ARTHRITIS & RHEUMATISM
Vol. 50, No. 4, April 2004, pp 1028–1039
REVIEW
Management of the Obstetric Antiphospholipid Syndrome
Ronald H. W. M. Derksen,1 Munther A. Khamashta,2 and D. Ware Branch3
Introduction
Over the past 2 decades, the antiphospholipid
syndrome (APS) has become a major research font in
rheumatology. Antiphospholipid antibodies (aPL) are
now recognized as representing the most frequent ac-
quired risk factor for thrombophilia and as being a
treatable cause of pregnancy loss (1). With the wide-
spread use of tests to detect aPL, rheumatologists and
obstetricians frequently have to make decisions regard-
ing the consequences of positive test results in women
who wish to conceive or are pregnant. We review herein
studies on the management of pregnancy in women with
aPL and provide guidelines for treatment, despite our
conclusion that the many shortcomings of currently
available data hamper evidence-based recommendations.
The obstetric APS
In the early 1980s, retrospective studies of pa-
tients with systemic lupus erythematosus (SLE) estab-
lished associations between aPL and thrombosis (2),
fetal loss, (3) and thrombocytopenia (4). This clinico-
serologic entity was termed APS (5). Soon, APS in
individuals without another autoimmune disease was
described as primary APS (6). Criteria for the diagnosis
of APS were proposed in 1987 (7), with (recurrent) fetal
loss being the obstetric criterion. Terms such as recur-
rent pregnancy loss (8) and recurrent spontaneous abor-
Dr. Khamashta’s work was supported by Lupus UK and the
St. Thomas’ Lupus Trust. Dr. Branch’s work was supported by the
H. A. and Edna Benning Presidential Endowed Chair at the University
of Utah.
1
Ronald H. W. M. Derksen, MD, PhD: University Medical
Center, Utrecht, The Netherlands; 2Munther A. Khamashta, MD,
FRCP, PhD: Lupus Research Unit, Rayne Institute, St. Thomas’
Hospital, London, UK; 3D. Ware Branch, MD: University of Utah
Health Sciences Center, Salt Lake City.
Address correspondence and reprint requests to Ronald
H. W. M. Derksen, MD, PhD, Department of Rheumatology and
Clinical Immunology (F02.127), University Medical Center, PO Box
85500, Utrecht 3508GA, The Netherlands. E-mail: r.h.w.m.derksen@
digd.azu.nl.
Submitted for publication June 18, 2003; accepted in revised
form December 3, 2003.
1028
DOI 10.1002/art.20105
© 2004, American College of Rheumatology
tion (9) were also used. This confusing nomenclature
refers to the traditional classification of pregnancy loss,
with losses prior to 20 weeks of gestation classified as
abortions, and death in utero thereafter classified as
stillbirth or fetal loss.
From a pathophysiologic point of view, this clas-
sification is inaccurate. Recent advances in reproductive
biology and observations in normal early pregnancies
allow pregnancy loss to be categorized into at least 3
developmental periods (10). The preembryonic period
lasts from conception through to the beginning of the
fifth menstrual week. This is followed by the embryonic
period, which lasts from 5 weeks through the ninth
menstrual week. The fetal period begins at 10 menstrual
weeks (i.e., 70 days from conception) and extends until
the time of delivery. In unselected obstetric patients,
10–15% of recognized pregnancies end in loss, with
⬎85% of losses occurring during the (pre)embryonic
periods (11,12). The rate of fetal loss after 14 weeks of
gestation is 2% (11). Chromosomal abnormalities of the
conceptus account for more than half of sporadic
(pre)embryonic losses, and, in many cases, a visible
embryo never forms. In contrast, genetic abnormalities
of the conceptus are less common in women with at least
3 consecutive pregnancy losses (12). In women with ⱖ3
spontaneous abortions, a normal embryonic ultrasound
beyond 6–8 weeks of gestation provides a favorable
prognosis with a ⱖ80% chance for a live birth (13). The
preliminary classification criteria for definite APS pub-
lished in 1999 (14) (Table 1) include this refined classi-
fication of pregnancy loss and recognize that a preterm
live birth accompanied by severe preeclampsia or severe
placental insufficiency is comparable with a loss late in
pregnancy.
The serologic criteria for APS are the persistent
presence of lupus anticoagulant (LAC) or medium-to-
high levels of IgG or IgM anticardiolipin antibodies
(aCL) (7,14). LAC refers to antibodies that prolong in
vitro clotting times of plasma by interference with as-
semblage of components of the coagulation cascade on a
phospholipid template (15). International guidelines for
MANAGEMENT OF OBSTETRIC APS
Table 1. Preliminary classification criteria for APS*
Clinical criteria
Vascular thrombosis
a. One or more clinical episodes of arterial, venous, or small-
vessel thrombosis in any tissue or organ, AND
b. Thrombosis confirmed by imaging or Doppler studies or
histopathology, with the exception of superficial venous
thrombosis, AND
c. For histopathologic confirmation, thrombosis should be
present without significant evidence of inflammation in the
vessel wall.
Pregnancy morbidity
a. One or more unexplained deaths of a morphologically
normal fetus at or beyond the 10th week of gestation, with
normal fetal morphology documented by ultrasound or by
direct examination of the fetus, OR
b. One or more premature births of a morphologically normal
neonate at or before the 34th week of gestation because of
severe preeclampsia or severe placental insufficiency OR
c. Three or more unexplained consecutive spontaneous
abortions before the 10th week of gestation, with maternal
anatomic or hormonal abnormalities and paternal and
maternal chromosomal causes excluded.
