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. 2021 Jun 25;100(25):e26264. doi: 10.1097/MD.0000000000026264

Meta-analysis on aspirin combined with low-molecular-weight heparin for improving the live birth rate in patients with antiphospholipid syndrome and its correlation with d-dimer levels

Ting Shi a, Zhong-Deng Gu b, Qi-zhi Diao c,∗
Editor: Milan Perovic
PMCID: PMC8238312  PMID: 34160390

Abstract

Background:

Antiphospholipid antibody syndrome (APS) is a systemic, autoimmune, prothrombotic disease characterized by persistent antiphospholipid antibodies, thrombosis, recurrent abortion, complications during pregnancy, and occasionally thrombocytopenia. At present, there is no consensus on the treatment of this disease. Long-term anticoagulation is recommended in most cases in patients with thrombotic APS. This study aimed to evaluate whether aspirin combined with low-molecular-weight heparin (LMWH) can improve the live birth rate in antiphospholipid syndrome and its correlation with D-dimer.

Methods:

The data were retrieved from the WanFang Data, CBM, VIP, CNKI, the Cochrane Library, PubMed, EMBASE, OVID, and Web of Science databases. We collected data on randomized controlled trials of aspirin combined with LMWH in the treatment of pregnant women with APS. The “Risk of Bias Assessment” tool and the “Jadad Scale” provided by the Cochrane Collaboration were used to evaluate the risk of bias and quality of the collected literature. The risk ratio (RR) and its 95% confidence interval (CI) were determined using Statase-64 software.

Results:

In this study, a total of 11 studies were included, comprising a total of 2101 patients. The live birth rate in pregnant women with APS was higher on administration of aspirin combined with LMWH than with aspirin alone (RR = 1.29, 95% CI = 1.22–1.35, P < .001). d-dimer concentration in plasma predicted the live birth rate, which was higher below the baseline than above it (RR = 1.16, 95% CI = 1.09–1.23, P < .001). The subgroup analysis of the live birth rate was carried out based on the course of treatment, and the results were consistent with the overall results. Begg funnel plot test revealed no publication bias. Sensitivity analysis showed that deleting any study did not affect the results.

Conclusion:

Aspirin combined with LMWH for APS may improve live birth rate, and detection of d-dimer levels in APS pregnant women may predict pregnancy complications and guide the use of anticoagulants.

Keywords: antiphospholipid syndrome, aspirin, d-dimer, live birth rate, low-molecular-weight heparin

1. Introduction

Antiphospholipid antibody syndrome (APS) is a systemic, autoimmune, prothrombotic disease characterized by persistent antiphospholipid antibodies (aPL), thrombosis, recurrent abortion, complications during pregnancy, and occasionally thrombocytopenia.[1]At present, there is no unified opinion on the treatment of this disease, especially the treatment via immunoglobulins and other drugs like glucocorticoids.[2] Administration of appropriate thromboprophylaxis helps prevent thromboembolic complications during pregnancy in women with APS and also in giving birth to healthy children.[3] For patients with thrombotic APS, long-term anticoagulation is recommended in most cases.[4] As APS is a rare disease, there are less well-designed clinical trials, resulting in a lack of reliable clinical data. Without formal clinical guidelines, APS diagnosis and treatment are largely based on consensus and expert opinion. It is not clear whether low-dose aspirin affects the risk of thrombosis.[5,6] With the combination of low-dose aspirin and low-molecular heparin, most aPL-related pregnancy loss can be prevented.[7] The study by Hamulyak et al could not conclude whether aspirin alone could contribute to a lower live birth rate than low-molecular-weight heparin (LMWH) plus aspirin.[8]d-dimer has high sensitivity and specificity in predicting pregnancy complications in patients with APS treated with LMWH. Its use also allows the dose of LMWH to be increased to improve the effectiveness of the treatment.[9] Randomized controlled trials (RCTs) comparing live birth rates in APS during pregnancy with aspirin combined with LMWH and aspirin alone were included in this study to provide more reasonable evidence for clinical practice.

