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2011;13:1521

Review

Review Diagnosis and

management of antiphospholipid
syndrome in pregnancy
Authors Bethan Myers / Sue Pavord

Key content:
The diagnosis of antiphospholipid syndrome (APS) requires both characteristic
clinical features and persistently abnormal laboratory tests.
Antiphospholipid syndrome can cause serious morbidity in mother and fetus.
Good management in an expert setting can result in a live birth rate of 80%.
Prepregnancy assessment and counselling play an important part in optimising
the chances of a subsequent successful pregnancy.

Learning objectives:
To understand the clinical features and pathophysiology of APS.
To learn the principles of management of APS in pregnancy.
To learn about the key points of prepregnancy assessment and counselling.

Ethical issues:
Prepregnancy assessment and counselling provide realistic guidance to women,
enabling them to make informed decisions regarding future pregnancies.
Some women with APS are at very high risk of thrombotic events during
pregnancy and expert opinion needs to be sought to give a clear plan for
thromboprophylaxis for these cases.
Keywords low dose aspirin / low molecular weight heparin / pregnancy morbidities /
systemic lupus erythematosus / thrombosis
Please cite this article as: Myers B, Pavord S. Diagnosis and management of antiphospholipid syndrome in pregnancy. The Obstetrician & Gynaecologist 2011;13:1521.

Author details
Bethan Myers MA FRCP FRCPath
Consultant Haematologist and Haemophilia
Director
Department of Haematology, Lincoln County
Hospital, Greetwell Road, Lincoln, Lincolnshire
LN2 4AX, UK; and

Obstetric Haematologist
Department of Haematology, Nottingham
University Hospitals NHS Trust, QMC Campus,
Derby Road, Nottingham NG7 2UH, UK
Email: bethan.myers@btinternet.com
(corresponding author)

2011 Royal College of Obstetricians and Gynaecologists

Sue Pavord FRCP FRCPath

Consultant Haematologist and Haemophilia
Director
Department of Haematology, Leicester Royal
Infirmary, Infirmary Square, Leicester
LE1 5WW, UK; and
Senior Lecturer in Medical Education
University Hospitals of Leicester, Leicester, UK

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Introduction
Antiphospholipid syndrome (APS) is an acquired
autoimmune disorder associated with vascular
thrombotic events, pregnancy failure and an array
of additional clinical manifestations involving
other organs, such as the heart, skin and central
nervous system. With effective management many
of the complications of the condition can be
avoided; the importance of early recognition and
diagnosis needs to be emphasised.
The disease can be a discrete entity (primary APS)
or it can occur in association with other
autoimmune disease, usually systemic lupus
erythematosus (SLE). Patients with primary APS
have similar clinical profiles to those with APS
plus SLE, although certain features such as
heart valve disease, haemolytic anaemia, low C4
levels and neutropenia are more common in the
latter.1

Prevalence
The syndrome occurs most commonly in young to
middle-aged adults. Women are more frequently
affected (female:male ratio of 5:1). There is no
racial predominance for primary APS, although a
higher prevalence of SLE occurs in the black and
Hispanic populations.

Clinical features
Diagnostic criteria for the classification of definite
APS were agreed by an international panel in 1999
and updated in 2006 (Box 1).2,3
Thrombosis is the most common presenting
feature of APS.4 It can occur in the venous, arterial
or small-vessel circulations. It can involve vascular
beds infrequently affected by other prothrombotic
states and is independent of atherosclerotic
vascular disease.
Box 1