Laboratory criteria
a. Anticardiolipin antibody of IgG and/or IgM isotype in blood,
present in medium or high titer, on at least 2 occasions at
least 6 weeks apart, measured by standard enzyme-linked
immunosorbent assay for ␤2-glycoprotein I–dependent
anticardiolipin antibodies, OR
b. Lupus anticoagulant present in plasma, on 2 or more
occasions at least 6 weeks apart, detected according to the
guidelines of the International Society on Thrombosis and
Hemostasis (17).
* Definite antiphospholipid syndrome (APS) is considered to be
present if at least 1 of the clinical and 1 of the laboratory criteria are
met.
the identification of LAC have been published (16,17).
Apart from defining suitable test samples, the guidelines
indicate that sensitive phospholipid-dependent clotting
tests should be used for screening, that mixing studies
using normal plasma are essential to rule out coagula-
tion factor deficiencies as a cause for prolonged clotting
times, and that extra phospholipids should be added to
the test system to show neutralization of the abnormal-
ity. It is advised to screen with more than 1 test, because
no coagulation assay is fully sensitive for LAC.
Standardization of the aCL enzyme-linked im-
munosorbent assay (ELISA), which proved difficult
(18–20), began with the introduction of standards based
on patient sera, such as the widely used Kingston
Antiphospholipid Study (KAPS) samples (18). Use of
these samples enables the definition of “standard” units
for ELISA results. Cutoff levels for IgG aCL (in IgG
phospholipid [GPL] units) and IgM aCL (in IgM phos-
pholipid [MPL] units) have been presented in guidelines
issued by the Association of Clinical Pathologists (9),
with negative results defined as ⬍5 GPL units and ⬍3
1029
MPL units, low-positive results defined as values ⬍15
GPL units and ⬍6 MPL units, medium levels defined as
15–80 GPL units and 6–50 MPL units, and high levels
defined as ⬎80 GPL units or ⬎50 MPL units. However,
variations in the performance of the assay itself and the
patient-derived standards (21) cause wide variations in
(semiquantitative) results (21–25) and make generaliza-
tion of a specific, clinically relevant cutoff (26) hazard-
ous. The fact that many important studies on the treat-
ment of obstetric APS (27–32) evoked letters to the
editor (33–39) disputing their reported cutoffs in the
aCL ELISA illustrates that consensus is urgently
needed.
Treatment of pregnancy in women with aPL
Studies on the management of aPL-related preg-
nancies comprise 3 groups of women: 1) those without a
poor obstetric history, SLE, or previous thrombosis
(low-risk pregnancies), 2) those with recurrent early
pregnancy loss or (at least) one fetal loss in the absence
of SLE or a history of thrombosis, and 3) those with a
high frequency of fetal loss, SLE, previous thrombosis,
or a combination of these. In contrast to women in the
second and third categories, patients in the first category
(low risk) did not receive pharmacologic treatment. We
will critically review these studies, emphasizing whether
or not patients met the classification criteria for APS
(14).
Low-risk pregnancies. Four studies described the
natural course of pregnancy related to aPL in women
regarded as being at low risk for pregnancy complica-
tions (28,40–42). Patients were defined as “a normal
pregnancy population” (28), “women with no more than
2 consecutive abortions and no stillbirth” (41,40), and
“absence of recurrent fetal wastage” (although women
with fetal loss after 24 weeks of gestation were included)
(42). Because all studies used results from a single blood
sample to categorize women as positive or negative for
aPL, by definition no patient met the serologic criteria
for APS (7,14). Other breaches of the criteria were
testing for IgG aCL only (42) and the absence of a
neutralization procedure (to confirm that the addition of
extra phospholipids corrects abnormal coagulation
times) in LAC tests (28,40,41). The studies included
16–95 women with aPL and 294–915 women negative for
aPL (28,40–42) (Table 2). The timing of blood sampling
for aPL tests varied from the first antenatal visit (28) to
9 weeks (42), 13 weeks (40), and 16 weeks (41) of
gestation. This timing is relevant, because the later in
pregnancy that this sample is obtained, the higher the
1030 DERKSEN ET AL

Table 2. Studies in which live-birth rates related to aPL in low-risk titers [41]) and is supported by results from a small
pregnancies were reported* randomized study in which the pregnancy outcome in
No. of women Live-birth rate (%) aPL-positive women at low risk for pregnancy complica-
First author aPL aPL aPL aPL tions was similar for those treated with aspirin (81 mg
(reference) positive negative positive negative per day) and those who received standard care (43).
