ACOG

PRACTICE
BULLETIN
CLINICAL MANAGEMENT GUIDELINES FOR
OBSTETRICIAN–GYNECOLOGISTS
NUMBER 68, NOVEMBER 2005
(Replaces Educational Bulletin 244, February 1998)

Antiphospholipid
This Practice Bulletin was Syndrome
developed by the ACOG Com- Antiphospholipid syndrome is an autoimmune disorder defined by the presence
mittee on Practice Bulletins— of characteristic clinical features and specified levels of circulating antiphos-
Obstetrics with the assistance
pholipid antibodies (Table 1). Because approximately 70% of individuals with
of M. Sean Esplin, MD. The
antiphospholipid syndrome are female (1), it is reasonably common among
information is designed to aid
practitioners in making deci- women of reproductive age. Antiphospholipid antibodies are a diverse group of
sions about appropriate obstet- antibodies with specificity for protein binding negatively charged phospholipids
ric and gynecologic care. These on cell surfaces. Despite the prevalence and clinical significance of antiphos-
guidelines should not be con- pholipid syndrome, there is controversy about the indications for antiphospho-
strued as dictating an exclusive lipid syndrome testing and the tests that should be ordered to diagnose the
course of treatment or proce- condition. Much of the debate results from a lack of well-designed and con-
dure. Variations in practice may trolled studies on the diagnosis and management of antiphospholipid syndrome.
be warranted based on the The purpose of this document is to evaluate the data for diagnosis and treat-
needs of the individual patient, ment of antiphospholipid syndrome.
resources, and limitations
unique to the institution or type
of practice. Background
The lupus anticoagulant and anticardiolipin antibodies, the most widely accept-
ed antibodies of clinical use, have been associated with a variety of medical
problems, including arterial and venous thromboses, autoimmune thrombocy-
topenia, and fetal loss (2–7). In addition to fetal loss, several obstetric compli-
cations have been associated with antiphospholipid antibodies, including
preeclampsia, intrauterine growth restriction, placental insufficiency, and
preterm delivery (8, 9). Primary antiphospholipid syndrome refers to patients
with antiphospholipid syndrome but no other recognized autoimmune disorders
(3, 4, 10). However, other autoimmune conditions such as systemic lupus ery-
thematosus often coexist with the condition. When it occurs in the setting
of other autoimmune disease, it is referred to as secondary antiphospholipid
syndrome (2, 4).

VOL. 106, NO. 5, PART 1, NOVEMBER 2005 OBSTETRICS & GYNECOLOGY 1113
Antiphospholipid such as lupus anticoagulant is present, the clotting time
remains prolonged despite the addition of normal plasma.
Antibodies A second confirmatory test involving the addition or
removal of phospholipid from the assay has been recom-
The two antiphospholipid antibodies that are best charac-
mended. For example, preincubation of plasma with
terized are lupus anticoagulant and anticardiolipin anti-
phospholipid binds and removes lupus anticoagulant
bodies. Although many women with lupus anticoagulant
from the sample being tested and normalizes clotting
also have anticardiolipin antibodies, the correlation is
time. Regardless of the assays used, lupus anticoagulant
imperfect (1, 11). Approximately 80% of patients with
cannot be quantified and is reported only as present or
lupus anticoagulant have anticardiolipin antibodies, and
absent.
20% of patients positive for anticardiolipin antibodies
have lupus anticoagulant. Although some investigators
suggest that lupus anticoagulant and anticardiolipin anti- Anticardiolipin Antibodies
bodies are the same antibody detected by different meth- Like lupus anticoagulants, anticardiolipin antibodies
ods (12), the fact that lupus anticoagulant and react to the complex of negatively charged phospho-
anticardiolipin antibodies may be separated in the labo- lipids, such as cardiolipin or phosphatidylserine bound to
ratory (13) would indicate that they may be related proteins such as β2-glycoprotein I, prothrombin, or
but different immunoglobulins. Regardless, lupus anti- annexin V. However, these antibodies are detected by
coagulant and anticardiolipin antibodies are both inde- conventional immunoassays using purified cardiolipin as
pendently associated with the clinical features of the phospholipid matrix. Historically, interlaboratory
antiphospholipid syndrome, and the presence of only one variation in this assay resulted in inappropriate diagnosis
of these antibodies is adequate for the laboratory diagno- and various treatments and outcomes (16, 17). The devel-
sis of antiphospholipid syndrome. opment of standard sera, available from the Antiphos-
pholipid Standardization Laboratory in Atlanta, Georgia
Lupus Anticoagulant (18), has greatly improved the reliability of this test
Lupus anticoagulant is present in many individuals with- among different laboratories. Assays using these stan-
out systemic lupus erythematosus and is associated with dard positive serum calibrators are quite reliable and
thrombosis, not anticoagulation. The presence of lupus allow for the semiquantitation of antibody levels.
anticoagulant is assessed indirectly, and a series of tests Standard sera have been assigned numeric values termed
are needed for the laboratory diagnosis (Table 1). The ini- GPL (immunoglobulin G [IgG] binding), MPL (IgM
tial laboratory test for lupus anticoagulant can be one of binding), and APL (IgA binding) units. Test results are
several phospholipid-dependent clotting assays, such as reported as negative, low-positive, medium-positive, or
the activated partial thromboplastin time (APTT), kaolin high-positive.
plasma clotting time, and dilute Russell’s viper venom Low-positive anticardiolipin antibodies (<20 GPL
time. Lupus anticoagulants are antibodies directed or MPL units) of any quantity are of questionable clini-
against plasma proteins (such as β2-glycoprotein I, pro- cal significance and should not be considered diagnostic
thrombin, or annexin V) that bind to anionic or hexago- of antiphospholipid syndrome (19). The relevance of
nal phase phospholipids (14, 15). Lupus anticoagulants positive test results for IgA anticardiolipin antibodies of
paradoxically block phospholipid-dependent clotting any level also is uncertain. Low levels of IgG anticardi-
assays by interfering with the assembly of the prothrom- olipin antibodies and IgM anticardiolipin antibodies are
bin complex. The sensitivity and specificity of each test sometimes found in healthy individuals (18) and can
for lupus anticoagulant are greatly affected by the result from infection (20) and nonspecific binding. In the
reagents used and vary among laboratories. general obstetric population, the prevalence of anticardi-
Because prolonged clotting times in these assays can olipin antibodies has been reported to be between 2.7%
result from factors other than lupus anticoagulant, such and 7.0% (21–23). In contrast, several studies have
as improperly processed specimens, anticoagulant med- shown a correlation between increasing titers of anticar-
ications, clotting factor deficiencies, and factor-specific diolipin antibodies and disorders related to antiphospho-
inhibitors, plasma suspected of containing lupus antico- lipid antibodies (5, 19, 24). Thus, only medium to high
agulant based on a prolonged clotting time is subjected to levels of IgG (>20 GPL units) or IgM (>20 MPL units)
additional testing. If the prolonged clotting time is caused anticardiolipin antibodies or positive lupus anticoagu-
by a factor deficiency, the addition of normal plasma lant are considered sufficient laboratory criteria for the
(containing the missing factor) results in a normal clot- diagnosis of antiphospholipid syndrome (2, 4). Positive
ting time on repeat testing. In contrast, if an inhibitor test results for antiphospholipid antibodies can be tran-

