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International Journal of Gynecology and Obstetrics 104 (2009) 223225

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International Journal of Gynecology and Obstetrics


j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o

CLINICAL ARTICLE

Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent


abortion associated with antiphospholipid antibody syndrome
Spiros Dendrinos a, Evangelos Sakkas b,, Evangelos Makrakis a
a
b

2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, University of Athens, Athens, Greece
MITERA Private Maternity, Athens, Greece

a r t i c l e

i n f o

Article history:
Received 13 July 2008
Received in revised form 28 October 2008
Accepted 7 November 2008
Keywords:
Antiphospholipid antibody syndrome
Intravenous immunoglobulin
Low-molecular-weight heparin
Recurrent abortion

a b s t r a c t
Objective: To compare low-molecular-weight (LMW) heparin plus low-dose aspirin with intravenous
immunoglobulin (IVIG) in the treatment of antiphospholipid antibody syndrome in women with recurrent
spontaneous abortions before 10 weeks of gestation. Method: This prospective, multicenter trial conducted
between 2002 and 2006 included 85 patients aged 1839 years. The women were allocated randomly to
receive LMW heparin plus low-dose aspirin, or IVIG. Data were compared using the t test and Fisher exact
test. Results: The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births
than those treated with IVIG (P = 0.003). Of those who completed the study, 29/40 (72.5%) and 15/38 (39.5%),
respectively, had live births. Intent-to-treat analysis revealed a signicant difference between the 2 groups
(OR 1.802; 95%CI, 1.142.84; P = 0.007). Conclusions: LMW heparin plus low-dose aspirin resulted in a higher
live birth rate than IVIG in the treatment of antiphospholipid antibody syndrome in women with recurrent
abortion.
2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Antiphospholipid (APL) antibodies are directed against phospholipids, and include anticardiolipin antibody and the antibodies
responsible for the lupus anticoagulant [1]. An association between
circulating maternal APL antibodies and recurrent abortion has been
acknowledged for many years. These antibodies are found in
approximately 15% of patients diagnosed with recurrent abortion
[2]. Several mechanisms have been suggested, the most accepted of
which is that APL antibodies cause placental thrombosis [3]. However,
placental pathology is variable; there may be infarction with
uteroplacental thrombus, perivillous brin deposits, or chronic
inammatory lesions [4]. Annexin-V, an anticoagulant phospholipidbinding protein found on normal placental villi, appears to be reduced
in the presence of APL antibodies, and it has been suggested that this
may play a role in the placental insufciency and consequent abortion
[5,6]. There is also in vitro evidence that these antibodies may inhibit
proliferation of trophoblasts and that this could result in impaired
implantation [7]. High levels of APL antibodies have also been
associated with other medical disorders such as thromboembolic
events, stroke, and thrombocytopenia [8].
The antiphospholipid syndrome is diagnosed according to the
Sapporo criteria [9]. Denite antiphospholipid antibody syndrome is
considered to be present if at least 1 of the clinical criteria and 1 of
Corresponding author. 169 Michalakopoulou Street, 11527, Athens, Greece. Tel.: +30
6944146944; fax: +30 2107758562.
E-mail address: sakvag@hotmail.com (E. Sakkas).

the laboratory criteria are met. The clinical criteria are: 1 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 1 or more
premature births of a morphologically normal neonate at or before the
34th week of gestation because of severe pre-eclampsia, eclampsia, or
severe placental insufciency; or 3 or more unexplained consecutive
spontaneous abortions before the 10th week of gestation, after
maternal anatomic or hormonal abnormalities and paternal and
maternal chromosomal causes have been excluded. The laboratory
criteria are: (1) anticardiolipin antibody of IgG and/or IgM isotype in
blood, present in medium or high titer, or on 2 or more occasions at
least 6 weeks apart, measured by a standardized enzyme-linked
immunosorbent assay for beta-2-glycoprotein I-dependent anticardiolipin antibodies; (2) lupus anticoagulant present in plasma on
2 or more occasions at least 6 weeks apart.
Although there are many studies focused on the treatment of
women with antiphospholipid syndrome and recurrent abortion,
available data are limited. Studies frequently include both women
with early and those with late abortion. Only a small number of
patients have been included in most individual studies, and only a few
randomized controlled trials have been conducted [10].
LMW heparins, which have been recently introduced into clinical
practice, have been demonstrated to be safe and effective for prevention
and treatment of acute deep vein thrombosis [11]. Moreover, it appears
that they are safer for the fetus compared with IVIG treatment.
The aim of the present study was to compare the two most effective
therapies, an anticoagulation therapy and IVIG, in women diagnosed

