J Infertil Reprod Biol, 2017, Volume 5, Issue 4, Pages: 15-19. https://doi.org/10.47277/JIRB/5(4)/15  
Anti-Coagulant Therapy in Unexplained Recurrent  
Pregnancy Loss Is It Indispensible?  
Bishista Bagchi, Sukanta Misra*, Ashish Seal  
Department of Obstetrics and Gynecology, Vivekananda Institute of Medical Sciences(VIMS), Ramakrishna Mission Seva Pratishthan (RKMSP), 99  
Sarat Bose Road, Kolkata  700026, India  
Received: 06/04/2017  
Accepted: 19/09/2017  
Published: 20/12/2017  
Abstract  
Recurrent pregnancy loss (RPL) is a heterogeneous reproductive problem with multiple aetiologies and contributing factors. It  
becomes quite challenging to form a work-up to detect the cause of RPL in the early months as a continuation of pregnancy involves  
many factors. In more than half of all recurrent miscarriage the cause still remains uncertain. Thrombophilia has been identified in about  
5
0% of women with recurrent miscarriage and thromboprophylaxis has been suggested as an option of treatment.. In obstetric APLA  
Syndrome (Antiphospholipid antibody) the combination of aspirin and heparin has improved outcomes. The use of low molecular weight  
heparin (LMWH) has become a common practise in women with inherited thrombophilia and also those with unexplained miscarriage  
to help safeguard the ongoing pregnancy. To evaluate if there is any effectiveness of low molecular weight heparin (enoxaparin) in  
women with a history of at least two miscarriages without any apparent aetiology for recurrent pregnancy loss. A prospective randomised  
controlled study held at Vivekananda Institute of Medical Sciences, Kolkata from August 2015- July 2018. The study assessed the effect  
of anticoagulant treatment on the live-birth rate (primary outcome) in 80 antenatal women with a history of at least two miscarriages  
without any apparent causes. Interventions included low molecular weight heparin administration in one group and the other one was  
not given any anti-coagulant therapy. Similar live birth rates were observed with enoxaparin and the patients who did not receive any  
anti-coagulant, respectively 84% and 82% (RR 0.97, 95% CI 0.81 to 1.16). There were no significant differences in live birth weight  
and other pregnancy outcomes between the two groups. Therefore, there is no evidence to support any incremental benefit of adding  
LMWH to the treatment as a routine in unexplained cases of recurrent pregnancy loss.  
Keywords: Abortion, Anti-coagulant, Enoxaparin, Live birth, Aspirin  
1
Introduction  
outcome. Secondary outcome being late pregnancy  
complications as pre-eclampsia, intrauterine growth restriction  
Recurrent pregnancy loss is a heterogeneous reproductive  
problem with multiple aetiologies and contributing factors. As  
such, evaluating and treating women with this condition is a  
complex task, and research in the field is a potential challenge.  
The definition of recurrent pregnancy loss is debated, ranging  
from two clinical miscarriages (not necessarily consecutive)  
according to the American Society for Reproductive Medicine  
(
IUGR), placental abruption, drug side effects as  
thrombocytopenia, thrombotic episodes, antepartum,  
postpartum bleeding, injection site hematoma, subcutaneous  
bruises and allergic skin reactions.  
(
ASRM) to three consecutive pregnancy losses (not necessarily  
Material and method  
intrauterine) as defined by both the European Society for  
Human Reproduction and Embryology (ESHRE) and the Royal  
College of Obstetricians and Gynaecologists (RCOG).  
