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Clinical manifestations and diagnosis of the antiphospholipid syndrome in
pregnancy
Charles J Lockwood, MD
Peter H Schur, MD
UpToDate performs a continuous review of over 375 journals and other resources.
Updates are added as important new information is published. The literature review
for version 15.3 is current through August 2007; this topic was last changed on July
5, 2007. The next version of UpToDate (16.1) will be released in March 2008.
INTRODUCTION — The antiphospholipid syndrome (APS) is characterized by arterial
or venous thromboembolism, or recurrent pregnancy loss, in association with
antibodies to certain plasma proteins that are often bound to anionic phospholipids.
This disorder is referred to as primary APS when these antibodies occur alone; it is
called secondary APS when they are found in association with systemic lupus
erythematosus (SLE), other rheumatic diseases, and with certain infections and
drugs.
The complications and diagnosis of the antiphospholipid syndrome in the
reproductive setting are discussed in this review. The treatment and monitoring of
pregnancies complicated by antiphospholipid antibodies and the clinical
manifestations and treatment in the nonpregnant population are presented
separately. (See "Management of pregnant women with antiphospholipid antibodies or the
antiphospholipid syndrome" and see "Clinical manifestations of the antiphospholipid
syndrome" and see "Treatment of the antiphospholipid syndrome").
ANTIPHOSPHOLIPID ANTIBODIES — Phospholipids are the basic constituents of cell
membranes. Exteriorization of anionic phospholipids to the endothelial cell
membrane's outer leaflet follows cell injury due to many different insults, including
ischemia, trauma, toxins, initiation of programmed cell death (apoptosis),
inflammation, infections, and drug interactions. These events may enhance the
development of antiphospholipid antibodies in some patients.
Three tests for detection of antiphospholipid antibodies (APA) have been described
(see "Clinical manifestations of the antiphospholipid syndrome", section on Assays for
antiphospholipid antibodies):

Lupus anticoagulant (LA) activity

Anticardiolipin antibodies

Anti-ß2-glycoprotein I antibodies
Before diagnosis of APS, one should demonstrate that the test(s) are positive on two
occasions at least 12 weeks apart (see "Diagnosis of antiphospholipid syndrome" below).
Lupus anticoagulants — Lupus anticoagulants (LA) are antibodies directed against
plasma proteins (such as ß2-glycoprotein I, prothrombin or annexin V) bound to
anionic phospholipids. The LA blocks in vitro assembly of the prothrombinase
complex, resulting in a prolongation of in vitro clotting assays such as the activated
partial thromboplastin time (aPTT), the dilute Russell viper venom time (dRVVT), the
kaolin plasma clotting time, and rarely the prothrombin time. (See "Clinical use of
coagulation tests"). These abnormalities are not reversed when the patient's plasma is
diluted 1:1 with normal platelet-free plasma, a procedure that will correct clotting
disorders due to deficient clotting factors. The abnormal clotting test results can be
largely reversed by incubation with a hexagonal phase phospholipid which
neutralizes the inhibitor. Although these changes suggest impaired coagulation,
patients with a LA have a paradoxical increase in frequency of arterial and venous
thrombotic events. (See "Pathogenesis of the antiphospholipid syndrome").
Anticardiolipin antibodies — Anticardiolipin antibodies (aCL) react with proteins (eg,
ß2-glycoprotein I, prothrombin, or annexin V) bound to anionic phospholipids, such
as cardiolipin and phosphatidylserine. Different immunoglobulin isotypes and
subclasses are associated with aCL, including IgA, IgM, and IgG subclasses 1 to 4.
Elevated levels of IgG aCL (particularly IgG2) incur a greater risk of thrombosis than
do other immunoglobulin isotypes [1]. Low levels of IgG and isolated elevations of
IgM or IgA antiphospholipid antibodies are of uncertain significance [ 2]. About onethird of aCL prolong phospholipid dependent clotting assays (ie, have LA properties)
either because they bind directly to prothrombin or because ß2-glycoprotein-I can
bind to prothrombin and the presence of certain aCL can impede thrombin activation.
Anti-ß2-glycoprotein I antibodies — Antibodies to ß2-glycoprotein I (ß2GPl), a
phospholipid-binding inhibitor of coagulation, are found in a large percentage of
patients with primary or secondary antiphospholipid syndrome (APS) [3]. Anti-ß2GPl
antibodies directly bind to ß2GPl as opposed to aCL, which frequently bind to a
complex of anionic phospholipids and ß2GPl.
Other — A history of a false positive serologic test for syphilis (STS) can be marker
for presence of anticardiolipin antibodies. This crossreaction was common when
syphilis serology was performed by the older VDRL and RPR tests, but does not occur
with the more modern specific anti-treponemal assays, which are currently the most
common method of testing for syphilis.
(See "Pathogenesis of the antiphospholipid syndrome" for a detailed discussion of these
antibodies and the pathogenesis of this syndrome in the nonpregnant population).
PATHOGENESIS OF OBSTETRICAL CONSEQUENCES — Thrombus formation,
infarction, and vasculopathy are assumed to account for many of the clinical
manifestations of the APS [4-6]. Experimental models suggest that additional factors
may also be responsible for adverse pregnancy outcomes [7-9], with aCL directly
causing fetal loss and growth restriction. Thus, the association of APS and pregnancy
complications may not be just an epiphenomenon occurring after antecedent
endothelial injury [10-12].
Effects on trophoblast — Normal implantation and fetal development require
trophoblastic invasion of the uterus and blood vessels. Antiphospholipid antibodies
appear to interfere with this process; a variety of mechanisms have been proposed:

