Antiphospholipid syndrome in pregnancy

Howard J. A. Carp
Purpose of review
Antiphospholipid syndrome is widely recognized as a risk factor
for numerous obstetric complications including miscarriage,
intrauterine growth restriction, preeclampsia, fetal death and
preterm labour. The many recent changes in concept regarding
this syndrome, the role of the relevant antibodies, mechanism of
action, diagnosis and treatment are assessed in this review.
Recent findings
In recent years, our understanding of antiphospholipid
syndrome has grown. The antigen has become better defined
and is now thought to be b2 glycoprotein 1. The classical
antibodies, lupus anticoagulant and anticardiolipin antibody are
known to be pathogenic even when passively transferred to
animal hosts. It seems, however, that the pathogenic antibodies
are those directed towards b2 glycoprotein 1, and that those
which are directed to phospholipids without binding to b2
glycoprotein 1 may not be pathogenic, but merely
epiphenomena. The treatment of this condition has also been
changed due to the influence of randomized trials in which
heparin or low molecular weight heparin has replaced the use of
steroids.
Summary
There are numerous pitfalls in managing this condition. As b2
glycoprotein 1 antibodies are not usually tested, the condition
may be over diagnosed or misdiagnosed. Similarly, the results
of treatment are not usually corrected for confounding factors
such as fetal chromosomal aberrations. In the absence of other
confounding factors low molecular weight heparins are
probably the treatment of choice.
Keywords
antiphospholipid syndrome, antiphospholipid antibodies, b2
glycoprotein 1 antibodies, recurrent pregnancy loss, recurrent
miscarriage, heparin, low molecular weight heparins, aspirin,
intravenous immunoglobulin
Curr Opin Obstet Gynecol 16:129135.

2004 Lippincott Williams & Wilkins.

Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer,

University of Tel Aviv, Israel
Correspondence to Prof. H.J.A. Carp MB BS FRCOG, Department of Obstetrics and
Gynecology, Sheba Medical Center, Tel Hashomer 52621, Israel
Tel: +972 9 9557075; fax: +972 9 9574779; e-mail: carp@netvision.net.il
Current Opinion in Obstetrics and Gynecology 2004, 16:129135
Abbreviations
aPL
APS
b2GP1
ELISA
IVIG

antiphospholipid antibody
antiphospholipid syndrome
b2-glycoprotein 1
enzyme-linked immunosorbent assay
intravenous immunoglobulin

2004 Lippincott Williams & Wilkins

1040-872X

DOI: 10.1097/01.gco.0000124163.64477.a3

Introduction
The most acceptable diagnostic criteria for the antiphospholipid syndrome (APS) are the Sapporo criteria
[1]. These criteria dene the clinical features of
pregnancy loss as either one unexplained fetal death of
a morphologically normal fetus over 10 weeks of
pregnancy, or three or more otherwise unexplained
consecutive abortions prior to 10 weeks. The laboratory
features have been modied and now require a positive
test for lupus anticoagulant, or a medium or high-titre
anticardiolipin IgG or IgM test on at least two occasions,
at least 6 weeks apart, before a positive diagnosis can be
made.
Most of the clinical features are related to thrombosis,
both venous and arterial. The presenting symptom
leading to gynaecological consultation is usually fetal
loss, typically fetal death in the second or third trimesters
[2,3], often after growth retardation. Antiphospholipid
antibodies (aPLs), however, have been implicated in
other forms of pregnancy loss including rst-trimester
miscarriage [4]. Hence the current trend is for gynaecologists to seek these antibodies in any case of unexplained pregnancy loss. The syndrome can be dened as
primary when no other autoimmune disease is present
and secondary in patients with other autoimmune
diseases.
Beyond these guidelines are many controversies as the
syndrome is still not fully dened. This review will
discuss some of the pitfalls which may be encountered in
interpreting this syndrome as well as the clinical features
of the condition.

