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Successful Pregnancy Outcome

in Women With Bad Obstetric History


and Recurrent Fetal Loss Due
to Thrombophilia: Effect of
Unfractionated Heparin
and LowMolecular Weight Heparin

Clinical and Applied


Thrombosis/Hemostasis
Volume 14 Number 2
April 2008 174-179
2008 Sage Publications
10.1177/1076029607306400
http://cath.sagepub.com
hosted at
http://online.sagepub.com

Kanjaksha Ghosh, MD, MRCP, MRCPI, FRC


Path, FACP, FAMS, FNASc, FICP, Shrimati Shetty, PhD,
Sonal Vora, BSc, and Vinita Salvi, MD
Acquired and inherited thrombophilias are known to be
associated with unfavorable pregnancy outcome including recurrent fetal loss. There are differences of opinion
whether these patients need to be treated with aspirin,
unfractionated heparin, lowmolecular weight heparin,
corticosteroids, or intravenous immunoglobulins. In all,
25 consecutive patients with a history of fetal loss and 7
patients who presented in early pregnancy with deepvein thrombosis were treated, and their pregnancy outcome was noted. All the women were positive either for
a solitary or for a combination of acquired and heritable
thrombophilia markers. In all, 23 patients were treated
with unfractionated heparin and 9 with lowmolecular
weight heparin. In all, 16 out of 23 patients (69.6%)
treated with unfractionated heparin and 9 out of 9
(100%) treated with lowmolecular weight heparin had

successful pregnancy outcome. There was a complete


resolution of thrombus in all the cases. None of the
patients had any adverse reactions such as heparininduced thrombocytopenia, thrombosis, or fracture.
Both unfractionated heparin and lowmolecular weight
heparin were effective in cases of bad obstetric history
and recurrent pregnancy loss due to thrombophilia.
However, lowmolecular weight heparin was found to
be more effective than unfractionated heparin along
with other advantages of not requiring laboratory monitoring and easy administration. None of the patients in
either group had to interrupt the therapy for any adverse
treatment-related complications.

placental infarction have been reported in women


with thrombophilia and recurrent pregnancy loss.3,4
The data on the use of anticoagulants for the
treatment of fetal loss in cases of thrombophilic women
are too limited, but there are a few systematic reviews
and meta-analyses available now.5,6 Given the convenience of lowmolecular weight heparin (LMWH), its
ease of administration, and its reduced requirements for monitoring, there is a growing opinion
that LMWH has an important role in reducing pregnancy-induced thromboembolism, recurrent fetal
abortions, or other associated pathologies compared
with unfractionated heparin (UFH). However, the

nherited or acquired thrombophilia accounts


for recurrent pregnancy loss with unknown
cause in 50-65% of the women and in women
with other placental vascular pathologies such as
preeclampsia, intrauterine growth restriction and
placental abruption.1,2 Reduced placental flow and

From the Deptartment of Obstetrics and Gynecology (VS) and


Deptartment of Haemostasis, Institute of Immunohaematology
(ICMR) (KG, SS, SV), KEM Hospital, Parel, Mumbai, India.
Address correspondence to: Kanjaksha Ghosh, Department of
Haemostasis, Institute of Immunohaematology (ICMR), KEM
Hospital, Parel, Mumbai 400 012; e-mail: kanjakshaghosh@
hotmail.com.

Keywords: recurrent spontaneous abortion; low


molecular weight heparin; unfractionated heparin

174
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Unfractionated Heparin and LowMolecular Weight Heparin / Ghosh et al

use of LMWH is limited in countries such as India


due to its exorbitant cumulative cost. In this article,
we present the outcome of gestation following the
use of both LMWH and UFH in a group of women
who presented to us with either pregnancy-associated
deep-vein thrombosis (DVT) or a history of recurrent
fetal loss with either a solitary or multiple thrombophilic defects.

175

(EPCR) 23-bp insertion was detected by PCR amplification without any further restriction digestion.13
Plasminogen activator inhibitor (PAI)-1 4G/5G polymorphism was detected by allele-specific PCR
amplification using 2 sets of primers as described.14
All the thrombophilia markers were assessed at least
3 months after abortion or delivery.

Anticoagulation Regimen

Methods
Patients
We analyzed 32 consecutive pregnant women (mean
age = 24 years) with either DVT associated with
pregnancy or a history of recurrent fetal loss for
evaluation of thrombophilia and subsequent management during pregnancy. All the women had a
thorough investigation (ie, cytogenetic, hormonal,
anatomical, and infective causes for fetal loss) and
were negative for the above-mentioned causes.