Diminished levels of annexin V in trophoblasts may be a significant factor in
defective placentation and pregnancy loss [13-17]. Annexin V binds to exteriorized
anionic phospholipids to render them nonthrombogenic [ 18,19]. Antiphospholipid
antibodies can reduce the levels of trophoblast-associated annexin V, thereby
promoting placental villus thrombosis [14].

Inhibition of endothelial anticoagulant activity including interference with
thrombomodulin, protein C and S and/or antithrombin III activity [20-23]

Crossreaction with platelet phospholipids, thereby producing damage that
increases platelet adhesiveness and initiates thrombosis [ 24-27]

Increased production of procoagulant by monocytes [28]

Inhibition of human chorionic gonadotropin (hCG) secretion [29,30]

Impairment of fibrinolysis [31,32]

Increased endothelial synthesis of von Willebrand factor multimers [33,34]

Inhibition of ß2GPI anticoagulant functions [35-38]

Complement activation and resulting placental injury [ 9,39]

Interference with kininogen by antibodies that cross react with
phosphatidylethanolamine [40]

Increased placental apoptosis and decreased proliferation resulting in
impaired trophoblast invasion [41]

Antibody binding to trophoblast that is mediated by ß2GPI [ 30]
Type of antiphospholipid antibody — Isolated antibodies directed against ß2GPl are
not strongly associated with fetal loss in some studies. By comparison, many studies
suggest that anticardiolipin antibodies enhance the risk of loss. The following are
some illustrative examples:

In one study of 325 patients at low-risk of fetal loss, as an example, the
presence of anticardiolipin antibodies, but not anti-ß2GPl antibodies, was strongly
associated with loss of pregnancy (odds ratio of 8.4) [ 42].

Both antibodies correlated with fetal loss in a second study of women with
spontaneous abortion and unexplained fetal death [43].

In a study of 147 women with at least three miscarriages and negative tests
for lupus anticoagulants (LAC), none of whom were treated with anticoagulation or
aspirin, the presence of repeatedly positive anticardiolipin (aCL) antibodies reduced
the chance of a live birth [44]. Depending on the cut-off value the likelihood of a live
birth was decreased by 36 to 48 percent compared to women with neither LAC nor
aCL antibodies.
PREVALENCE OF ANTIPHOSPHOLIPID ANTIBODIES — Although antiphospholipid
antibodies are associated with both a propensity for thrombosis and various
autoimmune disorders, they can also be found in normal asymptomatic individuals
[45,46]. In one study, 40 of 499 normal blood donors had a positive lupus
anticoagulant test, and 3 had elevated levels of aCL [47]. Antiphospholipid antibodies
are more common among young women than men. (See "Clinical manifestations of the
antiphospholipid syndrome" and see "Pathogenesis of the antiphospholipid syndrome",
section on Prevalence of antiphospholipid antibodies).
Prevalence in pregnant women — The prevalence of aCL in women with
uncomplicated pregnancies ranges from 0 to 11 percent, with a median value of
about 2 percent [48-56]. In a literature review of approximately 14,000 women, the
prevalence of antiphospholipid antibodies was 5 percent of normal obstetric patients,
24 percent of women undergoing in vitro fertilization, and 37 percent of women with
SLE [48].
OBSTETRICAL OUTCOMES — Several adverse pregnancy outcomes have been
attributed to the presence of antiphospholipid antibodies.
Definitions — In general, adverse pregnancy outcomes are defined in the following
way:

