Blood Reviews 23 (2009) 143147

Contents lists available at ScienceDirect

Blood Reviews
journal homepage: www.elsevier.com/locate/blre

REVIEW

Assessment and management of high-risk pregnancies in women

with thrombophilia
Galit Sarig *, Guy Vidergor, Benjamin Brenner
Thrombosis and Hemostasis Unit, Rambam Health Care Campus, and the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel

a r t i c l e

i n f o

Keywords:
Thrombophilia
LMWH
Anti-Xa
Pregnancy complications
Pregnancy loss
Gestational vascular complications

s u m m a r y
Pregnancy is an acquired hypercoagulable state which can lead to gestational vascular complications
especially in the presence of other prothrombotic risk factors. The use of anticoagulation for prevention
of pregnancy complications in women with thrombophilia is becoming more frequent. Efcacy and safety
issues of therapeutic and prophylactic regimens use and monitoring of LMWH therapy in pregnancy are
discussed in this review. In addition, a scoring system for women with thrombophilia is proposed which
includes severity of pregnancy outcomes, thrombotic history and type of thrombophilia.
Validation of this scoring system has revealed a signicant correlation between the proposed score and
LMWH dosages that were prescribed to the studied pregnant women.
Careful diagnosis, observation and monitoring can add signicant benet to LMWH therapy during
pregnancy.
2008 Elsevier Ltd. All rights reserved.

Thrombophilia and pregnancy complications

The rst review on thrombophilia and pregnancy complications
was published in Blood Reviews 10 years ago.1 Since then, research
in this eld has ourished regarding pathophysiology, epidemiology and management of women with thrombophilia and pregnancy complications. This review will focus on advances in
clinical management of these pregnancy complications.
Pregnancy is considered to be an acquired hypercoagulable
state due to increased concentration of coagulation factors, decreased levels of anticoagulants and decreased brinolytic capacity.2 The gradual increase in hypercoagulability during normal
pregnancy predisposes to venous thromboembolism (VTE) such
as deep vein thrombosis (DVT) and pulmonary embolism (PE)
and to gestational vascular complications (GVC), including recurrent pregnancy loss, intra-uterine growth restriction (IUGR), preeclampsia and placental abruption. These adverse pregnancy
outcomes affect up to 15% of gestations and are the major cause
of maternal and fetal morbidity and mortality.3
Several studies suggest that GVC are frequently associated with
maternal inherited or acquired thrombophilic risk factors.48 The
most compelling data for a link between thrombophilia and GVC
derives from studies in women with anti-phospholipid (APLA) syndrome.811

* Corresponding author. Tel.: +972 4 8543052; fax: +972 4 8543636.

E-mail addresses: g_sarig@rambam.health.gov.il (G. Sarig), guy_vidergor@
yahoo.com (G. Vidergor), b_brenner@rambam.health.gov.il (B. Brenner).
0268-960X/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.blre.2008.11.001

A recent meta-analysis of 25 studies in 11,183 women found

signicant associations of GVC and thrombophilia.8 In particular,
associations were observed with APLA, factor V Leiden and prothrombin 20210 mutations. Factor V Leiden and prothrombin
20210 mutations were found to be associated with both early
(OR 1.91, 95% CI, 1.013.61 and OR 2.7, 95% CI 1.375.34, respectively) and late (OR 2.06, 95% CI, 1.13.86 and 2.66 95% CI, 1.28
5.53, respectively) recurrent pregnancy losses.8 The strongest association for late fetal loss was seen in women with protein S deciency (OR 20.9, 95% CI, 3.7109.15).8
A more recent meta-analysis demonstrated that various confounders such as ethnicity, severity of illness and method of testing
affect the results of analysis the relationship between thrombophilia and GVC.12 In this meta-analysis, stronger relationships between FVL and recurrent pregnancy loss were documented in
Caucasians (OR 2.22, 95% CI, 1.852.67) and severity of GVC in
2nd and 3rd trimester (OR 2.28, 95% CI, 1.693.07) than 1st trimester (1.85, 95% CI, 1.352.53). In addition, genetic testing of FVL
without functional testing such as activated protein C resistance
(APCR) also affect the results showing a weaker association between thrombophilia and GVC.
Acquired APCR was found to be associated with pregnancy loss
in this meta-analysis (OR 2.30, 95% CI, 1.733.06)11 and a much
stronger association was documented with early pregnancy loss
(OR 4.04, 95% CI, 1.3728.42) in the previous systematic review.8
Although recent studies suggest that anti-thrombotic prophylaxis may improve gestational outcome in women with thrombophilia,1316 currently, the association of thrombophilia and
adverse pregnancy outcome is not yet clearly dened.17,18

