HIGH-RISK PREGNANCY SERIES: AN EXPERT’S VIEW
We have invited select authorities to present background information on challenging clinical problems and
practical information on diagnosis and treatment for use by practitioners.
Antiphospholipid Syndrome: Obstetric Diagnosis,
Management, and Controversies
D. Ware Branch, MD, and Munther A. Khamashta, MD, PhD
Antiphospholipid syndrome, a condition characterized by
one or more thrombotic or pregnancy-related clinical fea-
tures in association with medium to high levels of antiphos-
pholipid antibodies, has emerged as an important diagnos-
tic consideration in several medical fields. Antiphospholipid
syndrome is one of the few treatable causes of pregnancy
loss, and successful pregnancy rates of 70% or more can be
achieved with appropriate treatment. Heparin, usually
combined with low-dose aspirin, is used in patients at risk
for thrombosis. Pregnancy in these women is associated
with increased rates of preeclampsia, placental insuffi-
ciency, and preterm delivery, so that attentive clinical care
is required for best outcomes. Recent studies indicate that
women at low risk for thrombosis may be treated with
low-dose aspirin. However, remaining controversies and
unanswered questions in the field of antiphospholipid syn-
drome are a source of clinical confusion. This review high-
lights the most important controversies, taking into ac-
count the results of recent obstetric treatment trials and our
own clinical experience. (Obstet Gynecol 2003;101:
1333– 44. © 2003 by The American College of Obstetri-
cians and Gynecologists.)
Antiphospholipid antibodies are a family of autoantibod-
ies that bind to negatively charged phospholipids, phos-
pholipid-binding proteins, or a combination of the two.
Clinicians first recognized that antiphospholipid antibod-
ies were associated with hypercoagulability 50 years ago.
An association with pregnancy loss was established in
From the Department of Obstetrics and Gynecology, The University of Utah Health
Sciences Center, Salt Lake City, Utah; and Lupus Research Unit, Rayne Institute,
King’s College, St Thomas’ Hospital, London, United Kingdom.
DWB is supported by the H. A. and Edna Benning Presidential Endowed Chair
at the University of Utah. MAK is supported by Lupus UK and The St. Thomas’
Lupus Trust.
We thank the following individuals who, in addition to members of our Editorial
Board, will serve as referees for this series: Dwight P. Cruikshank, MD, Ronald
S. Gibbs, MD, Gary D. V. Hankins, MD, Philip B. Mead, MD, Kenneth L.
Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach, MD.
VOL. 101, NO. 6, JUNE 2003
© 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier.
the mid-1970s. The term “antiphospholipid syndrome”
was introduced in 1986 to formalize the association of
antiphospholipid antibodies with these clinical features.
Over a decade of subsequent international laboratory
and clinical experience led to the development of an
international consensus statement on preliminary crite-
ria for definite antiphospholipid syndrome, published in
1999.1 There is widespread recognition, however, that
refining the diagnostic criteria of antiphospholipid syn-
drome is an ongoing process.2 In this regard, no area has
generated more controversies than obstetric antiphos-
pholipid syndrome. Recent studies even bring the treat-
ment of some women with antiphospholipid antibodies
into question. This review involves the pathogenesis,
diagnosis, and management of the obstetric aspects of
antiphospholipid syndrome and addresses controversies
that have emerged in obstetric antiphospholipid syn-
drome.
Historically, the first antiphospholipid autoantibody
detected was the false-positive Wassermann reaction,
found especially in patients with systemic lupus erythem-
atosus. Lupus anticoagulant was first described in the
early 1950s as prolonging certain clotting assays. A few
years later, lupus anticoagulant was found to be associ-
ated with the false-positive test for syphilis and (paradox-
ically) thrombosis. The key antigenic component of the
Wassermann reaction was cardiolipin, a phospholipid
found in mitochondrial membranes, and a much more
sensitive immunoassay was developed in the early 1980s
using cardiolipin as the solid phase antigen. Anticardio-
lipin antibodies identified in this assay proved strongly
correlated with lupus anticoagulant and thrombosis. In
the early 1990s, anticardiolipin autoantibodies were
found to require the presence of the plasma phospholip-
id-binding protein ␤2-glycoprotein I to bind to cardio-
lipin (reviewed in Roubey3). In contrast, anticardiolipin
antibodies from patients with syphilis or other infections
0029-7844/03/$30.00 1333
doi:10.1016/S0029-7844(03)00363-6
are ␤2-glycoprotein I–independent, binding directly to
cardiolipin without requiring a cofactor. As a result of
these findings, antiphospholipid autoantibody research
has recently focused on phospholipid-binding proteins,
rather than phospholipids themselves, with regard to
pathophysiology and antibody specificity.3
The association of antiphospholipid antibodies with
thrombosis and pregnancy loss is now well established.
With regard to thrombosis, antiphospholipid syndrome
is an important diagnosis because the high recurrence
risk of thrombosis requires consideration of long-term
anticoagulation.4 With regard to pregnancy loss, an-
tiphospholipid syndrome is an important diagnosis be-
cause treatment may improve subsequent pregnancy
outcomes and because of potential maternal risks, in-
cluding thrombosis in pregnancy.5,6 Clinicians should
recognize, however, that detectable antiphospholipid an-
tibodies are found in up to 5% of apparently healthy
controls and up to 35% of patients with systemic lupus
erythematosus.2 The prospective risks of a positive test
for antiphospholipid antibodies in otherwise healthy
subjects are unknown.
