2. immunosorbent assay was used for the determination of
anticardiolipin titer. International standards were em-
ployed, and after construction of a normal range by
calculation of the mean values and three standard devi-
ations above the mean in a healthy population, levels of
immunoglobulin G and M anticardiolipin of more than 9
anticardiolipin U/mL and more than 5 anticardiolipin
U/mL, respectively, were considered positive. Blood
sampling and storage followed optimal preparation us-
ing double-spin centrifugation for plasma and storage at
⫺70C within 2 hours for plasma and serum. Samples
were sent for analysis to the Coagulation Department,
University of Sheffield.
Parental chromosomal abnormality, uterine anomaly,
previous arterial or venous thrombosis, use of steroids
during pregnancy, systemic lupus erythematosus requir-
ing medication or complicated by nephritis, and other
thrombophilia such as activated protein C resistance or
protein C/S deficiency.
The aim was to assess the efficacy of low molecular
weight heparin in the treatment of antiphospholipid syn-
drome during pregnancy by comparing low molecular
weight heparin combined with low-dose aspirin against
low-dose aspirin alone in women suffering pregnancy
loss. Before 12 weeks’ gestation, women were random-
ized to group A (low-dose aspirin tablets 75 mg daily
until delivery) or to group B (low-dose aspirin 75 mg
daily plus low molecular weight heparin 5000 U subcu-
taneously daily until delivery).
The type of pregnancy loss was classified as an em-
bryo loss where no visible crown rump length or fetal
heart activity could be visualized within the sac on
weekly ultrasound assessment starting at 5 completed
weeks’ gestation. After viability was confirmed, a fetal
loss was diagnosed when fetal heart activity disappeared
after clear identification on previous ultrasound scan.
For a trial with 80% power and significance at the 5%
level, using an anticipated baseline of 50% live-birth rate
(aspirin group A) with an expected improvement to 60%
live-birth rate with treatment (aspirin and heparin group
B), a power calculation required 110 women in each
treatment arm (n ⫽ 220). This was considered to be a
cautious prediction of power. For example, a power
calculation based on the study of Rai et al,6
the only
pre-existing randomized, controlled trial indicated a re-
quirement to recruit 54 patients. On this basis and in
consideration of the high success rate observed in the
aspirin group, an interim analysis was performed.
All analyses were completed on an intention-to-treat
basis. Twenty-four women did not follow the protocol
(nonadherent group). In group A, 11 women random-
ized to aspirin alone wished heparin as well. In group B,
13 women took aspirin only and did not wish heparin.
Demographic and clinical data were compared between
the two groups. Comparisons between groups were ex-
pressed as odds ratios (OR) and 95% confidence inter-
vals (CI). The 2
test was used for statistical analysis of
discrete and continuous variables, and a P value of ⬍ .05
was taken as statistically significant.
Compliance with low molecular weight heparin was
recorded by longitudinal inspection of injection sites,
which were clearly demarcated. Aspirin compliance
could not be accurately assessed except by repeat pre-
scription request and patient enquiry.
Individual women were randomly allocated to group
A or B by telephone randomization to the Trials Unit at
the Centre for Cancer Epidemiology at the University of
Manchester, which generated the random allocation se-
quence using a computer. The unit of randomization was
the individual patient. Randomization was stratified in
blocks of 20 to provide a 1:1 balance between interven-
tion and control groups. Each subject was given a unique
study number. At the time of enrollment by the authors,
details of patient identification using hospital number
and date of birth were given, followed by number of
pregnancy losses and antiphospholipid status. Allocation
to treatment group was concealed until a full checklist of
inclusion/exclusion criteria was completed after which
randomization was made. Of 119 patients invited to
participate, 12 declined randomization, five failed inclu-
sion/exclusion criteria, and four were nonpregnant (Fig-
ure 1).
Data collection was achieved using a separate inde-
pendent research officer who received copies of random-
ization data sheets from the Trials Unit at the Centre for
Cancer Epidemiology, Manchester University. The in-
dependent research officer collected all relevant informa-
tion directly from the patient’s notes after pregnancy
delivery. Secondary screening against inclusion/exclu-
sion criteria was undertaken, and a spreadsheet con-
structed of all variables required for analysis. The data-
base was stored in a separate facility based at the
University of Leeds.
Data analysis was undertaken by a research officer
(CC) and communicated to the authors.
RESULTS
We recruited 98 women: 47 to group A (low-dose aspirin
alone) and 51 to group B (low-dose aspirin plus low molec-
ular weight heparin). There were no significant differences
between groups in respect of maternal age, number of
previous consecutive miscarriages, or gestation at time of
randomization (Table 1). In addition, there was no signifi-
cant variation in the type or level of positive laboratory
criteria for diagnosis of antiphospholipid syndrome (Table
409
VOL. 100, NO. 3, SEPTEMBER 2002 Farquharson et al Antiphospholipid Syndrome in Pregnancy Trial
3. 2). Of the 98 patients, there were four patients with serolog-
ical markers for systemic lupus erythematosus when inves-
tigated for joint discomfort. None had other clinical evi-
dence of systemic lupus erythematosus nor had they
received immunosuppressive therapy.