Summary of the revised

classification criteria for APS

The Obstetrician & Gynaecologist

Venous thrombosis
Antiphospholipid antibodies (aPL) are found in
about 2% of patients presenting with acute venous
thromboembolism. The venous thrombosis often
occurs in unusual sites such as the cerebral, retinal,
splanchnic or axillary veins; APS accounts for
up to 70% of such presentations. Venous
thromboembolism, especially deep venous
thrombosis of the legs, occurs in 3050% of
patients with APS during an average follow-up of
less than 6 years.5 Following a first episode the risk
of future venous thrombosis increases significantly.
Arterial thrombosis
The most common site of arterial thrombosis is the
central nervous system, with cerebrovascular events
and transient ischaemic attacks accounting for 50%
of arterial events in APS. Myocardial infarction
accounts for about 20% and other vascular beds
that can be involved include those of the lungs,
retina, gut, spleen and extremities. In many cases
the event is otherwise unexplained, with no
identifiable risk factors for arterial disease, such
as smoking, diabetes or hypertension.
Obstetric complications
Some women with APS have no problems at all in
pregnancy; however, pregnancy complications, in
addition to maternal thrombosis, can occur at any
stage. These include recurrent first-trimester
miscarriages, late fetal loss, fetal growth restriction,
pre-eclampsia and placental abruption.
Pregnancy loss
Of women with recurrent pregnancy loss, defined
as three or more first-trimester miscarriages,
1020% have detectable aPL.6 These women have a
potential 90% risk of further fetal loss if left
untreated.7 The diagnostic criteria for APS suggest
that evaluation should begin after the third
consecutive early miscarriage, defined by less than

Antiphospholipid syndrome can be diagnosed if at least one of the clinical and one of the laboratory criteria are met (although not
if there is 12 weeks or 5 years between the positive antiphospholipid antibody test and the clinical manifestation).
Clinical criteria
Vascular thrombosis: one or more clinical episodes of arterial, venous or microvascular thrombosis occurring in any tissue or
organ (superficial venous thrombosis is not included)
Pregnancy morbidity:
o

one or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks of gestation; OR

one or more premature births of a morphologically normal neonate before 34 weeks of gestation because of
eclampsia, severe pre-eclampsia or recognised features of placental insufficiency;

three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal
anatomical or hormonal abnormalities and paternal and maternal chromosomal causes excluded

Laboratory criteria
Lupus anticoagulant present on two or more occasions at least 12 weeks apart detected according to the guidelines of the
International Society on Thrombosis and Haemostasis11
Anticardiolipin antibodies of IgG and/or IgM isotype in serum or plasma, present in medium or high titre (i.e. 40 GPL or MPL,
or 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardised ELISA
Anti-2-glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titre 99th percentile), present on two or more
occasions, at least 12 weeks apart, measured by standardised ELISA
ELISA  enzyme-linked immunosorbent assay; GPL  IgG anticardiolipin antibodies; IgG  immunoglobulin G;
IgM  immunoglobulin M; MPL  IgM phospholipid units

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10 weeks of gestation (Box 1). However, in practice,

evaluation after two early miscarriages is often
initiated at the discretion of the physician.
Late complications of aPL in pregnancy
These relate to placental insufficiency caused by
aPL. Gestational hypertension/pre-eclampsia
occurs in 3050% of untreated women with known
APS, but falls to 10% with effective management. By
contrast, there is no increase in aPL incidence
in general obstetric patients presenting with
pre-eclampsia.8 HELLP syndrome (haemolysis,
elevated liver enzymes and low platelets) may occur,
usually associated with pre-eclampsia/eclampsia;
this seems to occur earlier than in women without
APS, often in the second trimester.
Other clinical manifestations
In addition to thrombosis and obstetric morbidity,
there are additional clinical manifestations that
are not included in the official definition of APS
(Box 2).

2011;13:1521

Thrombocytopenia is common, with platelet-specific

antibodies distinct from aPL

Positive direct Coombs test with occasional cases of clinical

haemolytic anaemia

Heart valve defects, which are usually benign, but

thrombotic lesions may embolise

Skin involvement: mainly livedo reticularis

Cerebral involvement, with epilepsy, cerebral infarction,

chorea, migraine

Renal involvement, especially APS-associated

nephropathy; glomerulonephritis

Lupus nephritis, arterial hypertension , diffuse interstitial

kidney sclerosis, pauci-immune vasculitis

Evidence suggests that multiple mechanisms are

responsible for the varying clinical manifestations.
Notably, recurrence of complications often follows
a similar pattern of disease and recurrent
thrombosis usually occurs in the same vascular
field, although this is not always the rule.