PATHOGENESIS OF OBSTETRIC FEATURES OF
ANTIPHOSPHOLIPID SYNDROME
Whether antiphospholipid antibodies per se are the
cause of adverse obstetric outcomes associated with the
antibodies remains a subject of debate. Working with
mice, some investigators found administration of human
antiphospholipid antibodies results in clinical manifesta-
tions of antiphospholipid syndrome, including fetal
loss.7,8 The induction of fetal loss in this model is,
however, variable. One group has used a mouse venous
thrombosis model to show that circulating human and
mouse antiphospholipid antibodies are associated with
larger and more persistent thrombi than in mice treated
with control antibodies.9
A variety of mechanisms by which antiphospholipid
antibodies may cause pregnancy loss and thrombosis
have been suggested. Antiphospholipid antibodies may
interfere with the normal in vivo function of phospholip-
ids or phospholipid-binding proteins that are crucial to
the regulation of coagulation. Candidate molecules or
pathways that might be adversely affected include ␤2-
glycoprotein I (which has anticoagulant properties),
prostacyclin, prothrombin, protein C, annexin V, and
tissue factor. Antiphospholipid antibodies may activate
endothelial cells, as indicated by increased expression of
adhesion molecules, secretion of cytokines, and produc-
tion of arachidonic acid metabolites. Other evidence
suggests that antiphospholipid antibodies cross-react
with oxidized low-density lipoprotein and bind only to
oxidized cardiolipin,10 implying that antiphospholipid
1334 Branch and Khamashta Antiphospholipid Syndrome
antibodies may participate in oxidant-mediated injury of
the vascular endothelium.
The in vivo target(s) of antiphospholipid antibodies
remain unknown. Normal, living cells do not express
phospholipids bound by antiphospholipid antibodies on
their surface. The antibodies do, however, bind to phos-
pholipids expressed by perturbed cells, such as activated
platelets or apoptotic cells. Recent work points to the
complement system as having a major role in antiphos-
pholipid syndrome–related pregnancy loss, showing that
C3 activation is required for fetal loss in a mouse mod-
el.11
The negative effect of antiphospholipid syndrome on
pregnancy is most likely tied to abnormal placental func-
tion. Some authorities have focused on abnormalities in
the decidual spiral arteries as the immediate cause of fetal
loss in antiphospholipid syndrome pregnancies. Some
investigators have found narrowing of the spiral arte-
rioles, intimal thickening, acute atherosis, and fibrinoid
necrosis in cases of fetal loss associated with antiphos-
pholipid syndrome. Others have found extensive placen-
tal necrosis, infarction, and thrombosis. These abnor-
malities might result from thrombosis during the
development of the normal maternoplacental circula-
tion, perhaps via interference with trophoblastic annexin
V,12 which is abundant in the human placenta, or by
impairing trophoblastic hormone production or inva-
sion.13
DIAGNOSTIC APPROACH TO ANTIPHOSPHOLIPID
SYNDROME
The diagnosis of antiphospholipid syndrome is first and
foremost clinical—the patient must have one or more
thrombotic or obstetric features of the condition. Labo-
ratory testing for antiphospholipid antibodies is used to
confirm or refute the diagnosis. The 1999 international
consensus statement on preliminary classification criteria
for definite antiphospholipid syndrome1 provides simpli-
fied criteria for the classification of antiphospholipid
syndrome (Table 1). A patient with antiphospholipid
syndrome must manifest at least one of two clinical
criteria (vascular thrombosis or pregnancy morbidity)
and at least one of two laboratory criteria (positive lupus
anticoagulant or medium to high titer ␤2-glycoprotein
I– dependent immunoglobulin G [IgG] or IgM isotype
anticardiolipin antibodies, confirmed on two separate
occasions, at least 6 weeks apart). Vascular thrombosis
can occur in any organ or tissue and can involve vessels
of any size (including capillary networks), within either
the arterial or venous systems. Pregnancy morbidity,
which includes features of both the preembryonic– em-
bryonic and the fetal–neonatal periods, is divided into
three categories, one encompassing early pregnancy loss
OBSTETRICS & GYNECOLOGY
Table 1. International Consensus Statement on Preliminary Criteria for the Classification of the
Antiphospholipid Syndrome
Clinical criteria
1) Vascular thrombosis. One or more clinical episodes of arterial, venous, or small vessel thrombosis, occurring within any tissue
or organ. With the exception of superficial venous thrombosis, thrombosis must be confirmed by imaging or Doppler
studies or histopathology. For histopathologic confirmation, thrombosis should be present without significant evidence of
inflammation in the vessel wall.
2) Pregnancy morbidity
A) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation or
B) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation or
C) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation
In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly
encouraged to stratify groups of subjects according to A, B, or C above.
Laboratory criteria*
1) Anticardiolipin antibodies. Anticardiolipin antibodies of immunoglobulin G and/or immunoglobulin M isotype in blood,
present in medium or high titer,† on two or more occasions at least 6 weeks apart, measured by a standardized enzyme-
linked immunosorbent assay for ␤2-glycoprotein I–dependent anticardiolipin antibodies.
