Blood Coagulation, Fibrinolysis and Cellular Haemostasis
© Schattauer 2011
Thromboprophylaxis for recurrent miscarriage in women with
or without thrombophilia
HABENOX*: A randomised multicentre trial
Jantien Visser1; Veli-Matti Ulander2; Frans M. Helmerhorst1; Katja Lampinen3; Laure Morin-Papunen4; Kitty W. M. Bloemenkamp1;
Risto J. Kaaja2
1Department
of Obstetrics, Gynaecology and Reproductive Medicine, Leiden University Medical Center, Leiden, the Netherlands; 2Department of Obstetrics and Gynaecology,
Helsinki University Hospital, Helsinki, Finland; 3Department of Obstetrics and Gynaecology, Karolinska University Hospital, Stockholm, Sweden; 4Department of Obstetrics and
Gynaecology, Oulu University Hospital, Oulu, Finland
Summary
Recurrent miscarriage affects 1–2% of women. In more than half of all
recurrent miscarriage the cause still remains uncertain. Thrombophilia
has been identified in about 50% of women with recurrent miscarriage
and thromboprophylaxis has been suggested as an option of treatment. A randomised double-blind (for aspirin) multicentre trial was performed among 207 women with three or more consecutive first trimester (<13 weeks) miscarriages, two or more second trimester (13–24
weeks) miscarriages or one third trimester fetal loss combined with one
first trimester miscarriage. Women were analysed for thrombophilia.
After complete work-up, women were randomly allocated before seven
weeks’ gestation to either enoxaparin 40 mg and placebo (n=68), enoxaparin 40 mg and aspirin 100 mg (n=63) or aspirin 100 mg (n=76).
The primary outcome was live-birth rate. Secondary outcomes were
pregnancy complications, neonatal outcome and adverse effects. The
Correspondence to:
R. J. Kaaja
Department of Obstetrics and Gynaecology
Helsinki University Hospital
Haartmaninkatu 2, 00290 Helsinki, Finland
Tel.: +358 9 4711, Fax: +358 9 47172812
E-mail: [email protected]
trial was ended prematurely because of slow recruitment. A live birth
rate of 71% [relative risk (RR) 1.17, 95% confidence interval (CI)
0.92–1.48] was found for enoxaparin and placebo and 65% [RR 1.08,
95% CI 0.83–1.39] for enoxaparin and aspirin when compared to aspirin alone (61%, reference group). In the whole study group the live
birth rate was 65% (95% CI 58.66–71.74) for women with three or
more miscarriages (n=204). No difference in pregnancy complications,
neonatal outcome or adverse effects was observed. No significant difference in live birth rate was found with enoxaparin treatment versus
aspirin or a combination of both versus aspirin in women with recurrent
miscarriage.
Keywords
Pregnancy, clinical trials, heparins/LMWH, thrombophilia
Received: May 31, 2010
Accepted after major revision: November 2, 2010
Prepublished online: November 23, 2010
doi:10.1160/TH10-05-0334
Thromb Haemost 2011; 105: 295–301
* Trial registration number NCT0095962.
Introduction
Recurrent miscarriage has commonly been defined as three or
more consecutive spontaneous pregnancy losses (1). Approximately 10–15% of all conceptions end up in a miscarriage, which is
mostly due to chromosomal abnormalities. About 1–2% of
women suffer from recurrent miscarriage, having a major impact
on their lives (2, 3). The cause appears to be multifactorial, such as
uterine anomalies, endocrine disorders, immunological causes, infections, chromosomal abnormalities and maternal autoimmune
disorders. However, in 50–60% of all recurrent miscarriage the
cause remains unclear (4, 5).
In a large meta-analysis different thrombophilic polymorphisms have been identified to be associated with recurrent fetal
loss. However, the association depended on type of thrombophilic
disorder and type of fetal loss (6).
Subsequently, interventions with thromboprophylaxis for prevention of recurrent miscarriage have been proposed (7–9). The
idea of using low-molecular-weight heparin (LMWH) and aspirin
in women with recurrent miscarriage came from the positive effect
found in women with antiphospholipid syndrome, which has also
been associated with risk of thrombosis (10, 11). Nevertheless, insufficient evidence for the use of anticoagulants for women with
unexplained pregnancy loss was found in two systematic reviews
(12, 13). Additionally, LMWH has been identified, besides the anticoagulant mechanism, to have also an anti-inflammatory and immunomodulatory action (14–16). The positive effect in women
with antiphospholipid syndrome might therefore rather be an
anti-complement effect than an anticoagulation effect (17).