Pattison (28) 18 915 83 98 Women with recurrent early pregnancy loss or at
Lynch (40) 95 294 84 93 least one fetal loss in the absence of SLE or previous
Lockwood (41) 16 721 62 91 thrombosis. In those women whose pregnancy and clin-
Yasuda (42) 60 800 72 90
ical histories put them in the second category (those with
* aPL ⫽ antiphospholipid antibodies. recurrent early fetal loss or at least 1 fetal loss, without
SLE or previous thrombosis), 3 observational studies
chance that early losses are not taken into account when evaluated the outcome in women treated with aspirin
the outcome in women with aPL and those without aPL alone (44), those who received a combination of heparin
is compared. and aspirin (45), and those who declined pharmacologic
Despite these shortcomings and differences, all treatment and received standard care (46). In 9 prospec-
studies found lower live-birth rates in aPL-positive tive studies (12,29–32,47–50), 2 treatment strategies
women (range 62–84%) than in aPL-negative women were compared. All but 2 of these studies (47,50) were
(range 90–98%) (28,40–42) (Table 2). An association randomized studies. The treatments included placebo
between the presence of aPL and severe preeclampsia (12,29,32), aspirin alone (12,30–32,47,49), aspirin plus
was found in 2 studies (28,42), but not in another study prednisone (29,48,49), and heparin plus aspirin
(40). The Yasuda et al study (42) found a negative (30,31,47,48,50) (Table 3). Evaluation of pregnancies
association and the Lynch et al study (40) found a started with a positive pregnancy test (12,29,32,44,47,48,50)
positive association between aPL and neonatal birth or the presence of fetal heart activity (30,31,45,46,49). In
weight. contrast to the former studies, the latter studies could
All investigators advised against routine screen- not score blighted ovum or absent fetal heart beat as
ing of women with a low risk for pregnancy complica- pregnancy loss.
tions, because the frequency of aPL is low, and pharma- Most women in these studies met the criteria for
cologic treatment is not indicated in women in whom obstetric APS (14), because they had at least 3 consec-
aPL are found (28,40–42). The latter conclusion is based utive miscarriages (12,30–32,45–47,50), at least 2 unex-
on observations of uncomplicated pregnancies in un- plained pregnancy losses before 12 weeks of gestation or
treated healthy women with aPL (even those with high at least 1 pregnancy loss after 12 weeks (44,48,49), or at

Table 3. Studies on live-birth rates related to pharmacologic treatment in women with aPL and recurrent early pregnancy loss or at least 1 fetal
loss in the absence of SLE or previous thrombosis*
Live-birth rate (%) according to pharmacologic treatment

Low-dose Low-dose
First author No. of No Low-dose aspirin ⫹ aspirin ⫹
(reference) Study type women treatment aspirin heparin prednisone
Balasch (44) Prospective, observational 18 – 91 – –
Backos (45) Prospective, observational 150 – – 71 –
Rai (46) Prospective, observational 20 10 – – –
Tulppala (12) Randomized 12 17 17 – –
Pattison (32) Randomized 40 85 80 – –
Laskin (29) Randomized 88 52 – – 60
Silver (49) Randomized 34 – 100 – 100
Cowchock (48) Randomized 20 – – 75 75
Rai (30) Randomized 90 – 42 71 –
Farquharson (31) Randomized 98 – 72 78 –
Kutteh (47) Controlled, nonrandomized 50 – 44 80 –
Kutteh (50) Controlled, nonrandomized 50 – – 80/76† –

* aPL ⫽ antiphospholipid antibodies; SLE ⫽ systemic lupus erythematosus.

† Higher-dose/lower-dose heparin.
MANAGEMENT OF OBSTETRIC APS
least 2 consecutive fetal losses before 32 weeks of
gestation (29). All studies, except one that tested for IgG
aCL only (12), included tests for LAC as well as both
IgG aCL and IgM aCL. All women tested repeatedly as
aPL positive. In 4 studies (29,32,44,48), however, LAC
was not tested according to accepted guidelines (16,17),
because phospholipid dependency of coagulation abnor-
malities was not demonstrated. All but 2 studies (12,44)
used KAPS standards (18) in the aCL ELISA. The
cutoffs used for inclusion in the studies ranged from 5
GPL units (30,32,45) to 31 GPL units (48) and from 3
MPL units (30,45) to 21 MPL units (47,50). Three
studies (47,48,50) emphasized exclusion of women with
low aCL levels, and another (49) emphasized inclusion
of women with low aCL levels.
The studies differed widely regarding the propor-
tion in which LAC and aCL contributed to aPL positivity
in included women. Two studies (47,50) excluded
women with LAC, and another did not test for LAC
(12). In studies that tested women for both LAC and
aCL, the prevalence of LAC varied from 6% (49) to 91%
(30), whereas the frequency of LAC in the absence of
aCL was 6% (49), 22% (32,44), 47% (31), 55% (45), and
82% (30). We will review these studies in relation to
treatment (Table 3).
Prednisone and aspirin. Three randomized studies
included a regimen of prednisone and aspirin (29,48,49).
The pregnancy outcome of women receiving this treat-
ment was compared with that of women receiving a
combination of heparin and aspirin (48), aspirin alone
(49), or placebo (29). The daily dose of aspirin was
80–100 mg. Each study used a different dosage of
prednisone, as follows: a standard daily dose of 40 mg
throughout pregnancy, starting when pregnancy was
confirmed (48); a daily dose of 20 mg starting when
viability was confirmed, with dose adjustments through-
out pregnancy based on results of aPL tests (daily dose
10–40 mg) (49); and a daily dose of 0.8 mg/kg of body
weight (maximum 60 mg) for 4 weeks, followed by 0.5
mg/kg of body weight per day until delivery (29). In the
study by Cowchock et al (48), subcutaneous injections of
unfractionated heparin (10,000 units twice daily) were
begun when the presence of a viable pregnancy was
confirmed; downward dose adjustments were used to
obtain a mid-interval activated partial thromboplastin
time (APTT) that was within the normal range or was
similar to prolonged baseline values (mean dosage
17,000 IU/day).