2) Lupus anticoagulant antibodies. Lupus anticoagulant present in plasma, on two or more occasions at least 6 weeks apart,
detected according to the guidelines of the International Society on Thrombosis and Hemostasis in the following steps:
A) Prolonged phospholipid-dependent coagulation demonstrated on a screening test (eg, activated partial thromboplastin
time, kaolin clotting time, dilute Russell viper venom time, dilute prothrombin time, Textarin time)
B) Failure to correct the prolonged coagulation time on the screening test by mixing with normal, platelet-poor plasma
C) Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid
D) Exclusion of other coagulopathies (eg, factor VIII inhibitor) or heparin, as appropriate
Definite antiphospholipid syndrome may be diagnosed if at least one of the clinical criteria and at least one of the laboratory criteria are met. No
limits are placed on the interval of time between the clinical event and the positive laboratory findings.
Modified from Wilson et al1 and Levine et al.2
* The following antiphospholipid antibodies currently are not included in the laboratory criteria: anticardiolipin antibodies of the immunoglob-
ulin A isotype, anti–␤2-glycoprotein I antibodies, and antiphospholipid antibodies directed against phospholipids other than cardiolipin (eg,
phosphatidylserine, phosphatidylethanolamine) or against phospholipid-binding proteins (eg, prothrombin, annexin V, protein C, protein S).
†
The threshold used to distinguish “medium or high titer” from “low titer” anticardiolipin antibodies has not been standardized and may depend
on the population under study. Many laboratories use 15 or 20 international “phospholipid” units as the threshold separating low from medium titer
anticardiolipin antibodies. Others define the threshold as 2.0 or 2.5 times the median titer of anticardiolipin antibodies or as the 99th percentile of
anticardiolipin antibody titers within a normal population. Until an international consensus is reached, any of these three definitions seems
reasonable.

and the other two relating primarily to complications in
the second or third trimesters. “Primary” antiphospho-
lipid syndrome occurs in patients without clinical evi-
dence of another autoimmune disease, whereas “second-
ary” antiphospholipid syndrome occurs in patients with
autoimmune or other diseases.
The most commonly detected antiphospholipid anti-
bodies, and the only two currently recognized by the
1999 international consensus statement, are lupus anti-
coagulant and anticardiolipin antibodies. Lupus antico-
agulant is identified by in vitro coagulation assays, in
which the antibodies prolong clotting times. Published
laboratory criteria for the diagnosis of lupus anticoagu-
lant should be followed (reviewed in Levine et al2).
Anticardiolipin antibodies are detected by a standardized
enzyme-linked immunosorbent assay that measures ␤2-
glycoprotein I– dependent IgG and IgM anticardiolipin
antibodies. Note that the standard anticardiolipin anti-
body assay detects ␤2-glycoprotein I– dependent anticar-
diolipin antibodies because ␤2-glycoprotein I is present
in the diluted patient serum and in the bovine serum
typically used in the assay buffer– diluent. It is possible,
however, that the use of bovine serum biases the stan-
dard anticardiolipin antibody assay to detect antibodies
that react with both bovine and human ␤2-glycoprotein I
and explains differences in reactivity between anticardio-
lipin antibodies and anti–␤2-glycoprotein I assays.
Whereas lupus anticoagulant is reported as being
positive or negative, anticardiolipin antibodies are re-
ported in terms of international units (designated GPL
for IgG binding and MPL for IgM binding). In most
laboratories there is substantial concordance between
lupus anticoagulant activity and anticardiolipin antibod-
ies, with approximately 70% of patients with definite
antiphospholipid syndrome having both lupus anticoag-
ulant and anticardiolipin antibodies. However, these
antibodies may not be identical, either because they
detect different epitopes altogether or because they have
different affinities to various epitopes in different test
systems. The anticardiolipin antibody enzyme-linked
immunosorbent assay is the more sensitive test for an-
tiphospholipid syndrome, whereas lupus anticoagulant

VOL. 101, NO. 6, JUNE 2003 Branch and Khamashta Antiphospholipid Syndrome 1335
Table 2. Subcutaneous Heparin Regimens Used in the Treatment of Antiphospholipid Syndrome During Pregnancy
Prophylactic regimens
Recommended in women with no history of thrombotic events—diagnosis because of recurrent preembryonic and embryonic
loss or prior fetal death or early delivery because of severe preeclampsia or severe placental insufficiency
Standard heparin
1) 7500–10,000 U every 12 hours in the first trimester, 10,000 U every 12 hours in the second and third trimesters
Low molecular weight heparin
1) Enoxaparin 40 mg once daily or dalteparin 5000 U once daily or
enoxaparin 30 mg every 12 hours or dalteparin 5000 U every 12 hours
Anticoagulation regimens
Recommended in women with a history of thrombotic events
Standard heparin
1) Every 8–12 hours adjusted to maintain the midinterval heparin levels* in the therapeutic range
Low molecular weight heparin
1) Weight adjusted (eg, enoxaparin 1 mg/kg every 12 hours or dalteparin 200 U/kg every 12 hours)
2) Intermediate dose (eg, enoxaparin 40 mg once daily or dalteparin 5000 U once daily until 16 weeks of gestation and
every 12 hours from 16 weeks of gestation onwards)
See text for postpartum thromboprophylaxis recommendations.
* Heparin levels ⫽ anti–factor Xa levels. Women without a lupus anticoagulant in whom the activated partial thromboplastin time is normal can
be observed using the activated partial thromboplastin time.