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G. Sarig et al. / Blood Reviews 23 (2009) 143147

Therefore, the latest American College of Chest Physicians (ACCP)

guidelines on VTE, thrombophilia, antithrombotic therapy and
pregnancy recommend women with GVC to be screened only for
APLA,19 however, in women with GVC without APLA, further
thrombophilic risk factors evaluation can be advised.
Antithrombotic therapy during pregnancy
Anticoagulant therapy is indicated during pregnancy for the
prevention and treatment of VTE, systemic embolism in patients
with mechanical heart valves and, in combination with aspirin,
for prevention of recurrent pregnancy loss in women with APLA.19
Anti-thrombotics currently available include un-fractionated
heparin (UFH), low molecular weight heparin (LMWH) and antiplatelet agents. In the past, UFH was the drug of choice for the prevention and treatment of VTE during pregnancy. However, because
of its signicant adverse effects, such as osteoporosis and heparin
induced thrombocytopenia (HIT), as well as the need for laboratory
monitoring, UFH is being replaced by LMWH in gestational settings.20 Both UFH and LMWH do not cross the placenta and are
not secreted in breast milk; however, LMWHs exhibit a number
of clinical advantages over UFH, including superior bioavailability,
longer plasma half-life allowing once-daily dosing, and an improved safety prole.21 The anticoagulant effect of heparin is mediated largely through its interaction with antithrombin; this
produces a conformational change in antithrombin and so markedly enhances its ability to inactivate the coagulation enzymes
thrombin, factor Xa, and factor IXa.22 In addition, LMWH increases
production and secretion of TFPI from endothelial cells.23,24
Safety of LMWH prophylaxis during pregnancy
Although women with prior VTE have an increased risk of
recurrence during gestation, no large clinical trials assessing the
role of prophylaxis in pregnant women with previous VTE are
available.19
A recent review of close to 2800 treated pregnancies evaluated
safety and efcacy of LMWH in pregnancy.25 The main indications
were prophylaxis of VTE and prevention of pregnancy loss. The rate
of bleeding complications was low and thrombocytopenia was
rare, with no cases of heparin-induced thrombocytopenia. Likewise, clinically signicant osteoporosis was extremely rare. Live
birth rates were 8596%, depending on the indication for treatment.26 A good safety prole on the use of enoxaparin during
624 pregnancies was also documented in a retrospective French
study.26
While the evidence level is low due to lack of large clinical trials,
expert opinion is based on available literature and common
practice.19
Anti-thrombotic prophylaxis for pregnancy complications
Until recently studies on treatment of women with inherited
thrombophilia and pregnancy loss were predominantly uncontrolled and included small series of patients treated mostly with
LMWH. A recent collaborative study demonstrated the safety of
using LMWH during 486 gestations. A successful outcome was reported in 83 (89%) of 93 gestations in women who had a history of
recurrent pregnancy loss and in all 28 gestations in women who
experienced pre-eclampsia during a previous pregnancy.27
In an earlier study, 61 pregnancies in 50 women who had
thrombophilia and who were presented with recurrent fetal loss
were treated with the LMWH enoxaparin throughout gestation
and 46 weeks into the postpartum period.13 Of the 61 pregnancies, 46 (75%) resulted in live birth, compared with a success rate