1114 ACOG Practice Bulletin Antiphospholipid Syndrome OBSTETRICS & GYNECOLOGY

sient and should be confirmed on two occasions at least patients with an antiphospholipid syndrome–associated
several weeks apart (4, 25). The diagnosis of antiphos- thrombosis will have at least one pulmonary embolus.
pholipid syndrome is not based on laboratory testing One retrospective cohort study of 147 subjects found a
alone. Rather, a diagnosis of antiphospholipid syndrome thrombosis recurrence rate of 25% per year in untreated
must be based on an appropriate clinical history and lab- patients with antiphospholipid syndrome and prior
oratory criteria. thrombosis, but that recurrence can be minimized with
anticoagulation (27).
Other Antibodies Associated With The risk of thrombosis is significantly increased
Antiphospholipid Syndrome during pregnancy in patients with antiphospholipid syn-
The antibody responsible for the biologic false-positive drome. In a large cohort study, up to 25% of throm-
serologic test for syphilis (BFP STS) also is an antiphos- botic events in patients with antiphospholipid syndrome
pholipid antibody and often is present in patients with occurred during pregnancy or the postpartum period
lupus anticoagulant or anticardiolipin antibodies. (31). These findings were confirmed in prospective
Compared with lupus anticoagulant and anticardiolipin studies indicating a 5–12% risk of thrombosis during
antibodies, the BFP STS correlates poorly with the pregnancy or the puerperium in women with antiphos-
development of medical problems associated with pholipid syndrome (8, 9).
antiphospholipid antibodies. Thus, the BFP STS is not Arterial thrombosis also is associated with antiphos-
recommended in the routine evaluation of antiphospho- pholipid antibodies and can occur in atypical sites, such
lipid syndrome. Laboratories often report antibodies as retinal, subclavian, digital, or brachial arteries. Stroke
to other phospholipids (ie, antiphosphatidylserine, anti- is the most common arterial event, and the most fre-
phosphatidylinositol, antiphosphatidylethanolamine, quently involved vessel is the middle cerebral artery.
antiphosphatidylcholine, and antiphosphatidylglycerol). Transient ischemic attacks (TIAs) and amaurosis fugax
However, these assays have not been subjected to quali- also are associated with antiphospholipid antibodies (19,
ty control or standardization and are of uncertain clinical 31). Antiphospholipid antibodies are present in 4–6% of
value. In contrast, tests for antiphospholipid antibodies otherwise healthy individuals with stroke who are
other than lupus anticoagulant and anticardiolipin anti- younger than 50 years (32, 33). Coronary occlusions
bodies that appear to correlate with thrombotic risk also are reported (3). Individuals with unexplained arte-
include antiprothrombin, antiannexin V, and anti-β2-gly- rial thrombosis, stroke, amaurosis fugax, or transient
coprotein I antibodies. However, although they may ischemic attacks should undergo testing for antiphos-
prove useful in the future, they cannot be recommended pholipid antibodies.
for clinical use at this time. Autoimmune thrombocytopenia occurs in 40–50%
of individuals with primary antiphospholipid syndrome
(2, 3, 34). Thrombocytopenia associated with antiphos-
Medical Complications of pholipid antibodies is extremely difficult to distinguish
from idiopathic thrombocytopenic purpura, although
Antiphospholipid the pertinent platelet antigens appear to differ in
Syndrome antiphospholipid syndrome and idiopathic thrombocy-
topenic purpura. Thrombocytopenia caused by idio-
The most common and serious complications associated pathic thrombocytopenic purpura is treated the same as
with antiphospholipid syndrome are venous and arterial thrombocytopenia caused by antiphospholipid syn-
thromboses (4, 5, 26). Most thrombotic events (65– drome.
70%) are venous (27, 28). Approximately 2% of all A variety of other medical conditions have been
patients with venous thrombosis will test positive for associated with antiphospholipid antibodies, including
antiphospholipid antibodies (29). Although the most autoimmune hemolytic anemia, livedo reticularis, cuta-
frequent site of venous thrombosis is a lower extremity, neous ulcers, chorea gravidarum, multiinfarct dementia,
thrombosis can occur in almost any blood vessel in the and transverse myelitis (2, 3). A recently described con-
body, and occlusions in unusual locations should dition termed catastrophic antiphospholipid syndrome
prompt clinicians to consider the diagnosis of antiphos- occurs in some individuals who develop progressive
pholipid syndrome. It is estimated that between 0.5% thromboses and multiorgan failure (35). Others have a
and 2% of the asymptomatic people incidentally found severe illness postpartum primarily consisting of car-
to have antiphospholipid antibodies eventually will diopulmonary failure and fever, as well as renal insuffi-
develop thromboses each year (30). Up to one half of ciency and multiple thromboses (36–38).