is more specific. However, the specificity of anticardio-
lipin antibodies for antiphospholipid syndrome increases
with an increasing antibody titer. Low positive anticar-
diolipin antibody results should be viewed with suspi-
cion—they may be found in up to 5% of normal individ-
uals and should not be used to make the diagnosis of
antiphospholipid syndrome. Only medium to high titer
anticardiolipin antibodies should be considered in the
classification of definite antiphospholipid syndrome.
The specificity is also higher for anticardiolipin antibod-
ies of the IgG versus IgM isotype. In spite of well-
intentioned efforts at standardization and the availability
of positive standard sera, substantial interlaboratory
variation when testing the same sera remains a serious
problem. This is due in part to the large number of
commercial kits and homemade assays used worldwide
that may not conform to the standard anticardiolipin
antibody method. Because there is no definitive associa-
tion of specific clinical manifestations with particular
antiphospholipid antibodies, multiple antiphospholipid
antibody tests (most commonly lupus anticoagulant and
IgG and IgM anticardiolipin antibodies) should be used
in seeking the diagnosis of antiphospholipid syndrome.
Clinicians must be aware that the diagnosis of definite
antiphospholipid syndrome requires both strict clinical
and laboratory criteria. With regard to the latter, the
diagnosis of antiphospholipid syndrome should only be
made in patients positive for antiphospholipid antibod-
ies, either lupus anticoagulant or moderate to high posi-
tive anticardiolipin antibodies, on at least two occasions
and at least 6 weeks apart.
Clinicians should also recognize that the international
consensus criteria were developed primarily for research
purposes to insure more uniform characterization, as
well as subcategorization, of patients included in studies.
We view this objective as crucial for credible investiga-
tive efforts and for appreciation of subtleties of treat-
ment. The consensus criteria also serve to emphasize
standardization of laboratory testing, an area of proven
concern in antiphospholipid antibodies. As with other
autoimmune conditions, such as systemic lupus ery-
thematosus, there are individuals who present with one
or more clinical or laboratory features suggestive of
antiphospholipid syndrome but in whom the diagnosis
cannot be made by the relatively strict international
consensus criteria. In such cases, experienced clinical
judgment is required for best care.
THERAPEUTIC APPROACH TO ANTIPHOSPHOLIPID
SYNDROME IN PREGNANCY
The ideal treatment for antiphospholipid syndrome dur-
ing pregnancy would 1) improve maternal and fetal–
neonatal outcome by preventing pregnancy loss, pre-
eclampsia, placental insufficiency, and preterm birth and
2) reduce or eliminate the maternal thrombotic risk of
antiphospholipid syndrome during pregnancy. Treat-
ment of antiphospholipid syndrome in pregnancy to
improve fetal outcome has evolved considerably. Early
enthusiasm for glucocorticoids waned when a small,
randomized trial found maternally administered heparin
to be as effective as prednisone.14 Maternally adminis-
tered heparin is widely considered the treatment of
choice at present (Table 2), usually initiated in the early

1336 Branch and Khamashta Antiphospholipid Syndrome OBSTETRICS & GYNECOLOGY

first trimester after ultrasonographic demonstration of a
live embryo. The dose of heparin required for safe and
effective treatment is debated, however. In one trial of
nearly 100 women, two thirds of whom had recurrent
preembryonic and embryonic pregnancy loss and none
of whom had a history of thromboembolic disease, a
heparin dose of 5000 U twice daily was associated with a
71% live-birth rate.15 Another study of women with
antiphospholipid antibodies and predominantly preem-
bryonic and embryonic pregnancy loss, none of whom
had a history of thromboembolic disease, with heparin
administered in a twice daily regimen and adjusted to
keep the midinterval activated partial thromboplastin
time approximately 1.5 times the control mean, was
associated with an 80% live-birth rate.16 In most case
series and trials, daily low-dose aspirin is included in the
treatment regimen. A paradigm for the management of
antiphospholipid syndrome in pregnancy is shown in
Figure 1.
Clinicians should be aware that the heparin doses
recommended for antiphospholipid syndrome patients
with prior thrombosis are considerably higher than the
5000 U twice daily used by Rai and colleagues15 for
women with recurrent pregnancy loss and no history of
thromboembolic disease. Indeed, full anticoagulation is
urged by some experts.17 The optimal dose of heparin
for women whose antiphospholipid syndrome is diag-
nosed because of prior fetal loss or neonatal death after
delivery at less than 34 weeks’ gestation for severe
preeclampsia or placental insufficiency, but who do not
have a history of thromboembolism, is controversial.
These women are at risk for thromboembolic disease,18
and it is our opinion that these cases should receive
sufficient thromboprophylaxis (Table 2).
In Europe, low molecular weight heparins are widely
used for the treatment of antiphospholipid syndrome
pregnancy, whereas cost considerations limit the use of
low molecular weight heparins in the United States.
There is little reason to suspect that one preparation
would be better than the other if used in regimens that
provide equivalent anticoagulant effects over 24 hours.
However, a direct comparison of standard heparin ver-
sus low molecular weight heparin in pregnancy is lack-
ing.
Women with particularly egregious thrombotic histo-
ries, such as recurrent thrombotic events or cerebral
thrombotic events, are understandably viewed as being
at very high risk for thrombosis during pregnancy. In
selected such cases, we recommend the judicious use of
warfarin anticoagulation rather than heparin.