0020-7292/$ see front matter 2008 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijgo.2008.11.010

224

S. Dendrinos et al. / International Journal of Gynecology and Obstetrics 104 (2009) 223225

with antiphospholipid syndrome and with recurrent spontaneous


abortion before 10 weeks of gestation.

Table 2
Major outcomes of pregnancy in the study groups a
Outcome

LMW heparin plus low-dose


aspirin group (n = 40)

IVIG group
(n = 38)

Pregnancy
Live birth
Preterm delivery
First trimester abortion
Intrauterine death
Birth weight, kg
Vaginal delivery
Cesarean delivery

40
29
2
11
0
3.134 0.233
24
8

38
15
1
21
2
3.232 0.324
11
2

2. Materials and methods


The study population included patients referred to the authors'
department for recurrent abortions between March 2002 and March
2006. A total of 216 women with recurrent abortion were evaluated
over the time period. Recurrent abortion was dened as 3 or more
consecutive spontaneous abortions. All women with recurrent
abortion were interviewed and had a complete evaluation that
included a history and physical examination; karyotype analysis on
both partners when the woman had had more than 4 consecutive
abortions; hysterosalpingography or hysteroscopy; progesterone test
on day 21 of the cycle; prolactin, thyroid-stimulating hormone, lupus
anticoagulant, anti-2 glycoprotein 1 (GP1) IgG, IgG and IgM anticardiolipin and antiphosphatidylserine antibody tests; and cervical
cultures for mycoplasma, ureaplasma, and chlamydia. Moreover, to
exclude patients with thrombophilia the following factors were
evaluated: factor V Leiden and prothrombin G20210A mutation,
protein C and protein S, antithrombin III, factor XII coagulant,
activated protein C resistance, plasminogen and 5,10-methylenetetrahydrofolate reductase (MTHFR 677C N T).
Criteria for inclusion in the present study were: age 1839 years, 3
or more consecutive spontaneous abortions before 10 weeks of
gestation, and positive APL antibodies (anticardiolipin antibody of IgG
and/or IgM isotype in blood, present in medium or high titer, or on 2 or
more occasions at least 6 weeks apart; and lupus anticoagulant
present in plasma, on 2 or more occasions at least 6 weeks apart).
Exclusion criteria included women who had systemic lupus erythematosus; aspirin allergy or sensitivity to aspirin; a chromosomal or
anatomic abnormality or a luteal phase defect; conrmed peptic ulcer;
previous thromboembolism, hypertension or current treatment with
antihypertensive drugs; previous prednisone therapy; an abnormal
chest radiograph result; or a positive result of a tuberculin skin test. Of
the 216 women, 85 patients were found to have antiphospholipid
syndrome according to the Sapporo criteria and were instructed to
have quantitative human chorionic gonadotropin tests with any
missed period. None of the included women had only anti-2 GP1 or
antiphosphatidylserine antibodies.
The patients were randomly assigned to receive treatment with
LMW heparin (Innohep; Leo Pharma A/S, Ballerup, Denmark) plus
low-dose aspirin or IVIG (Sandoglobulin; Novartis AG Corporation,
Basel, Switzerland). Randomization was performed in blocks of 8 and
6 with the use of random number tables. Women in the LMW heparin
plus low-dose aspirin group started taking a daily dose of 75 mg of
low-dose aspirin and 4500 IU of heparin as soon as they had a positive
pregnancy test result; aspirin was discontinued at 32 weeks of
gestation or at the time of an abortion, and heparin at 38 weeks of
gestation or at the time of an abortion. The initial dose of LMW
Table 1
Baseline characteristics of the women in the study groups a
Characteristics

