean delivery have
persistently elevated risks for 6 weeks, while the risk of those with postpartum hemorrhage
(PPH) or preterm birth was only elevated for 3 weeks after delivery.[36] This adds uncertainty to the optimal duration of postpartum thromboprophylaxis,
which is largely unknown.
With regard to the combination of risk factors, a Norwegian hospital-based case control
study offered an intriguing perspective. In total, 559 people with objectively confirmed
VTE during pregnancy or the postpartum period and 1,229 controls were enrolled in
this study.[15] Some risk factors exhibited additive interaction (as seen with the combination of
assisted reproductive technology [ART] with multiple pregnancy and emergency cesarean
section [CS] with infection), while others appeared to act as multipliers. For example,
adjusted ORs of antepartum immobilization in people with BMI of <25 and ≥25 kg/m2 were 7.7 (95% CI: 3.2–19.0) and 62.3 (95% CI: 11.5–337.6), respectively. We view
these findings as exploratory, given the wide confidence intervals around these possible
interactions and the possibility of selection bias in this study.
Understanding how these VTE risk variables affect absolute pregnancy-associated VTE
in particular is crucial. A risk prediction model for postpartum VTE was derived and
externally validated, utilizing data from 433,353 deliveries in the United Kingdom
Clinical Practice Research Datalink linked to Hospital Episode Statistics. In total,
662,387 deliveries in Swedish datasets were used to externally validate this model.
The strongest VTE predictors in the final multivariable model were emergency CS, stillbirth,
varicose veins, preeclampsia/eclampsia, infection, and medical comorbidities. The
model performed reasonably well in predicting postpartum VTE with a C statistic of
0.70 (95% CI: 0.67–0.73) in the United Kingdom cohort and 0.73 (95% CI: 0.71–0.75)
in the Swedish cohort.[20] Limitations of this tool lie in possible bias from misclassification of VTE events
and of risk factors in both development and validation efforts, the fact that it should
not be used for people with thrombophilia, and that very few people have predicted
postpartum VTE risks greater than 0.2 to 1%.
Reducing the Risk of VTE in Pregnancy
Reducing the Risk of VTE in Pregnancy
Two VTE prevention strategies are expected to be most effective: the prevention of
postpartum VTE among people with risk factors, as the incidence of pregnancy-associated
VTE peaks in the 3 weeks after delivery, and the prevention of pregnancy-associated
VTE among people with a prior VTE, who have the greatest risk.
However, answering the question “Does pharmacological thromboprophylaxis reduce the
risk of pregnancy-associated VTE?” has proven to be difficult. In fact, a 2014 Cochrane
review's authors came to the conclusion that “there is insufficient evidence on which
to base recommendations for thromboprophylaxis during pregnancy (and that) large scale,
high-quality randomised [sic] trials of currently used interventions are warranted.”[37] The same conclusions arise from a recent (2023) systematic review and meta-analysis,
stating that the existing literature is insufficient.[38]
VTE Risk Reduction in People with Prior VTE
The multicenter, multinational academic Highlow RCT was published in 2022 and tested the risk–benefit of two doses of low-molecular-weight
heparin (LMWH) during pregnancy and the postpartum period in women at high risk of
VTE.[39] This RCT included 1,110 pregnant people aged ≥18 years and ≤14 weeks' gestation
with a history of prior objectively confirmed VTE (either unprovoked/provoked by a
hormonal-/pregnancy-related risk factor). Nine countries took part in the study with
70 sites in total. People were randomized to weight-adjusted intermediate-dose or
fixed low-dose LMWH. No significant difference was observed in the primary efficacy
outcome of objectively confirmed, adjudicated VTE up to 6 weeks postpartum. The primary
outcome was reported in 3 and 2% of people in the low- and intermediate-dose groups,
respectively (RR: 0.69 [95% CI: 0.32–1.47]; p = 0.33). There was also no significant difference between the groups in the primary
safety outcome, major bleeding (RR: 1.16 [95% CI: 0.65–2.09]). Based on this study,
low-dose LMWH is appropriate for prevention of recurrent VTE in pregnancy, although
the risk of VTE despite prophylaxis is not negligible. Interestingly, antepartum VTE
was numerically similar in both study arms (1% in both), whereas postpartum VTE recurrence
was more frequent in those receiving low-dose LMWH compared with intermediate-dose
LMWH (2 and 1%, respectively). While this suggests the hypothesis that intermediate-dose
LMWH may be more favorable after delivery or in the late third trimester, this finding
is exploratory and needs confirmation in future randomized controlled studies.