2. Materials and methods

2.1. Literature search

We searched the literature with “low molecular weight heparin,” “antiphospholipid syndrome,” and “aspirin” as the main headings with a free word. The database included WanFang Data, CBM, VIP, CNKI, Cochrane Library, PubMed, EMBASE, OVID, and Web of Science. The retrieval time was before August 2020 and the language was limited to Chinese and English.

2.2. Literature selection

The inclusion criteria were as follows: RCTs; studies in which all subjects were pregnant women with clinical diagnosis of APS; experimental groups treated with aspirin combined with LMWH and control group with aspirin alone; and outcome indicator of live birth rate. Studies were excluded according to the following criteria: conference abstracts, reviews, case reports, and comments; and samples of studies derived from cell lines or animals. All studies were screened independently by 2 authors based on inclusion and exclusion criteria. When the studies were published by the same group, only the latest research with the largest sample size was included.

2.3. Data extraction and quality assessment

The 2 authors (TS and ZDG) independently extracted data from qualified studies and used the Jadad rating scale[10] for quality evaluation, and the risk assessment criteria for bias recommended by the Cochrane manual were used to assess the risk of bias in the included studies.[11] The scoring items mainly included randomization sequence generation (0–2 points), blindness method (0–2 points), allocation and conceal (0∼2 points), and exit or loss of follow-up (0–1 points), as shown in Figure 1. The following relevant details were extracted from each study: first author name, year of publication, country, number of patients, average age, dose, course of treatment, outcome indicators, and score. Aspirin combined with LMWH and aspirin alone in APS pregnant women had a live birth rate of risk ratio (RR) and 95% confidence interval (95% CI) were obtained directly in reported studies.

Figure 1.

Figure 1

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11 Summary of risk assessment of the included literature.

2.4. Statistical analysis

The meta-analysis was performed using Statase-64 software (StataCorp LP, College Station, TX). RR and 95% CI were used for representing data. If only the median and upper and lower limits were given, x ± s (mean and standard deviation model) can be obtained by using the conversion formula.[12] Higgins et al[13] research showed that: I2 > 50% implies heterogeneity and the effect of combined application of random effects model; therefore, there is a need to further find out the cause of high heterogeneity and sources by subgroup analysis, sensitivity analysis, or eventually eliminating obvious heterogeneity in the studies. I2 < 50% implies that the heterogeneity of the included data is low, and a fixed-effect model is applied. This meta-analysis was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.[14]

2.5. Ethics approval

Patients were not directly involved in the study; therefore, ethical approval was not required.

3. Results

3.1. Eligible studies

The literature retrieval flow chart is shown in Figure 2. A total of 2598 related clinical studies were retrieved in this study. By screening the research titles and abstracts and the full text, 11 RCTs[15–25] were finally included in this study based on the selection criteria.

Figure 2.

Figure 2

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Literature screening flow chart.

3.2. Study characteristics

A total of 2101 pregnant women (1102 in the experimental group and 999 in the control group) diagnosed with APS were included in this study. Basic information on these patients is shown in Tables 1 to 3. Eleven studies were conducted in 4 countries, including China, the United States, United Kingdom, and Egypt. Two doses of low-dose aspirin (LDA), 4100 U, or 5000 U LMWH were used. Seven[15,16,21–25] studies used the data throughout the course of pregnancy (long-term therapy), and three[18–20] identified continuous use of LDA and LMWH for 30 days and 10 days after pregnancy (short-term therapy). Eleven studies used live birth rates as the primary outcome. The correlation between d-dimer and the fetal live birth rate was analyzed in 2 studies.[15,22] All the 11 studies were of high quality: one had a score of 6 on the Jadad scale, and the other 10 had a score of 5 each. Among them, 10 studies were at high risk in the blinding method, because such drug therapy studies had to obtain informed consent from patients, and it was impossible to blind the method.

Table 1.

Basic characteristics of included literature.

3.2.

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Table 3.

d-Dimer below baseline versus above baseline live birth rate.