Very recently two placebo controlled randomised trials have
found no beneficial effect of thromboprophylaxis for women with
two or more miscarriages (18, 19). The aim of this multicentre ranThrombosis and Haemostasis 105.2/2011
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Visser et al. Thromboprophylaxis for recurrent miscarriage
domised controlled trial (RCT) was to compare aspirin and/or
LMWH in women with recurrent miscarriage with or without
thrombophilia.
Materials and methods
We performed a randomised controlled multicentre study in Helsinki University Hospital, and Oulu University Hospital, Finland;
Leiden University Medical Centre, the Netherlands and Karolinska
University Hospital, Sweden. The enrolment was performed from
January 2002 until December 2007. The trial was approved by the
Ethics Committee of all participating centres. Written informed
consent was obtained from all patients prior to randomisation. At
the start of the trial, registration was not yet necessary, therefore
the trial was registered in 2009 in ClinicalTrials.gov, trial register
number NCT0095962. The study was ended prematurely by the
authors because of slow recruitment in six years.
Participants
Women aged 18–41 years with recurrent miscarriage with or without thrombophilia were assessed for eligibility after referral. Recurrent miscarriage was defined as three or more consecutive first trimester (<13 weeks) miscarriages, two or more second trimester
miscarriages (13–24 weeks) or one third trimester fetal loss (>24
weeks) combined with at least one first trimester miscarriage.
Thrombophilia testing was performed before pregnancy and defined as factor V Leiden mutation, prothrombin gene mutation,
protein C deficiency (<0.73 IU/ml), protein S deficiency (< 0.57 IU/
ml), high factor VIII (≥1.5 IU/ml), anticardiolipin antibodies (8–40
GPL) or beta-2 glycoprotein (>20 U/ml). Beta-2 glycoprotein was
only tested in Finland (116 women). A second test was performed
after 12 weeks, but before inclusion in the study, to confirm positive
thrombophilia testing. Women with combined thrombophilia (two
or more findings) or “high-risk” thrombophilia, defined as positive
lupus anticoagulant, antithrombin deficiency, anticardiolipin antibodies > 40 GPL or homozygosity for factor V Leiden, were included in a separate study (Habenox III), in which they were randomised to aspirin 100 mg and enoxaparin 80 mg or enoxaparin 80
mg alone. Other exclusion criteria were history of thromboembolism or bleeding disorders, allergy to aspirin or enoxaparin, uterine
anomalies, cervical insufficiency, untreated thyroid disease, poorly
treated diabetes mellitus, parental chromosomal abnormalities and
pregnancies achieved by assisted reproductive techniques.
Study design
Women with thrombophilia were enrolled in Habenox I, women
without thrombophilia were enrolled in Habenox II, followed by
Thrombosis and Haemostasis 105.2/2011
identical study protocols. Randomisation was performed after a
positive HCG urine test and before seven weeks’ gestation by computer in blocks of six patients and stratified by centre (4 centres)
and history of early (<13 weeks’ gestation) or late miscarriage (≥13
weeks’ gestation). Patients were allocated to randomisation code
numbers in chronological order. The allocation list was stored at
an independent secretary and randomisation was performed with
communication by telephone per centre. Information about the
treatment each woman was given was stored in a sealed envelope,
which was not opened until the study was completed, unless such
information was necessary in case of severe complications or serious side effects. The study was double-blinded for aspirin. To ensure blindness for care provider and patient, tablets were placed in
identical opaque capsules and stored in sealed identical containers.
Women were randomly allocated to three different intervention
groups. All interventions were given once daily. The first group received enoxaparin 40 mg as subcutaneous injection and placebo
orally. The second group received enoxaparin 40 mg as subcutaneous injection and aspirin 100 mg orally. The third group received aspirin 100 mg orally. Women randomised to enoxaparin
were taught to self-inject the medication subcutaneously. After
starting enoxaparin, platelets were checked at every visit for heparin-induced thrombocytopenia. At the first visit a physical examination was performed, body mass index (BMI) and blood pressure were checked. Follow-up was performed by their own obstetrician at 8, 10, 14, 18, 24, 28, 32 and 36 weeks of gestation. During all
visits an ultrasound was performed and patients were asked for adverse effects and vaginal bleeding complications, which were filled
out on a case report form (CRF). Aspirin and placebo were discontinued at 36 weeks gestation. Enoxaparin was continued until the
first signs of labour. Women with thrombophilia restarted enoxaparin after delivery and continued until six weeks postpartum.
