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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 34  |  Issue : 2  |  Page : 108-112

Aspirin versus low-molecular-weight heparin in treating recurrent miscarriages in women without antiphospholipid antibody syndrome


1 Department of Obstetrics and Gynecology, Faculty of Medicine, Al-Azher University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Al-Azher University, Cairo, Egypt
3 Department of Obstetrics and Gynecology, El-Galaa Maternity Teaching Hospital, Cairo, Egypt

Date of Submission09-Feb-2017
Date of Acceptance27-Apr-2017
Date of Web Publication20-Nov-2017

Correspondence Address:
Osama M Hamoda
345 Faisl Street, Giza, Cairo, 12555
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bmfj.bmfj_20_17

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  Abstract 


Background As hypercoagulability may result in recurrent miscarriages, anticoagulants (clexane) and aspirin (aspocid) could potentially increase live-birth rate in subsequent pregnancies in women with either inherited thrombophilia or unexplained recurrent miscarriages.
Patients and methods This randomized trial included 120 pregnant women who were recruited by the closed-envelope method from the outpatient clinics of El-Hussien University Hospital and El-Galaa Maternity Teaching Hospital with history of at least three recurrent miscarriages. The trial was designed to compare the effects of low-dose aspirin (aspocid 75 mg tab) and low-molecular-weight heparin (LMWH) (clexane) on pregnancy outcome and live-birth rate. Pregnant women were divided into two groups: group 1 (60) was administered oral, low-dose aspirin (aspocid 75 mg tab) daily, and group 2 (60) was administered LMWH (clexane) 1 mg/kg subcutaneously daily.
Results Regarding primary outcome (live-birth rate), the two groups did not differ significantly. Both drugs increased live-birth rate with an incidence of 81.7% in group 1 and 83.3% in group 2.
Conclusion Low-dose aspirin (aspocid 75 mg tab) and LMWH (clexane 1 mg/kg) improve pregnancy outcome and increase live-birth rate, with no significant differences between the two drugs in patients with history of recurrent miscarriages without antiphospholipid antibody syndrome.

Keywords: antiphospholipid antibody syndrome, aspirin, low-molecular-weight heparin, recurrent miscarriage


How to cite this article:
Abd Elfattah AT, Amer SA, Hablas WR, Elmohandes MI, Hamoda OM. Aspirin versus low-molecular-weight heparin in treating recurrent miscarriages in women without antiphospholipid antibody syndrome. Benha Med J 2017;34:108-12

How to cite this URL:
Abd Elfattah AT, Amer SA, Hablas WR, Elmohandes MI, Hamoda OM. Aspirin versus low-molecular-weight heparin in treating recurrent miscarriages in women without antiphospholipid antibody syndrome. Benha Med J [serial online] 2017 [cited 2018 Feb 24];34:108-12. Available from: http://www.bmfj.eg.net/text.asp?2017/34/2/108/218828




  Introduction Top


Recurrent miscarriages are the loss of three or more consecutive pregnancies before the 24th week of gestation. It is either primary (in women without a previous live-born infant) or secondary (in women with at least one previous live-born infant) [1].

The etiology of most recurrent miscarriages remains unclear. The majority of cases − after excluding anatomical, genetic, microbiological, and hormonal causes of abortions and complete medical, surgical, and social history − remain idiopathic [2].

Although controversial, various reports have claimed that hereditary thrombophilias may predispose to thrombosis in decidual vessels, and subsequent fetal hypoxia and pregnancy loss [3].

According to the literature, after three or more pregnancy losses, the live-birth rate is expected to be 60%, and after four losses the live-birth rate is expected to be only 40%, if blighted ova are not excluded [4].

Patients with recurrent miscarriages have been successfully treated with aspirin (aspocid) and low-molecular-weight heparin (LMWH) (clexane) with average-to-very high success rates, a treatment, although confined only to those associated with antiphospholipid syndrome, which does not represent more than 15% of all cases [5].

Pregnancy itself is a hypercoaguable state associated with increased levels of procoagulant factors and decreased levels of naturally occurring anticoagulants such as protein S. The overall fibrinolytic activity is impaired due to increase in plasminogen activator inhibitor-2 [6].

A study carried out in 2006 on the randomized use of low-dose aspirin (aspocid) and LMWH (clexane) on women with unexplained recurrent pregnancy loss (RPL) found that the regimen was associated with high live-birth rates and a few late pregnancy complications [7].

