Anti-Coagulant Therapy in Unexplained Recurrent Pregnancy Loss

J Infertil Reprod Biol, 2017, Volume 5, Issue 4, Pages: 15-19. https://doi.org/1 0.47277/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

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

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

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

J Infertil Reprod Biol, 2017, Volume 5, Issue 4, Pages: 15-19. https://doi.org/1 0.47277/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

2/06/2015. Written informed consent has been obtained from

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.

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

05 patients with recurrent miscarriage

87 visited during pregnancy

218 for pre-pregnancy evaluation

26 patients had unexplained pregnancy loss; 15 of them declined treatment

with anti-coagulant; 23 women were excluded from the study

8 patients were included in the study

4 women in study group; 4

4 women in control group;

lost follow up

did not complete treatment

Figure 1. Study plan

J Infertil Reprod Biol, 2017, Volume 5, Issue 4, Pages: 15-19. https://doi.org/1 0.47277/JIRB/5(4)/15

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

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

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)

C/s rate

17(42)

8(20)

0.06

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)

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)

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

J Infertil Reprod Biol, 2017, Volume 5, Issue 4, Pages: 15-19. https://doi.org/1 0.47277/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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