Of 47 women in group A, there were 34 live births and
13 pregnancy losses. Of 51 women in group B, there
were 40 live births and 11 pregnancy losses (live-birth
OR 1.39, 95% CI 0.55, 3.47, P ⫽ .49; fetal loss OR 2.00,
95% CI 0.56, 7.14, P ⫽ .29) (Table 3).
There were no significant differences between groups
with respect to birth weight, gestation at delivery, pre-
term delivery, pregnancy-induced hypertension, or
number of cesareans (Table 3).
Figure 1. Consensus Statement for Reporting Randomized Trials diagram of patients and events during the trial.
Farquharson. Antiphospholipid Syndrome in Pregnancy Trial. Obstet Gynecol 2002.
410 Farquharson et al Antiphospholipid Syndrome in Pregnancy Trial OBSTETRICS & GYNECOLOGY
4. Of 13 pregnancy losses in group A, there were nine
embryo losses before 10 weeks’ gestation and four fetal
deaths at 7, 8, 10, and 30 weeks’ gestation. Of 11 preg-
nancy losses in group B, there were three embryo losses
before 10 weeks’ gestation and eight fetal deaths at 7, 8,
8, 8, 9, 12, 22, and 23 weeks’ gestation.
Analyses for the adherent group (n ⫽ 74) and the
nonadherent group (n ⫽ 24) are given separately. Within
the subset of 24 women who altered their allocated
treatment (nonadherent group), the outcomes for fetal
loss type (OR 0.38, 95% CI 0.03, 4.81, P ⫽ .45) and
obstetric outcome (live-birth OR 3.14, 95% CI 0.45,
21.9, P ⫽ .25) were not significantly different either from
the whole group (n ⫽ 98) or from the adherent group
(n ⫽ 74).
Within the adherent group (n ⫽ 74), the outcomes
were not significantly different (live-birth OR 1.07, 95%
CI 0.37, 3.11, P ⫽ .89), although an increased number of
fetal losses was observed in the heparin/aspirin arm (OR
3.83, 95% CI 0.74, 19.9, P ⫽ .11).
DISCUSSION
This study demonstrates no significant difference be-
tween the two treatment arms whether on intention-to-
treat analysis or adherent group analysis. The combina-
tion of low molecular weight heparin with low-dose
aspirin in the prevention of miscarriage in women with
antiphospholipid syndrome and recurrent pregnancy
loss has not been clearly demonstrated to be superior to
low-dose aspirin alone. Although the study number was
small, the sample size represents the largest recruitment
population to date. The prospective fetal death rate in
the groups varied between 10% (four of 38) in group A
and 16% (eight of 48) in group B. The higher fetal loss
rate with heparin is similar to that previously reported,6,7
where a 20% loss rate was found. The success rate for
aspirin alone is compatible with reported retrospective
studies.8,9
A recent and smaller randomized, controlled
trial has shown that aspirin alone is associated with an
80% success rate but interestingly reported a significant
placebo effect.10
As a result, the practice of routine
heparin use during pregnancy with antiphospholipid
syndrome becomes more questionable as the fetal sur-
vival rate is similar for all treatment arms. Furthermore,
no case of de novo maternal thrombosis has been re-
ported from a prospective randomized trial.
Previously, there has been inconsistency in the diag-
nosis of antiphospholipid syndrome, both clinically and
in relation to laboratory parameters. Persistent positivity
in tests for lupus anticoagulant and/or anticardiolipin
antibody using carefully validated techniques in a subject
with the appropriate clinical history is considered to be
necessary. In relation to pregnancy complications, the
clinical criteria are:
Table 1. Baseline Patient Characteristics
Group A (n ⫽ 47)
LDA
Group B (n ⫽ 51)
LDA ⫹ heparin
Age (y) 33 (4.9); 23–41 33 (4.8); 22–41
Number of
previous
losses
3 (0.9); 2–12 3 (0.8); 2–6
2 13 14
3 20 24
4 10 6
⬎4 4 7
Gestation at
randomization
(wk)
6.3 (2.0); 4–12 7.1 (2.2); 4–12
LDA ⫽ low-dose aspirin.
Values are expressed as means (standard deviation); range.