Study/d-dimer level Year Negative live birth (n) Negative total (n) Positive live birth (n) Positive total (n)
Shi et al[15](b) 2020 40 56 24 65
Shi et al[15](a) 2020 84 116 77 125
Bao et al[22](b) 2017 165 197 198 321
Bao et al[22](a) 2017 182 209 267 288
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Treatment a = aspirin combined with low molecular weight heparin, Treatment b = aspirin.

Table 2.

Subgroup analysis of studies included in the outcome of treatment.

Analysis No. of studies No. of patients RR (95% CI) Heterogeneity P
Treatment course 10 2053 1.28 (1.21–1.35) I2 = 34.8%, P = .129 <.001
A 7 1699 1.27 (1.19–1.34) I2 = 54.6%, P = .040 <.001
B 3 354 1.34 (1.18–1.52) I2 = 0%, P = .986 <.001
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A = confirm pregnancy to 37w or termination of pregnancy (long-term therapy), B = confirmation of pregnancy and continuous medication for 30 days and 10 days (short-term therapy), CI = confidence interval, RR = risk ratio.

3.3. Effect of LDA with LMWH on live birth rate

Eleven studies[15–25] reported the live birth rate in women with APS treated with aspirin combined with LMWH compared with aspirin alone. The degree of heterogeneity among studies was low (I2 = 34.1%), and the fixed effect model was used to combine the effect size (RR = 1.29, 95% CI = 1.22–1.35, P < .001) (Fig. 3). The results showed that the combination of aspirin and LMWH could significantly improve the live birth rate of the fetus in women with APS. According to the subgroup analysis of the course of treatment[15,16,18–25] (Fig. 4), RR was 1.27 (95% CI = 1.19–1.34) and 1.34 (95% CI = 1.18–1.52) for the treatments A and B, respectively. Compared with the heterogeneity of the course of treatment A, that of course B decreased significantly (I2 = 54.6%, P = .040 vs I2 = 0%, P = .986). The combination of aspirin and LMWH has been shown to improve the live birth rate of the fetus in women with APS, regardless of the course of treatment.

Figure 3.

Figure 3

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Forest map assessing the difference in live birth rates between aspirin combined with low molecular weight heparin and aspirin antiphospholipid antibody syndrome alone.

Figure 4.

Figure 4

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Subgroup analysis of the difference in live birth rate between long and short course aspirin combined with low molecular weight heparin in antiphospholipid antibody syndrome pregnant women.

3.4. Effect of d-dimer levels on thrombus formation and fetal viability

According to the definition of pulmonary embolism level, the d-dimer baseline levels of above 0.50 mg/L fibrinogen equivalent units is positive, whereas that <0.50 mg/L fibrinogen equivalent units is negative. Two studies[15,22] reported the difference in live birth rates between negative and positive d-dimers. The heterogeneity among studies was high (I2 = 95.1%), and the random-effect model was used to combine the effect size (RR = 1.16, 95% CI = 1.09–1.23, P < .001) (Fig. 5). The live birth rates of those with d-dimer below baseline were higher than those above baseline, and the difference was statistically significant.

Figure 5.

Figure 5

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Forest map of the difference in live birth rates below and above baseline for d-dimer.

3.5. Publication bias and sensitivity analysis

For each deletion of a study, there was no statistically significant difference in the effect size after deletion compared with the total effect size before deletion, indicating that the results of this study are indeed statistically reliable (Fig. 6). A total of 11 RCTs were included in this study. Begg test (P = .35) (Fig. 7) indicated that the possibility of publication bias in the included literature was relatively small.

Figure 6.

Figure 6

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The Begg funnel plot was used to evaluate potential publication bias in meta-analyses.

Figure 7.

Figure 7

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Sensitivity analysis of the meta-analysis.