Postpartum syndrome
This is a rare syndrome characterised by
pleuropulmonary disease, fevers and cardiac
manifestations.9 The mechanism is unknown,
although extensive immunoglobulin IgG, IgM,
IgA and C3 deposition in the myocardium has
been reported.

Obstetric morbidity
The pathophysiological mechanisms underlying
obstetric morbidity also appear to be multiple,
involving either thrombotic or non-thrombotic
phenotypes in the placenta. It is likely, also, that
genetic and environmental factors affecting the
maternalfetal interface influence the potential
pathogenicity of these antibodies.

2011 Royal College of Obstetricians and Gynaecologists

Other features of APS

Pathophysiology and aetiology

Procoagulant effects
2GPI antibodies disrupt normal coagulation
mechanisms in several ways: direct cellular effects
caused by bound 2GPI-antibody complexes,
activating platelets, endothelial cells and
monocytes, hence inducing tissue factor
expression; interference with haemostatic factors;
resistance to activated protein C; and reduction in
fibrinolysis.

It was originally thought that aPL were directed

against negatively charged phospholipids but it is
now clear that they target plasma proteins with
affinity for these phospholipids. The main antigens
involved are 2-glycoprotein I (2GPI) (also known
as apolipoprotein H) and prothrombin, although
many more antigenic targets have been described.
Implicated antibodies include lupus anticoagulant,
anticardiolipin antibodies (aCL) and anti-2GPI.
There is concordance between them but they are
not identical and some lupus anticoagulants react
with phospholipids other than cardiolipin and
proteins other than 2GPI, whereas some aCL and
anti-2GPI have no lupus anticoagulant activity.
Antibodies to the 2GPI are persistent and
associated with thrombotic complications, whereas
those independent of 2GPI tend to be present only

Box 2

transiently, associated with infectious diseases or

drugs.

Catastrophic APS
This term defines a severe, accelerated form of APS
resulting in multi-organ failure from widespread
thromboses, which are usually microvascular rather
than large-vessel occlusions. The syndrome is of
acute onset, defined by the involvement of at least
three different organ systems over a period of
days to weeks. The pathogenesis appears to be
dependent on a multi-hit phenomenon. Triggers
such as infection or surgery exacerbate an already
procoagulable state.

Antiphospholipid antibodies

Review

Early histological studies demonstrated decidual

vasculopathy and placental thrombosis.
Displacement of annexin V from trophoblasts
contributes to a procoagulant state through
acceleration of coagulation reactions. In addition,
a mouse model10 demonstrated activation of
complement, causing inflammation-mediated
placental injury leading to fetal loss or growth
restriction. In this model, heparin prevented
pregnancy loss by blocking activation of
complement, rather than primarily via an
anticoagulant effect.
More recently, direct trophoblastic damage by
aPL, independent of mechanisms involving
thrombosis and complement activation, has been
demonstrated. Interaction of aPL with 2GPI,
exposed during trophoblast syncytium formation,
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has been shown to cause inhibition of trophoblast

invasiveness. This mechanism has been
hypothesised to contribute to early pregnancy loss.