Intravenous immune globulin has also been used dur-
ing pregnancy, usually in conjunction with heparin and
low-dose aspirin, especially in women with particularly
VOL. 101, NO. 6, JUNE 2003
poor histories or recurrent pregnancy loss during hepa-
rin treatment.19 However, a randomized, controlled,
pilot study of intravenous immune globulin treatment
during pregnancy in unselected antiphospholipid syn-
drome cases found no benefit to this expensive therapy
relative to heparin and low-dose aspirin.20
Clinicians should realize that otherwise healthy
women with recurrent pregnancy loss and low titers of
antiphospholipid antibodies do not require treatment.
The controlled trial of Pattison and colleagues21 in-
cluded a majority of such women and found no differ-
ence in live-birth rates using either low-dose aspirin or a
placebo.
Anticoagulant coverage of the postpartum period in
women with antiphospholipid syndrome and prior
thrombosis is critical.17 We prefer switching the patient
to warfarin thromboprophylaxis as soon as she is clini-
cally stable after delivery. In most cases, an international
normalized ratio of 3.0 is desirable. There is no interna-
tional consensus regarding the postpartum management
of those women without prior thrombosis in whom
antiphospholipid syndrome is diagnosed because of
prior fetal loss or neonatal death after delivery at or
before 34 weeks’ gestation for severe preeclampsia or
placental insufficiency, though all agree there is an in-
creased risk of thrombosis. Postpartum thromboprophy-
laxis using heparin for 3–5 days, especially in the event
of cesarean delivery, is recommended in the United
Kingdom. The recommendation in the United States is
anticoagulant therapy for 6 weeks after delivery. The
need for postpartum anticoagulation in women with
antiphospholipid syndrome diagnosed solely on the ba-
sis of recurrent preembryonic or embryonic losses is
uncertain. Both heparin and warfarin are safe for nursing
mothers.
COMPLICATIONS OF ANTIPHOSPHOLIPID SYNDROME IN
PREGNANCY
The potential complications of pregnancy in women
with antiphospholipid syndrome include recurrent preg-
nancy loss (including fetal death), preeclampsia, placen-
tal insufficiency, maternal thrombosis (including stroke),
and complications due to treatment. In women with
systemic lupus erythematosus, the potential complica-
tions also include lupus exacerbation.
In case series of antiphospholipid syndrome pregnan-
cies that included women with systemic lupus erythem-
atosus and prior thrombosis, the median rate of gesta-
tional hypertension–preeclampsia is 32% and ranges up
to 50%.5,6,22–25 Placental insufficiency requiring delivery
is also relatively frequent in some of these case se-
ries.5,6,23 Not surprisingly, the rate of preterm birth in
Branch and Khamashta Antiphospholipid Syndrome 1337
Figure 1. Suggested algorithm for the management of antiphospholipid syndrome in pregnancy. *See Table 2 for dosing.
†In the United Kingdom, Doppler assessment of the uterine arteries is commonly used at 20 –24 weeks’ gestation for the
prediction of preeclampsia and placental insufficiency risks. This is not commonly done in the United States.
Branch. Antiphospholipid Syndrome. Obstet Gynecol 2003.

these series ranges from 32% to 65%.5,6,23–25 In contrast
to the high rate of preeclampsia observed in some case
series of women previously diagnosed with antiphospho-
lipid syndrome, antiphospholipid antibodies are not
found in a statistically significant proportion of a general
obstetric population presenting with preeclampsia26 or in
women at moderate risk to develop preeclampsia be-
cause of conditions such as underlying chronic hyperten-
sion or preeclampsia in a prior pregnancy.27
The potential complications of heparin treatment dur-
ing pregnancy include hemorrhage, osteoporosis with
fracture, and heparin-induced thrombocytopenia. Fortu-

1338 Branch and Khamashta Antiphospholipid Syndrome OBSTETRICS & GYNECOLOGY

nately, the reported rate of osteoporosis and associated
fracture is low, though cases have occurred, even with
low molecular weight heparin.6 It is likely, though, that
the risk is higher in women with underlying autoimmune
disease who have required glucocorticosteroid treatment.
Heparin-induced thrombocytopenia, which may be le-
thal, is also fortunately infrequent in pregnant women.28
Given the array of potential complications in antiphos-
pholipid syndrome pregnancy, appropriate obstetric
care calls for frequent prenatal visits, at least every 2
weeks before midgestation and every week thereafter.
The objectives are close observation for maternal hyper-
tension and other features of preeclampsia, periodic pa-
tient evaluation and obstetric ultrasound to assess fetal
growth and amniotic fluid volume, and appropriate fetal
surveillance testing. The latter should begin at 32 weeks’
gestation, or earlier if the clinical situation is suspicious
for placental insufficiency, and continue at least weekly
until delivery. Best patient care also calls for frequent
rheumatological consultation every 2– 4 weeks during
pregnancy, especially in women with systemic lupus
erythematosus.