Outcome measures
Primary outcome was live birth rate, defined as live birth after 24
weeks gestation. Secondary outcomes were preeclampsia, abruptio
placentae, premature delivery (24–37 weeks gestation), intrauterine growth restriction (birth weight <2 SD), adverse effects and
vaginal bleeding complications, defined as first, second and third
trimester blood loss and postpartum haemorrhage (>500 ml
blood loss).
Sample size calculation
The sample size estimation was based on, at the start of the study,
the only RCT on this subject by Rai et al. (11) showing that aspirin
and unfractioned heparin improved the live birth rate in women
with phospholipid antibodies from 42% to 71% compared to aspirin alone. Therefore, for an increase of 30% in live birth rate, a
sample size of 90 patients per treatment group was required to re© Schattauer 2011
Visser et al. Thromboprophylaxis for recurrent miscarriage
Figure 1: Trial profile.
ject the null-hypothesis on a 5% level with a power of 80% and approximately 270 patients were required to enter the study.
Statistical analysis
Data were analysed according to the intention to treat principle.
Habenox I and II were analysed together as study protocols were
identical. No interim analysis was planned. A subanalysis was
planned for thrombophilia versus no thrombophilia and for a history of early versus late miscarriages. Data were expressed as the
mean ± standard deviation (SD) for continuous variables. Additionally ranges were given for maternal age, BMI and previous miscarriages. A median was given for number of previous miscarriages. An ANOVA test was performed for comparisons between
means. Categorical variables were expressed as 95% confidence interval (CI), and the Chi square test was used to compare proportions. Statistical significance was defined as p<0.05. Live birth rates
were additionally expressed as relative risks with associated 95%
© Schattauer 2011
CI, with aspirin as the reference group. Statistical analyses were
performed using SPSS version 16.0 (Statistical Package for Social
Science; SPSS Inc., Chicago, IL, USA).
After primary analysis, subgroup analysis was performed to assess treatment effects between different categories of women.
Women were classified into subgroups based on their characteristics at trial entry: thrombophilia (yes or no), maternal age (<35
or ≥35), number of previous miscarriages (<4 or ≥4), parity (primary, previous live birth versus secondary, no previous live birth)
and history of early versus late miscarriage/fetal loss (<13 weeks
versus ≥13 weeks gestation).
Results
A total of 219 women were assessed for eligibility after referral
(씰Fig. 1). Twelve women with combined or “high-risk” thrombophilia were excluded and randomised in another trial (see
above). We randomly assigned 76 women to aspirin, 63 women to
Thrombosis and Haemostasis 105.2/2011
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Visser et al. Thromboprophylaxis for recurrent miscarriage
Characteristic
Enoxaparin
and placebo
(n=68)
Enoxaparin and
aspirin (n=63)
Aspirin
(n=76)
Maternal age (years)
Range
≥35 years
32.5 ± 4.29
(22–40)
24 (35.3)
31.6 ± 4.57
(22–41)
17 (27.0)
32.0 ± 4.47
(22–40)
26 (34.2)
Body mass index (Kg/m2)
Range
23.4 ± 3.71
(18–36)
23.1 ± 3.13
(18–33)
25.4 ± 5.38
(17–40)
Blood pressure (mmHg)
Systolic
Diastolic
117±11.31
70 ± 9.15
114 ± 11.00
70 ± 6.08
116 ± 11.67
72 ± 10.22
Maternal smoking
7 (10.3)
6 (9.7)
11 (15.9)
Previous miscarriages
Median (range)
≥4 miscarriages
3.9 ± 1.41
3 (2–10)
30 (44.1)
3.6 ± 0.90
3 (3–7)
28 (44.4)
3.9 ± 1.48
3 (2–9)
21 (27.6)
Nulliparous
32 (47.1)
42 (66.7)
46 (60.5)
History of late miscarriages
17 (25.0)
8 (12.7)
15 (19.7)
Thrombophilia
Factor V Leiden
Prothrombin gene mutation
Protein C deficiency
Protein S deficiency
High factor VIII
Anticardiolipin antibodies
Beta-2 glycoprotein
17 (25.0)
4
3
1
1
1
4
3
15 (23.8)
9
1
0
0
1
2
2
19 (25.0)
4
1
2
0
2
5
5
Gestation at inclusion (days)
35.8 ± 4.64
36.5 ± 4.07
36.8 ± 4.15
Enoxaparin
and placebo
(n=68)
Enoxaparin and
aspirin (n=63)
Aspirin
(n=76)
P-value
Live birth no. (%)
48 (71)
41 (65)
46 (61)
0.45
Relative risk (95% CI)
1.17 (0.92–1.48)
1.08 (0.83–1.39)
1.00
enoxaparin and aspirin and 68 women to enoxaparin and placebo.