Laboratory diagnosis
As well as the two main antibody assays, lupus
anticoagulant and anticardiolipin, other aPLs have been
reported to be associated with APS, but their association
remains to be conrmed. Phosphatidylinositol, phosphatidylserine and phosphatidylethanolamine are three
such examples. Recently, b2 glycoprotein 1 (b2GP1)
has been recognized as the cofactor required for lupus
anti-coagulant and anticardiolipin to act. Although antib2GP1 antibodies have high specicity for APS (98%),
their assessment cannot be relied upon in normal clinical
practice as the sensitivity of testing is low (4050%)
[5,6 . .].
There is frequent concordance between lupus anticoagulant and anticardiolipin [7] and anti-b2GP1
antibodies [8]. These antibodies, however, are not
129

130 Maternalfetal medicine

identical. Lupus anticoagulant may react with phospholipids other than cardiolipin or proteins other than
b2GP1, whereas some anticardiolipin and b2GP1 antibodies have no lupus anticoagulant activity.
Lupus anticoagulant was rst described by Colney and
Hartman in 1952 in certain patients with systemic
lupus erythematosus. Lupus anticoagulant seems to be
the most specic test for APS [9]. Its diagnosis in vitro
depends on prolongation of the phospholipid-dependent coagulation tests such as prothrombin time,
recalcication time and the kaolin clotting time. The
activated partial thromboplastin test is the most widely
used diagnostic test, as it is the most readily available.
The dilute Russells viper Venom test seems to be
more sensitive than the previously used kaolin clotting
time [10], and has tended to replace it. It is interesting
that lupus anticoagulant can have seemingly opposing
actions in vitro and in vivo. Prolongation of the
coagulation tests is due to the inhibitory action of
the antibody on the phospholipid reagent, which is
added to tested blood in the laboratory (e.g. thromboplastin in the activated partial thromboplastin test).
Those reagents in vitro take the place of the
thrombocyte membrane and tissue thromboplastin that
accumulate at injured tissues sites in vivo. Thromboplastin is a clotting factor and induces thrombocyte
aggregation.
It was Harris et al. [11] who rst suggested that the
antibody could be examined directly and not indirectly
by its effect on clotting. He introduced a test using the
enzyme-linked immunosorbent assay (ELISA), using
chemically pure cardiolipin as the antigen. This
antibody is therefore known as anticardiolipin antibody.
The test is relatively easy to perform and most
laboratories are able to obtain the standard sera. The
ELISA assay, however, has a number of drawbacks.
The test is not specic when results are low positive.
In general, the higher the anticardiolipin level, the
greater the likelihood of APS [12]. There have been
numerous efforts at standardization, including the
introduction of standard calibrators derived from
monoclonal anticardiolipin antibodies. Anticardiolipin
ELISA is the most frequently performed test in
patients with suspected APS in Europe [13]. In a
survey of 24 centres, however, Tincani et al. [13] found
that when 10 serum samples were evaluated independently by the 24 centres in their study, there was
difculty in getting comparable results. Hence, skill
and experience are necessary in interpreting the
results, and additional features are necessary, such as
repeat positive values 6 weeks apart, a high level of
antibody (above 40 GPL units), concurrent thromboses
and additional antibodies such as lupus anticoagulant
before the diagnosis of APS is made.