4. Discussion

APS is characterized by arterial and venous thromboembolism events and persistent laboratory evidence of aPL. Obstetric complications such as recurrent abortion, preterm birth, oligohydramnios, intrauterine growth restriction, fetal distress, fetal or neonatal thrombosis, preeclampsia/eclampsia, and hemolysis, elevated liver enzyme levels, and low platelet levels/HELLP syndrome are also hallmarks of APS. Changes in the hemostatic system during normal pregnancy can also lead to hypercoagulability, which increases the risk of thrombosis. Thromboembolic events are responsible for the vast majority of maternal and fetal deaths.[3]

Aspirin is currently the most widely prescribed medication for the prevention of cardiovascular complications.[26] LMWH have been shown to be a safe and effective therapy in conditions similar to APS, such as hereditary thrombophilia.[27,28] Low-dose aspirin is widely used to prevent pregnancy-related vascular diseases, such as preeclampsia and intrauterine growth restriction as well as APS.[29] The combined use of LMWH and aspirin in patients with recurrent spontaneous abortion who test positive for aPL has become routine practice.[30,31] In recent years, a number of clinical trials have shown that the combination of low-dose aspirin and LMWH is superior to aspirin alone in preventing pregnancy loss, and that there is no difference in the live birth rate among women on aspirin, aspirin combined with LMWH, and placebo.[32,33] Xuefenglu et al[34] found that the LMWH therapy could maintain function and a state of hemostasis among patients with unexplained recurrent spontaneous abortion. In addition, they indicate that platelet aggregation in response to arachidonic acid and d-dimer levels are both good indicators for the use of aspirin and LMWH. d-dimer increases early in pregnancy and continues throughout pregnancy. During pregnancy, the hemostatic system activates hypercoagulable blood, which increases the risk of maternal bleeding. Detection of d-dimer levels can predict the risk of thrombosis to a certain extent.[35]

We included 2101 patients from 11 studies. The combined results showed that the combination of aspirin and LMWH significantly increased the live birth rate in women with APS. Subgroup analysis based on the course of treatment showed that aspirin combined with LMWH increased the live birth rate in women with APS regardless of course A or B. Therefore, both short and long courses of treatment can improve the live birth rate of the fetus. The significant decrease in the heterogeneity of course B may be related to the small number of included studies. The concentration of d-dimer in plasma may predict the fetal live birth rate, which was higher below the baseline than above it. Detection of d-dimer levels in the prevention of thrombosis may predict pregnancy complications and guide the use of anticoagulants, but more studies are needed to support this conclusion due to the lack of included literature. A sensitivity analysis of the main results showed that the outcome was not affected after the cancellation of any study.

There are several limitations to this meta-analysis. First, studies published in languages other than Chinese and English were not included. Second, the number of studies included in the merger analysis was limited. Third, of the 11 studies, 6 were in Chinese and 5 in English, and the results showed certain regional deviation. Finally, there are many factors affecting obstetric complications, including some confounding factors, which cannot be completely avoided in this study. Future studies can expand the geographic scope and try to control for obstetric uncertainties.

5. Conclusions

Both short and long courses of treatment with aspirin combined with LMWH in the treatment of APS can improve the live birth rate in pregnant women. Detection of d-dimer levels in APS pregnant women for thromboprophylaxis may predict the risk of pregnancy complications and guide the use of anticoagulants. However, this needs to be supported by more adequate clinical trials to determine d-dimer's role in preventing thrombosis and obstetric complications.

Author contributions

Writing – original draft: Ting Shi, Zhong Deng Gu.

Writing – review & editing: Qi zhi Diao.

Footnotes

Abbreviations: 95% CI = 95% confidence interval, aPL = antiphospholipid antibodies, APS = antiphospholipid antibody syndrome, LDA = low-dose aspirin, LMWH = low-molecular-weight heparin, RCT = randomized controlled trial, RR = risk ratio.

How to cite this article: Shi T, Gu ZD, Diao Qz. Meta-analysis on aspirin combined with low-molecular-weight heparin for improving the live birth rate in patients with antiphospholipid syndrome and its correlation with d-dimer levels. Medicine. 2021;100:25(e26264).

The authors report no conflicts of interest.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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