Pregnancy-Associated VTE Risk Reduction in People with Multiple, Common VTE Risk Factors
Following the publication of data from the Highlow study,[39] we now have high-quality data to support optimal management of pregnant people who
have a personal prior VTE history. However, this risk factor is thankfully uncommon
among the entire pregnant population (0.5% [95% CI: 0.5–0.7%] of all people recruited
to a recent large observational study[25]). Wide variations in worldwide guideline recommendations,[22]
[26]
[40]
[41]
[42] as well as heated debate,[43]
[44] demonstrate the important information gap that still exists about the best method
for pregnancy-associated VTE prevention in people with more prevalent VTE risk factors.
It is noteworthy that the 2018 ASH guideline panel[26] emphasized critical research requirements, including a desire for greater evidence
on the absolute VTE risk in people with combinations of known risk factors, and that
the balance of thrombosis and bleeding risk remains uncertain.
A multicenter study conducted by the STRATHEGE investigators of the French INNOVTE
Network evaluated the rates of pregnancy-associated VTE and placental vascular complications
before and after a risk scoring system was put in place to identify antenatal and
postpartum thromboprophylaxis techniques in 2,085 people with major VTE risk factors.
Before and after the application of risk score–driven prophylaxis, vascular incidents
(pregnancy-associated VTE including SVT and placental vascular complications) occurred
in 190 (19.2%) and 140 (13%) cases, respectively (RR: 0.68 [95% CI: 0.55; 0.83]),
with an associated increase of low-dose LMWH use during pregnancy and puerperium from
59 to 71%. In addition, there was a decrease in the incidence of pregnancy-associated
DVT (RR: 0.30 [95% CI: 0.14; 0.67]), mainly driven by a reduction of antepartum SVT.
PPH was noted in 3.2% of people prior to implementation and 4.5% afterward (RR: 1.38
[95% CI: 0.89; 2.13]; p = 0.15).[45] These findings are encouraging, with improved outcomes following a risk score and
a greater use of LMWH, but given the lack of randomization these cannot be interpreted
as causal and definite.
Postpartum Prevention
Conducting RCTs for people with (in this case, postpartum) VTE risk factors can prove
to be quite difficult, as the PROSPER investigators' experience has shown.[46]
[47] To ascertain the viability of carrying out a full-scale multicenter trial, Rodger
et al conducted a multinational, double-blind pilot RCT comparing LMWH for 21 days
with placebo injections in postpartum people at high VTE risk.[46] In six centers, recruiting for a mean of 6.3 months, with a recruitment rate of
0.7 per site per month and just 25 (6.6%) of the 378 eligible people being randomized,
the authors came to the conclusion that a double-blind RCT design for this intervention
was not practical in North America. The feasibility of a randomized, open-label trial
contrasting 10 days of LMWH medication with no treatment for postpartum thromboprophylaxis
in people at risk of VTE was investigated in a second pilot study by the same team.[47] With a recruitment rate of 0.9 per center each month, only 37 of the 343 eligible
people were randomized throughout 4.9 months. According to the authors, “poor recruitment
is a frequent and significant threat to the completion of RCTs, especially notable
in the peri-partum population.” As a result, guideline recommendations are currently
primarily based on expert opinion rather than high-quality data.[22]
[26]
[41]
[48]
[49] The conflicting dangers and difficulties of pharmaceutical thromboprophylaxis, which
are rather prevalent[50] and include bleeding, bruising, skin responses, pain, possible increased wound complications,[51] and, in many jurisdictions, significant out-of-pocket costs, can make this highly
challenging for health care professionals.