VOL. 106, NO. 5, PART 1, NOVEMBER 2005 ACOG Practice Bulletin Antiphospholipid Syndrome 1115
Obstetric Complications pregnancies in women with antiphospholipid syndrome
resulted in live births that occurred before 34 weeks of
A large proportion of pregnancy losses related to gestation (8).
antiphospholipid antibodies are second-trimester or
third-trimester fetal deaths. Although fetal deaths nor-
mally account for only a small proportion of all preg-
nancy losses in the general population (39), 50% of
Clinical Considerations and
pregnancy losses in a cohort of 76 women (333 pregnan- Recommendations
cies) with antiphospholipid syndrome were fetal deaths
Who should be tested for antiphospholipid

▲
(40). Of the 76 women in this study, 80% had at least
one fetal death. antibodies?
Antiphospholipid antibodies also are associated with
recurrent early pregnancy loss. Observational studies The principal manifestations of antiphospholipid syn-
have consistently documented positive test results for drome are venous or arterial thromboses, pregnancy
antiphospholipid antibodies in a higher proportion of loss, and morbidity. Generally accepted indications for
women with recurrent spontaneous abortion than in con- antiphospholipid antibody testing are listed in Table 1.
trols (25, 41–49). Most studies report positive test results Although most are straightforward, the obstetric indica-
for antiphospholipid antibodies in 5–20% of women with tions are a matter of some controversy. In part, this results
recurrent pregnancy loss. However, many positive results from poorly characterized obstetric details in available
are low titer or IgM isotype only. Although low levels of studies and the need for additional information. The pre-
antiphospholipid antibodies may prove relevant to obstet- liminary criteria for antiphospholipid syndrome (10)
ric outcome, as stated earlier, they identify a distinct developed in 1999 by an international group of experts
population at lower risk for disorders related to antiphos- recognized obstetric complications occurring in both the
pholipid antibodies than patients with antiphospholipid preembryonic–embryonic period and the fetal–neonatal
syndrome (19). In contrast to recurrent pregnancy loss, periods and divided them into three categories, one
antiphospholipid antibodies are not associated with spo- encompassing early pregnancy loss and the other two
radic preembryonic or embryonic pregnancy loss (50). relating primarily to complications in second or third
Preeclampsia is associated with antiphospholipid syn- trimesters. Thus, the accepted obstetric clinical criteria
drome (8, 9). In one observational study of 54 women, are 1) one or more unexplained deaths of a morpho-
50% of those with antiphospholipid syndrome had logically normal fetus at or beyond the 10th week of
preeclampsia and 25% had severe preeclampsia (8). gestation, 2) one or more premature births of a morpho-
Between 11% and 17% of women with preeclampsia will logically normal neonate at or before the 34th week of
test positive for antiphospholipid antibodies (51–54). The gestation resulting from preeclampsia, eclampsia, or pla-
association is strongest in women with severe, early onset cental insufficiency, or 3) three or more unexplained con-
(<34 weeks of gestation) preeclampsia. However, term secutive spontaneous abortions before the 10th week of
preeclampsia is not associated with increased levels of gestation. Unexplained venous or arterial thrombosis, or
antiphospholipid antibodies (55). a small-vessel thrombosis (in the absence of inflamma-
Intrauterine growth restriction (IUGR) complicates tion of the vessel wall), are the nonobstetric clinical cri-
pregnancies in women with antiphospholipid syndrome, teria for antiphospholipid syndrome.
occurring in 15–30% in most series (8, 9, 43, 56). There Other conditions associated with antiphospholipid
is conflicting evidence of the link between antiphospho- syndrome include hemolytic anemia, autoimmune
lipid antibodies and IUGR (57). Although some studies thrombocytopenia, amaurosis fugax, livedo reticularis,
have not found a correlation between antiphospholipid systemic lupus erythematosus, and a false-positive RPR.
antibodies and IUGR (22, 58), this discrepancy may These conditions are not considered clinical criteria for
result from the inclusion of some women with low-posi- antiphospholipid syndrome; therefore, testing individuals
tive test results for antiphospholipid antibodies (9, 24, with these conditions alone is not warranted.
43). Antiphospholipid antibodies, especially low-level or
Uteroplacental insufficiency, preeclampsia, and IgM anticardiolipin antibodies, are present in a few
IUGR all increase the risk of indicated preterm delivery healthy people (18, 21) and are probably meaningless.
in women with antiphospholipid syndrome. The risk is Clinicians who test for antiphospholipid antibodies in
greatest in women with high titers of antiphospholipid women without clinical features of antiphospholipid syn-
antibodies who meet strict criteria for antiphospholipid drome may be left with an uninterpretable positive test
syndrome. In one report, approximately one third of result and a management dilemma. It is best to avoid such