One woman allocated to the aspirin group developed a pulmonary
embolism at eight weeks of gestation. She had not been diagnosed
with thrombophilia before pregnancy and was additionally treated
with LMWH according to local protocol. Two women in the enoxaparin and aspirin group used no medication or discontinued taking their medication. The enoxaparin and placebo group and the
enoxaparin and aspirin group both included a carrier woman of a
chromosomal abnormality associated with recurrent miscarriage.
In no case was it necessary to reveal the used medication before the
end of the study and open the sealed envelope.
Baseline characteristics of the study participants are shown in
씰Table 1. Women allocated to aspirin were found to have a significant higher BMI compared to the other two intervention groups
(p=0.003). In the whole group the median number of miscarriages
was 3 (range 2–10). Only three (1%) of the included women had a
history of two second trimester miscarriages and 38% of the
women were found to have a history of four or more consecutive
miscarriages.
Thrombosis and Haemostasis 105.2/2011
Table 1: Demographic and baseline characteristics. Values are mean ± SD or number
(%). For maternal age, body mass index and
previous miscarriages ranges were given. A
median was given for previous miscarriages.
Table 2: Primary outcome. Values are
number (%) or relative risk with associated
95% CI.
Live birth rate
A live birth rate of 71% [relative risk (RR) 1.17, 95% CI 0.92–1.48]
was found for enoxaparin and placebo and 65% [RR 1.08, 95% CI
0.83–1.39] for enoxaparin and aspirin when compared to aspirin
alone (61%, reference group) (see 씰Table 2). Exclusion of the five
protocol violations from analysis gave no significant difference in
live birth rate. Exclusion of the three women with only two miscarriages gave a live birth rate of 65% (95 % CI 58.66–71.74) for all
women (n=204).
Most of the miscarriages during the study occurred in the first
trimester (93%), and 28% even before seven weeks gestation. One
monochorionic, diamniotic twin pregnancy in the enoxaparin and
aspirin group developed a twin-to-twin syndrome. Despite laser
therapy, the pregnancy was lost at 18 weeks gestation. Another late
miscarriage was identified at 17 weeks gestation in this intervention group. Chromosomal analysis of this fetus showed no abnormalities. One pregnancy in the enoxaparin and placebo group was
terminated at 15 weeks gestation because of aneuploidy, Turner’s
© Schattauer 2011
Visser et al. Thromboprophylaxis for recurrent miscarriage
Table 3: Subgroups. Live birth number and
relative risk with associated 95% CI were calculated in all subgroups for enoxaparin and
placebo intervention versus aspirin and for
enoxaparin and aspirin intervention versus
aspirin.
Enoxaparin and
placebo
no./total RR (95%CI)
Enoxaparin and
aspirin
no./total RR (95%CI)
Aspirin
no./total RR
(95% CI)
Thrombophilia
Yes
No
13/17 1.21 (0.79–1.87)
35/51 1.15 (0.87–1.53)
9/15 0.95 (0.56–1.63)
32/48 1.05 (0.78–1.42)
12/19 1.00
34/57 1.00
History of miscarriages
Early
Late
36/51 1.16 (0.89–1.52)
12/17 1.18 (0.70–1.97)
36/55 1.08 (0.82–1.43)
5/8 1.04 (0.53–2.05)
37/61 1.00
9/15 1.00
History of miscarriages
Primary
Secondary
26/32 1.25 (0.95–1.63)
22/36 1.15 (0.75–1.75)
27/42 0.99 (0.72–1.34)
14/21 1.25 (0.80–1.96)
30/46 1.00
16/30 1.00
Age
<35 years
≥35 years
32/44 1.17 (0.88–1.56)
16/24 1.16 (0.75–1.78)
31/46 1.09 (0.81–1.46)
10/17 0.72 (0.41–1.29)
31/50 1.00
15/26 1.00
Number of miscarriages
<4
≥4
26/38 1.02 (0.77–1.35)
22/30 1.71 (1.00–2.93)
23/35 0.98 (0.72–1.32)
18/28 1.50 (0.85–2.64)
37/55 1.00
9/21 1.00
Table 4: Pregnancy complications and
neonatal outcome. Values are mean ± SD or
number (%). * NICU, neonatal intensive care
unit.
