Tranexamic acid for postpartum hemorrhage prevention in vaginal delivery: A meta-analysis.

BACKGROUND: Tranexamic acid (TA) has been demonstrated to reduce blood loss and the incidences of postpartum hemorrhage (PPH) during caesarean sections. We compared the clinical efficacy of TA administration on vaginal deliveries with recently published papers.
METHODS: Electronic databases of PubMed, Cochrane Library, Embase and Chinese CNKI (Chinese database) and Wanfang were searched through November 2019.The randomized controlled trials were selected between TA and control groups. The relevant studies included four trials with a total of 4579 patients.
RESULTS: Patients treated with TA had a reduction in total blood loss (P = .009), lower postoperative blood loss (P < .00001), a reduced number of PPH (P = .02). However, the occurrence of nausea or/and vomiting is higher in the TA group (the incidence of nausea or vomiting [P < .00001], nausea [P < .00001] and vomiting [P < .00001]).
CONCLUSION: TA resulted in fewer occurrence rates of PPH, and no significant increase in occurrences of dizziness or photopsia, but higher incidence of vomiting and nausea.

Introduction

Postpartum hemorrhage (PPH), 1 of the most common complications after delivery both in caesarean sections and vaginal deliveries is a leading cause of maternal mortality worldwide.[ Since the direct cause of PPH is poor contracting of the uterus, obstetric intervention, and uterotonic medications are recommended interventions.[

Recent findings have demonstrated that antifibrinolytic drugs like tranexamic acid (TA) can reduce excessive blood loss during cardiac surgery, major trauma, liver transplantation, and so on by decreasing fibrinolysis.[ Moreover, TA has been shown to be safe for clinical use during pregnancy and breastfeeding.[

Previous randomized clinical trials (RCT) and meta-analyses suggest that TA reduces blood loss during and after caesarean delivery.[ However, the only meta-analysis on the topic is limited to three trials totaling 740 patients, resulting in weak evidence on the effectiveness on vaginal delivery due to small samples and low methodology quality.[

After a thorough search of essential databases for studies on comparing TA treatment to a randomized control group, we found 1 emerging RCT[ with 3891 patients. In order to assess the effects of prohylactic administration of tranexamic acid on global blood loss or on PPH incidence in vaginal delivery,we performed the present meta-analysis to compare the clinical efficacy of TA treatment for vaginal delivery.

Methods

Search strategy

The present study was conducted by searching the electronic databases of PubMed, Cochrane Library, Embase and Chinese CNKI (Chinese database) and Wanfang through November 2019 to collect relevant trials of TA treatment in vaginal deliveries. We applied the initial search involving the terms (TA OR TA OR TXA OR AMCA OR Cyclokapron) and (pregnancy OR gestation) and (randomized OR RCT OR RCT) and (vaginal delivery). Since the analyses were based on previously published papers, neither ethical approval nor patient consent is needed. The articles searched were limited to English or Chinese language.

Study selection

The first step of the procedure was to screen candidate abstracts and titles. In the second round, we performed full-text reviews. The trials were defined as eligible if they followed inclusion criteria:

Clinical comparisons between tranexamic and control groups;

RCTs;

The outcomes of interest were total blood loss, intraoperative blood loss, postoperative blood loss, number of PPH, severe PPH, transfusion needs, and adverse effects, such as nausea and vomiting, dizziness and photopsia.

Data collection and risk of bias

Y.M. Xia and B.B. Griffiths performed the electronic search and data extraction independently. Any disagreements were resolved by a third author (Q.S. Xue). The data were extracted according to the following standard form: last name of the first author, publication year, country, the number of patients, age of patients, the dosage and time of intervention, and the definition of PPH.

According to Cochrane handbook criteria, we established a table to label ‘risk of bias’ of the selected studies as the following 6 parameters: adequate sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data, and selective outcome reporting. Each parameter as “low,” “high” or “unclear” was listed to clarify the risk of bias.