Over the last 5 years, there has been a large increase in the use of aspirin (aspocid) and LMWH (clexane) in attempts to prevent pregnancy loss. Until recently, clinical evidence to examine this practice was lacking. In 2009, the Cochrane review of anticoagulants for nonantiphospholipid RPL identified only two studies of 189 women. The Cochrane review concluded that there was no evidence for this practice and identified the urgent need for further practices [8].


  Patients and methods Top


The study was carried out from March 2016 to January 2017. The study was approved by Scientific ResearchCommittee of Benha University an informed consent is taken from all participants. The study included 120 patients who were divided into two groups:
  1. Group 1 (60): this group was treated with low-dose aspirin (aspocid 75 mg tablet) orally once per day from the time of a positive pregnancy test.
  2. Group 2 (60): this group was treated with LMWH (clexane) 1 mg/kg subcutaneously once per day from the time of a positive pregnancy test.


Inclusion criteria

Women with a definite history of recurrent miscarriages with no obvious cause (unexplained recurrent miscarriage) were included.

Exclusion criteria

  1. Documented cause of recurrent miscarriages − for example, antiphospholipid syndrome.
  2. History of medical disorders such as diabetes mellitus.
  3. History of chronic disorders such as renal, cardiac, or liver diseases.
  4. History of thromboembolic manifestations.
  5. Structural anomalies of the uterus.
  6. Contraindications to the use of heparin such as sensitivity to heparin.


Procedure: women were recruited from the outpatient clinics. The purpose of the study and the protocols used were explained to each woman, and consent was obtained from all of them. History taking (including personal, menstrual, obstetric, and family history) and examinations (including general, abdominal, and ultrasound examination) were carried out.

Primary outcome measures

The primary outcome measure was live-birth rate.

Secondary outcome measures

Secondary outcome measures were as follows:

Miscarriage less than 28 weeks.

Preterm delivery less than 37 weeks.

Obstetric complications (pre-eclampsia or intrauterine growth restriction (IUGR).

Data are statistically described as mean±SD or as ranges, frequencies (number of cases), and percentages as appropriate. Data were analyzed by the statistical package for the social science software program, version 21 (SPSS Inc., Chicago, Illinois, USA) for statistical analyses.


  Results Top


A total of 120 patients were enrolled for this study, with history of at least three recurrent miscarriages after exclusion of antiphospholipid antibody syndrome, subsequent to a positive pregnancy test. Patients were divided into two groups: group 1 patients were administered low-dose aspirin (aspocid 75 mg tablet) oral, and group 2 patients were administered LMWH (clexane) 1 mg/kg subcutaneously.

Comparisons between the two groups are shown in [Table 1].
Table 1 Age, weight, and number of previous miscarriages in the two study groups

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The mean age of women in group 1 was 29.3±4 years, whereas the mean age of women in group 2 was 28.1±4.4 years. The mean weight of women in group 1 was 72.5±11.8 kg, whereas in group 2 it was 73±13.1 kg. The median number of miscarriages in group 1 was 3 (3–6), and in group 2 the median was 3 (3–5) ([Table 2]).
Table 2 Incidence of pre-eclampsia and intrauterine growth restriction in the two study groups

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Pre-eclampsia occurred in four patients in the aspirin (aspocid 75 mg) group and in three patients in the LMWH (clexane) group. One case of IUGR occurred in each group ([Table 3]).
Table 3 Live-birth rate and incidence of preterm delivery in the two study groups

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  Discussion Top


In the present study, 49 patients in the group 1 taking low-dose aspirin (aspocid 75 mg tab) had live births and delivered after 28 weeks of gestation (81.7%), whereas 11 patients failed to cross the 28-week gestation period (18.3%). Among those 49 patients, eight patients had preterm delivery before 37 weeks (16.3%) and 41 cases delivered after 37 weeks of gestation.

On the other hand, in group 2, taking LMWH (clexane) 1 mg/kg, 50 patients had live births and delivered after 28 weeks of gestation (83.3%), whereas 10 patients failed to cross the 28-week gestation period (16.7%). Among these 50 patients, 10 patients had preterm delivery before 37 weeks (20%) (P=0.810) and 40 cases after 37 weeks of gestation.

Another study was carried out in 2006 including 104 patients. Fifty-four patients were randomized to the LMWH (clexane) group, whereas the other 50 patients were randomized to the low-dose aspirin (aspocid) group. In the LMWH (clexane) group, 44 (82%) patients had live births and 10 (18%) patients had abortions. However, in the aspirin (aspocid) group, 42 (84%) patients had live births and eight (16%) patients had abortions (P=0.73) [7].