Abortion is the delivery of a pregnancy, either spontaneously (also called
miscarriage) or electively, before 20 weeks of gestation. A first trimester abortion
occurs before 13 weeks of gestation, a second trimester abortion occurs between 14
to 20 weeks.

Recurrent pregnancy loss (also known as recurrent abortion) refers to two or
more consecutive spontaneous abortions.

Preembryonic loss occurs from conception through the end of the fourth week
of gestation.

Embryonic loss occurs from the fifth through the ninth week of pregnancy.

Preterm delivery constitutes a livebirth or stillbirth after 20 and before 37
weeks of gestation. After this period, the birth is considered a term delivery.

A fetal demise refers to an intrauterine death at anytime after 10 weeks of
pregnancy. Stillbirth refers to demise after 20 weeks gestation.
Fetal loss is an imprecise term that may be used to refer to an abortion or fetal
death at a gestational age defined by the author (eg, after 10 weeks of gestation, in
the second or third trimester). Pregnancy loss can mean an abortion, fetal death at
any gestational week, or delivery of an infant of any gestational age that does not
survive. The broad usage of these terms for case selection in studies of adverse
pregnancy outcome has contributed to variable, and sometimes conflicting, results.
Adverse outcomes — Adverse pregnancy outcomes attributed to the presence of
antiphospholipid antibodies include the following [57]:

Unexplained fetal death after 10 weeks gestation

Early, severe preeclampsia or eclampsia

Fetal growth restriction

Pregnancy-related maternal thromboembolic disease (venous and/or arterial)

In some reports, an increased incidence of in vitro fertilization failures have
been associated with the presence of antiphospholipid antibodies [48,58]. However, a
meta-analysis of seven studies failed to confirm this association [59].

Three or more unexplained consecutive spontaneous abortions before the
10th week of gestation (ie, recurrent pregnancy loss). This a very controversial area;
many investigators believe these antibodies are not a cause of embryonic loss before
10 weeks [51,60,61].
There is no association between APA and infertility [62-64].
Difficulties with causality — Since antiphospholipid antibodies can be found in
normal asymptomatic individuals, it is sometimes unclear whether there is a causal
relationship between these antibodies and a clinical event in any one individual,
particularly among those with a relatively common adverse obstetrical outcome (eg,
spontaneous abortion before 10 weeks). Additional explanations for the poor
predictive value of a given positive LA or APA result include the following:

Reliance upon non-standardized assays for antiphospholipid antibodies and
failure to use internationally recognized standards

Failure to control for the severity of co-existing diseases (eg, SLE, diabetes,
renal disease, hypertension, and infections) known to cause adverse obstetrical
outcomes

Failure to recognize co-existing inherited coagulopathies (See "Inherited
thrombophilias in pregnancy")

Inclusion of patients with low positive antiphospholipid antibody levels among
patients considered positive

Broad definitions for case selection in series involving pregnancy wastage
(preembryonic versus later loss)

The variable thrombogenic potential of a given patient's antiphospholipid
antibodies