Tests for Antiphospholipid Antibodies


Lupus anticoagulants were studied by mixing studies,
kaolin clotting time, and dilute Russells viper venom
time as described earlier7,8 using commercial reagents
(Dade Behring, Marburg, Germany). Immunoglobulin
G/M antibodies for anticardiolipin antibodies, 2GP1,
and annexin V were measured by enzyme-linked
immunosorbent assay (ELISA) using commercial kits
(Varelisa; Pharmacia, Freiburg, Germany).

Tests for Inherited Thrombophilia


Protein C and protein S were measured by ELISA
using commercial kits (Diagnostic Stago, Asniers,
France), and antithrombin III was measured by
chromogenic assays using commercial reagents
(Diagnostica Stago). Deoxyribonucleic acid was
extracted from citrated cell pellet using standard
methods.9
Factor V Leiden mutation was identified by polymerase chain reaction (PCR) amplification of a 220bp fragment using Mnl1 enzyme for restriction
digestion.10 The PT G20210A polymorphism was
identified by HindIII cleavage of a 322-bp PCRamplified product.11 The C677 T polymorphism of
methylene tetrahydrofolate reductase (MTHFR) was
detected using HinfI cleavage of a 175-bp PCR
product,12 whereas endothelial protein C receptor

Unfractionated heparin was given at a dose of 5000


IU subcutaneously, twice daily until 30 weeks of gestation, followed by 7500 IU subcutaneously twice
daily until delivery. No heparin was given at the
onset of labor. Lowmolecular weight heparin was
given at 2500 IU subcutaneously once daily until 30
weeks of gestation and then twice daily until delivery. The anticoagulation was continued 6 weeks in
postpartum period.

Laboratory Monitoring
of Heparin Dosage
Activated partial thromboplastin time (APTT) was
performed once a week to keep the APTT 1.2 to 1.5
times the baseline of patients in cases of UFH therapy. The blood sample was taken once in every 2
weeks before the next dose of heparin until 30 weeks
of gestation and thereafter, every week when the
dose of UFH was increased to 7500 IU subcutaneous, twice daily. No anti-Xa or anti-IIa activity was
studied in the case of women treated with LMWH.
During each visit, a detailed history of bleeding was
taken from each patient. The patients had routine
blood counts during follow-up, with special reference to thrombocytopenia.
The heparin was injected subcutaneously
around the umbilicus by rotation using a 26-gauge
needle. All the deliveries were induced between 36
and 37 weeks and took place per via naturalis.

Results
The study group consisted of 32 women with thrombophilia.
Table 1 shows the characteristics of women with
recurrent pregnancy loss. The mean age of patients
was 24 years (range 20-37 years), and the mean
number of abortions in the group was 3.0 (range
2-9). Nine patients had only early pregnancy losses

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176

Clinical and Applied Thrombosis/Hemostasis / Vol. 14, No. 2, April 2008

Table 1.

Characteristics of Patients With Recurrent Fetal Loss, Treatment Details, and Their Outcome

No

Patient
ID

Age
(y)

No of
Abortions

Time
of Loss

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24

49
242
32
114
33
508
311
98
352
438
38
231
303
367
76
216
213
72
177
37
92
375
199
285

26
30
22
25
30
28
22
34
31
25
25
30
26
29
20
28
22
25
36
31
26
24
24
37

4
5
2
5
5
3
3
9
5
3
3
4
2
6
3
5
3
3
2
3
3
3
2
3

Early
Early
Early
Early
Early
Early
Early
Late
Late
Late
Early + late
Early + late
Early + late
Early + late
Early + late
Early + late
Early + late
Early
Early
Early + late
Early + late
Early + late
Early + late
Early + late

25

100

27

Early + late

Thrombophilia Marker
LA, ACA, FVL het
LA, ACA
ACA, fib448 het
LA, ACA
High fib (>800 mg/dL)
LA, ACA
ACA
ACA, 2GP1, weak annexin
High fib, MTHFR het
2GP1, EPCR het, weak annexin
LA, ACA, weak annexin
LA, ACA, PS def
ACA, antiannexin
High fib (>800 mg/dL)
ACA
LA, ACA
LA, ACA, 2GP1, PAI-1 4G/4G
LA, ACA, FVL het
FVL het
LA, ACA, 2GP1
LA, ACA, 2GP1
High fib (>800 mg/dL), high factor VIII
ACA
High fib (>800 mg/dL), antiannexin,
FVL het
LA, ACA, antiannexin

UFH/
LMWH

Live
Birth/Abortion

UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
UFH
LMWH
LMWH
LMWH
LMWH
LMWH
LMWH
LMWH

Live birth
Live birth
Live birth
Live birth
Live birth
Abortion
Abortion
Live birth
Live birth
Abortion
Live birth
Live birth
Abortion
Live birth
Live birth
Abortion
Abortion
Live birth
Live birth
Live birth
Live birth
Live birth
Live birth
Live birth

LMWH

Live birth

NOTE: LA = lupus anticoagulants; ACA = anticardiolipin antibodies; FVL het = factor V Leiden heterozygous; fib448 het =
fibrinogen 448 Arg/Lys heterozygous; PS def = protein S deficiency; High fib = high fibrinogen; LMWH = lowmolecular weight
heparin; UFH = unfractionated heparin.