Table 2. Laboratory Criteria for Antiphospholipid Syn-
drome Diagnosis
Group A
(n ⫽ 47)
LDA
Group B
(n ⫽ 51)
LDA ⫹ heparin
DRVVT ratio (DRVVT)
positive
18 23
Raised anticardiolipin
antibody titer IgG
(anticardiolipin U/mL)
2 6
Raised anticardiolipin
antibody titer IgM
(anticardiolipin U/mL)
5 3
Dual parameter positive
(DRVVT and IgG or
IgM)
22 18
Strongly positive tests,
arbitrarily defined as:
DRVVT ⬎ 1.30,
anticardiolipin U/mL ⬎
20, IgM ⬎ 10
4 7
LDA ⫽ low-dose aspirin; DRVVT ⫽ dilute Russell viper venom time;
IgG ⫽ immunoglobulin G; IgM ⫽ immunoglobulin M.
Table 3. Pregnancy Outcome
Group A
(n ⫽ 47)
LDA
Group B
(n ⫽ 51) LDA
⫹ heparin
Live-birth rate (%) 72 78
Mean birth weight
(g)
3221 (781);
890–5300
3127 (657);
718–4319
Gestation at delivery
⬍30 wk 1 1
30–36 wk 3 1
⬎36 wk 30 38
Embryo loss 9 3
Fetal loss 4 8
Abbreviation as in Table 1.
Values are expressed as means (standard deviation); range.
411
VOL. 100, NO. 3, SEPTEMBER 2002 Farquharson et al Antiphospholipid Syndrome in Pregnancy Trial
5. ● three or more consecutive spontaneous losses before
the 10th week of gestation
● one or more premature births before 34 weeks for
severe preeclampsia or impaired fetal growth
● one or more unexplained intrauterine deaths beyond
10 weeks’ gestation11
These criteria were adhered to during recruitment. In
addition to prepregnancy testing, recent evidence sug-
gests that a first-trimester test is beneficial in excluding
antiphospholipid syndrome, as antiphospholipid syn-
drome activity is most prominent within the first 12
weeks of pregnancy.12
The association of recurrent pregnancy loss with an-
tiphospholipid syndrome has become increasingly ac-
cepted since the first description of apparently successful
intervention in 1983.13,14
Although our results are in
apparent conflict with some other studies, this may be
due to superior study design with less potential for bias.
Previously reported treatment trials have lacked formal
randomization,6
defined miscarriage without evidence of
past fetal death,15,16
and included patients without an-
tiphospholipid syndrome.17
It is noteworthy that, in the
absence of antiphospholipid syndrome, the live-birth
rate for a prospectively observed group with idiopathic
recurrent miscarriage is 75%, with a 20% embryo loss
and 5% fetal loss rate.18
We used low molecular weight
heparin, in contrast to the study of Rai et al,7
where
unfractionated heparin was reported to provide an 80%
success rate compared with a 40% success with aspirin
alone. Although there are pharmacokinetic differences
between heparin preparations, this is unlikely to explain
the different outcomes as we found a relatively high
success rate in women treated with aspirin alone. Patient
preference for aspirin alone in women with fetal loss
history (five of 13) compared with the heparin preference
group (one of 11) serves to highlight the state of patient
equipoise for randomization without deleterious effect.
Historically, the proposed pathogenesis has focused
on placental thrombosis and end-stage infarction, associ-
ated with the known procoagulant state, causing fetal
demise. Early in vitro studies showed decreased prosta-
cyclin production from vascular endothelial cells incu-
bated with affected patient serum.19
Recent work casts
doubt on a thrombotic pathogenesis of pregnancy failure
in antiphospholipid syndrome by suggesting direct inhi-
bition of trophoblast cell proliferation.3
The common
appearance of sudden fetal death with antiphospholipid
syndrome especially between 12 and 24 weeks has been
considered to result from interference with spiral artery
remodeling during secondary trophoblast invasion in
the second trimester. If treatment intervention is to im-
prove the established excess fetal death rate with an-
tiphospholipid syndrome, further avenues of research
need to be explored to elucidate a clearer pathogenesis.
Whether aspirin can have a beneficial effect on these
processes is not known.
In conclusion, in a randomized, controlled trial of
women with pregnancy failure and antiphospholipid
antibodies, we have demonstrated a high rate of success
using low-dose aspirin, with no apparent benefit
achieved through addition of low molecular heparin.
Our data suggest that first-line treatment in women with
antiphospholipid syndrome and recurrent pregnancy
failure should be with low-dose aspirin. Whether addi-
tion of heparin may be effective in the minority of
women in whom aspirin alone is ineffective remains to
be determined.
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Address reprint requests to: Roy G. Farquharson, MD,
FRCOG, Liverpool Women’s Hospital, Department of Ob-
stetrics and Gynaecology, Crown Street, Liverpool, L8 7SS,
United Kingdom; E-mail: roy.farquharson@lwh-tr.nwest.
nhs.uk.
Received December 28, 2001. Received in revised form March 7, 2002.
Accepted March 14, 2002.
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