Live-birth rates were 75% for both treatment
groups in the study by Cowchock et al (48) and 100% in
that by Silver et al (49). Laskin et al (29) reported live
1031
births in 60% of treated pregnancies and in 52% of
pregnancies in which placebo was given. All studies
(29,48,49) found that use of prednisone was associated
with significantly more maternal morbidity and more
preterm deliveries (often associated with preterm rup-
ture of membranes and preeclampsia). In one study (49),
lower neonatal birth weights were observed in patients
who were receiving prednisone.
Heparin and aspirin. Three randomized studies
compared pregnancy outcome in women receiving a
combination of heparin and aspirin with the outcome in
women receiving aspirin alone (30,31,47), and one study
evaluated pregnancy outcome in women treated with
aspirin combined with different doses of heparin (50). A
study comparing treatment with heparin and aspirin with
treatment with prednisone and aspirin was discussed
above (48).
The daily dose of aspirin used in these studies was
75 mg (30,31) or 81 mg (47,50). In some studies, aspirin
was started before conception (47,50), and in others
aspirin was initiated at the time of a positive pregnancy
test (30) or at the time of randomization (before 12
weeks) (31). Heparin was started at the time of a positive
pregnancy test (47,50), when fetal heart activity was
recorded (30), or before 12 weeks of gestation (31).
Three studies used unfractionated heparin (30,47,50),
and another used a single, fixed dose (5,000 IU) of low
molecular weight heparin (31). The daily dose of unfrac-
tionated heparin was either fixed (5,000 IU subcutane-
ously twice daily) (30) or adjusted to maintain an APTT
value that was either 1.2–1.5 times the value at baseline
(range 16,000–40,000 IU/day) (47,50) or at the upper
limits of the normal range (range 10,000–25,000 IU/day)
(50).
Two (30,47) of the 3 studies that compared a
combination of heparin and aspirin with aspirin alone
(30,31,47) found higher live-birth rates in women who
received combination therapy. Live-birth rates in women
treated with heparin plus aspirin were 71%, 78%, and
80%, and in those treated with aspirin alone the rates
were 42% (30), 72%, and 44%, respectively (30,31,47).
High and low doses of unfractionated heparin, given in
combination with low-dose aspirin, were associated with
similar live-birth rates (80% and 76%, respectively) (50).
Rai et al (30) found that the superiority of combination
therapy holds only for the first 13 weeks of gestation.
Because this is the time when the first wave of tropho-
blast invasion is complete and placentation is estab-
lished, it was speculated that heparin may protect tro-
phoblast cells from aPL-induced damage. The same
group of investigators affirmed a live-birth rate of 71%
1032
Table 4. Studies on live-birth rates in treated women with aPL and fetal loss, SLE, thrombosis, or a combination of these*
First author No. of No. of
(reference) Study type women pregnancies
Lockshin (51) Retrospective 25 30
Branch (52) Retrospective 54 82
Lima (53) Retrospective 47 60
Rosove (54) Retrospective 14 15
Branch (55) Randomized 16 16
* aPL ⫽ antiphospholipid antibodies; SLE ⫽ systemic lupus erythematosus; any ⫽ treatment according to patient’s and physician’s judgment (no
pharmacologic treatment, low-dose aspirin, prednisone, heparin, high-dose intravenous gamma globulin [IVIG], or a combination of these).
in a prospective observational study in which women
received either fixed dosages of unfractionated heparin
(5,000 IU twice daily) or enoxaparin (20 mg once daily)
(45).
In most studies, the overall frequency of prema-
turity (birth at ⬍37 weeks of gestation) was between 7%
(31) and 13% (47), but a frequency of 24% was found in
2 studies from a single clinic (30,45). None of the studies
found an association between prematurity and the ther-
apeutic regimen used. Also, there was no association
between the therapeutic regimen used and the frequency
of preeclampsia, a complication that was absent in some
studies (31) but reached a prevalence of 2% (30) to
⬎10% in other studies (47,50). In 2 studies, preeclamp-
sia and intrauterine growth restriction accounted for
more than one-third of prematurity (30,45).
Aspirin alone (supportive care only). The live-birth
rate in aspirin-treated aPL-positive women with recur-
rent pregnancy loss was relatively good in most studies
(72% [31], 80% [32], 91% [44], and 100% [49]) but was
strikingly low in another 3 studies (17% [12], 42% [30],
and 44% [47]). With placebo, live-birth rates of 17%
(12), 52% (29), and 85% (32) were reported. In the
smallest study (12), live-birth rates were spuriously low,
because blighted ovum and ectopic pregnancy accounted
for the majority of losses. Pattison et al (32) emphasized
that the high live-birth rate with placebo makes it
questionable that pharmacologic treatment had addi-
tional value over and above that of supportive care
alone. This opinion contrasts sharply with that of Rai et
al (46), who reported a live-birth rate of only 10% in 20
aPL-positive women with recurrent pregnancy loss who
declined pharmacologic treatment in their current preg-
nancies.
Thrombosis. The chance of pregnancy-related
thrombosis developing in healthy aPL-positive women
with recurrent pregnancy loss appears to be low. Only
one case of thrombosis was reported (49) among a total
DERKSEN ET AL
Live-birth rate (%) according to pharmacologic treatment
Low-dose Low-dose aspirin ⫹
Any Heparin aspirin ⫹ heparin heparin ⫹ IVIG
33 – – –
63 – – –
70 – – –
– 93 – –
– – 100 100
of 673 such women included in 12 studies (12,29–32,44–
50). That case originated from the only study that
included patients (n ⫽ 2) with previous thrombosis (49).