(ie, in the first trimester), whereas 3 patients had


only late recurrent fetal losses (ie, in the second or
third trimester). Thirteen patients had a history of
both early and late pregnancy losses. In all, 20 out of
25 patients were positive for any one of the antiphospholipid antibodies (APA) tested, whereas the
remaining 5 patients were positive for any one of the
genetic thrombophilia markers assessed in this study.
Table 2 shows the characteristics of women who
presented with DVT during pregnancy with or without a history of fetal losses. The mean age of the
patients was 26 years (range 19-32 years). Five
patients had pregnancy-associated DVT, whereas in
the remaining 2 patients, along with DVT, there was
a history of fetal losses (ie, both early and late pregnancy losses). In all, 4 out of 7 patients had APA,
whereas in the remaining 3, either high fibrinogen
level or a solitary genetic thrombophilia marker was
responsible for adverse pregnancy outcomes.
Figure 1 shows the effect of UFH and LMWH in
the 2 groups. Out of 25 women with a history of

fetal losses, 17 were treated with UFH. Treatment


with UFH in 11 women resulted in live births,
whereas the remaining 6 cases aborted at varied gestation periods. In the remaining 8 women who were
treated with LMWH, the treatment resulted in live
births in all. Out of the 7 women with DVT with or
without a history of fetal losses, except 1 all were
treated with UFH. In the case of 6 UFH-treated
women, there was abortion in only in 1 woman,
whereas in the remaining 5 women, treatment
resulted in live births. Only 1 woman in this group
was treated with LMWH, which resulted in successful live birth. No treatment-related side effects
such as heparin-induced thrombocytopenia (HIT),
thrombosis, or fractures were observed in any of the
women treated with UFH and LMWH. None had
any excessive blood loss, petechiae, or bruises.
Postpartum blood loss was within normal range in
all the patients. Differences in outcome between the
2 groups were not statistically significant (Fisher
exact test 0.57, P > .05).

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Unfractionated Heparin and LowMolecular Weight Heparin / Ghosh et al

Table 2.

Characteristics of Patients With Deep-Vein Thrombosis During Pregnancy With or Without Fetal Loss,
Treatment Details, and Their Outcome

Patient
ID

Age
(y)

1
2
3
4
5

36
58
113
377
305

30
24
22
24
20

6
7

361
181

27
32

No

177

No of
Abortions
No
No
No
No
No

Time
of Loss

loss
loss
loss
loss
loss

2
1

Thrombophilia Marker
ACA, PS def
MTHFR het
LA, ACA, antiannexin
High platelets, FVL het
ACA,weak annexin, Fib448 homo,
PAI14G/4G
FVL het, weak annexin
High fib (>800 mg/dL)

Early
Early

UFH/
LMWH

Live
Birth/Abortion

UFH
UFH
UFH
LMWH
UFH

Live
Live
Live
Live
Live

birth
birth
birth
birth
birth

UFH
UFH

Live birth
Live birth

NOTE: LA = lupus anticoagulants; ACA = anticardiolipin antibodies; FVL het = factor V Leiden heterozygous; fib448 homo =
fibrinogen 448 Arg/Lys homozygous; PS def = protein S deficiency; MTHFR het = methylene tetrahydrofolate reductase heterozygous;
High fib = high fibrinogen; LMWH = lowmolecular weight heparin; UFH = unfractionated heparin.

18

17

Total Patients

16

Live Birth

14
12
10

6
5

6
4

2
0

RFL + UFH

RFL + LMWH

DVT + UFH

DVT + LMWH

Figure 1. Live birth rates achieved by lowmolecular weight


heparin and unfractionated heparin in cases with recurrent fetal
loss and deep-vein thrombosis. RFL, recurrent fetal loss; UFH,
unfractionated heparin; LMWH, lowmolecular weight heparin;
DVT, deep-vein thrombosis.