Enoxaparin
and placebo
(n=48)
Aspirin
(n=46)
P-value
0.83
Preeclampsia
2 (4.2)
1 (2.4)
1 (2.2)
Abruptio placentae
0
0
1 (2.2)
Gestation at delivery (weeks)
Range
38.9 ± 1.97
(32–42)
38.6 ± 2.87
(27–42)
39.1 ± 1.87
(32–42)
0.62
Premature delivery (weeks)
5 (10.4)
6 (14.6)
3 (6.5)
0.46
Birth weight (grams)
3455 ± 685.8
3345 ± 763.0
3456 ± 587.3
0.69
Intrauterine growth restriction
4 (8.3)
4 (9.8)
1 (2.2)
0.31
syndrome. In two other pregnancies in this intervention group intrauterine fetal demise was identified at 15 and 24 weeks gestation.
Both fetuses had normal chromosomal analysis.
Subanalysis of the women with identified thrombophilia
showed a live birth rate of 76% [RR 1.21, 95% CI 0.79–1.87] for enoxaparin and placebo and 60% [RR 0.95, 95% CI 0.56–1.63] for
enoxaparin and aspirin when compared to aspirin alone (63%, reference group). A high live birth rate was found for women with primary recurrent miscarriages [81%, RR 1.25, 95% CI 0.95–1.63]
and women with four or more recurrent miscarriages [73%, RR
1.71, 95% CI 1.00–2.93] receiving enoxaparin and placebo compared to aspirin (씰Table 3).
Pregnancy complications and neonatal outcome
For pregnancy complications and neonatal outcome see 씰Table 4.
One abruptio placentae occurred in the aspirin group for which an
emergency caesarean section was performed at 34 weeks gestation.
Additionally, no significant difference in preeclampsia, intrauterine growth restriction or premature labour was observed between
© Schattauer 2011
Enoxaparin
and aspirin
(n=41)
the three groups. One neonate in the enoxaparin and aspirin group
died of respiratory distress syndrome one week after birth. This
neonate was born severely intrauterine growth restricted (680
grams) at 27 weeks gestation. Another neonate in this group was
diagnosed with an imperforate anus. In the enoxaparin and placebo group one neonate was born with a gastroschizis and one with
cystic fibrosis.
Adverse effects
For adverse effects see 씰Table 5. No heparin-induced thrombocytopenia was observed during the trial and no allergies were reported. Minor vaginal bleedings were observed during the first,
second and third trimester of the pregnancy in all three groups. No
significant difference was found between the three groups. However more blood transfusions were needed in four women in the
enoxaparin and placebo group, compared to none in the other two
groups. Minor side-effects such as skin reactions at injection site,
bruising, itching, and nose bleeding were mentioned by the
women, but of the whole study-group only one woman disconThrombosis and Haemostasis 105.2/2011
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Visser et al. Thromboprophylaxis for recurrent miscarriage
Enoxaparin
and placebo
(n=48)
Enoxaparin Aspirin
and aspirin (n=46)
(n=41)
P-value
First trimester bleeding
9 (18.8)
7 (17.1)
0.96
Second/third trimester bleeding
1 (2.1)
Mean blood loss postpartum (cc)* 637 ± 663
9 (19.6)
1 (2.4)
4 (8.7)
0.23
420 ± 278
490 ± 336
0.10
0.64
Postpartum haemorrhage
13 (27.1)
7 (17.1)
10 (21.7)
Blood transfusion
4 (8.3)
0
0
Patients
no.
ALIFE
Miscarriages Start of
Treatment
no. (%)
medication
364 itt*
2 (40.1)
299 pregnant ≥3 (59.9)
Live
birth
P-value
<6 weeks
1. LMWH+ aspirin
2. Aspirin
3. Placebo
69%
62%
67%
0.63
HABENOX 207
2 (1.0)
≥3 (99.0)
<7 weeks
1. LMWH+ aspirin
2. Aspirin
3. LMWH
65%
61%
71%
0.45
SPIN
2 (57.1)
≥3 (42.9)
<7 weeks
1. LMWH+ aspirin
2. Placebo
78%
80%
0.85
294
tinued her mediation at 12 weeks of her ongoing gestation. During
the trial no women switched to another type of LMWH because of
side-effects.