It was not specified whether the current bilateral deep
vein thrombosis was a recurrent event. The other studies
indicated that pharmacologic treatment was given
“throughout pregnancy,” but most did not specify when
it was stopped. Two reports (47,50) mentioned that
patients continued receiving heparin treatment in the
postpartum period, and in another 2 studies (30,45) it
was reported that treatment with heparin and aspirin
was stopped at 34 weeks.
Women with a history of fetal loss, SLE, throm-
bosis, or a combination of these. The pregnancy out-
comes in women in the third category (those with a high
frequency of fetal loss, SLE, thrombosis, or a combina-
tion) were reported in 3 retrospective studies in which
patients received treatment according to the patient’s
and physician’s judgment (51–53), one retrospective
study in which all women received monotherapy with
heparin (54), and one placebo-controlled study that
evaluated the effects of high-dose intravenous immuno-
globulins (IVIG) added to treatment with heparin and
aspirin (55).
In the retrospective studies, several patients con-
tributed ⬎1 pregnancy (Table 4). Many patients in these
studies had SLE (77% [53], 36% [54], 32% [52], 13%
[55], not specified [51]), previous thrombotic events
(56% [55], 41% [52], 30% [53], 29% [54], not specified
[51]), or both. All patients had APS according to the
1987 criteria (7), but many did not fulfill the obstetric
criteria (7,14), because several studies included primi-
gravidae (accounting for 11% [52], 17% [53], 36% [51],
and an unspecified percentage [55] of included women)
or included women with 1 or 2 first trimester losses or
only successful pregnancies (52–54). All patients fulfilled
the serologic criteria for APS, because all studies appar-
ently used adequate tests for LAC and aCL and included
MANAGEMENT OF OBSTETRIC APS
patients with at least medium levels of aCL. In one study
(51), an insensitive LAC test was used, and another
study (52) excluded patients with IgM aCL only.
In the studies in which pharmacologic treatment
was administered according to the patient’s and physi-
cian’s judgment, therapy in individual patients included
no treatment (51), monotherapy with low-dose aspirin
(51,53), prednisone (51,52) or heparin (52), a combina-
tion of aspirin and prednisone (51–53), a combination of
aspirin, prednisone, and heparin (52), a combination of
heparin and prednisone (53), a combination of aspirin
and heparin (52), and a combination of IVIG, aspirin,
and heparin (55). The daily dose of aspirin was 75–80 mg
(51–53) and that of prednisone was 10–30 mg (51), 40
mg (with adjustments upon evaluation of LAC) (52), or
was not specified (53). Treatment with heparin was
either low molecular weight heparin in a dose aiming for
target values of 0.15–0.2 IU/ml of anti–factor Xa activity
preinjection (53) or unfractionated heparin in a daily
dose of 10,000–20,000 IU divided into 2 or 3 injections,
with dosage adjustments to 15,000–20,000 IU/day at the
beginning of the second trimester (52) or an unadjusted
dose of 10,000–15,000 IU divided into 2 doses (53).
Branch et al (55) started with a dosage of 15,000 IU of
unfractionated heparin per day and increased the dosage
to 20,000 IU/day in the second trimester. Rosove et al
(54) used unfractionated heparin with a daily dose
divided into 2 subcutaneous injections, with dose adjust-
ments to obtain a mid-interval APTT of 1.5–2 times the
control value (daily dose 10,000–36,000 IU).
The gestational age at which pharmacologic
treatment started was 7.5 weeks (range 2–25 weeks)
(52), 9 weeks (range 0–21 weeks) (51), and 10 weeks
(range 6–18 weeks) (54) and was not specified in 2
studies (53,55). Lima et al (53) indicated that patients
with a history of thrombosis were switched from warfa-
rin to heparin preconception or after a positive preg-
nancy test, and that patients continued to receive hepa-
rin for 6 weeks after delivery or were converted back to
warfarin. Rosove et al (54) reported that they discontin-
ued treatment of patients with heparin briefly at the time
of delivery and then resumed and continued heparin for
variable periods thereafter.
The study by Lockshin et al (51) clearly showed
that prior fetal death (unfortunately, this term was not
defined by the authors) and aCL levels of ⱖ40 GPL
units contributed independently, in an additive manner,
to current fetal loss. Their results did not demonstrate a
beneficial effect of aspirin on pregnancy outcome and
suggested that prednisone may worsen fetal outcome.
Analysis of the study by Branch et al (52) re-
1033
vealed that with treatment, 63% of pregnancies resulted
in a surviving newborn (73% when spontaneous abor-
tions were excluded). Of these infants, 92% were born
before 37 weeks of gestation, and 37% were born before
32 weeks of gestation. Fetal or neonatal deaths attribut-
able to complications of prematurity (related to pre-
eclampsia, fetal distress, or both) occurred in 19 (23%)
of 82 pregnancies. There was no statistically significant
difference among the treatment groups in terms of the
rate of surviving neonates. A comparison between the
patient’s first untreated pregnancy following a fetal
death and the first treated pregnancy (n ⫽ 32) showed
that a statistically significantly higher percentage of
surviving neonates was associated with treatment (6% in
untreated pregnancies versus 53% in treated pregnan-
cies). Factors that were not related to outcome included
a diagnosis of SLE, a history of preeclampsia or throm-
bosis, the IgG aCL level, or the number of previous fetal
deaths. The overall rates of preeclampsia (51%) and
severe preeclampsia (27%) were similar in all treatment
groups. Fetal distress occurred in 53% of pregnancies
resulting in live births, and 31% of the newborns were
small for gestational age. The rates of both complica-
tions were similar in all treatment groups. In 3 patients,
4 thrombotic events occurred (overall thrombotic rate
5%). Two events occurred in a single patient who was
receiving heparin and was found to have protein C
deficiency. All events occurred within 2 weeks postpar-
tum.