Mechanisms of action
Antiphospholipid antibodies have been shown to cause
pregnancy loss directly. Injection of serum from mice
with a high titre of aPL to naive mice induces resorbtion
of pregnancies in the recipient [14], and active immunization with human pathogenic monoclonal anticardiolipin antibody induced the clinical manifestations
of antiphospholipid syndrome in BALB/c mice [15]. It
has been shown that the serum from women with APS is
highly teratogenic to rat embryos in culture and also
affects embryonic growth [16]. Moreover, purication of
the IgG faction of the sera of women with APS directly
affected the embryo and yolk sac, reducing their growth
[17 .].
It has long been known that aPLs require a cofactor
(apolipoprotein H or b2GP1). Today this cofactor is
thought to be the antigen to which aPLs bind. Binding
of aPLs to the b2GP1 forms divalent IgGb2GP1
complexes that have increased afnity for membrane
phospholipid [6 . .]. The physiological function of b2GP1
has not been elucidated, and b2GP1 deciency does not
appear to be associated with disease. Homozygous
b2GP1 null mice also appear anatomically and histologically normal [18]. The binding of aPLb2GP1 to cell
membranes including trophoblast results in injury or
activation. Activation may be cytokine mediated, as IL3, a cytokine which is involved in implantation, has been
reported to be decreased in APS [19]. Administration of
IL-3 prevented fetal loss in experimental APS [20], and
the balance of Th-1/Th-2 cytokines may be altered in
APS [21]. Additionally, tumour necrosis factor-a levels
were found to be signicantly higher in patients with
APS than healthy controls [22].
aPLs are thought to have their actions by one or more of
three main mechanisms: thrombosis, interference with
the prostacycline thromboxane balance, and affecting the
adhesion molecules between trophoblastic elements.
Cellular activation increases the expression of cell
adhesion molecules [23,24], which may promote leukocyte adhesion to the endothelial surface. aPLs have
thrombogenic effects that are mediated by intercellular
cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin [25]. aPLs may disrupt the
annexin-V shield around cells and trophoblasts. Annexin-V is a phospholipid-binding protein with potent
anticoagulant properties [26]. IgG fractions from APS
patients reduce annexin-V on cultured human trophoblasts and endothelial cells [6 . .]. aPL-mediated reduction of annexin-V requires b2GP1 [27]. aPLs with
reactivity against annexin-V induce apoptosis in endothelial cells [28]. Some of these apoptotic (microparticles) have been shown to be stimulated by lupus
anticoagulant [29].

Antiphospholipid syndrome in pregnancy Carp 131

aPLs may also interfere with the protein C antithrombotic pathway. aPLs decrease protein C activation by
thrombomodulin, inhibit activated protein C activity,
and bind to factors Va and VIIIa preventing their lysis by
activated protein C [30].
aPLs have been reported to inhibit arachidonic acid
release [31]. Arachidonic acid release is an essential
prerequisite for prostacycline production. Prostacycline is
a potent physiologic inhibitor of thrombocyte aggregation, and a potent vasodilatator. aPLs have been shown
to increase the concentration of thromboxane, thus
altering the thromboxane/prostacycline balance [32].
Additionally, in a mouse model of experimental APS,
Shoenfeld and Blank [33] infused anticardiolipin to
pregnant mice in order to induce APS. Mice that were
cotreated with a thromboxane receptor antagonist had a
signicant reduction in fetal resorption rate from 45 to
19.8% and an increase in mean placental and embryo
weights. There was also an increased platelet count
(from 597 100 to 1 075 000 platelets/mm3) in treated
mice, indicating the effect of thrombocyte aggregation in
APS.
aPLs, however, may also affect the adhesion molecules
between the elements of syncytiotrophoblast. Cytotrophoblast cells express phospholipids on their surface,
and aPLs may damage the trophoblast unrelated to
thrombosis. This concept is supported by histological
evidence from patients with aPLs and fetal death.
Women with aPLs have decreased vasculosyncitial
membranes, increased synctial knots, substantially more
brosis, hypovascular villi and infarcts than women
without APS [34]. The changes in syncitial membranes
may be secondary to thrombosis, but thrombosis could
also be secondary to placental damage which allows free
transplacental passage of maternal aPLs.
Infection may be one of the mechanisms giving rise to
APS. In certain mouse models, immunization with
Haemophilus inuenzae, Neisseria gonorrhoeae, or tetanus
toxoid resulted in the development of antibodies against
b2GP1 [35 . .]. Infusion of these antibodies into pregnant
mice resulted in APS, including thrombocytopenia,
prolonged activated partial thromboplastin time, and
increased fetal loss. In humans, infection with varicella
has been associated with APS [36]. Although HIV,
hepatitis A, hepatitis B, and hepatitis C are also
associated with an increased prevalence of anticardiolipin antibodies, most of these are not b2GP1 dependent
[37]. The difference between APS and the mere
presence of aPLs may be due to diseases such as
syphilis and Lyme disease, raising antibodies which
recognize phospholipids directly, whereas in APS the
infections raise antibodies which recognize epitopes on
phospholipid-binding proteins such as b2GP1.