of only 20% in these 50 women in previous gestations without antithrombotic therapy.13 In a cohort study undertaken to assess the
effect of enoxaparin on subsequent live birth rate in women who
had three or more consecutive pregnancy losses and hereditary
thrombophilia, live birth rate was higher in women treated with
enoxaparin: 26/37 (70.2%), compared with 21/48 (43.8%) in untreated patients. The benecial effect was mainly seen in women
who had primary losses and in those who had ve or more miscarriages.14 A recent study by Gris and colleagues15 demonstrated that
in women who had thrombophilia and previous one pregnancy
loss after 10 weeks gestation, enoxaparin at a dose of 40 mg daily
resulted in a signicantly better live birth rate compared with lowdose aspirin (86% vs. 29%, respectively). The differences were found
in women who had FVL and factor II G20210A and in women who
had protein S deciency.
The optimal dosage of LMWH is yet unknown and should be
determined by prospective randomized trials. Ideally large placebo-controlled trials should be advocated. Logistic and ethical difculties, however, limit such an approach.
LIVE-ENOX is a multicenter, prospective, randomized study
comparing two doses of enoxaparin, 40 mg/d and 40 mg/every
12 h, in women with thrombophilia and a history of pregnancy
loss.16,28 Of the 180 women enrolled, live birth rate before the
study was only 28%, but during the study, live birth rates were
84% for the 40 mg/d group and 78% for the 80 mg/d group. Late
gestational complications decreased after enoxaparin treatment.
The incidence of pre-eclampsia in the enoxaparin treated pregnancies was 3.9% compared with 10.5% in previous gestations. Both
doses of enoxaparin seemed to be safe and well tolerated. Postpartum bleeding (1.1% of women in each group) and enoxaparin-related allergic local skin reactions at the injection sites were
observed in a small number of women (2.2% and 3.3% of those
receiving 40 mg/day and 80 mg/day, respectively).
Prophylaxis with enoxaparin (40 mg/day or 80 mg/day) is thus
safe and effective for improving pregnancy outcome and potentially for reducing late pregnancy complications in thrombophilic
women who have a history of pregnancy loss.
While these studies are encouraging large prospective randomized placebo, controlled studies have not been preformed. Several
multicenter studies are currently ongoing and results are expected
in the near future. These studies vary in inclusion criteria, numbers
of pregnancy losses, severity and type of pregnancy complications.
Moreover, LMWH type, dosage and timing of treatment also differ
among studies.
Monitoring of LMWH therapy during pregnancy
Since LMWH preparations inhibit preferentially FXa and only to
a low extent thrombin and activated partial thromboplastin time,
anti-Xa assays have been developed and validated to determine
their anticoagulant effect.29 For the vast majority of patients,
LMWH have proved to be effective and safe without the need for
anticoagulant monitoring.30 However, the need to adapt the
LMWH dosage to the weight of the pregnant woman or to monitor
LMWH treatment during pregnancy remains controversial.31,32
While several studies demonstrated lower than expected anti-Xa
activity levels during pregnancy, and lower than in the non pregnant state,3134 the need to adapt the LMWH dosage to the antiXa activity level remains controversial and no guidelines on monitoring anti-Xa activity during pregnancy are available.19
Our group studied the modulation of systemic hemostatic
parameters by LMWH in 87 pregnancies of women participating
in the LIVE-ENOX trial.16,23,28 The control group included 40 women with normal pregnancies. Out of the 87 LMWH treated pregnancies, successful pregnancy outcome with live newborn was
recorded in 70 (80.5%) women, without correlation to enoxaparin

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G. Sarig et al. / Blood Reviews 23 (2009) 143147

dosage. Seventeen women (19.5%) suffered pregnancy loss at

16 7 (632) weeks of gestation. Anti-Xa levels at 1015 gestation
weeks were higher (0.39 0.38 u/ml) in the successful pregnancy
outcome group compared to the group with the miscarriages
(0.22 0.2 u/ml). Prophylactic anti-Xa levels (0.28 0.13 u/ml)
were achieved from 15 week of gestation until delivery in the live
born group, without signicant differences between gestational
ages or LMWH dosages. A signicant increase in anti-Xa and tissue
factor pathway inhibitor (TFPI) levels (P < 0.001) was achieved
after beginning of LMWH prophylaxis in the successful pregnancy
outcome group but not in the miscarriage group. These results suggest that plasma levels of anti-Xa activity and TFPI may help to predict the outcome in LMWH treated pregnancies.23

The patient is offered a complete thrombophilia work-up which

includes:, Factor V Leiden, prothrombin G20210A, Methylenetetrahydrofolate reductase (MTHFR) 677TT mutations, levels of proteins
C, S, Antithrombin, factor VIII, homocysteine, titer of anticardiolipin and anti b2GPI antibodies and lupus anticoagulant. Thrombophilic traits are scored relative to observed prothrombotic
tendency during pregnancy with antithrombin and homozygous
factor V Leiden scored highest as single traits. Combined thrombophilia also has a higher score, and is sub-classied as combined
moderate (i.e. heterozygous for both factor V Leiden and prothrombin G20210A mutations) and combined severe (i.e. strong
lupus anticoagulant and homozygous for factor V Leiden or Antithrombin deciency).