Laboratory evaluation
Limitations of laboratory testing include lack of
laboratory standardisation for aPL and the
heterogeneous nature of the antibodies, resulting
in low specificity of the assays. Antiphospholipid
antibodies are found in 35% in those without
thrombosis or obstetric morbidity. They are often
transient and associated with infection or drugs.
The clinical importance of these aPL is uncertain.
To satisfy APS laboratory classification criteria,
persistently positive antibody tests in at least one of
the three assays (aCL, lupus anticoagulant or 2GPI
antibody) for at least 12 weeks is required. Testing
should occur away from the time of the acute
event.2,3 There is no indication for screening for aPL
in asymptomatic women prior to interventions
such as in vitro fertilisation.
Lupus anticoagulant
This is the most relevant assay in relation to
vascular events and obstetric morbidity. These
antibodies are detected by their ability to prolong
phospholipid-dependent coagulation reactions,
not corrected by mixing patient and normal
plasmas. As aPL showing lupus anticoagulant
activity are heterogeneous, it is recommended that
at least two methods are performed: activated
partial thromboplastin time (APTT) and a direct
anti-Xa assay such as the dilute Russell viper venom
assay (dRVVT). It should be confirmed, using a
phospholipid neutralisation procedure, that the
anticoagulant is directed against protein bound to
negatively charged phospholipids.11
Anticardiolipin antibodies
These are measured by enzyme-linked
immunosorbent assay, although, again,
concordance among laboratories is poor and it
is difficult to distinguish between significant
antibodies associated with 2GPI from those
bound to other plasma proteins or directly bound
to cardiolipin. The correlation between aCL titre
and thrombotic risk is well established, with the
IgG subtype having stronger association than IgM
or IgA.12 The revised classification criteria for APS
uses an IgG aCL threshold of 40 iu. Low levels of
aCL, although statistically abnormal, may not be
associated with a significant risk of thrombosis and
in a systematic review of the literature, Galli et al.13
observed no correlation with venous thrombosis
and only a weak correlation with arterial
thrombosis.
Anti-2-glycoprotein I antibodies
These are now included in the revised criteria for
the diagnosis of APS (Box 1).2 They show better
correlation with thrombosis than aCL but there is a
18

The Obstetrician & Gynaecologist

high false-positive rate as there are non-pathogenic

antibodies that bind 2GPI.

Management of APS in
pregnancy
General issues
The aims of management of APS in pregnancy are
threefold:
1. To maximise the chance of successful fetal
outcome.
2. To prevent thrombosis and other clinical
manifestations of APS in the mother.
3. To ensure good counselling and planning for
future pregnancies.
Wherever possible, women should be seen in a
prepregnancy counselling setting, so that a full
review can be carried out and their general health
optimised.
A detailed past medical and obstetric history
should be taken and the circumstances of any
past thrombotic event (provoked or
spontaneous, arterial or venous) assessed.
Asessment should also be made of any associated
conditions, such as SLE, and evidence of any
organ damage. Other risk factors contributing to
thrombotic risk or pregnancy morbidity such as
obesity and maternal age must be taken into
account in the overall assessment and will
contribute to making an appropriate
individualised treatment plan.14
There is debate regarding what constitutes the most
appropriate pharmacological management for
pregnant women with APS: guidelines often leave
exact treatment to the discretion of the physician
involved. The heterogeneity of the condition
complicates this decision further. The standard
anticoagulant for prevention and treatment of
venous thromboembolism in pregnancy is heparin,
usually low molecular weight. With respect to the
pathophysiology of APS, it is the logical drug of
choice, as it has both anticomplement and
anti-inflammatory actions in addition to its
anticoagulant effect. Two randomised studies15
performed in the late 1990s concluded that a
combination of aspirin plus heparin is the optimal
treatment. A Cochrane review16 of small studies
concluded that this regimen may reduce pregnancy
loss by 54%. Subsequently, combination treatment
became standard practice. However, a recent large
randomised trial17 contests this, finding no
advantage in dual treatment in the study and no
advantage when these data are analysed together
with previously published studies. A meta-analysis
published in 2010 which analysed five studies came
to the opposite conclusion.18 Hence, this remains a
controversial area. It may be that the conflicting
results are due to heterogeneity in the cases and that
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further stratification is necessary in treatment

according to clinical phenotype, as suggested by
Bramham et al.19 A summary of management of
women with APS or aPL is given in Table 1 and
discussed in the following sections.
Management of an acute episode of thrombosis in
pregnant women with APS
The immediate management of thrombosis is the
same in those with or without APS. This standard
treatment consists of low molecular weight heparin
in a therapeutic dosage. The various treatment
schedules for different low molecular weight
heparins are summarised in Table 2.
Management of women with aPL and a previous
thrombotic event
It is likely that these women will be on long-term
anticoagulation, although this depends on the
circumstances of the thrombotic event. If there was
clearly a temporary provoking factor, they may have
had a limited duration of anticoagulation.