Surprisingly, the difficulty of conducting trials of postpartum thromboprophylaxis
contrasts with the views and preferences of people. Very recently, in the “PREFER-Postpartum”
study, we elicited the desire for postpartum thromboprophylaxis among 122 pregnant/postpartum
people in Geneva and Paris. Using structured interviews, most people favored receiving
short-term postpartum prophylaxis with LMWH, even at low projected risks of postpartum
VTE (0.1%). This result was somewhat sensitive to the bleeding risk associated with
the drugs and varied substantially across people. Hence, while postpartum people are
reluctant to participate in clinical trials, most value measures to prevent postpartum
VTE.[52]
The lack of strong evidence for the risk–benefit of LMWH has led to extremely varying
guidance and clinical practice. We recently conducted an analysis of prospectively
collected Irish data from 21,019 continuous comprehensive postpartum VTE risk assessments,
applying the recommendations of representative international guidelines, and calculating
the percentage of people who would have received a recommendation for postpartum thromboprophylaxis
under each guideline.[25] This analysis was done to reflect the lack of data. According to the recommendations
from the American College of Obstetricians and Gynecologists (ACOG)[53] and the Royal College of Obstetricians and Gynaecologists (RCOG)[22] of the United Kingdom ([Table 2]), the percentage of people who would have received a recommendation for postpartum
thromboprophylaxis ranged from 7 to 37%. A similar range from 9 to 40% was found in
a similar work from Switzerland.[54]
Table 2
Estimated proportion of people recommended postpartum thromboprophylaxis according
to international guidelines
|
Guideline
|
Year
|
Jurisdiction
|
Estimated proportion of people recommended postpartum thromboprophylaxis (N = 20,775)
|
|
Total (N = 21,019)
|
Caesarean delivery (n = 6,717)
|
Vaginal delivery (n = 14,302)
|
|
n
|
% (95% CI)
|
n
|
% (95% CI)
|
n
|
% (95% CI)
|
|
Australia and New Zealand[42]
|
2012
|
Australia and New Zealand
|
4,895
|
23 (23–24)
|
4,559
|
68 (67–69)
|
336
|
2.3 (2.1–2.6)
|
|
American College of Chest Physicians (ACCP)[41]
|
2012
|
United States
|
1,521
|
7 (6.9–7.6)
|
1,435
|
21 (20–22)
|
86
|
0.6 (0.5–0.7)
|
|
American College of Obstetricians and Gynecologists (ACOG)[53]
|
2018
|
United States
|
1,678
|
8 (7.6–8.4)
|
1,594
|
24 (23–25)
|
84
|
0.6 (0.5–0.7)
|
|
National Partnership for Maternal Safety (NPMS)[59]
|
2016
|
United States
|
4,381
|
21 (20–21)
|
4,268
|
63 (62–65)
|
113
|
0.8 (0.7–1.0)
|
|
Royal College of Obstetricians and Gynaecologists (RCOG)[22]
|
2015
|
United Kingdom
|
7,858
|
37 (37–38)
|
5,673
|
85 (84–85)
|
2,185
|
15[15]
[16]
|
|
Swedish Society of Obstetrics and Gynecology (SFOG)[49]
|
2011
|
Sweden
|
2,302
|
11 (11–11)
|
2,074
|
31 (30–32)
|
228
|
1.6 (1.4–1.8)
|
|
Society of Obstetricians and Gynecologists of Canada (SOGC)[48]
|
2014
|
Canada
|
3,091
|
15 (14–15)
|
2,306
|
34 (33–36)
|
785
|
5.5 (5.1–5.9)
|
Abbreviation: CI, confidence interval.
Source: O'Shaughnessy et al.[25]
We foresee different strategies to improve the evidence on postpartum thromboprophylaxis.