Population heterogeneity in concentrations of clotting, anti-clotting and
fibrinolytic proteins
Despite these difficulties, significant and reproducible LA activity and/or high
concentrations of aCL are frequently, but not invariably, associated with
thromboembolism, recurrent fetal demise, intrauterine growth restriction, and severe
preeclampsia. It remains uncertain as to whether these antibodies promote recurrent
early first trimester loss.
Recurrent abortion and fetal loss — The presence of antiphospholipid antibodies has
been linked to recurrent fetal loss (10 or more weeks gestation) and some studies
suggest that there is also an association with preembryonic (less than 6 weeks
gestation) and embryonic (6 through 9 weeks gestation) loss [ 61,65]. Other studies
fail to establish a link between antiphospholipid antibodies and embryonic loss [66].
There is evidence that late first trimester losses (ie, those with initially demonstrable
fetal cardiac activity) are more likely to be associated with such antibodies [ 67].
However, there are many other disorders that are associated with recurrent
pregnancy loss. (See "Definition and etiology of recurrent pregnancy loss").
We have examined this last issue in a cohort of 491 patients with a history of
adverse pregnancy outcomes [61]. These women were evaluated for activated
protein C resistance, factor V Leiden and prothrombin G20210A mutations,
hyperhomocysteinemia; deficiencies of antithrombin, protein C and S; and both
anticardiolipin antibodies and lupus anticoagulants. In our high-risk cohort, the
presence of a maternal thrombophilia was found to be protective of recurrent losses
at <10 weeks (OR 0.55, 95% CI 0.33-0.92), but was associated with a modestly
increased risk of loss >10 weeks (OR 1.76, 95% CI 1.05-2.94). Women who
experienced only euploid losses were not more likely to have an identified
thrombophilia than women who experienced only aneuploid losses (OR 1.03; 95% CI
0.38-2.75).
The paradoxical observation that factor V Leiden and the other maternal
thrombophilias including antiphospholipid antibodies are protective of early loss is
not unexpected [61]. Early pregnancy is normally associated with a low oxygen
environment (oxygen pressures of 17+/- 6.9 mm Hg and 60.7 +/- 8.5 mm Hg at 8
to 10 and 13 weeks gestation), trophoblast plugging of the intervillous space, and
low Doppler flow of the uteroplacental circulation prior to 10 weeks gestation [ 68,69].
The undetectable levels of superoxide dismutase, an enzyme responsible for the
conversion of the superoxide anions, in trophoblast prior to 10 weeks suggests that
oxygen may actually be harmful during the embryonic period [70].
Most, but not all, studies suggest that patients with antiphospholipid antibodies and
SLE and/or history of fetal loss, as well as those with specific types of
antiphospholipid antibodies, may be at an increased risk for adverse obstetrical
outcomes.
Women with SLE — Patients with SLE and antiphospholipid antibodies appear to be
at an increased risk for spontaneous abortion, with some correlation between the
level of IgG aCL and the risk of pregnancy loss [71]. As examples:

A review of 10 studies involving 554 women with SLE found fetal loss was
more common in those with than in those without: antiphospholipid antibodies (38 to
59 versus 16 to 20 percent), lupus anticoagulant (36 versus 13 percent), or
anticardiolipin antibodies (39 versus 18 percent) [24].