Prevalence
The prevalence of APS varies according to the population assessed, and how strict are the criteria used to
assess the antibodies. aPLs have been found in women
with normal pregnancies, but the prevalence is low.
Lupus anticoagulant has been found in 0.2% of women
with normal pregnancies, and anticardiolipin antibodies
in 2% of women [3,38,39]. The author has found a 5%
prevalence of lupus anticoagulant in a group of 360
patients with recurrent miscarriage [40]. In a slightly
larger series of 500 women with recurrent miscarriage,
however, Rai et al. [41] reported a 15% prevalence of
aPLs with b2GP1. Vinatier et al. [42] have reviewed 16
publications on the prevalence of aPLs in recurrent
miscarriage. The prevalence of anticardiolipin antibodies
varied between 4.6 and 50.7% with a mean of 15.5%.
The prevalence of lupus anticoagulant varied between 0
and 14% with a mean incidence of 8.3%. In women with
mid-trimester losses, however, the prevalence has been
reported to be as high as 30% [43].

Clinical features
The features of APS are numerous and range from the
most mild to the most severe. The clinical features can
affect pregnancy only or there may be other associated
autoimmune phenomena. Most of the systemic features
of the syndrome can be explained by vasculopathy and
occlusion of small vessels due to platelet aggregation and
subsequent thrombosis. There may be a history of deep
venous thromboses, arterial thrombosis, pulmonary
embolus, transient ischaemic attacks, stroke, renal
infarcts, and so on. These may lead to subsequent
hypertension, proteinuria and renal failure, amongst
other conditions. Dementia can occur after multiple
cerebral infarcts. There may also be associated Reynauds phenomenon, livido reticularis, pulmonary hypertension, amaurosis fugax, transient ischemic attacks,
hemiplegia, hemiesthesia and Singer neurosis.
Systemic lupus erythematosus is not a prerequisite for
APS, but is often present. Rarely a catastrophic
syndrome may occur with abrupt widespread vascular
occlusion [44].
In pregnancy, aPLs have been implicated to be the
cause of pregnancy loss at all stages of pregnancy,
placental dysfunction in the third trimester, intrauterine
growth restriction and preeclampsia. Each of these may
or may not be associated with thrombocytopenia. The
placenta is small, and usually has a vasculopathy.
APS has also been reported to cause preclinical
pregnancy loss, presenting as infertility. Although Lyden
et al.s [45] classical work on the effects of aPLs on the
development of trophoblasts supports the concept of
an association between aPLs and infertility, most

132 Maternalfetal medicine

authorities have failed to nd an association with

infertility [46].
Most pregnancy losses in APS are in the later stages of
pregnancy. Rai et al. [47] found that fetal heart activity
was present in 86% of recurrently miscarrying women
with APS, but in only 43% of recurrently miscarrying
women without APS; in the others no fetal heart activity
was detected. The author [48] has only found fetal heart
activity in 11% of unexplained recurrent pregnancy loss.
Hence the syndrome seems to be associated with missed
abortions in which a fetal heart was previously detected.
Lockshin [3] has reported that typically pregnancies start
normally, and a fetal heart is detected early in the rst
trimester. Intrauterine growth restriction or second or
third trimester fetal death ensues. The author [49] has
found an increased prevalence of second trimester
miscarriages in APS compared with women with
unexplained recurrent pregnancy losses. Oshiro et al.
[50] have also reported that women with APS tend to
lose their pregnancies a mean of 4 weeks later than
controls. More recently, a study of 366 women with two
or more pregnancy losses [51] showed that in women
with anticardiolipin at medium to high titres and lupus
anticoagulant, 50% of losses were fetal deaths, in contrast
to 10% in women who were anticardiolipin-negative.
Tests of fetal well-being may show signs of fetal
compromise.
There is disagreement as to the incidence of pregnancy
loss in the presence of aPLs. In patients with APS, Rai
et al. [47] have reported the incidence of pregnancy loss
to be as high as 90%. However, Rai et al.s [47] series
was a small series with only 20 patients. There are now
three papers which have compared the use of aspirin
with placebo [5254]. The three papers have been
combined in a metaanalysis [55 . .]. Fifty-two of 61
pregnancies developed normally in the placebo group.
It must be borne in mind, however, that the four trials
may have used different criteria for the laboratory
diagnosis of aPLs. No trial used the strict Sapporo
criteria. None of the above trials assessed b2GP1.
Hence it is difcult to draw any conclusions about the
incidence of pregnancy loss in the presence of aPLs or
APS without treatment.