In the study by Lima et al (53), 70% of treated
pregnancies ended with a live birth. Among successful
pregnancies, 43% of the infants were born before 37
weeks; 31% of the neonates were small for gestational
age, and 5% had fetal distress. Preterm delivery was
significantly more common in women receiving pred-
nisone. There were 3 neonatal deaths (all at 26 weeks).
The 18 unsuccessful pregnancies comprised 1 therapeu-
tic abortion because of severe active lupus, 9 fetal deaths
(median gestational age 21 weeks [range 12–27 weeks]),
and 8 spontaneous abortions. Preeclampsia necessitated
induction of labor in 11 pregnancies (9 live births and 2
with fetal deaths). Preeclampsia was not related to the
use of prednisone. There were 7 pregnancy-related
thrombotic events in 7 women. Three of these were in
the postnatal period, and none of the women was
receiving low molecular weight heparin. It was not
reported whether these were first or recurrent events.
In the small retrospective study of heparin treat-
ment by Rosove et al (54), pregnancy outcome was very
good, with live birth in 14 of 15 pregnancies (93%) and
1 miscarriage at 12 weeks. Half of the live births
1034
occurred before 37 weeks of gestation. No case of
preeclampsia or pregnancy-related thrombosis was re-
ported.
The results of the only randomized study of
patients in this category (55) were surprising. Based on
previous reports (52,53), the authors expected in current
pregnancies a 20–30% risk of fetal or neonatal death
related to prematurity, a 20–50% risk of preeclampsia
(18–27% severe), a 50% risk of fetal distress or oligo-
hydramnios necessitating delivery, a 30% risk of intra-
uterine growth restriction, and a ⱖ30% risk of prema-
ture delivery with the treatment that was given to all
patients (heparin in combination with aspirin). They
hoped to improve these values by the addition of IVIG
(1 gm/kg for each of 2 consecutive days every 4 weeks
through 36 weeks of gestation). After randomization, 9
patients received heparin, aspirin, and intravenous 5%
albumin solution and 7 patients received a combination
of heparin, aspirin, and IVIG. In both groups, all women
were delivered of live-born infants after 32 weeks of
gestation. In the IVIG group the rate of preterm deliv-
ery was significantly higher (100% versus 33% in the
group that did not receive IVIG), with preeclampsia and
oligohydramnios being the most frequent reasons. No
significant differences were found for gestational age at
delivery, mean birth weight, oligohydramnios, fetal dis-
tress, and preeclampsia (44% versus 11% in the IVIG
group versus the control group). Deep vein thrombosis
occurred in one woman in the IVIG group 4 weeks after
delivery, while she was receiving 20,000 IU of unfrac-
tionated heparin. As possible explanations for the unex-
pected salutary maternal and fetal outcome, the authors
mention early institution (at 4–6 weeks of gestation) of
aspirin and heparin, an organized and focused approach
to fetal surveillance, and a Type II error. It was hypoth-
esized that the early initiation of aspirin and heparin
treatment benefited the pregnancies, perhaps by improv-
ing placentation.
Conclusions
In healthy aPL-positive women with only success-
ful pregnancies or ⬍3 consecutive early losses, there is
no indication for aPL testing or pharmacologic treat-
ment during pregnancy. This statement is based on
results from studies in low-risk pregnancies (28,40–43)
and epidemiologic evidence that the definition of recur-
rent miscarriage should be 3 or more consecutive preg-
nancy losses (56). We realize, however, that in current
daily practice, many pregnant women, in the absence of
a poor outcome of previous pregnancies, are offered
DERKSEN ET AL
pharmacologic treatment (mostly aspirin) if aPL are
found, based on their own or their physician’s choice.
Unfortunately, several studies on aPL-related
pregnancy included primigravidae (51–53,55) and
women with ⬍3 early pregnancy losses (29,44,48,49),
and this may have influenced their results. Adhering to
strict criteria for obstetric APS is important to minimize
the role of causes other than aPL (particularly abnormal
karyotypes), because even among losses in treated aPL-
positive women with ⱖ3 previous early losses, abnormal
fetal karyotypes may be expected in up to 24% of
conception products (45). Apart from using deviating
criteria for obstetric APS, many studies did not adhere
to the definition of aPL as described in the APS criteria
(14). For aCL, the currently poor standardization of the
aCL ELISA provided an easy argument to express
doubts regarding whether randomized trials included
women with at least medium levels of aCL (33–39).