Results of this study agree with the results of the current study

The Habenox study was carried out in 2011 and included 207 patients. Sixty-eight patients were randomized to the LMWH (clexane 40 mg) and placebo group, 63 patients were randomized to the LMWH (clexane 40 mg) and aspirin (aspocid 75 mg tablet) group, and the other 76 patients were randomized to the aspirin (aspocid 75 mg) group. In the LMWH (clexane 40 mg) and placebo group, the live-birth rate was 71%, whereas in the group taking LMWH (clexane 40 mg) and aspirin (aspocid 75 mg tablet), the live-birth rate was 65%, and in the group taking aspirin (aspocid 75 mg tablet) only the live-birth rate was 61%. Therefore, no significant difference in live-birth rate was found among LMWH (clexane) treatment versus aspirin (aspocid) or a combination of both versus aspirin (aspocid) only in women with recurrent miscarriages [9].

Results of this study agree with the results of the current study

Another study was carried out in 2010 on 100 patients. Fifty patients were on a prophylactic dose of LMWH (clexane) and low-dose aspirin (aspocid), whereas the other 50 patients were on placebo. In the treatment group, 41 (83.7%) patients had live births and nine (16.3%) had abortions. However, in the placebo group, 27 (54%) patients had live births and 23 (46%) had abortions (P=0.001) [10].

Results of this study agree with the results of the current study

Another study was carried out in 2010 on 202 patients with a history of unexplained recurrent miscarriages. Ninety-nine women were randomized to the low-dose aspirin (aspocid 75 mg tablet) group, whereas the other 103 women were randomized to the placebo group since a positive pregnancy test. Among the group taking aspirin (aspocid 75 mg tablet), the live-birth rate was 61%, whereas in the group taking placebo the live-birth rate was 66%. One preterm delivery occurred in the aspirin group, whereas three preterm deliveries occurred in the placebo group. One case of pre-eclampsia was found in each group. Seven cases of IUGR were found in the aspirin group, whereas five cases of IUGR were found in the placebo group [11].

Results of this study disagree with the results of the current study

A study was carried out in 2008 on 107 patients with a history of unexplained recurrent miscarriages. Fifty-seven women were randomized to the LMWH (clexane) group, whereas 50 women were randomized to the placebo since a positive pregnancy test. In the LMWH (clexane) group, the live-birth rate was 80.7%, whereas in the placebo group the live-birth rate was 48%. One preterm labor occurred in the LMWH group, whereas two preterm labors occurred in the placebo group. No pre-eclampsia occurred in the LMWH group, whereas one case of pre-eclampsia was found in the placebo group. One case of IUGR was found in the LMWH group, whereas two cases of IUGR were found in the placebo group [12].

Results of this study agree with the results of the current study

A study was carried out in 2013 to evaluate the effect of adjunct LMWH (clexane) on improvement in live-birth rate after recurrent implantation failure. In women with more than or equal to three recurrent implantation failures, the use of adjunct LMWH (clexane) significantly improved live-birth rate by 79% compared with the control group; however, this has to be considered with caution, as the overall number of participants in the study was small. Further evidence from adequately powered, multicentered, randomized controlled trials is required before recommending LMWH for routine clinical use. This review highlights the need for future basic science and clinical research in this important field [13].

Results of this study agree with the results of the current study

Another study was carried out in 2015 to evaluate the effect of LMWH (clexane) on improving pregnancy outcomes in cases with unexplained recurrent miscarriages. The live-birth rates were 86.0% (185 of 215 women) and 86.7% (183 of 211 women) in the intervention and control groups, respectively [absolute difference, −0.7 percentage point (confidence interval (CI), −7.3 to 5.9 percentage points)]. Daily LMWH (clexane) injections do not increase ongoing pregnancy or live-birth rates in women with unexplained RPL. Given the burden of injections, they are not recommended for preventing miscarriage [14].

Results of this study agree with the results of the current study

A study was carried out in 2016 to determine whether the use of the combination of LMWH (clexane) and aspirin (aspocid 75 mg tab) is better than aspirin (aspocid 75 mg tab) alone in women with hereditary thrombophilia. Four trials were included in the quantitative analysis including a total of 222 randomized women. Effect of LMWH+aspirin versus aspirin alone with regard to live births was evaluated in all four randomized controlled trials with a similar overall treatment effect for the therapies [odds ratio (OR) 1.7] (95% CI 0.72–4.0) and without heterogeneity [I (2)=0%]. No significant differences or heterogeneity were observed between groups for secondary outcomes − namely, first-trimester miscarriages OR 0.69 (0.22–2.16), prematurity OR 0.99 (0.4–2.08), pre-eclampsia OR 1.49 (0.63–3.5), and small-for-gestational-age babies OR 2.08 (0.96–4.47). There were no significant differences in live-birth weight and other pregnancy outcomes between LMWH+aspirin versus aspirin alone. However, these findings were based on a few trials presenting methodological limitations. Therefore, there is no evidence to support any incremental benefit of adding LMWH to aspirin alone in women with inherited thrombophilia [15].