In a multicenter study of 368 patients with SLE, spontaneous abortion
(among other outcomes) was significantly associated with elevated levels of IgG
anticardiolipin antibodies (P<0.001) [ 72].
However, not all studies have found this association. Another report of patients with
SLE and antiphospholipid antibodies noted that the presence of aCL was associated
with thrombocytopenia, a prolonged activated PTT, and a positive direct Coombs, but
not spontaneous abortions or recurrent fetal loss [73].
Nevertheless, it may be possible to decrease the risk of fetal loss in these patients.
Thus, all pregnant women with SLE should be tested for the presence of
antiphospholipid antibodies (see below).
Women without SLE — As with SLE, there are conflicting data concerning the
relationship between a history of fetal loss and antiphospholipid antibodies in the
absence of lupus. However, a literature review that included studies involving more
than 13,000 patients found that antiphospholipid antibodies were more common
among those with recurrent fetal loss than in healthy women (20 versus 5 percent,
respectively) [60]. A 2006 meta-analysis that included 2000 patients also supported
an association between first and second trimester pregnancy loss which was stronger
for LA (odds ratio [OR] 13) than for Ig-G aCL (OR 3.6) or Ig-M aCL (OR 5.6) [ 74].
In addition, a small series in patients with poor obstetrical histories observed that
women with either LA or a moderate titer of IgG aCL had a risk of miscarriage in the
first pregnancy of approximately 30 percent [75]. This risk increased to 70 percent if
the patient had two previous miscarriages.
In general, ascertainment biases may overestimate the risk of pregnancy loss in
patients with antiphospholipid antibodies and known medical or obstetrical
complications.
Fetal growth restriction — The link between fetal growth restriction (IUGR) and
antiphospholipid antibodies is controversial [49,76,77]. In a prospective study of 860
unselected Japanese women evaluated for aCL in the first trimester, the rate of fetal
growth restriction was higher among the 60 aCL positive compared to 800 aCL
negative women (12 versus 2 percent) [78]. Among patients with symptomatic
antiphospholipid syndrome, the frequency of IUGR approaches 30 percent [79,80]. In
contrast, other studies have not found a higher prevalence of aCL among women
with growth restricted versus normally grown fetuses [77,81]. Excess
neurodevelopmental abnormalities have not been observed in these children [82].
Preeclampsia — Severe, early preeclampsia and HELLP (Hemolysis, Elevated Liver
function enzymes, and Low Platelet count) syndrome have also been associated with
antiphospholipid antibodies in some, but not all, studies [75,78-81,83-86]. However, it
does not appear useful to screen women with mild or near term preeclampsia or a
history of preeclampsia for APA. One study identified 317 women with a history of
preeclampsia at any stage of pregnancy in whom 62 developed recurrent disease
[87]. Positive results from second trimester testing for antiphospholipid antibodies
were not predictive of recurrent preeclampsia. Testing women with severe
preeclampsia before 34 weeks of gestation may be justified [ 88]. (See "Clinical
features, diagnosis, and long-term prognosis of preeclampsia" and see "Prevention of
preeclampsia").
Maternal thrombosis — Pregnancy and the puerperium are associated with an
increased incidence of thromboembolic disease, including stroke. (See "Deep vein
thrombosis and pulmonary embolism in pregnancy"). The risk of thromboembolism among
antiphospholipid antibody positive patients is highly variable and is exacerbated by
co-existent hereditary coagulopathies (eg, factor V Leiden) [ 79,89]:

In one historic cohort study, 24 percent of thrombotic events in women with
antiphospholipid antibodies occurred in association with pregnancy [90].

In another prospective study, the risk of thrombosis during pregnancy was 5
percent among women with known antiphospholipid syndrome [ 80].

Among patients with recurrent pregnancy loss, the risk of thrombosis appears
to be 15.7 per 100 patient years [90].
(See "Evaluation of the patient with established venous thrombosis", and see "Inherited
thrombophilias in pregnancy").
Risk in unselected populations — Whether asymptomatic women with
antiphospholipid antibodies and no prior adverse pregnancy outcome (no thrombotic
event or pregnancy complication) have an increased risk of complications with
pregnancy is also unclear. There are studies showing no or little association:

Among 1449 healthy pregnant women, positive anticardiolipin tests occurred
infrequently and were rarely associated with adverse pregnancy outcome [ 50].

An elegant study comparing women with spontaneous abortion or fetal death
with pregnant controls also found no association between antiphospholipid antibodies
and an adverse pregnancy outcome [51]. Among 331 women with spontaneous
abortion or fetal death and 993 control women, no increased risk of miscarriage was
observed in first pregnancies in women with antiphospholipid antibodies. This study
concluded that routine screening of women with one pregnancy loss for
antiphospholipid antibodies is not indicated.
By comparison, other reports have found that patients with adverse pregnancy
results were more likely to have antiphospholipid antibodies:

In one study of 360 patients with antiphospholipid antibodies, pregnancy
complications were more common among women with a history of miscarriage or
thrombosis than in asymptomatic women (56 versus 17 percent) [91].