1116 ACOG Practice Bulletin Antiphospholipid Syndrome OBSTETRICS & GYNECOLOGY

Table 1. Preliminary Classification Criteria for positive screening test result for lupus anticoagulant must
Antiphospholipid Syndrome* be further investigated according to established criteria
(Table 1). A prolongation of the phospholipid-based clot-
Criteria Definition ting assay must be confirmed by mixing with normal plas-
Clinical ma. The subsequent normalization of the clotting time is
Obstetric 1) Three or more consecutive spontaneous abortions an indication of other causes and not the presence of
before the 10th week of gestation antiphospholipid antibodies. Although lupus anticoagu-
2) One or more unexplained fetal deaths at or beyond lant is interpreted as either present or absent, anticardi-
the 10th week of gestation olipin must be abnormal in moderate to high (>20 GPL or
3) Severe preeclampsia or placental insufficiency >20 MPL) titers to be considered clinically significant.
necessitating birth before the 34th week of Positive results require a repeat test after several weeks to
gestation exclude a transient, clinically unimportant antibody. Other
Vascular 1) Unexplained venous thrombosis antibodies, such as antiphosphatidylserine, antiphos-
thrombosis 2) Unexplained arterial thrombosis phatidylinositol, antiphosphatidylethanolamine, antiphos-
3) Small-vessel thrombosis in any tissue or organ, phatidylcholine, and antiphosphatidylglycerol, are not
without significant evidence of inflammation used as laboratory criteria for the diagnosis of antiphos-
of the vessel wall
pholipid syndrome.
Laboratory

▲
Anticardiolipin Anticardiolipin antibody of IgG or IgM isotype in How should antiphospholipid syndrome be
medium to high titers, on two or more occasions at managed during pregnancy and the postpar-
least 6 weeks apart, measured by standardized
enzyme-linked immunosorbent assay tum period?
Lupus Lupus anticoagulant present in plasma, on two or The goals of treatment for antiphospholipid syndrome
anticoagulant more occasions at least 6 weeks apart, detected during pregnancy are to improve maternal and fetal–
according to guidelines of the International Society on neonatal outcome by reducing the risk of pregnancy loss,
Thrombosis and Hemostasis, in the following steps:
preeclampsia, placental insufficiency, and preterm birth
1) Demonstration of a prolonged phospholipid- and to reduce or eliminate the maternal thrombotic risk of
dependent coagulation screening test (eg, activated
partial thromboplastin time, kaolin clotting time,
antiphospholipid syndrome during pregnancy. Two
dilute Russell’s viper venom time, dilute prothrom- recent reviews (59, 60) have emphasized that case series
bin time) and treatment trials tend to include individuals whose
2) Failure to correct the prolonged screening test by antiphospholipid syndrome diagnosis falls into one of
mixing with normal platelet-poor plasma two groups: those with a history of thrombotic events and
3) Shortening or correction of the prolonged screening those without a history.
test by the addition of excess phospholipids Treatment of women with antiphospholipid syn-
4) Exclusion of other coagulopathies (eg, factor VIII drome without a thrombotic event is controversial. A
inhibitor, heparin) as clinically indicated recent meta-analysis suggested that, for women with
recurrent miscarriage as the clinical criteria, prophylactic
*Definite antiphospholipid syndrome is considered to be present if at least one
of the clinical criteria and one of the laboratory criteria are met. heparin and low-dose aspirin may reduce pregnancy loss
Adapted from Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette by 50% (61). This combined therapy appears superior to
JC, et al. International consensus statement on preliminary classification criteria low-dose aspirin alone or prednisone. Few data from con-
for definite antiphospholipid syndrome: report of an international workshop. trolled trials are available on the efficacy of various treat-
Arthritis Rheum 1999;42:1309–11. Copyright © Wiley-Liss Inc. Reprinted with
permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc.
ment regimens for women with antiphospholipid
syndrome with other obstetric clinical events (severe
preeclampsia, uteroplacental insufficiency). Many
problems by testing only patients with disorders clearly experts recommend prophylactic heparin and aspirin in
related to antiphospholipid antibodies. these women. For women with antiphospholipid syn-
drome without a history of a thrombotic event, some
What laboratory criteria are used for the physicians recommend initiation of heparin before con-
▲

diagnosis of antiphospholipid syndrome? ception, although no clinical trial supports this recom-
mendation. Most experts recommend 6–8 weeks of
The initial diagnosis of antiphospholipid syndrome postpartum thromboprophylaxis in women with obstetric
requires testing for anticardiolipin antibodies by enzyme- antiphospholipid syndrome (59).
linked immunosorbent assay and lupus anticoagulant with For women with antiphospholipid syndrome who
two sensitive phospholipid-dependent clotting assays. A have had a thrombotic event, most experts recommend