Scoring system for women with thrombophilia

Stratication

Currently, there are no clear criteria or guidelines for diagnosis

or treatment of women with thrombophilia in pregnancy. In fact,
the management of these women depends largely on clinical judgment. The latest ACCP guidelines on antithrombotic therapy and
pregnancy, also recognize that the use of anticoagulation for prevention of pregnancy complications in women with hereditary
thrombophilia is becoming more frequent.19
Therefore, we would like to propose a novel scoring system for
women with thrombophilia including standardization to evaluate
severity of pregnancy outcomes, thrombotic history and type of
thrombophilia.
The scoring system is composed of four major categories:
obstetrical history, previous thromboembolic events, family history and type of thrombophilia (Table 1). The questionnaire includes information on history of venous thromboembolism (deep
vein thrombosis, pulmonary embolism, splanchnic, cerebral or
other thromboses), major stroke, and the underlying clinical background which led to these events (idiopathic, pregnancy, use of
oral contraceptives, immobilization, etc.). Higher scores are given
to more signicant locations and the nature of thrombotic and idiopathic onset. In addition, the patient is questioned for the possibility that one or more rst degree relatives have suffered from
thromboembolic events or gestational vascular complications.

A total score is achieved by summing the scores of the four categories of thrombosis, obstetrical, family histories and thrombophilia. Based upon the score achieved, pregnancy risk for an
individual woman may be stratied into four levels of risk: low
(score 6 5), intermediate (score 610), high (score 1114) and extremely high (score P 15).
Validation
In order to examine the feasibility of this scoring system, we
studied, retrospectively, 90 pregnancies that were followed at the
Thrombosis and Hemostasis clinic at Rambam, Health Care Campus from 2002 to 2006.
Inclusion criteria were LMWH treated pregnancies for which all
the information on thrombosis, obstetric complications and thrombophilia for the score was available. Pregnancies were monitored
monthly by medical examination and by testing anti-Xa activity
levels.
Out of the 90 LMWH treated pregnancies, successful pregnancy
outcome with live newborn was achieved in 74 (82%) women, the
majority were at intermediate risk (score 610) (Table 3). A significant correlation was found between the proposed score and
LMWH dosages that were prescribed to this group of patients

Table 1
Scoring system for women with thrombophilia.
Obstetrical history
Premature Labors
Week of delivery
3236 w
2932 w
628 w
Pregnancy Loss
Timing of lossa
69 w
1019 w
P20 w (incl. IUFD)
Number of loses
1
2
P3
Previous VTE

Type of thrombophilia
Score
1
2
3

0
2
3

2
4

Major Stroke (CVA)

Life threatening VTE

4
2b

Score

Thrombophilia type

Score

Mild-moderate (310th p)
Severe (63rd p)
Pre-eclampsia
Mild-moderate
Severe HELLP
Placental Abruption
Mild
Severe

1
3

1
3

Age > 35

Factor V Leiden Heterozygote

Factor V Leiden Homozygote
Prothrombin 20210 Heterozygote
Prothrombin 20210 Homozygote
MTFHR C677T Homozygote
Protein C deciency
Protein S deciency
Antithrombin deciency
Hyperhomocysteinemia
Elevated Factor VIII levels
Anticardiolipin Ab, low titer
Anticardiolipin Ab, high titer
Lupus anticoagulant, weak
Lupus anticoagulant, strong

2
4
2
3
1
3
2
4
2
2
1
2
1
3

Risk-associated
Idiopathic, pregnancy
Oral contraceptives

4
3

Combined moderate
Combined severe
Family history

4
8

Immobilization, surgery

Family history of VTE

Family history of gestational vascular complications

2
1

1
3

1
2
3

Location/type
DVT of leg/arm
Other VTE (PE, cerebral, etc.)

IUGR

Latest timing amongst all pregnancy losses.

If the VTE event was life threatening, two additional points should be added to the score of the previous VTE category.

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G. Sarig et al. / Blood Reviews 23 (2009) 143147

Table 2
Patient characteristics.

Womens age
Mean STD (Y)
Womens weight at the
beginning of pregnancy
Mean STD (kg)
Week of delivery
Week of miscarriage
Newborn weight (kg)
71 singles
5 twins

Pregnancies with
live born (n = 74)

Pregnancies with
miscarriage (n = 16)

30.9 4.8

33.7 5.8

0.05

64.7 13.3

73.1 18.0

0.035

37.5 2.5
16.0 7.0 (632)
2.985 0.66
2.340 0.5

Table 3
Mean STD of target LMWH that was prescribed and anti Xa activity level in each
score group.
Score

Pregnancies with live born (n = 74)

Pregnancies with miscarriage

(n = 16)