A prospective study of asymptomatic nulliparous women with normal
pregnancies found to have high-titer IgG aCL before 25 weeks of gestation described
a higher risk of fetal loss compared to aCL negative controls, 28 versus 7 percent
[83].
WHEN TO EVALUATE FOR ANTIPHOSPHOLIPID ANTIBODIES — Given the confusion
surrounding causality and association with adverse outcomes, the population that
should be evaluated for antiphospholipid antibodies is controversial. The American
College of Obstetricians and Gynecologists recommends testing women with
"appropriate medical or obstetrical histories" for antiphospholipid syndrome [57]. We
suggest that patients with the following pregnancy complications be tested for the
presence of LA and aCL antibodies [57]:



Unexplained stillbirth or fetal death after 10 weeks of gestation.
Premature birth due to severe intrauterine growth restriction <34 weeks of
gestation
Premature birth due to severe preeclampsia/eclampsia at <34 weeks of
gestation
As previously mentioned, it is less clear whether patients with recurrent first
trimester loss (prior to 10 weeks) should be evaluated. In one study, more than 80
percent of patients with recurrent pregnancy loss and antiphospholipid antibodies
had at least one stillbirth [92]. Moreover, the combination of antiphospholipid
antibodies and a prior stillbirth was associated with higher sensitivity and specificity
for recurrent pregnancy loss than was the combination of antiphospholipid antibodies
and recurrent first trimester loss (84 and 76 percent versus 50 and 6 percent,
respectively) [92]. Thus, some clinicians advocate that antiphospholipid antibodies
screening should be limited to those patients with recurrent pregnancy loss and an
unexplained fetal death or no more than one live birth [ 88]. Other clinicians,
however, advocate that patients with two or three [57] or more unexplained
spontaneous abortions before 10 weeks of gestation should be screened.
Reproductive age women with the following clinical features and/or disorders should
also be evaluated for antiphospholipid antibodies [88,93]:











False positive syphilis serologies
Nontraumatic thromboembolism
Stroke
Systemic lupus erythematosus
Hemolytic anemia
Transient ischemic attacks or amaurosis fugax
Livedo reticularis
Unexplained prolongations of the activated partial thromboplastin time (aPTT)
Unexplained thrombocytopenia
Positive antinuclear antibodies
Family history of the antiphospholipid syndrome
If the test is positive, it should be repeated in twelve weeks. (See "Clinical
manifestations of the antiphospholipid syndrome").
DIAGNOSIS OF ANTIPHOSPHOLIPID SYNDROME — Criteria for diagnosis of
antiphospholipid syndrome are discussed separately. (See "Clinical manifestations of the
antiphospholipid syndrome").
A synopsis of diagnosis criteria is provided below [94]:
Definite APS is considered present if at least one of the following clinical criteria and
at least one of the following laboratory criteria are satisfied.

Clinical — Either one or more episodes of venous, arterial, or small vessel
thrombosis and/or morbidity with pregnancy.
- Thrombosis — Unequivocal imaging or histologic evidence of thrombosis in any
tissue or organ
- Pregnancy morbidity — Otherwise unexplained death at 10 or more weeks of
gestation of a morphologically normal fetus, or
- One or more premature births before 34 weeks of gestation because of
eclampsia, preeclampsia, or placental insufficiency, or
- Three or more embryonic (<10 weeks of gestation) pregnancy losses
unexplained by maternal or paternal chromosomal abnormalities or maternal
anatomic or hormonal causes

Laboratory — The presence of aPL, on two or more occasions at least 12
weeks apart and no more than five years prior to clnical manifestations, as
demonstrated by one or more of the following:
- IgG and/or IgM anticardiolipin antibody (measured by a standardized enzymelinked immunosorbent assay for ß2-glycoprotein I-dependent anticardiolipin
antibodies) in moderate or high titer (>40 units GPL or MPL or >99th percentile for
the testing laboratory)
- Antibodies to ß2-glycoprotein I of IgG or IgM isotype at a titer >99th percentile
for the testing laboratory when tested according to recommended procedures
- lupus anticoagulant activity detected according to published guidelines
SUMMARY AND RECOMMENDATIONS

Thrombus formation, infarction, and vasculopathy are assumed to account for
many of the clinical manifestations of the APS, but additional factors may also be
responsible for adverse pregnancy outcomes. For example, aCL may directly cause
fetal loss and growth restriction. (See "Pathogenesis of obstetrical consequences" above).

We suggest that patients with the following pregnancy complications be
tested for the presence of LA and aCL antibodies:
- Unexplained stillbirth or fetal death after 10 weeks of gestation.
- Premature birth due to severe intrauterine growth restriction <34 weeks of
gestation
- Premature birth due to severe preeclampsia/eclampsia at <34 weeks of gestation
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