VOL. 106, NO. 5, PART 1, NOVEMBER 2005 ACOG Practice Bulletin Antiphospholipid Syndrome 1117
 ▲
full heparin anticoagulation (62). Patients enrolled in What is appropriate long-term management
most published series also received low-dose aspirin, but of antiphospholipid syndrome?
the benefit of adding aspirin is unknown. Several
approaches to the peripartum management of anticoagu- Long-term risks for women with antiphospholipid syn-
lation therapy in these patients are available, thus treat- drome include thrombosis and stroke. In studies of
ment should be individualized. women with antiphospholipid syndrome, including stud-
Anticoagulation should be continued for a minimum ies of women without prior thrombosis, one half devel-
of 6 weeks postpartum to minimize the risk of maternal oped thromboses during 3–10 years of follow-up and
thromboembolism (59). After delivery, this can be safely 10% developed systemic lupus erythematosus (30, 31,
accomplished with coumarin. Patients with antiphospho- 68). The studied populations were highly selected refer-
lipid syndrome should be referred to an internist or hem- ral populations; thus selection may have been biased
atologist after delivery to prescribe anticoagulation toward severe disease. However, no method currently
therapy outside of pregnancy. predicts which patients with antiphospholipid syndrome
using anticoagulants will develop recurrent thrombosis
Other therapies that have been suggested for treatment
once treatment is discontinued. In addition, no evidence
of pregnant women with antiphospholipid syndrome
exists to support long-term treatment when thrombotic
include corticosteroids and intravenous immunoglobulin
events occur in the presence of other risk factors (30).
(IVIG). Several case series have reported a 60–70% rate of
Therefore, for long-term management, patients with
successful pregnancies in women with antiphospholipid
antiphospholipid syndrome should be referred to a physi-
syndrome treated with prednisone and low-dose aspirin
cian with expertise in treatment of the syndrome, such as
(63). However, a meta-analysis of therapeutic trials an internist or hematologist.
showed no reduction in pregnancy loss in women treated Pregnancy and the use of estrogen-containing oral
with prednisone and low-dose aspirin (61). Direct com- contraceptives appear to increase the risk for thrombosis
parison of studies is difficult because subjects had differ- in women with antiphospholipid syndrome. In retrospec-
ent clinical and laboratory features and dosing regimens, tive analyses of women with antiphospholipid syndrome,
and many trials were nonrandomized and poorly con- most thromboses occurred in association with pregnancy
trolled. Thus, the efficacy of prednisone in pregnancies or oral contraceptive use (8, 31). Thus, estrogen-contain-
complicated by antiphospholipid syndrome remains ing oral contraceptives in women with well-characterized
uncertain. antiphospholipid syndrome should be avoided.
Treatment with IVIG has been promising in a small
number of cases refractory to heparin or prednisone
(64–66). Obstetric complications have been rare in Summary of
patients treated with IVIG (66). However, most of these
women also were treated with heparin or prednisone and Recommendations and
low-dose aspirin. A recent small randomized controlled Conclusions
study demonstrated no greater benefit from IVIG (plus
heparin and aspirin) than with heparin and aspirin alone The following recommendation is based on limited
(67). Because the efficacy of IVIG has not been proved in or inconsistent scientific evidence (Level B):
appropriately designed studies and the drug is extremely
▲

expensive, it is not recommended as primary therapy. Testing for antiphospholipid antibodies should be
limited to those women with appropriate medical or
obstetric histories.
▲

Should women with antiphospholipid

syndrome have antepartum surveillance?
The following recommendations are based prima-
Pregnant women with antiphospholipid syndrome should rily on consensus and expert opinion (Level C):
be examined frequently and instructed about the signs
▲

and symptoms of preeclampsia and thrombosis. The pri- Women with antiphospholipid syndrome and no
mary goal of prenatal visits after 20 weeks of gestation is thrombotic history should receive prophylactic doses
the detection of preeclampsia or growth restriction. of heparin and low-dose aspirin during pregnancy
Because of the risk for growth restriction, consideration and the postpartum period (6–8 weeks).
▲

should be given to serial ultrasonographic assessment. Women with antiphospholipid syndrome and previ-
Antepartum testing should be considered after 32 weeks ous history of thrombosis should receive full antico-
of gestation, or earlier if there are signs of growth agulation throughout pregnancy and the postpartum
restriction. period (6–8 weeks).

1118 ACOG Practice Bulletin Antiphospholipid Syndrome OBSTETRICS & GYNECOLOGY

▲ Women with antiphospholipid syndrome should be anticoagulant activity specific for phospholipids? Br J
referred to an internist or hematologist for long-term Haematol 1993;85:124–32. (Level II-3)
follow-up. 13. Chamley LW, Pattison NS, McKay EJ. Separation of
lupus anticoagulant from anticardiolipin antibodies by
▲

Women with antiphospholipid syndrome should ion-exchange and gel filtration chromatography.
avoid estrogen-containing oral contraceptives. Haemostasis 1991;21:25–9. (Level III)
Because of the risk for growth restriction, consider- 14. Passam F, Krilis S. Laboratory tests for antiphospholipid
▲