CONTROVERSIES IN OBSTETRIC ANTIPHOSPHOLIPID
SYNDROME
Laboratory Testing for Antiphospholipid Antibodies
Despite international efforts to standardize laboratory
testing for antiphospholipid antibodies (reviewed in Le-
vine et al2), significant variation in the performance of
antiphospholipid antibody assays (and hence the results)
remains a critical problem. Large interlaboratory varia-
tion in anticardiolipin antibody testing has been amply
documented.29 Agreement among commercially avail-
able kits is also poor.30 It is not surprising that the
prevalence of antiphospholipid antibodies varies from
center to center. In turn, this contributes to the contro-
versies in our current understanding of antiphospholipid
syndrome. Indeed, the authors believe that substantial
further progress in antiphospholipid syndrome can only
be made when well-characterized and well-standardized
assays and calibrators are widely available and used in
periodic interlaboratory comparisons.
The important issue of interlaboratory variation in
antiphospholipid antibody testing aside, there are cur-
rently four other areas of controversy in the laboratory
testing for antiphospholipid antibodies: 1) the definition
and relevance of low positive IgG antiphospholipid an-
tibodies, 2) the relevance of isolated IgM or IgA an-
tiphospholipid antibodies (without either lupus anticoag-
ulant or IgG anticardiolipin antibodies), 3) the relevance
of antiphospholipid antibodies other than lupus antico-
VOL. 101, NO. 6, JUNE 2003
agulant and anticardiolipin antibodies (eg, antiphos-
phatidylserine), and 4) the relevance of antibodies to
␤2-glycoprotein I.
Many studies of patients with recurrent pregnancy
loss and antiphospholipid antibodies have included pa-
tients with low levels of IgG antiphospholipid antibod-
ies.15,21,31 Two groups32,33 have found that a significant
proportion of women with recurrent pregnancy loss had
normalized values indicating low levels of IgG anticar-
diolipin antibodies (defined as more than the 95th per-
centile or the 99th percentile). One of these studies
showed marked differences between the low levels of
anticardiolipin antibodies in the recurrent pregnancy
loss population and the much higher levels found in a
population of women with antiphospholipid syndrome
characterized by fetal death or thrombosis.34 Silver and
colleagues35 found that women with low positive IgG
anticardiolipin antibodies had no greater risk for an-
tiphospholipid antibody–related events than women
who tested negative. Currently, low levels of antiphos-
pholipid antibodies should be regarded as of question-
able clinical significance.
Isolated IgM or IgA antiphospholipid antibodies are
also of uncertain clinical significance. Early criteria did
not recognize isolated IgM anticardiolipin antibodies in
the diagnosis of antiphospholipid syndrome. Silver and
colleagues35 found that women with isolated IgM anti-
cardiolipin antibodies had no greater risk for antiphos-
pholipid antibody–related events than women who
tested negative. More recently, patients with isolated
IgM antiphospholipid antibodies have been entered into
treatment trials,15,16,21,31 but their outcomes were not
separately analyzed. The 1999 international consensus
statement recognizes IgM anticardiolipin antibodies lev-
els in medium to high titer for the diagnosis of the
antiphospholipid syndrome, but we would urge caution
in making a diagnosis of antiphospholipid syndrome on
the basis of isolated IgM antiphospholipid antibodies.
Isolated IgA anticardiolipin antibodies are viewed by
many experts with the same suspicion as isolated IgM.
Immunoglobulin A anticardiolipin antibodies were not
measured or compared with IgG and IgM isotypes until
recently, though, in part because reference sera for IgA
anticardiolipin antibodies were not available until 1994.
Studies of the significance of IgA anticardiolipin antibod-
ies are mixed, with some experts finding them to be of
little additional diagnostic significance compared with
IgG and IgM anticardiolipin antibodies, and the 1999
international consensus statement does not recognize
IgA anticardiolipin antibodies in the diagnosis of the
antiphospholipid syndrome. Immunoglobulin A anti–
␤2-glycoprotein I antibodies have been associated with
thrombosis in systemic lupus erythematosus patients,
Branch and Khamashta Antiphospholipid Syndrome 1339
though they may not add to the diagnosis of antiphos-
pholipid syndrome when compared with testing for lu-
pus anticoagulant or IgG or IgM isotypes.36
Some investigators have attempted to link antiphos-
pholipid antibodies other than lupus anticoagulant and
anticardiolipin antibodies to recurrent pregnancy loss,
including antibodies to phosphatidylserine, phosphati-
dylethanolamine, phosphatidylinositol, phosphatidyl-
glycerol, phosphatidylcholine, and phosphatidic ac-
id.32,37 Others remain skeptical, finding that these
antibodies are not associated with recurrent pregnancy
loss once patients positive for lupus anticoagulant or
anticardiolipin antibodies are excluded.33 Similarly, an-
other experienced group found that multiple antiphos-
pholipid antibody tests do not increase the diagnostic
yield in antiphospholipid syndrome.38 Indeed, substitut-
ing negatively charged phospholipids, such as phospha-
tidylserine or phosphatidylinositol, for cardiolipin in the
immunoassay system yields comparable results. Also, no
assay other than the anticardiolipin antibody assay has
been standardized, a persuasive argument against using
alternative phospholipid assays for the diagnosis of an-
tiphospholipid syndrome.
The demonstration that autoimmune anticardiolipin
antibodies are directed against a ␤2-glycoprotein I or an
epitope formed by the interaction of phospholipids and
␤2-glycoprotein I led to the development of assays for
anti–␤2-glycoprotein I antibodies (reviewed in Roubey3).