Discussion
Lowmolecular weight heparin has become the routine treatment for women with fetal loss and with
acquired and heritable thrombophilias. However,
there are limited data on its utility in cases of recurrent fetal loss. Unfractionated heparin is an attractive alternative in a developing country such as India
because of the low cost; however, it has some side
effects and needs regular laboratory monitoring by
APTT assays. A recent systematic review,5 in which
the data on both LMWH and UFH were pooled,
showed that there was only a 35% reduction in pregnancy loss. However, most of the studies included in

the review were based on small trials or those that


lacked adequate allocation concealment. It has been
shown that heparin and aspirin results in significantly better pregnancy outcomes than low-dose
aspirin alone in women with APA and RPL.15 In
another study in APA-positive cases, a failure rate of
30% was reported when the patients were treated
only with heparin and aspirin,16 whereas in a comparatively larger series published recently in women
with thrombophilia, a combination of aspirin with
either UFH or LMWH yielded upto 94% live births
without any treatment-related complications.17 Even
the different dosages of LMWH have yielded
extremely variable outcomes in women with adverse
pregnancy outcomes.18
The live birth rate achieved in this study is much
higher than that in many of the studies reported earlier.
There may be several reasons for the underestimation
of live births in women with the adverse pregnancy outcomes who are treated with UFH or LMWH. In some
of the studies reported earlier, the efficacy of both
LMWH and UFH has not been reported to be as high
as has been observed in the present study.19 There may
be differences in the treatment regimen between various centers20 as the exact dosage of LMWH or UFH
has not yet been established.
There are no reported fetal side effects of
heparin during pregnancy as heparin does not cross
the placental circulation. The major concerns of
long-term heparin therapy, specifically, with UFH
are osteoporosis, fracture, HIT, and bleeding.21
However, 2 recent studies have shown that bone loss
occurring during pregnancy22 did not differ between
treated and untreated pregnancies when bone mineral density was measured. Thrombocytopenia is

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178

Clinical and Applied Thrombosis/Hemostasis / Vol. 14, No. 2, April 2008

another complication associated with LMWH or


UFH; however, it is more common in UFH-treated
pregnancies than in those treated with LMWH.23
Lowmolecular weight heparin has an additional
fibrinolytic effect, which may have an additional
effect in thrombophilia-complicated pregnancies. In
the present study, we did not find thrombocytopenia
in both UFH-treated and LMWH-treated women.
Heparin-induced thrombocytopenia is one of the
dreaded complications of UFH therapy. However, it
is rarely reported in India, even in those specialties
such as cardiothoracic surgery and nephrology
where it is frequently used. One of the reasons for
low incidence of HIT may be lack of awareness, but
another important reason could be overall low use of
the product in our population.
Lowmolecular weight heparin for a standard
dose of 2500 IU subcutaneously, once daily from the
16th to 30th week of pregnancy and twice daily from
the 31st to 36th week will cost a substantial amount
of money (approximately Rs 50 000 or $1250 only
on injections), whereas with UFH the cost will be
less than Rs 5000 or $100, which may be affordable
by many patients. In the present study, the UFH
used was sodium heparin. It needs to be seen
whether calcium heparin is more effective than
sodium heparin and whether it can be given at less
frequent intervals. None of our patients were on any
other medicines such as aspirin, corticosteroids, or
intravenous immunoglobulins. As LMWH was
found to be excellent and UFH good in the present
study, the available clinical knowledge dictates the
use of single agent only rather than polytherapy in
similar situations unless some additional complications or the clinical ferocity of thrombophilia dictates
its use. There exist some reports on stratification of
risks and corresponding modification of therapeutic
regimens.24 Thrombophilic markers are classified as
strongly thrombophilic and weakly thrombophilic
according to their relative risk associated with
adverse events. Furthermore, approximately 30% to
50% of vascular gestational pathologies cannot be
accounted for by currently available tests for thrombophilia. Where the involved mechanism has not
been established, it is difficult to predict the outcome of the treatment.
In conclusion, the present study demonstrates that
100% live birth rate can be achieved with LMWH
in women with recurrent fatal loss or pregnancyassociated DVT. Though the efficacy of UFH in
women with and without recurrent fetal loss is

approximately 70%, its efficacy in the second group


(ie, pregnancy with DVT) has been found to be
much higher in the small number of patients studied, but the difference was not statistically significant. But considering the fact that LMWH has
increased bioavailability, longer half-life, ease of
administration, and reduced need of monitoring and
reduced risk of treatment-associated complications,
it can be the standard treatment for adverse pregnancy outcomes.

Acknowledgment
The authors would like to acknowledge Gland
Pharma, Hyderabad, India, for providing LMWH
(Indeparin) for our patients.

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