Results of this study agree with the results of the current study

In the present study, the mean age was 29.3±4 in the low-dose aspirin (aspocid 75 mg tablet) group, whereas the mean age in the LMWH (clexane) group was 28.1±4.4 (P=0.118); no difference in age was found between the two groups.

In another study, the mean age in the low-dose aspirin (aspocid 75 mg tablet) group was 30.65±6.18, whereas it was 31.37±5.3 in the LMWH (clexane) group, with no significant difference between the two groups [7].

In the same previous study, the mean number of pervious abortions in the low-dose aspirin (aspocid 75 mg tablet) group was 3.9±1.4, and in the LMWH (clexane) it was 3.8±1.4, with no significant difference between the two groups (P=0.63) [7].In the present study, the median number of miscarriages in the low-dose aspirin (aspocid 75 mg tablet) group was 3 (3–6), whereas in the other group it was 3 (3–5), with no significant difference between the two groups (P=0.299). The number of preterm deliveries in the low-dose aspirin (aspocid 75 mg tablet) group was eight (16.3%), whereas in the group taking LMWH (clexane) it was 10 (20%) (P=0.636). The number of preterm deliveries did not differ significantly between the two groups.

In the present study, pre-eclampsia was found in four patients in the low-dose aspirin (aspocid 75 mg tablet) group and in three patients in the LMWH (clexane) group (P=1.000), whereas in the other study pre-eclampsia occurred in three cases in the low-dose aspirin group (aspocid) and in none of them in the LMWH (clexane) group [7].

In the present study, one case of intrauterine growth restriction occurred in each group; these results are similar to the results of the other study [7].


  Conclusion Top


We conclude that low-dose aspirin (aspocid 75 mg tablet) and LMWH (clexane 1 mg/kg) improve pregnancy outcomes and increase the live-birth rate with no significant difference between the two drugs in patients with history of recurrent miscarriages without antiphospholipid antibody syndrome.

Recommendations

We recommend low-dose aspirin (aspocid 75 mg tablet) for patients with recurrent miscarriage without antiphospholipid syndrome, as it has the same effect of LMWH (clexane). In addition, it is cheap, has better compliance with the patient, and has lesser side-effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Farquharson R, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized controlled trial of treatment. Obstet Gynecol 2002; 100:408–413.  Back to cited text no. 1
    
2.
El Far M, ElSayed IH, El Motwally AE. Serum levels of TNF-α and antioxidant enzymes and placental TNF-α expression in unexplained recurrent spontaneous miscarriage. J Physiol Biochem 2007; 65:175–182.  Back to cited text no. 2
    
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Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343:1015–1018.  Back to cited text no. 3
    
4.
Carp HJA. Investigation and treatment for recurrent pregnancy loss. A practical guide to reproductive medicine. Lancs, UK: Parthenon & Co; 1997. pp. 337–362.  Back to cited text no. 4
    
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Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J 2000; 314:253–257.  Back to cited text no. 5
    
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Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev 2009; 1:CD004734.  Back to cited text no. 8
    
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Visser J, Ulander V, Blommenkamp K, Kaaja R. 0978 A randomized controlled multicenter study: the effect of enoxaparin and/or aspirin on prevention of recurrent miscarriage in women with or without thrombophilia, HABENOX study. Int J Obstet Gynecol 2011; 107 (Suppl 2):s371.  Back to cited text no. 9
    
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Fawzy M, Shokir T, El-Tatongy M, Warda O, El Refaiey AA, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage, a randomized placebo-controlled study. Arch Gynecol Obstet 2008; 278:33–38.  Back to cited text no. 12
    
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Potdar N, Gelbaya TA, Konje JC, Nardo LG. Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis. Hum Reprod Update 2013; 19:674–684.  Back to cited text no. 13
    
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Schleussner E, Kamin G, Seliger G, Rogenhofer N, Ebner S, Toth B et al. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med 2015; 162:601–609.  Back to cited text no. 14
    
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Areia AL, Fonseca E, Areia M, Moura P. Low-molecular-weight heparin plus aspirin versus aspirin alone in pregnant women with hereditary thrombophilia to improve live birth rate: meta-analysis of randomized controlled trials. Arch Gynecol Obstet 2016; 293:81–86.  Back to cited text no. 15
    



 
 
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