Treatment
Various regimens of treatment have been used, either
alone or in combinations, for example, aspirin, steroids,
anticoagulants such as unfractionated heparin, and, more
recently, low molecular weight heparins and immunoglobulin. In early trials, treatment was administered for
the presence of anticardiolipin and lupus anticoagulant
alone. Even if the strict Sapporo criteria are used, no
trial of treatment has assessed anti-b2GP1 antibodies.
Additionally, no trial has corrected for fetal causes of

pregnancy loss which may confound the results. The

fetal causes may include structural malformations which
are incompatible with life, and chromosomal aberrations.
In missed abortion, Philipp and Kalousek [56] have
performed 19 embryoscopies on missed abortions. Ten
were morphologically abnormal; only some of these
morphological abnormalities could be explained by
chromosomal aberrations. In sporadic miscarriage, 50
60% of embryos lost will be lost due to karyotypic
aberrations in the embryo. In recurrent miscarriage,
between 29 and 57% of abortuses will be lost due to
chromosomal rearrangements [5759]. In recurrent miscarriage with APS, 2040% of abortuses are also
chromosomally abnormal [5860]. The results of treatment should be interpreted against this background of
uncertainty.
Steroids are used infrequently today due to uncertainty
as to efcacy and the side effects (Cushings syndrome,
acne, osteoporosis, etc.). There have been two randomized controlled trials assessing the effects of steroid
therapy for APS in pregnancy. Cowchock et al. [61]
compared prednisone and aspirin with heparin and
aspirin in a randomized trial of 20 women. The live
birth rate was identical (75%) in both groups. Silver et al.
[62] compared the effect of aspirin with that of aspirin
with the addition of prednisone. The live birth rate was
100% in both groups. In both studies prednisone was
associated with a higher incidence of premature and
growth retarded infants. Neither of these trials corrected
for b2GP1 antibodies, however, nor confounding factors
such as chromosomal aberrations in the aborted fetuses.
There is still a place for steroids in the presence of
vasculitis.
The most commonly used form of treatment today is
heparin together with low-dose aspirin [63 . .]. Three
trials have compared aspirin alone with aspirin with the
addition of heparin. Both Kutteh et al. [64] and Rai et al.
[65] reported that the live birth rate increased by 36 and
29%, respectively, when heparin was added to the
regimen (Fig. 1). Farquharson et al. [66], in contrast to
previous studies, found the live birth rate to be similar in
both groups (72% with aspirin alone compared with 78%
when heparin was added to the regimen). When the
three trials are combined in a metaanalysis (Fig. 1) there
was a common odds ratio of 2.63 in favour of heparin
(95% CI 1.464.75). As with steroids and also aspirin, the
explanation for the discordant results between Farquarson et al.s trial and the other trials may be due to failure
to correct for b2GP1 antibodies and the loss of
chromosomally abnormal embryos in the subsequent
pregnancy. Additionally, Kutteh et al. [64] used unfractionated heparin, whereas Rai et al. [65] used the low
molecular weight heparin enoxaparin, and Farquharson
et al. [66] used the low molecular weight heparin

Antiphospholipid syndrome in pregnancy Carp 133

Figure 1. Metaanalysis on the beneficial effects on pregnancy of low molecular weight heparin