LMW heparin plus low-dose


aspirin group (n = 40)

IVIG group
(n = 38)

P values

Mean age, y
Anticardiolipin antibodies,
U/mL
Number of previous abortions
IgM only antibodies, U/mL
IgG anti-2 GP1, U/mL
IgG antiphosphatidylserine
antibodies, U/mL
Current smokers

31.1 1
42.4 18.4

32 0.8
46 14.3

0.25
0.09

3.8 1.4
17
8.3 10.4
7.1 2.2

3.9 1.2
20
8.0 9.3
6.2 1.8

0.81
0.37
0.54
0.09

0.28

Abbreviations: Ig, immunoglobulin; IVIG, intravenous immunoglobulin; LMW, lowmolecular weight.


a
Values are given as mean SD, or number.

P values

0.003
0.58
0.01
0.14
0.32
0.46
0.28

Abbreviations: IVIG, intravenous immunoglobulin; LMW, low-molecular weight.


a
Values are given as number, or mean SD.

heparin was 4500 IU/day and it was adapted so that factor Xa levels
were within the recommended prophylactic range. Women taking
LMW heparin had dual X-ray absorptiometry bone densitometry
performed before the beginning of the therapy. Women in the IVIG
group did not have densitometry performed because there is no
association between treatment with IVIG and bone density loss.
Platelet counts and factor Xa levels were obtained 8 hours after
injecting heparin, after the initiation of heparin therapy bimonthly.
These women also received 500 mg of calcium daily.
Women in the IVIG group started IVIG as soon as they had a
positive pregnancy test result. The dosage of IVIG was 400 mg/kg
every 28 days until 32 weeks of gestation.
Each pregnant participant's prenatal care included rst trimester
screening (nuchal translucency scan, pregnancy-associated plasma
protein-A and human chorionic gonadotropin serum evaluations);
second trimester fetal anatomy scan, oral glucose tolerance test, blood
pressure measurements; third trimester scans for fetal growth and
Doppler analysis; and monthly blood tests and obstetric appointments
and more intense follow-up when indicated.
The study was approved by the Institutional Review Board and Ethics
Committee of Aretaieion Hospital and by the Institutional Review Board
and Ethics Committee of MITERA Maternity. Informed consent was
obtained from all the study participants. The primary outcome was live
birth. The secondary outcomes included maternal adverse effects during
pregnancy and post delivery (hemorrhages, pregnancy-associated
hypertension, fractures during pregnancy or up to 2 months post
partum, reduced maternal bone mineral density, and death).
For the sample size of 85 patients, the study achieved a power of
82.54% (alpha = 0.05) to detect a difference of 30% in live birth rates.
Statistical analysis was performed with the t test and Fisher exact test,
as appropriate. P b 0.05 were considered signicant.
3. Results
Table 1 shows the characteristics of the patients. No signicant
differences were noted between the 2 groups concerning age, number
of previous abortions, levels of APL antibodies, number of women with
only IgM antibodies, number of smokers, levels of IgG anti-2 GP1,
and antiphosphatidylserine antibodies.
Of the 44 women who received LMW heparin plus low-dose
aspirin, 4 discontinued the therapy for personal reasons; of the 41
women who received IVIG, 3 were excluded owing to poor compliance
with the therapy.
Table 2 demonstrates the pregnancy outcomes in the two study
groups. The women who received LMW heparin plus low-dose aspirin
had a higher percentage of live births 29/40 (72.5%) than those who
received IVIG 15/38 (39.5%). The difference in live birth rate between
the two groups was signicant (P = 0.003). The difference in live births
between the two groups remained signicant in an intent-to-treat
analysis (OR 1.802; 95% CI, 1.142.84, P = 0.007). Among the women
who received LMW heparin plus low-dose aspirin, 2 had preterm
vaginal delivery and no intrauterine death was diagnosed. One patient