ation should be given to serial ultrasonographic syndrome: current concepts. Pathology 2004;36:129–38.
(Level III)
assessment. Antepartum testing should be consid-
ered after 32 weeks of gestation, or earlier if there 15. Roubey R. Autoantibodies to phospholipid-binding plas-
ma proteins: a new review of lupus anticoagulants and
are signs of growth restriction. other “antiphospholipid” autoantibodies. Blood 1994;84:
2854–67. (Level III)
16. Coulam CB, McIntyre JA, Wagenknecht D, Rote N.
References Interlaboratory inconsistencies in detection of anticardi-
olipin antibodies. Lancet 1990;335:865. (Level II-3)
1. Lockshin MD. Antiphospholipid antibody. Babies, blood 17. Peaceman AM, Silver RK, MacGregor SN, Socol ML.
clots, biology. JAMA 1997;277:1549–51. (Level III) Interlaboratory variation in antiphospholipid antibody
2. Alarcon-Segovia D, Perez-Vazquez ME, Villa AR, testing. Am J Obstet Gynecol 1992;166:1780–4; discus-
Drenkard C, Cabiedes J. Preliminary classification criteria sion 1784–7. (Level III)
for the antiphospholipid syndrome within systemic lupus 18. Harris EN, Spinnato JA. Should anticardiolipin tests be
erythematosus. Semin Arthritis Rheum 1992;21:275–86. performed in otherwise healthy pregnant women? Am J
(Level II-2) Obstet Gynecol 1991;165:1272–7. (Level II-2)
3. Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, 19. Silver RM, Porter TF, van Leeuween I, Jeng G, Scott JR,
Machin SJ, Barquinero J, et al. The “primary” antiphos- Branch DW. Anticardiolipin antibodies: clinical conse-
pholipid syndrome: major clinical and serological fea- quences of “low titers.” Obstet Gynecol 1996;87:
tures. Medicine (Baltimore) 1989;68:366–74. (Level III) 494–500. (Level II-3)
4. Harris EN. Syndrome of the black swan. Br J Rheumatol 20. Vaarala O, Palosuo T, Kleemola M, Aho K. Anti-
1987;26:324–6. (Level III) cardiolipin response in acute infections. Clin Immunol
5. Harris EN, Chan JK, Asherson RA, Aber VR, Gharavi AE, Immunopathol 1986;41:8–15. (Level II-3)
Hughes GR. Thrombosis, recurrent fetal loss, and throm- 21. Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster
bocytopenia. Predictive value of the anticardiolipin anti- B, Hobbins JC. The prevalence and biologic significance
body test. Arch Intern Med 1986;146:2153–6. (Level II-3) of lupus anticoagulant and anticardiolipin antibodies in a
general obstetric population. Am J Obstet Gynecol
6. Levine JS, Branch DW, Rauch J. The antiphospholipid
1989;161:369–73. (Level II-2)
syndrome. N Engl J Med 2002;346:752–63. (Level III)
22. Lynch A, Marlar R, Murphy J, Davila G, Santos M,
7. Viard JP, Amoura Z, Bach JF. Association of anti-beta 2
Rutledge J, et al. Antiphospholipid antibodies in predict-
glycoprotein I antibodies with lupus-type circulating anti- ing adverse pregnancy outcome. A prospective study. Ann
coagulant and thrombosis in systemic lupus erythemato- Intern Med 1994;120:470–5. (Level II-2)
sus. Am J Med 1992;93:181–6. (Level II-3)
23. Yasuda M, Takakuwa K, Tokunaga A, Tanaka K.
8. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott Prospective studies of the association between anticardi-
JR. Outcome of treated pregnancies in women with olipin antibody and outcome of pregnancy. Obstet
antiphospholipid syndrome: an update of the Utah experi- Gynecol 1995;86:555–9. (Level II-2)
ence. Obstet Gynecol 1992;80:614–20. (Level II-3)
24. Lockshin MD, Druzin ML, Qamar T. Prednisone does not
9. Lima F, Khamashta MA, Buchanan NM, Kerslake S, Hunt prevent recurrent fetal death in women with antiphospho-
BJ, Hughes GR. A study of sixty pregnancies in patients lipid antibody. Am J Obstet Gynecol 1989;160:439–43.
with the antiphospholipid syndrome. Clin Exp Rheumatol (Level II-3)
1996;14:131– 6. (Level II-3)
25. Rai RS, Regan L, Clifford K, Pickering W, Dave M,
10. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch Mackie I, et al. Antiphospholipid antibodies and beta 2-
DW, Piette JC, et al. International consensus statement on glycoprotein-I in 500 women with recurrent miscarriage:
preliminary classification criteria for definite antiphos- results of a comprehensive screening approach. Hum
pholipid syndrome: report of an international workshop. Reprod 1995;10:2001–5. (Level II-3)
Arthritis Rheum 1999;42:1309–11. (Level III)
26. Hughes GR, Harris NN, Gharavi AE. The anticardiolipin
11. Triplett DA, Brandt JT, Musgrave KA, Orr CA. The rela- syndrome. J Rheumatol 1986;13:486–9. (Level III)
tionship between lupus anticoagulants and antibodies to
27. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt
phospholipid. JAMA 1988;259:550–4. (Level II-3)
BJ, Hughes GR. The management of thrombosis in the
12. Pierangeli SS, Harris EN, Gharavi AE, Goldsmith G, antiphospholipid-antibody syndrome. N Engl J Med
Branch DW, Dean WL. Are immunoglobulins with lupus 1995;332:993–7. (Level II-2)