Recurrent miscarriage affects 1-2% of women (1, 2). In more  
than half of all recurrent miscarriage the cause still remains  
uncertain (2). Thrombophilia has been identified in about 50%  
of women with recurrent miscarriage and thromboprophylaxis  
has been suggested as an option of treatment (3). In obstetric  
APLA Syndrome (Antiphospholipid antibody) the combination  
of aspirin and heparin has improved outcomes (4). By analogy,  
the use of low molecular weight heparin (LMWH) has become  
commonplace in women with inherited thrombophilia and also  
those with unexplained miscarriage to help safeguard the  
pregnancy. The objective of the current study was assessment  
A prospective randomised controlled study held at  
Vivekananda Institute of Medical Sciences, Kolkata from  
August 2015- July 2018. The study assessed the effect of  
anticoagulant treatment on the live-birth rate (primary  
outcome) in 80 antenatal women aged between 18-40years with  
a history of at least two miscarriages without any apparent  
causes. Interventions included low molecular weight heparin  
administration in one group and the other one was not given  
any anti-coagulant therapy. Inclusion criteria were 80 women  
of age 18-40 yrs. with history of at least two first trimester  
pregnancy losses, with normal parental karyotype; normal  
TSH, GTT, coagulation profile, were included. We excluded  
patients with history of thrombophilia, renal disease,  
cardiovascular disease or any autoimmune disease. Data was  
statistically analyzed for 80 women satisfying inclusion  
criteria; routine antenatal investigations were done for both  
groups; with monitoring of platelet count and serum creatinine.  
Written consent form were signed by patients after explaining  
the  
efficacy,  
safety  
and  
cost-effectiveness  
of  
thromboprophylaxis with LMWH in women of unexplained  
recurrent miscarriage versus no treatment. Assessing the live  
birth rate in the study and control group being the primary  
*
Corresponding author: Prof. Dr. Sukanta Misra, Department of Obstetrics and Gynecology, Vivekananda Institute of Medical  
Sciences (VIMS), Ramakrishna Mission Seva Pratishthan (RKMSP) 99 Sarat Bose Road, Kolkata 700026. E-mail:  
bishista.bagchi@gmail.com  
15  
J Infertil Reprod Biol, 2017, Volume 5, Issue 4, Pages: 15-19. https://doi.org/10.47277/JIRB/5(4)/15  
about the medication. LMWH was given from the time of  
confirmation of fetal cardiac activity to 37 completed weeks  
Outcome was assessed. Figure 1 demonstrates work plan.  
especially enoxaparin alone or others have reported that  
combination treatment of prednisone, aspirin, folate and  
progesterone might be as effective treatment as enoxaparin  
alone (6). A prospective randomized study conducted by  
Dolitsky et al., in which 40 mg enoxaparin and 100 mg oral  
aspirin were administered to women with URM, and as soon as  
fetal cardiac activity was detected (about 7-9 weeks of  
pregnancy),prophylaxis was started and live birth rate was  
Ethical consideration  
The Ethical Committee of Vivekananda Institute of  
Medical Sciences (VIMS) has given clearance for the study on  
1
2/06/2015. Written informed consent has been obtained from  
8
1.5% in enoxaparin group and 84% in aspirin group (7).  
Fawzy et al. achieved a live birth rate of 81% using enoxaparin  
0 mg a day in women with ≥3 RPLwhen compared with  
all women who participated in the study.  
2
Statistical Analysis  
control group with a live birth rate of 48% (6). LMWH given  
in first trimester and continued throughout pregnancy, has been  
seen to reduce early and late spontaneous abortions for women  
with RPL, with unexplained etiology (8). This effect might be  
due to the anti-inflammatory action of heparin that act on the  
decidua of women with recurrent miscarriage, showing  
necrosis, acute and chronic inflammation and vascular  
thrombosis compared to those of women with normal  
pregnancies (9). Heparin also seems to have an anti-  
complement effect which prevents pregnancy loss and  
thrombosis (10, 11). On the contrary, no effects of use of  
enoxaparin or nadoparin, combination of nadoparin and aspirin  
or only aspirin, have been reported in improving live birth rates  
of women with RPL (12, 13). Similarly, a multicentric  
randomized controlled trial of LMWH and low-dose aspirin  
plus intensive pregnancy surveillance resulted in a 22%  
miscarriage rate in women with URM versus 20% in the group  
receiving intensive surveillance alone, without any such  
medication (14). In our study there was no significant  
difference in both the groups with respect to live birth rate and  
miscarriage rate.  
Categorical variables are expressed as Number of patients  
and percentage of patients and compared across the groups  
using Pearson’s Chi Square test for Independence of Attributes/  
Fisher's Exact Test as appropriate. The statistical software  
SPSS version 20 has been used for the analysis. An alpha level  
of 5% has been taken, i.e. if any p value is less than 0.05 it has  
been considered as significant.  