In some patients with clinical features of antiphospho-
lipid syndrome, anti–␤2-glycoprotein I antibodies are the
sole antibodies detected. Anti–␤2-glycoprotein I antibod-
ies are not currently included in the international con-
sensus statement on preliminary classification criteria for
definite antiphospholipid syndrome, but these antibod-
ies are strongly associated with thrombosis and other
features of antiphospholipid syndrome (reviewed in Car-
reras et al39). Thus, some authorities recommend testing
for anti–␤2-glycoprotein I in patients strongly suspected
to have antiphospholipid syndrome but in whom tests
for lupus anticoagulant and anticardiolipin antibodies
are negative.2,39 Internationally standardized anti–␤2-
glycoprotein I assays may replace lupus anticoagulant
and anticardiolipin antibody assays for the diagnosis of
antiphospholipid syndrome in the future. If these stan-
dardized assays perform as preliminary work suggests,
their reproducibility and reliability will be a welcome
change to the field.
Clinical Features and Diagnosis
Initially, “fetal loss” was proposed as the obstetric crite-
rion for antiphospholipid syndrome.1 Indeed, obstetric
histories detailed in some case series of women with
1340 Branch and Khamashta Antiphospholipid Syndrome
antiphospholipid syndrome suggest that 40% or more of
pregnancy losses reported by women with lupus antico-
agulant or medium to high positive IgG anticardiolipin
antibodies occurred in the fetal period (at least 10 men-
strual weeks’ gestation). This contrasts sharply with
unselected populations of women with sporadic or recur-
rent pregnancy loss, for whom loss of the pregnancy
occurs far more commonly in the preembryonic (less
than 6 menstrual weeks’ gestation) or embryonic (6 –9
menstrual weeks’ gestation) periods. In addition to a
high rate of fetal death, prospectively followed pregnan-
cies in several large case series that included women with
systemic lupus erythematosus, prior thrombosis, and
other medical conditions have demonstrated high rates
of premature delivery for gestational hypertension–pre-
eclampsia and uteroplacental insufficiency as manifested
by fetal growth restriction, oligohydramnios, and nonre-
assuring fetal surveillance.5,6,25
More recent work focusing on women with recurrent
preembryonic and embryonic pregnancy loss without
significant medical history has shown that 10 –20% of
these more typical cases of recurrent miscarriage have
detectable antiphospholipid antibodies.33,37 Six of the
seven prospective treatment trials14 –16,21,31,40 have in-
cluded a majority of such cases— otherwise healthy
women with recurrent early miscarriage—and found rel-
atively low rates of adverse second- or third-trimester
outcomes. The median rates of fetal death, preeclampsia,
and preterm birth in these trials were 4.5% (range
0 –15%), 10.5% (range 0 –15%), and 10.5% (range
5– 40%), respectively. Among all six trials, comprising
over 300 patients, only one woman suffered a throm-
botic event, and there were no neonatal deaths due to
complications of prematurity. It would appear, then, that
women identified in the clinical setting of recurrent early
pregnancy loss, particularly recurrent preembryonic and
embryonic losses, without other important medical his-
tories represent a different population from those identi-
fied because of thromboembolic disease, systemic lupus
erythematosus, or adverse second- or third-trimester
obstetric outcomes.
The relationship between antiphospholipid syndrome
cases resulting in complications during the fetal period
(fetal death or premature delivery due to obstetric com-
plications) and those during the preembryonic and em-
bryonic periods (identified by recurrent pregnancy loss)
is seen as a continuum by some41 and questioned by
others.42 The former view would hold that the same
underlying mechanism (eg, antiphospholipid antibody–
mediated hypercoagulability) can operate along the con-
tinuum of gestation to cause either predominantly first-
trimester or predominantly second- and third-trimester
complications. Certainly it is easy to envisage a common
OBSTETRICS & GYNECOLOGY
mechanism for fetal death and preterm birth resulting
from severe preeclampsia or placental insufficiency—
hypercoagulability causing a defective uteroplacental cir-
culation and, in turn, diminished intervillous blood flow.
But would the same mechanism also be responsible for
recurrent preembryonic and embryonic losses and be
associated with relatively low rates of second- and third-
trimester complications in treated patients, even those
treated with low-dose aspirin alone?
The alternative view holds that women presenting
with recurrent preembryonic and embryonic losses and
antiphospholipid antibodies represent a largely different
patient population. Their pregnancy losses are likely to
be due to different mechanism(s) than later pregnancy
complications, perhaps relating to different antiphospho-
lipid antibody specificities or antiphospholipid antibod-
ies operating on a fundamentally different pathophysio-
logic background.
Pregnancy Treatment in Different Patient Groups
Treatment of women with antiphospholipid syndrome
and prior thrombosis is little debated. Based on a high
risk for recurrent thrombosis, authorities agree that such
patients receive heparin during pregnancy, and many
recommend full anticoagulation.17 Women diagnosed
with antiphospholipid syndrome without a history of
thromboembolic disease fall into the two categories out-
lined above: 1) those with one or more prior fetal losses
or neonatal deaths after delivery at less than 34 weeks’
gestation for severe preeclampsia or placental insuffi-
ciency and 2) those with recurrent preembryonic and
embryonic pregnancy loss. Regarding the group with
adverse pregnancy outcomes during the fetal period,
most authorities recommend heparin during pregnancy
based on the widely held perception that anticoagulant
therapy is likely to benefit both the mother and fetus. It
must be said, however, that this particular group has
never been singled out for a randomized treatment trial
to determine if heparin is efficacious and at what dose. In
a small randomized treatment trial,20 over 80% of those
included had suffered one or more prior fetal losses
(women with systemic lupus erythematosus and prior
thromboembolic disease were also included). Using
doses of heparin between 17,000 and 20,000 U per day
in divided doses, all women had a live birth, and none
suffered a thrombotic event.