VOL. 106, NO. 5, PART 1, NOVEMBER 2005 ACOG Practice Bulletin Antiphospholipid Syndrome 1119
28. Rosove MH, Brewer PM. Antiphospholipid thrombosis: 44. MacLean MA, Cumming GP, McCall F, Walker ID,
clinical course after the first thrombotic event in 70 Walker JJ. The prevalence of lupus anticoagulant and anti-
patients. Ann Intern Med 1992;117:303–8. (Level II-2) cardiolipin antibodies in women with a history of first
29. Malm J, Laurell M, Nilsson IM, Dahlback B. Throm- trimester miscarriages. Br J Obstet Gynaecol 1994;101:
boembolic disease—critical evaluation of laboratory inves- 103–6. (Level II-3)
tigation. Thromb Haemost 1992;68:7–13. (Level II-2) 45. Out HJ, Kooijman CD, Bruinse HW, Derksen RH.
30. Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Histopathological findings in placentae from patients with
Lockshin MD. High thrombosis rate after fetal loss in intra-uterine fetal death and anti-phospholipid antibodies.
antiphospholipid syndrome: effective prophylaxis with Eur J Obstet Gynecol Reprod Biol 1991;41:179–86.
(Level II-3)
aspirin. Arthritis Rheum 2001;44:1466–7. (Level III)
46. Parazzini F, Acaia B, Faden D, Lovotti M, Marelli G,
31. Silver RM, Draper ML, Scott JR, Lyon JL, Reading J,
Cortelazzo S. Antiphospholipid antibodies and recurrent
Branch DW. Clinical consequences of antiphospholipid
abortion. Obstet Gynecol 1991;77:854–8. (Level II-2)
antibodies: an historic cohort study. Obstet Gynecol 1994;
83:372–7. (Level II-3) 47. Parke AL, Wilson D, Maier D. The prevalence of antiphos-
pholipid antibodies in women with recurrent spontaneous
32. Brey RL, Hart RG, Sherman DG, Tegeler CH.
abortion, women with successful pregnancies, and women
Antiphospholipid antibodies and cerebral ischemia in
who have never been pregnant. Arthritis Rheum
young people. Neurology 1990;40:1190–6. (Level II-2)
1991;34:1231–5. (Level II-3)
33. Ferro D, Quintarelli C, Rasura M, Antonini G, Violi F.
48. Petri M, Golbus M, Anderson R, Whiting-O’Keefe Q,
Lupus anticoagulant and the fibrinolytic system in young
Corash L, Hellmann D. Antinuclear antibody, lupus anti-
patients with stroke. Stroke 1993;24:368–70. (Level II-2)
coagulant, and anticardiolipin antibody in women with
34. Harris EN, Asherson RA, Gharavi AE, Morgan SH, Derue idiopathic habitual abortion. A controlled, prospective
G, Hughes GR. Thrombocytopenia in SLE and related study of forty-four women. Arthritis Rheum 1987;30:
autoimmune disorders: association with anticardiolipin 601–6. (Level II-2)
antibody. Br J Haematol 1985;59:227–30. (Level II-3)
49. Yetman DL, Kutteh WH. Antiphospholipid antibody pan-
35. Asherson RA, Cervera R, Piette JC, Font J, Lie JT, els and recurrent pregnancy loss: prevalence of anticardi-
Burcoglu A, et al. Catastrophic antiphospholipid syn- olipin antibodies compared with other antiphospholipid
drome. Clinical and laboratory features of 50 patients. antibodies. Fertil Steril 1996;66:540–6. (Level II-2)
Medicine (Baltimore) 1998;77:195–207. (Level III) 50. Infante-Rivard C, David M, Gauthier R, Rivard GE. Lupus
36. Hochfeld M, Druzin ML, Maia D, Wright J, Lambert RE, anticoagulants, anticardiolipin antibodies, and fetal loss. A
McGuire J. Pregnancy complicated by primary antiphos- case-control study. N Engl J Med 1991;325:1063–6.
pholipid antibody syndrome. Obstet Gynecol 1994; (Level II-2)
83:804–5. (Level III) 51. Branch DW, Andres R, Digre KB, Rote NS, Scott JR. The
37. Kochenour NK, Branch DW, Rote NS, Scott JR. A new association of antiphospholipid antibodies with severe
postpartum syndrome associated with antiphospholipid preeclampsia. Obstet Gynecol 1989;73:541–5. (Level
antibodies. Obstet Gynecol 1987;69:460–8. (Level III) II-2)
38. Kupferminc MJ, Lee MJ, Green D, Peaceman AM. Severe 52. Milliez J, Lelong F, Bayani N, Jannet D, el Medjadji M,
postpartum pulmonary, cardiac, and renal syndrome asso- Latrous H, et al. The prevalence of autoantibodies during
ciated with antiphospholipid antibodies. Obstet Gynecol third-trimester pregnancy complicated by hypertension or
1994;83:806–7. (Level III) idiopathic fetal growth retardation. Am J Obstet Gynecol
39. Goldstein SR. Embryonic death in early pregnancy: a new 1991;165:51–6. (Level II-2)
look at the first trimester. Obstet Gynecol 1994;84:294–7. 53. Moodley J, Bhoola V, Duursma J, Pudifin D, Byrne S,
(Level III) Kenoyer DG. The association of antiphospholipid anti-
40. Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW. bodies with severe early-onset pre-eclampsia. S Afr Med J
Antiphospholipid antibodies and fetal death. Obstet 1995;85:105–7. (Level III)
Gynecol 1996;87:489–93. (Level II-2) 54. Sletnes KE, Wisloff F, Moe N, Dale PO. Antiphospholipid
41. Balasch J, Creus M, Fabregues F, Reverter JC, Carmona antibodies in pre-eclamptic women: relation to growth
F, Tassies D, et al. Antiphospholipid antibodies and retardation and neonatal outcome. Acta Obstet Gynecol
human reproductive failure. Hum Reprod 1996;11: Scand 1992;71:112–7. (Level II-2)
2310–5. (Level II-2) 55. Scott RA. Anti-cardiolipin antibodies and pre-eclampsia.
42. Barbui T, Cortelazzo S, Galli M, Parazzini F, Radici E, Br J Obstet Gynaecol 1987;94:604–5. (Level III)
Rossi E, et al. Antiphospholipid antibodies in early repeat- 56. Caruso A, De Carolis S, Ferrazzani S, Valesini G, Caforio
ed abortions: a case-controlled study. Fertil Steril 1988; L, Mancuso S. Pregnancy outcome in relation to uterine
50:589–92. (Level II-2) artery flow velocity waveforms and clinical characteristics
43. Kutteh WH. Antiphospholipid antibody-associated recur- in women with antiphospholipid syndrome. Obstet
rent pregnancy loss: treatment with heparin and low-dose Gynecol 1993;82:970–7. (Level II-3)
aspirin is superior to low-dose aspirin alone. Am J Obstet 57. Polzin WJ, Kopelman JN, Robinson RD, Read JA, Brady
Gynecol 1996;174:1584–9. (Level II-1) K. The association of antiphospholipid antibodies with