In those women on long-term anticoagulation,

a change from warfarin should be made once a

positive pregnancy test is obtained. It is important
to emphasise the necessity of an early pregnancy
test, to ensure a change to heparin before 6 weeks
of gestation and, therefore, to minimise the risk of
warfarin embryopathy. The dosage of heparin
should be at intermediate or therapeutic levels,
depending on assessment of overall risk.
In those women not on anticoagulation, a high
prophylactic or intermediate dosage should be
commenced early in the first trimester, on
confirmation of a viable pregnancy.
Aspirin at a low dosage (75 mg) should also be
started.
Women then require regular, frequent review
throughout the pregnancy: fetal biometry to
assess fetal growth should be performed at
monthly intervals from 20 weeks of gestation.
Studies show that analysis of uterine artery
Doppler at 1822 weeks predicts poor pregnancy
outcome.20 Subsequent regular monitoring of
umbilical artery Doppler is recommended.
Postnatally, the woman may be re-established on
warfarin or continue on heparin for at least
6 weeks.

Management of women with aPL and multiple

previous venous events, or venous plus arterial
events
This group of women will be on long-term
warfarin, possibly at higher range international
normalised ratio,3,4 and are at very high risk during
pregnancy. In this group, prepregnancy counselling
is particularly important, so that the extent of risk
can be clarified on an individual basis,
prepregnancy health optimised, and this risk and
a clear plan conveyed to the woman and
documented. Heparin in therapeutic dosages
2011 Royal College of Obstetricians and Gynaecologists

2011;13:1521

Table 1

Clinical feature

Management

APS with prior fetal death or

recurrent pregnancy loss

Aspirin 75 mg once daily  LMWH

prophylactic dosage. Doppler
ultrasound for fetal assessment
Low molecular weight heparin at
intermediate or therapeutic dosage,
plus aspirin
No treatment or low dose aspirin

APS with prior venous or arterial

thrombosis
Antiphospholipid antibodies without
clinical features and healthy
previous pregnancies
Primigravida with isolated aPL
APS with recurrent thrombotic events

Review

Pharmacological management of
APS in pregnancy

Low dose aspirin and fetal monitoring

Full therapeutic dose LMWH; aspirin;
consider warfarin

LMWH  low molecular weight heparin

Enoxaparin
Body weight <50 kg
Body weight 5090 kg
Body weight 91130 kg
Body weight 131170 kg
Body weight 170 kg
High prophylactic dose
(for weight 5090 kg)
Intermediate dose
Therapeutic dose

20 mg daily
40 mg daily
60 mg daily
80 mg daily
0.6 mg/kg/day
40 mg b.d.
~0.75 mg/kg b.d.
1 mg/kg b.d.

Dalteparin

Tinzaparin

2500 iu daily 3500 iu daily

5000 iu daily 4500 iu daily
7500 iu daily 7000 iu daily
10 000 iu daily 9000 iu daily
75 iu/kg/day
75 iu/kg/day
5000 iu b.d.
4500 iu b.d.
~70 iu b.d.
90 iu/kg b.d.

Table 2

Approximate prophylaxis and

treatment schedules for different
low molecular weight heparins2

~70 iu b.d.
90 iu/kg b.d.

b.d.  twice daily

should be substituted for warfarin, together with

low dose aspirin and regular fetal growth
assessment as above.
Occasionally, there are women in an ultra-high
risk group, where it may be appropriate to consider
warfarin usage from the second trimester, or even
all trimesters. These women include those who
continue to develop new thrombotic events despite
anticoagulation. The risks of warfarin to the fetus
must be explained: in the first trimester this
includes a 12% risk of teratogenicity and, later, the
ongoing risk of fetal loss, haemorrhage and subtle
neurological changes.
Management of women with aPL and pregnancy
morbidity
In the randomised trial by Rai et al.,15 low dose
aspirin plus heparin increased the live birth rate to
71%, compared with 42% with low dose aspirin
alone. Two meta-analyses concurred, showing
reduction in pregnancy losses by 54%; other studies
are conflicting, one showing a good success rate
with aspirin alone, and others demonstrating no
superiority of aspirin to placebo. There is no place
for steroids in the management of these women
since this is associated with maternal morbidity and
premature delivery.
Generally, prophylactic dosages of low molecular
weight heparin and low dose aspirin are
recommended in women with recurrent pregnancy
loss and other pregnancy morbidities.
In addition, fetal monitoring with umbilical artery
Doppler ultrasound every 34 weeks from
2426 weeks provides important information
on fetal wellbeing. Huong et al.20 analysed the
predictive value of Doppler ultrasound
examination for late pregnancy outcome, together
with clinical examination and laboratory tests in
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Box 3