Discussion
This study was conducted to identify which thromboprophylactic
treatment is best to prescribe to women with recurrent miscarriage
without known cause or with thrombophilia. Our study shows no
significant difference in success rate for treatment with enoxaparin
versus aspirin or a combination of both.
Unfortunately, due to slow patient flow, only 3/4 of the women
needed were recruited despite of the six years enrolment. The study
had to be closed prematurely, leading to small intervention groups
and skewed randomisation. Additionally, the sample size calculation of our study was based on an increase of live birth rate of
30% for treatment with enoxaparin, leaving our study not being
able to exclude a benefit of enoxaparin only treatment. In order to
have an 80% power to detect an increase of 10% in live birth rate at
the 95% confidence level, a trial would need to randomise 356
women per treatment group. A trial of this size would take an enormous effort, time and finance. Still, the Habenox trial included in
comparison with the other seven RCTs on thromboprophylaxis
(18–24) most cases of women with three or more early miscarriages with initiating treatment before seven weeks gestation. With
all studies being underpowered for showing an absolute risk of
10%, conclusions about the ineffectiveness of the used interventions must be made with caution, as the problem might be the
number of patients (18–24).
Thrombosis and Haemostasis 105.2/2011
Table 5: Bleeding complications. Values are
mean ± SD or number (%). * cc, cubic centimetre.
Table 6: Recent RCTs. *itt, intention-to-treat
population.
A limitation of our study was that it included no placebo intervention group. It is therefore difficult to predict the a priori chance
of our patients to miscarry in the subsequent pregnancy. The generally assumed live birth rate of 75% comes from a prospective
longitudinal observational study and is higher than found in any of
our treatment groups (25). More recent studies have found live
birth rates ranging from 57%-95% (18–21, 26). The large range
found for live birth rate in women with recurrent miscarriage
might be explained by the use of different definitions of recurrent
miscarriage (2 versus 3 miscarriages). This becomes clear when
comparing the live birth rates of the Habenox trial with two other
very recently published trials (씰Table 6) (18, 19).
Subgroup analysis showed a high (76%) but not significant live
birth rate for women with thrombophilia treated with enoxaparinonly. This subgroup (n=51) was unfortunately very small as surprisingly we only tested 25% of the women positive for thrombophilia, and only 13% were found carrier of heritable thrombophilia. This was although comparable to the 16% found for inherited thrombophilia in the ALIFE trial (19).
In our study more obese women included in the aspirin group
could have had an influence on the success rate (27). In recurrent
miscarriage patients, Metwally et al. identified women with a BMI
of >30 kg/m2 to have a small but significant increased risk of miscarriage in the subsequent pregnancy (28).
The use of thromboprophylaxis during pregnancy appears to be
safe for the mother and child as was found in a large systematic review (29). Our study however found an increase in the risk of postpartum blood loss and more blood transfusions in the enoxaparin
and placebo group, this increased risk was not seen in the enoxaparin and aspirin group. This leads us to assume that it could be
caused by chance and not treatment dependently.
© Schattauer 2011
Visser et al. Thromboprophylaxis for recurrent miscarriage
What is known about this topic?
●
●
Thromboprophylaxis prevents recurrent miscarriage in women
with antiphospholipid syndrome.
LMWH and/or aspirin did not improve live birth rate compared to
placebo in the group of women with two or more early miscarriages.
What does this paper add?
●
●
LMWH did not improve live birth rate compared to aspirin in
women with three or more miscarriages.
The Habenox study found a live birth rate of 65% (95% CI
58.66–71.74] for women with three or more miscarriages (n=204)
on treatment.
In conclusion, no significant difference in live birth rate was
found with enoxaparin treatment versus aspirin or a combination
of both. All RCTs so far failed to reach enough power for showing
an absolute risk of 10%, to exclude a possible effect of LMWH.
Therefore an individual patient data meta-analysis might be the
only possibility to provide us with evidence-based advice for the
more homogenous group of women with three or more miscarriages or women with thrombophilia.
Acknowledgements
We would like to thank Eija Kortelainen for her assistance with data
collecting.
Disclosures
The study was supported by an unrestricted grant from Sanofiaventis for paying the salary of the study nurse (Finland), providing the randomisation list and aspirin and placebo medications. This funding source had no role in the study design, collection, analyses, and interpretation of data, writing of the report
or the decision to submit the paper for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit for publication.
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