1120 ACOG Practice Bulletin Antiphospholipid Syndrome OBSTETRICS & GYNECOLOGY

 pregnancies complicated by fetal growth restriction.
Obstet Gynecol 1991;78:1108–11. (Level II-2) The MEDLINE database, the Cochrane Library, and the
American College of Obstetricians and Gynecologists’ own
58. Pattison NS, Chamley LW, McKay EJ, Liggins GC, internal resources and documents were used to conduct a
Butler WS. Antiphospholipid antibodies in pregnancy: literature search to locate relevant articles published be-
prevalence and clinical associations. Br J Obstet Gynaecol tween January 1985 and June 2005. The search was re-
1993;100:909–13. (Level II-3) stricted to articles published in the English language.
59. Branch DW, Khamashta MA. Antiphospholipid syn- Priority was given to articles reporting results of original
drome: obstetric diagnosis, management, and controver- research, although review articles and commentaries also
sies. Obstet Gynecol 2003;101:1333–44. (Level III) were consulted. Abstracts of research presented at sympo-
sia and scientific conferences were not considered adequate
60. Derksen RH, Khamashta MA, Branch DW. Management
for inclusion in this document. Guidelines published by or-
of the obstetric antiphospholipid syndrome. Arthritis ganizations or institutions such as the National Institutes of
Rheum 2004;50:1028–39. (Level III) Health and ACOG were reviewed, and additional studies
61. Empson M, Lassere M, Craig JC, Scott JR. Recurrent were located by reviewing bibliographies of identified arti-
pregnancy loss with antiphospholipid antibody: a system- cles. When reliable research was not available, expert opin-
atic review of therapeutic trials. Obstet Gynecol 2002;99: ions from obstetrician–gynecologists were used.
135–44. (Level III) Studies were reviewed and evaluated for quality according
62. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of to the method outlined by the U.S. Preventive Services Task
antithrombotic agents during pregnancy: the Seventh Force:
ACCP Conference on Antithrombotic and Thrombolytic I Evidence obtained from at least one properly de-
Therapy. Chest 2004;126(suppl 3):627S– 44S. (Level III) signed randomized controlled trial.
63. Lubbe WF, Walkom P, Alexander CJ. Hepatic and splenic II-1 Evidence obtained from well-designed controlled
haemorrhage as a complication of toxaemia of pregnancy trials without randomization.
in a patient with circulating lupus anticoagulant. N Z Med II-2 Evidence obtained from well-designed cohort or
J 1982;95:842–4. (Level III) case–control analytic studies, preferably from more
than one center or research group.
64. Carreras LD, Perez GN, Vega HR, Casavilla F. Lupus II-3 Evidence obtained from multiple time series with or
anticoagulant and recurrent fetal loss: successful treat- without the intervention. Dramatic results in uncon-
ment with gammaglobulin. Lancet 1988;2:393–4. (Level trolled experiments also could be regarded as this
III) type of evidence.
65. Scott JR, Branch DW, Kochenour NK, Ward K. III Opinions of respected authorities, based on clinical
Intravenous immunoglobulin treatment of pregnant experience, descriptive studies, or reports of expert
patients with recurrent pregnancy loss caused by committees.
antiphospholipid antibodies and Rh immunization. Am J Based on the highest level of evidence found in the data,
Obstet Gynecol 1988;159:1055–6. (Level III) recommendations are provided and graded according to the
following categories:
66. Spinnato JA, Clark AL, Pierangeli SS, Harris EN.
Intravenous immunoglobulin therapy for the antiphospho- Level A—Recommendations are based on good and consis-
lipid syndrome in pregnancy. Am J Obstet Gynecol tent scientific evidence.
1995;172:690–4. (Level III) Level B—Recommendations are based on limited or incon-
67. Branch DW, Peaceman AM, Druzin M, Silver RK, El- sistent scientific evidence.
Sayed Y, Silver RM, et al. A multicenter, placebo-con- Level C—Recommendations are based primarily on con-
trolled pilot study of intravenous immune globulin sensus and expert opinion.
treatment of antiphospholipid syndrome during pregnan-
cy. The Pregnancy Loss Study Group. Am J Obstet
Gynecol 2000;182:122–7. (Level I) Copyright © November 2005 by the American College of Obstetricians
68. Shah NM, Khamashta MA, Atsumi T, Hughes GR. and Gynecologists. All rights reserved. No part of this publication may
Outcome of patients with anticardiolipin antibodies: a 10 be reproduced, stored in a retrieval system, or transmitted, in any form
year follow-up of 52 patients. Lupus 1998;7:3–6. (Level or by any means, electronic, mechanical, photocopying, recording, or
II-2) otherwise, without prior written permission from the publisher.
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