Prepregnancy planning

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1.

Clinical: review medical and obstetric history

2.

Laboratory:

The Obstetrician & Gynaecologist

(a) document and confirm persistent antiphospholipid antibodies

(b) assess renal function
(c) assess full blood count for presence of thrombocytopenia and/or anaemia
(d) antibody testing: lupus anticoagulant, aCL, anti-2GPI, anti-Ro and La antibodies (even if there is no evidence of SLE:
these antibodies are associated with a 2% risk of complete heart block in the fetus and up to a 5% risk of neonatal lupus)
3.

Treatment prepregnancy:
(a) optimise the woman's clinical state and pharmacological treatment
(b) postpone pregnancy if a thrombotic event has occurred within the last 6 months
(c) postpone if SLE has been active or hypertensive
(d) assess individual additional risk factors such as obesity and maternal age and give a clear indication to the woman
regarding the degree of risk for both thrombosis and obstetric complications
(e) provide contact information for prompt, early referral at the onset of pregnancy
(f) ensure that the plan is understood, e.g. substituting heparin for warfarin at the time of the first missed period
(g) ideally, provide the woman with a supply of low molecular weight heparin and lessons in self-injection

women with SLE and/or APS. A notched uterine

artery at the second trimester was the only
predictor for adverse pregnancy outcome from
a multivariate analysis of 100 cases.
Occasionally, other treatments are used if the
above management fails, including increasing the
dosage of heparin, intravenous immunoglobulin
infusions and, in rare cases, plasma exchange.
These have been successfully used in anecdotal
cases.21,22
Management of women with aPL but no
clinical features
These women do not fulfil the criteria for the
diagnosis of APS. Management of women
who have isolated aPL, with no prior pregnancy
loss or thromboembolic phenomena, do not
generally merit antenatal pharmacological
treatment, although low dose aspirin is often
used.
The best predictor of maternal and fetal outcome in
APS pregnancies is the previous obstetric history.
Where there is a previously normal obstetric
history despite aPL, any future pregnancy is likely
to have a low risk of complications and women
should be reassured of this.
Management of women with APS as part of SLE
Women with SLE may have a flare-up of
symptoms during pregnancy and require steroids.
Hydroxychloroquine and azathioprine are regularly
used in SLE: they are safe in pregnancy and so
should be continued as necessary.
Management of women with APS and
thrombocytopenia
Many patients with APS have thrombocytopenia
(platelets 100  109/l). The pathogenic
antibodies are directed towards platelet membrane
glycoproteins and are distinct from aPL. Patients
should be managed in the same way as for immune
thrombocytopenia. Where there has been previous
20

thrombosis, the fine balance between bleeding

and thrombotic risk must be carefully managed
and a platelet count 50  109/l should be
maintained to allow safe pharmacological
thromboprophylaxis.

Prepregnancy planning
This should be offered to all women with APS,
taking all risk factors into consideration. It may be
necessary to recommend deferring pregnancy in
order to improve general health and reduce risk,
such as the need for weight loss, following an acute
thrombotic event or treatment of active SLE. There
may be circumstances where pregnancy should be
actively discouraged; for example, if pulmonary
hypertension is present the risk of maternal death is
estimated at 35%.
A clear plan for pregnancy management should be
developed as outlined in Box 3.

Conclusion
Although problems remain with laboratory
testing, the heterogeneity of this syndrome and
the lack of consensus regarding standard
treatment, the current management of APS in
pregnancy has significantly improved outcome
for many women.
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