Kutteh et al. [64]

Rai et al. [65]

Farquharson et al . [66]

Overall RR

0.1

daltaparin. The different types of heparin used may also

explain the discordant results.
Low molecular weight heparins have a number of
advantages over unfractionated heparin: they are more
bioavailable and have a longer half life. Hence only one
injection is required per day, as opposed to two to three
injections of unfractionated heparin for the same effect.
Heparin-induced thrombocytopenia also seems to be less
frequent. The main advantage, however, is that there is
no overlap between the anticoagulant effect and the
antithrombotic effect. There is no bleeding with low
molecular weight heparins; even Caesarean sections can
be safely performed, and there is little need for
monitoring. However, heparin, while increasing the live
birth rate, seems to have little effect on the obstetric
complications such as preeclampsia, intrauterine growth
restriction and preterm labour.
There have recently been three descriptive studies
and two comparative trials of intravenous immunoglobulin (IVIG) in APS. The three descriptive studies
[6769], which used IVIG in addition to other forms
of treatment, reported a subsequent 8090% live birth
rate. The two comparative trials, however, do not
show IVIG to be benecial in terms of live births
compared with prednisone and aspirin [70] or heparin
and aspirin [71]. Although IVIG offers little advantage
in terms of live births, a different picture emerges
when the late complications are considered. Harris
and Pierangeli [72] reviewed the literature and
reported that preeclampsia, intrauterine growth restriction, and premature births were reduced after IVIG
compared with prednisone and aspirin, or heparin and

10

aspirin. Valensie et al. [73] reported on 14 patients

who received IVIG for APS. Only one had preeclampsia with placental abruption; all the other 13
had no maternal or fetal complications. The best
evidence that IVIG lessens the prevalence of late
complications comes from the two comparative trials
mentioned above. In Vaquero et al.s [70] trial the
prevalence of pregnancy-induced hypertension and
gestational diabetes was signicantly lower (P 50.05)
in patients who received IVIG than those receiving
prednisone and aspirin (5% of 41 patients as opposed
to 14% of 22 patients) for each condition. Branch et
al. [71] reported that there were fewer cases of fetal
growth restriction in the IVIG group when compared
with the heparin and aspirin group (14% of seven
patients compared with 33% of nine patients, respectively). There were also fewer admissions to the
neonatal intensive care unit (14% of seven patients in
the IVIG group compared with 44% of nine in the
heparin and aspirin group). IVIG is the only
intervention to lower anticardiolipin levels rather than
to inhibit the actions of aPLs. In Spinnato et al.s [67]
series, three of the four patients with live births had a
concomitant decrease in anticardiolipin IgM levels. In
Kwak et al.s [74] series, aPL titres of both IgG and
IgM were signicantly decreased after each IVIG
infusion. Three pregnancies of six were complicated
by intrauterine growth restriction the development
of which correlated to rising antibody titres.
The prohibitive cost of IVIG probably prevents this
treatment ever becoming a rst-line treatment in APS.
However, it probably has a place as second-line
treatment in patients who are refractory to heparin or

134 Maternalfetal medicine

who continue to suffer the late obstetric complications of

APS.

Conclusion
There are numerous pitfalls in the diagnosis and
treatment of APS, some of which have been mentioned
above.
(1) Patients must be properly dened. Some reports in
the literature summarize patients with only two
pregnancy losses. In these patients there is an 80%
chance that the next pregnancy will result in a live
birth. In any trial which includes patients with two
pregnancy losses, the 80% live birth rate in the
control group will obscure any benecial effect in the
patient with a poor prognosis.
(2) Confounding factors such as fetal chromosomal
aberrations must be included in future trials if the
results of therapy are to be meaningful.
(3) The fact that there is no denite correlation between
antibody levels and fetal death is a problem. Where a
denitive test is available, it would permit withholding unnecessary treatment. It would also enable
modication of treatment as the situation demands
during pregnancy. Hopefully, the test for b2GP1 will
become more specic and may full this role.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:
.
of special interest
..
of outstanding interest

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