S. Dendrinos et al. / International Journal of Gynecology and Obstetrics 104 (2009) 223225

was diagnosed at the 28th week with abruption of the placenta, which
was treated conservatively. Among those receiving IVIG, 1 patient had
preterm vaginal delivery and intrauterine death was diagnosed in 2
cases. Nausea, hypotension, and tachycardia were observed in 3
patients taking IVIG. No women developed thromboembolic complications during pregnancy or post partum. No decrease in lumbar spine
bone density was observed in the 12 women taking heparin plus
aspirin, in whom dual X-ray absorptiometry bone densitometry was
performed at 14 weeks of gestation and post partum. In the LMW
heparin group, an abnormal karyotype was seen in the products of
conception in 1 patient compared with 3 patients in the IVIG group;
the difference was not signicant (P = 0.57).
4. Discussion
Recurrent abortion is dened as 3 or more consecutive spontaneous abortions and it affects approximately 1%3% of reproductiveaged women [12]. Various causes of recurrent pregnancy loss include
genetic, anatomic, endocrinologic, immunologic, microbiologic, and
unknown factors. Of the immunologic causes, several investigators
have correlated increased levels of APL antibodies and the presence of
lupus anticoagulant with increased obstetric complications, including
intrauterine growth restriction, pregnancy-induced hypertension, and
stillbirth [2,1315].
Aspirin and heparin may improve pregnancy outcome by blocking
platelet cyclooxygenase and thromboxane production and by promoting implantation in early pregnancy and anticoagulation, respectively
[16,17]. Low-dose aspirin also acts as a potent stimulator of
interleukin-3, which has been found to be decient during antiphospholipid syndrome-associated abortion [18]. The primary role of IVIG
is inhibition of anticardiolipin antibodies and lupus anticoagulant,
resulting in an increase in antibody clearance, but IVIG also results in
anti-idiotype antibody-mediated decreases in anticardiolipin antibody production by interaction with B-cell antigen receptors [19].
Reviewing the literature, Laskin et al. [20] demonstrated that
prednisone was not effective in preventing recurrent abortions in
women with APL antibodies. The benecial effect of IVIG has been
proved only in uncontrolled studies [21]. To date, the combined use of
low-dose aspirin and heparin is considered the standard therapy for this
condition [22].
The results of the present study are in accordance with those
published by Triolo et al. [23], who compared the effect of LMW heparin
plus low-dose aspirin with that of IVIG in the treatment of recurrent
abortion in 40 women and found that the women treated with LMW
heparin plus low-dose aspirin had a higher rate of live births (84%) than
those treated with IVIG (57%). Potential heparin-related hazards,
including maternal thrombocytopenia and signicant hemorrhage,
have not occurred in important trials [10,24,25]. The possibility of
osteoporosis developing while on long-term heparin is also a matter of
concern. Fractures did not occur during the follow-up period, but may
have been missed if they occurred late, as seen in studies by Rai et al. [10]
and Kutteh and Ermel [25]. Only one trial measured the bone mineral
density [10]. Control patients were not assessed, but the nding of a 5.4%
decrease in lumbar spine bone mineral density in those treated with
heparin is concordant with a prospective study demonstrating a 5%
decrease in lumbar bone mineral density in pregnant study participants
treated with LMW heparin compared with 3% in the pregnant control
patients [26]. On the other hand, studies investigating the use of IVIG for
the treatment of recurrent abortions show that IVIG may be benecial
for these patients, but the studies included small series of patients
[27,28]. A larger study, which took place in 1996, showed the positive
role if IVIG in the treatment of recurrent abortions. However, this was a
pilot study and it did not include a control group [29].
In conclusion, treatment with LMW heparin and low-dose aspirin
leads to a signicantly higher percentage of live births in women with
recurrent abortions associated with antiphospholipid syndrome than

225

that obtained with IVIG. However, more and larger randomized trials
are needed.
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