LMWH mg/kg/
day

Anti Xa (u/
ml)

LMWH mg/kg/
day

Anti Xa (u/
ml)

65
610
11
14
P15

12
43
11

0.7 0.3
0.9 0.3
1.0 0.5

0.46 0.2
0.48 0.25
0.48 0.2

2
10
4

0.7 0.07
0.8 0.2
0.7 0.2

0.5 0.03
0.37 0.18
0.33 0.27

1.6 0.4

0.73 0.3

Total

74

0.9 0.4

0.5 0.2

0.7 0.2*

0.4 0.19

0
16

P = 0.007, pregnancies with live born vs. pregnancies with miscarriage.

r=0.62
P<0.0001

3.0

LMWH mg/Kg/day

2.5
2.0
1.5
1.0
0.5
0.0
0

10

15

20

25

Score
Fig. 1. Correlation between score and LMWH dosages in the live born group
(n = 74).

(r = 0.62, P < 0.0001) (Fig. 1). Of note, 16 women (18%) suffered

pregnancy loss at 16 7 (range 632) weeks of gestation. In this
group, no correlation was found between score and LMWH dosages
(r = 0.06, P = 0.8).
A signicant difference was documented in LMWH dosages between women with live birth and women with miscarriages
(0.9 0.4 mg/kg/day vs. 0.7 0.2 mg/kg/day, P = 0.007) (Table 3).
Signicant differences in LMWH dosage levels were recorded
between lower risk (score 6 10) and higher risk (score P 11) pregnancies (P = 0.0001), and between pregnancies with a risk
score < 15 and extremely high risk (score P 15) in the live born
group (P = 0.0001) (Table 2).
A weak correlation between the proposed score and anti-Xa
activity levels was documented in pregnancies with live born
(r = 0.35, P = 0.002) but not in pregnancies with miscarriages
(r = 0.09, P = 0.7). In addition, a signicant correlation between
LMWH dosages and anti-Xa activity levels was recorded in the successful pregnancy outcome group (r = 0.61, P < 0.0001), but not in
the pregnancy loss group (r = 0.06, P = 0.8). These results suggest

Fig. 2. Anti-Xa activity level during LMWH treated pregnancies with live born.
P = 0.03 indicates signicant difference in anti-Xa activity levels between 510 and
3035 weeks of gestation in pregnancies with score 6 10. *P 6 0.02, pregnancies
with score P 11 vs. score 6 10. **P 6 0.003, pregnancies with score P 11 vs.
score 6 10.

that monitoring of anti-Xa activity levels may enable detection of

the response in pregnant women to the prescribed LMWH therapy.
LMWH dose change, based on clinical diagnosis and/or anti-Xa
activity level, was required in 9/55 (16.4%) of the low risk group
(score 6 10), 12/19 (63%) of the high risk group (score P 11) and
in 6/8 (75%) of the extremely high risk group (score P 15).
Anti-Xa activity levels during pregnancy were signicantly
higher in high risk compared to low risk pregnancies (Fig. 2).
According to our validation, all extremely high risk pregnancies
resulted in live born, moreover, a correlation between score, appropriate LMWH dosage and anti-Xa activity level was associated with
successful pregnancy outcome.
Based on our practices we suggest assessing anti-Xa activity 1
week after LMWH administration. In pregnancies treated with therapeutic dosages more frequent monitoring should be considered (at
least once a month). In pregnancies treated with prophylactic LMWH,
we suggest assessing anti-Xa activity at the beginning of the third trimester in order to detect the LMWH after body weight gain.
Even though the validation of this score system is a single center experience, our ndings suggest that this score may be a basis
for prospective multicenter trials which will further validate this
score.
Risk assessment of clinical history and thrombophilic risk factors and careful monitoring of LMWH therapy can signicantly
benet women with high risk pregnancies.
Practice points
 Pregnancy complications are commonly associated with
hypercoagulability.
 Risk assessment is essential for adequate management.
 LMWH are increasingly used in women with pregnancy
complications.
 Close team work approach by obstetricians, hematologists and
coagulation experts for optimization of diagnosis and management of high risk pregnancies in women with thrombophilia.

Research agenda
Prospective multicenter studies evaluating pregnancy outcome
utilizing the scoring system applying appropriate LMWH regimens
with clinical and laboratory monitoring.

G. Sarig et al. / Blood Reviews 23 (2009) 143147

Conict of interest statement

Benjamin Brenner served on advisory board and speaker bureau
Sano-Aventis. Other authors have nothing to declare.
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