In contrast, there are six published treatment trials
that included women whose antiphospholipid syndrome
was diagnosed in a majority of cases because of recurrent
pregnancy loss in the first trimester.14 –16,21,31,40 Five
were randomized, and one16 alternated treatments every
VOL. 101, NO. 6, JUNE 2003
other patient. Substantial differences in patients included
in these trials deserve mention. The proportion of
women having one or more prior fetal losses in these
trials ranged from 11%16 to 47%.40 One trial40 included
women with thromboembolic disease, though only two
patients (6%) actually had such a history. Two trials did
not specifically exclude women with systemic lupus ery-
thematosus, though neither recruited any.14,40 The other
four trials specifically excluded women with systemic
lupus erythematosus and prior thromboembolic dis-
ease,15,16,21,31 and one specifically excluded women with
lupus anticoagulant.18 Low positive IgG anticardiolipin
antibody results and isolated IgM results were allowed in
five trials,14,15,21,31,40 and one trial included women with
antibodies to phosphatidylserine.16
Given these substantial differences in patient selection,
one might expect equally substantial differences in study
pregnancy outcomes. One trial compared prednisone
and low-dose aspirin with heparin and low-dose aspirin
and found live-birth rates of 75% in each group. Two
trials found low-dose aspirin to be as efficacious as the
study treatment,31,40 and one found placebo as effective
as low-dose aspirin.21 The live-birth rates in each arm of
these three trials, including two low-dose aspirin arms
and a placebo arm, exceeded 75%. Two trials15,16 found
that a combination of heparin and low-dose aspirin was
more effective than low-dose aspirin alone for achieving
live births, reporting 71% and 80% live-birth rates, re-
spectively, in patients treated with aspirin and heparin
versus live-birth rates under 50% in patients treated with
aspirin alone. Different doses of heparin were used in
each of these two trials, with only 10,000 U of heparin
per day used in one.15
The clinician is bound to be confused by the discrep-
ant results from these trials. At the heart of the problem
is patient selection, both clinical and laboratory. The
obvious differences in patient selection and subsequent
obstetric outcomes with a variety of treatments have led
three groups to call for subcategorization of obstetric
antiphospholipid syndrome patients.41– 43 Moreover, the
1999 international consensus statement specifically calls
for stratification of populations that include more than
one type of pregnancy morbidity. Based on existing data,
the most important obstetric subcategorization would
distinguish women with prior thromboembolic events
from those without and women with recurrent preem-
bryonic or embryonic losses from those with fetal losses.
Also, women with low levels of anticardiolipin antibod-
ies or only IgM anticardiolipin antibodies should be
distinguished from those with lupus anticoagulant or
medium to high levels of IgG anticardiolipin antibodies.
Branch and Khamashta Antiphospholipid Syndrome 1341
Treatment of Antiphospholipid Syndrome Pregnancy in
“Refractory” Cases
Despite treatment with heparin, recurrent pregnancy
losses occur in 20 –30% of cases in most case series and
trials. The best approach to such cases in subsequent
pregnancies is unknown, though clinicians and patients
understandably feel as if they should try an alternative
therapy or add another drug to their regimen in a next
pregnancy attempt. In the early 1990s, experts were
often inclined to use glucocorticoids, often in substantial
doses. This approach may have merit in refractory cases,
but it is untested in clinical trials. By the mid-1990s,
intravenous immune globulin, usually used in conjunc-
tion with heparin and low-dose aspirin, was touted as
beneficial based on selected cases.19 As with a combina-
tion of glucocorticoids and heparin, a properly designed
trial of this intravenous immune globulin in refractory
antiphospholipid syndrome cases has never been done.
Hydroxychloroquine has been shown to diminish the
thrombogenic properties of antiphospholipid antibodies
in a murine thrombosis model. Past concerns about
ocular damage or defects in exposed embryos and fe-
tuses have been allayed to some degree by a series of
recent reports.44 There are few case reports and no trials
of antiphospholipid syndrome patients being treated
during pregnancy with hydroxychloroquine.
Because there are no properly designed trials evaluat-
ing treatments of “refractory” antiphospholipid syn-
drome, we can only offer speculative opinion as to
promising and acceptable treatment alternatives. In
women whose treated pregnancy failure occurred on a
prophylactic regimen, full anticoagulation in the next
pregnancy would seem rational. If the treated pregnancy
failed while on full anticoagulation, we would be inclined
to add an immunomodulatory agent such as glucocorti-
coids, immune globulin, or hydroxychloroquine to the
anticoagulation regimen.
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1344 Branch and Khamashta Antiphospholipid Syndrome
Address reprint requests to: D. Ware Branch, MD, Depart-
ment of Obstetrics and Gynecology, University of Utah Health
Sciences Center, 30 North 1900 East, Suite 2B200 MC, Salt
Lake City, Utah 84132; E-mail: ware.branch@hsc.utah.edu.
Received April 22, 2002. Received in revised form August 7, 2002.
Accepted August 15, 2002.
OBSTETRICS & GYNECOLOGY