The first is to test an oral drug to prevent postpartum VTE to eliminate the burden
of subcutaneous injections. Unfortunately, the excretion of oral direct anticoagulants
in maternal milk greatly limits their use.[55] Low-dose aspirin has some effect on VTE prevention, albeit weak.[56]
[57] This is the focus of the Postpartum Aspirin to Reduce Thromboembolism Undue Morbidity
(PARTUM) pilot trial, assessing the feasibility of randomizing people with some risk
factors for postpartum VTE to 6 weeks of aspirin or placebo (NCT04153760). A second
strategy is to infer the risk–benefit of LMWH from observational studies, but this
is very challenging. Large sample sizes with varying prevalences of LMWH are required
for the somewhat rare VTE outcome, with a need to limit VTE misclassification and
to adjust for many confounding variables, with the persisting possibility of residual
confounding. Retrospective before/after evaluations of protocols for postpartum VTE
prevention in individual large hospitals have remained underpowered to detect differences
in clinical outcomes.[58] A third strategy is to challenge the perception that a large-scale postpartum VTE
is unfeasible. The Postpartum Heparin Against Venous Thromboembolism (PP-HEP) pilot
trial in Geneva has recently shown that one out of four people was willing to participate
in a pragmatic, open-label trial of 10 days of LMWH after delivery, with a promising
recruitment rate, contrasting with previously pessimistic results in North America.[52]
We hope that this effort will be followed by a practice-changing randomized clinical
trial to finally guide practice for postpartum thromboprophylaxis. While awaiting
future data, how should we handle postpartum VTE prevention? There is agreement that
people without any risk factors should not receive postpartum LMWH and that people
at high risk (prior VTE, see below, or strong thrombophilia) should be administered
LMWH. The clinical equipoise concerns people with some risk factors for VTE, usually
in combination, where the evidence is insufficient. Here, hospital-based recommendations
based on local preferences and individual shared decision-making are the only advisable
processes at this time.
Conclusions
VTE is the leading cause of maternal mortality in developed countries. The pathophysiology
of derangements in hemostasis during pregnancy are well described, at both the patient
and molecular levels. Despite this, there remains a paucity of high-quality data surrounding
optimal VTE prevention strategies for pregnant people. This lack of data is multifactorial,
but it can largely be attributed to poor recruitment rates—particularly in the crucial
postpartum period—as well as the fact that pregnant people are frequently excluded
from clinical research studies. Encouragingly, recent efforts demonstrate that while
postpartum people are reluctant to participate in clinical trials, they strongly value
the prevention of postpartum VTE, and that the feasibility of a postpartum thromboprophylaxis
trial is better than previously believed.[48]
At present, two prevention strategies prevail: preventing postpartum VTE among people
with risk factors and preventing pregnancy-associated VTE among people with a prior
VTE. Risk assessment is a fundamental component in combating pregnancy-associated
VTE, and it is crucial to carry out a risk assessment at various points throughout
pregnancy. It is important to classify risk factors by their strength of association
with VTE. Even in thrombophilia, the indication for pharmacological VTE prophylaxis
depends on the subtype. It is intriguing to consider the conjecture that risk factors
in combination can exhibit additive or exponential interactions.[16] Similarly, the possibility that individual risk factors may impact the risk of postpartum
VTE for different durations adds uncertainty to the optimum duration of postpartum
thromboprophylaxis. Although highly susceptible to bias, a recently developed risk
prediction model was shown to successfully distinguish between postpartum people with
and without VTE. This is an exciting potential avenue in the pursuit of pregnancy-associated
VTE prevention.
At present, strategies for prevention of pregnancy-associated VTE are based on expert
opinion or observational data. Astonishingly, there is still insufficient evidence
to confirm that pharmacological thromboprophylaxis reduces the risk of pregnancy-associated
VTE.[35] Thankfully recent trials have aimed to bridge this knowledge gap and following the
publication of data from the Highlow study,[39] we now have high-quality data to support optimal management of pregnant people who
have a history of VTE. However, a question remains regarding the optimal dose in the
postpartum period.
While the Highlow study succeeded in answering a critical clinical question, the evidence is still
lacking for the vast majority of pregnant people who do not have the risk factor of
prior VTE. Despite the fundamental challenges in conducting RCTs with pregnant people,
we are optimistic that the recent phenomenal efforts will translate into clinical
guidance. In the interim, individual risk assessments and shared decision-making remain
the best practice.