Results and discussion  
In women with either congenital or acquired thrombophilia,  
LMWH plays an important role in respect to live birth rates,  
abortion and late obstetrical complication rates (4, 5). However,  
the use of LMWH to prevent recurrent miscarriages in  
thrombophilia remains controversial because of the small  
number of women treated with LMWH in the existing trials, or  
significant methodological problems in the study designs. On  
the other hand, the management of women with a history of  
pregnancy loss without an identified cause is unclear and the  
role of anticoagulants for women with unexplained recurrent  
miscarriage (URM) remains controversial. Previous literature  
have always focused on the use of thromboprophylaxis  
4
05 patients with recurrent miscarriage  
1
87 visited during pregnancy  
218 for pre-pregnancy evaluation  
1
26 patients had unexplained pregnancy loss; 15 of them declined treatment  
with anti-coagulant; 23 women were excluded from the study  
8
8 patients were included in the study  
4
4 women in study group; 4  
4
4
4 women in control group;  
lost follow up  
did not complete treatment  
Figure 1. Study plan  
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Table 1: Age, BMI, Previous miscarriage of women in control and study group  
Study group  
Control group  
p-value  
Age (yrs); mean  
28 (+ 5)  
25.3 (+ 3)  
3 (2-4)  
28.8 (+ 6)  
25.7 (+ 2)  
2(2-5)  
0.40  
0.64  
0.08  
2
BMI (Kg/m ); mean  
Previous abortion count; mean  
Table 2: Comparison of study and control groups based on maternal and foetal outcome  
Study group (n = 53)  
13(33)  
Control group (n = 60)  
p-value  
0.68  
0.85  
0.24  
0.28  
0.36  
1
Abortion rate n (%)  
POG of miscarriage (+-sd)  
POG of live birth(+-sd)  
Pre-eclampsia  
15(37)  
9.4(+_1.4)  
38.3(2.3)  
1(2.5)  
9.3(+_2.4)  
39.3(2.2)  
3(7.5)  
IUGR  
3(7.5)  
2(5)  
IUD  
1(2.5)  
1(2.5)  
C/s rate  
17(42)  
8(20)  
0.06  
1
Thromboembolic event  
0(0)  
1(2.5)  
Table 3: Maternal safety outcome in control and study group  
Study group  
Control group  
0(0)  
p-value  
Subcutaneous bruises  
Allergic reaction  
1(2.5%)  
2(5%)  
0(0)  
1
1
1
0(0)  
Postpartum eclampsia  
1(2.5%)  
Table 4: Neonatal outcome in control and study group  
Study group  
Control group  
3142(537)  
1(2.5)  
p-value  
0.09  
Birth weight (gm);mean  
NICU admission  
3283(554)  
2(5)  
0.52  
Preterm delivery  
<
>
32 weeks  
32weeks  
3(7.5)  
5(12.5)  
2(5)  
8(20)  
1
0.2  
Caesarean deliveries were seen to be higher in the study group  
though not statistically significant (p= 0.06) One patient in the  
control group had deep vein thrombosis. The use of emprical  
LMWH in women with URM is undoubtedly unneccessary in  
view of the fact that supportive care alone offers a chance of  
upto 75% for a successful pregnancy (15). However, there is a  
substantial amount of patients given LMWHs without adequate  
evidence and the prognosis of these patients were unknown.  
RPL has been associated with a higher incidence of late  
obstetric complications (16). In Dolitzky et al. study these  
obstetric complications were not seen and they commented that  
either the obstetric complications are associated with  
thrombophilias or the treatment had a beneficial effect on both  
enoxaparin and aspirin group (7). Both enoxaparin and  
tinzaparin showed no statistically significant difference with  
respect to live birth rate and abortion rate. However, Tinzaparin  
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J Infertil Reprod Biol, 2017, Volume 5, Issue 4, Pages: 15-19. https://doi.org/10.47277/JIRB/5(4)/15  
has been shown to be safe and effective anticoagulant in the  
Authors’ contribution  
management of RPL in thrombophilic disorders (7). A study  
comparing the antithrombotic properties of enoxaparin,  
tinzaparin and deltaparin revealed significant differences in  
anti-FXa and anti-FIIa activity between products, but the  
clinical relevance of these biochemical and pharmacologic  
differences between LMWH molecules is still questionable  
All authors of this study have a complete contribution for  
data collection, data analyses and manuscript writing.  
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