Results from randomized studies led to discon-
tinuation of the use of prednisone to improve pregnancy
outcome in women with aPL. However, many study
results are confusing and difficult to understand. For
instance, it is unclear why in 2 studies (30,47) live-birth
rates in women being treated with aspirin alone were low
(42% and 44%) compared with those in women receiv-
ing a combination of heparin and aspirin (71% and
80%), whereas in another study using comparable ob-
stetric inclusion and exclusion criteria (31) the rates
were similar in women receiving aspirin alone and those
receiving a combination of heparin and aspirin (72% and
78%, respectively). This discrepancy can be explained
neither by obvious differences in the heparin regimens
used, which were (unfractionated) heparin in fixed doses
(30) or adjusted doses (47) or low molecular weight
heparin (31), nor by differences in serologic character-
istics of the included women (LAC was present in 0%
[47], 41% [31], and 91% [30]) or the notion that 2 studies
(30,31) included women with aCL levels that were lower
than those in women in the third study (47). Further-
more, although inclusion of women with low aCL levels
possibly explains the 80% live-birth rate with aspirin
alone in one study (32), this explanation does not hold
for other studies with rates of 91% (44) and 100% (49).
Although most data suggest that treatment im-
proves the rate of live births, it is questionable whether
the frequencies of pregnancy complications such as
prematurity, small-for-gestational-age newborns, fetal
distress, preeclampsia, or cesarean delivery for compli-
cated pregnancy courses (32,45,52,53) were influenced
by treatment. In all published series maternal–fetal
monitoring was optimized by including frequent antena-
MANAGEMENT OF OBSTETRIC APS 1035

Figure 1. Algorithm for pharmacologic treatment of women with lupus anticoagulant (LAC), medium or high
levels of anticardiolipin antibodies (aCL), or a combination of these during pregnancy and the postpartum period.
ⴱ ⫽ The dosages advocated for low molecular weight heparin (LMWH) and unfractionated heparin (H) can be
derived from Tables 5 and 6. APS ⫽ antiphospholipid syndrome; R/ ⫽ pharmacologic treatment.

tal visits, continuity of the care providers, a liberal
admissions policy, a multidisciplinary approach to the
management of autoimmune diseases, obstetric ultra-
sound scans every 2–4 weeks, monthly Doppler veloci-
metry of the umbilical arteries starting at 16 weeks of
gestation, and weekly cardiotocography starting at 24
weeks, with more frequent testing if clinically indicated
(30,32,44,49,53,54). Some studies additionally included
weekly nonstress testing beginning at 26–30 weeks
(44,49). Previous studies established the impact of sup-
portive care alone in women with unexplained recurrent
miscarriage; supportive care only resulted in live-birth
rates of ⬎85% (57–59).
Taken together, these data support the hypothe-
sis that recognition of aPL as a risk factor for adverse
pregnancy outcome by itself contributed significantly to
higher live-birth rates in aPL-positive women who re-
ceived treatment during their pregnancies (32,44,51–55).
One should realize that almost all randomized treatment
trials in pregnancy outcome involved aPL-positive
women who were otherwise healthy. We do not know
whether the presence of SLE, a history of thrombosis, or
both augment aPL-related risks for poor pregnancy
outcome.
Recommendations
We recommend that healthy women with ⱕ2
(pre)embryonic losses in the absence of fetal loss should
not be advised to undergo aPL tests, because there is no
evidence for the beneficial effects of any pharmacologic
treatment during pregnancy. There are no data indicat-
ing that such advice should be different when SLE is
present. We recommend close maternal–fetal monitor-
ing during all pregnancies of aPL-positive women.
Figure 1 depicts an algorithm for the pharmaco-
logic treatment of women with aPL. During the preg-
nancies of women meeting the criteria for APS (14), we
recommend combined treatment with heparin and aspi-
rin (75–100 mg/day). We realize that with such advice we
rely heavily on the results of a recent systematic review
of therapeutic trials (60). The conclusion drawn from
that meta-analysis (i.e., that aspirin alone is ineffective)
was based on the outcomes of only 71 pregnancies
1036
Table 5. Terminology for heparin regimens*
Unfractionated heparin
Mini-dose
5,000 units subcutaneously every 12 hours
Moderate-dose
Subcutaneously every 12 hours adjusted to target an anti–factor
Xa level of 0.1–0.3 units/ml
Adjusted-dose
Subcutaneously every 12 hours to target a mid-interval APTT
(or, if LAC is present, an anti–factor Xa level) into the
therapeutic range
Low molecular weight heparin (LMWH)
Prophylactic-dose
Dalteparin, 2,500 or 5,000 units subcutaneously every 24 hours;
OR enoxaparin 20 or 40 mg subcutaneously every 24 hours;
OR nadroparin 2,850 units subcutaneously every 24 hours;
OR any once-daily LMWH adjusted to target a peak anti–
factor Xa level of 0.2–0.6 units/ml
Adjusted-dose
Weight-adjusted, full treatment doses of dalteparin, 200 units/kg
subcutaneously in 1 or 2 injections; OR enoxaparin 1 mg/kg
subcutaneously every 12 hours or 1.5 mg/kg subcutaneously
every 24 hours; OR nadroparin, 171 units/kg subcutaneously
in 1 or 2 injections
* Adapted from recommendations in ref. 62. APTT ⫽ activated partial
thromboplastin time; LAC ⫽ lupus anticoagulant.
(12,32,43) in women with dissimilar obstetric histories
and for whom different definitions of aPL were used.
Furthermore, the conclusion regarding superiority of a
combination of heparin and aspirin was based on results
of only 2 trials (30,47) (a total of 140 pregnancies) that
observed remarkably low live-birth rates (⬍45%) in
women treated with aspirin alone and enrolled patients
who were substantially different with regard to labora-
tory tests. We also realize that the meta-analysis could
not include results of the randomized trial by Farquhar-
Table 6. Advocated heparin regimens according to different clinical situations*
Clinical situation
Patient meets criteria for obstetric APS
(obstetric indication), OR
Previous thrombotic event and aPL, no
long-term use of oral anticoagulation
Previous thrombotic event and receiving
long-term oral anticoagulation
Postpartum period
Patient meets criteria for obstetric APS,
OR aPL-positive SLE patient
Previous thrombotic event
Indication for long-term anticoagulation
* APS ⫽ antiphospholipid syndrome; aPL ⫽ antiphospholipid antibodies; LMWH ⫽ low molecular
weight heparin; SLE ⫽ systemic lupus erythematosus (see Table 5 for other definitions).
DERKSEN ET AL
son et al (31), which found similar outcomes with aspirin
and combination therapy. We recognize that the basis to
advise combination therapy is weak, and that other
investigators legitimately may conclude that selected
patients should be treated with aspirin alone or with
thorough and careful expectant care.
Low-dose aspirin should be started preconcep-
tion (44,47,49,50) or at the time of a positive pregnancy
test (12,30–32,45,48,55), and heparin therapy should be
initiated at the time of a positive pregnancy test (47,50)
or when fetal heart activity is proven (30). The optimal
timing is unknown. An argument in favor of withholding
therapy until fetal cardiac activity is verified is the
avoidance of administering unnecessary drugs to women
who have a positive pregnancy test but no developing
embryo.
The absence or presence of previous thrombotic
events dictates the dosage of heparin that we propose
(Tables 5 and 6). The lowest dosage will be given to
healthy women who meet the obstetric criteria for APS.
For women with a previous aPL-related arterial throm-
botic event who are receiving long-term aspirin treat-
ment (61), the obstetric history dictates additional use of
heparin, although some experts would be more comfort-
able with the administration of heparin in any such case.
In patients with previous venous thrombotic events, the
heparin dosage should be individualized, taking into
account whether or not there is an indication for long-
term anticoagulation, the circumstances under which the
previous events occurred, the number and severity of
such events, comorbidity, and bleeding risk assessment.
When patients have a history of thrombosis, we advise a
Heparin regimen
Mini- or moderate-dose unfractionated
heparin, OR
Prophylactic-dose LMWH
Adjusted-dose unfractionated heparin, OR
prophylactic- or adjusted-dose LMWH
Mini-dose unfractionated heparin, OR
prophylactic-dose LMWH
Mini- or moderate-dose unfractionated
heparin, OR prophylactic-dose LMWH
Adjusted-dose unfractionated heparin, OR
adjusted-dose LMWH; resume long-
term anticoagulation
MANAGEMENT OF OBSTETRIC APS
switch from oral anticoagulants to heparin before con-
ception or, at the latest, within 2 weeks of the first
missed period, because oral anticoagulants cross the
placenta, are teratogenic when given between 6 and 12
weeks of gestation, and may cause intracranial bleeding
in the fetus (62). As pregnancy progresses the volume of
distribution for heparin increases, and dose adjustments
in proportion to weight gain or based on APTT or
anti–factor Xa levels can be considered. In selected
patients a switch from heparin to oral anticoagulants
may be practical between 15 and 34 weeks of gestation
(63).
Low molecular weight heparin has the advantage
over unfractionated heparin of a longer plasma half-life
and a more predictable dose response and therefore the
potential for once daily administration. Furthermore,
low molecular weight heparin causes less heparin-
induced thrombocytopenia and heparin-induced osteo-
porosis (62,64). Given these advantages, we prefer low
molecular weight heparin, although this approach is
more expensive. With prolonged use of heparin we
recommend the intake of extra oral calcium (1,000–
2,000 mg/day) and vitamin D (400–800 IU) as prophy-
laxis for heparin-induced osteoporosis.
We advise thromboprophylaxis (heparin, low mo-
lecular weight heparin, or warfarin) during the postpar-
tum period (6 weeks) in aPL-positive women with, based
on the foregoing, an indication for treatment during
pregnancy (Table 6). This recommendation is based on
notions that thrombosis in patients with APS is often
related to pregnancy (52), and that cesarean deliveries
(particularly emergency cesarean deliveries) constitute a
high risk for venous thromboembolic events (62). We
recognize, however, that in prospective studies in
healthy aPL-positive women very few thrombotic events
were reported. Both heparin and warfarin are safe for
nursing mothers.
There are no data showing that the approach to
an aPL-positive woman with SLE should be different
from what we discussed previously. However, although
scientific proof is lacking, most experts will agree with
the use of postpartum thromboprophylaxis in an aPL-
positive patient with SLE. We fully recognize that
chronic organ damage, immunosuppressive treatment,
and active disease per se contribute to adverse preg-
nancy outcome in patients with SLE (53,65).
Future considerations
For further progress in the management of ob-
stetric APS, the wide availability and use of well-
1037
characterized and well-standardized aPL assays and
calibrators are essential. Periodic interlaboratory com-
parisons and quality control should abolish doubts about
clinically relevant cutoff values. Future clinical trials
need indisputable definitions of relevant aPL and ob-
stetric entry criteria.
To establish any benefit of pharmacologic ther-
apy, a trial with these prerequisites should compare
optimal fetal–maternal supportive care plus placebo
with similar supportive care plus pharmacologic treat-
ment. Furthermore, randomized trials in patients with
previous thrombotic events and aPL-positive women in
whom treatment failed are much desired. It is hoped
that, by such efforts, the misty research field on man-
agement of obstetric APS will clear up within the near
future.
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