Statistical analysis

All statistical analyses were performed with Review Manager 5.3 software (Cochrane Collaboration, Copenhagen). When the outcome measure was dichotomous we reported the relative risks (RRs). When outcomes were represented as continuous data we reported the weighted mean difference (WMD). For both types of outcomes we reported the 95% confidence intervals (CIs). In cases of statistical heterogeneity, we calculated pooled estimates using a random effects model chi-square test. In cases of homogeneity we used a fixed effects model and calculated the Z-score to evaluate outcomes between studies sample variation is represented as the mean± standard deviation for continuous data and the I2 statistic for heterogeneity data. P < .05 was regarded as statistically significant.

Results

Figure 1 displays the flowchart of the literature search and selection process. A total of 39 studies were found with electronic searches. After deleting duplicates, 29 papers were identified. Following the primary reviews of article titles and abstracts, 5 studies were included. However, 1 trial only comparing biological factors[ was also excluded. Finally, 4 studies with a total of 4579 patients were included in the analysis.[ The evaluated trials were obtained up until Nov. 2019. The baseline characteristics of the pooled studies were presented in Table 1, such as last name of the first author, publication year, country, the number and age of patients in different groups, the dosage and time of intervention, and the definition of PPH. The bias of risk assessment for each study was listed in Table 2.

Figure 1

The process applied and studies identified in the present meta-analysis.

Table 1

Basic characteristics of included studies.

Table 2

Risk of bias in included studies.

Primary outcome

Blood loss (total, intraoperative, and postoperative)

All 4 trials[ reported total blood loss. These studies indicated that TA resulted in a reduction in total blood loss compared to the control group. The pooled mean difference was significantly different (WMD: −65.61, 95% CI: −115.01 – −16.21, P = .009; Fig. 2A) between the TA and control group, suggesting the positive effect of TA administration.

Figure 2

Comparison of primary outcomes between tranexamic acid (TA) and control groups for vaginal delivery. (A) total blood loss, (B) intraoperative blood loss, and (C) postoperative blood loss. 95% CI = 95% confidence interval, IV= inverse variance, random = random effect.

For postoperative blood loss blood volume after TA treatment was evaluated in 2 trials.[ The results suggested that TA significantly lowered the volume of postoperative blood loss with (TA vs control; WMD: –41.24, 95% CI: –55.50 – –26.98, P < .0001; Fig. 2C). However, 3 papers[ that reported intraoperative blood loss observed no significant difference between the TA and control groups (WMD: –14.30, 95% CI: –28.39 – – 0.22, P = .05; Fig. 2B).

PPH and transfusion needs

The incidence of PPH was investigated in all included studies,[ and all concluded that TA treatment could significantly reduce the number of PPH (TA vs control; RR:0.48, 95% CI: 0.25 – 0.91, P = .02; Fig. 3A). However, the incidence of severe PPH seemed no difference in the 2 groups of 3 studies[ (TA vs control; RR: 0.78, 95% CI: 0.54 – 1.13, P = .19;Fig. 3B).The number of required transfusions showed no significant difference (TA vs control; RR:0.87, 95% CI: 0.46 – 1.64, P = .66; Fig. 3C) in 2 trials.[

Figure 3

Forest plot diagram demonstrating the effect of tranexamic acid (TA) administration in vaginal delivery. (A) number patients with postpartum hemorrhages (PPH), (B) severe PPH and (C) those requiring transfusions.

Secondary outcomes

Adverse effects (nausea or vomiting, nausea and vomiting)

Two studies[ that included a total of 4164 patients reported the occurrence of nausea or vomiting, which was higher in the TA treatment group than control group (RR: 2.17, 95% CI: 1.62 – 2.90, P < .00001; Fig. 4A). In addition, 3 trials[ compared nausea alone and the results also showed that TA resulted in increased incidence (RR: 2.24, 95% CI: 1.67 – 3.01, P < .00001; Fig. 4B). The incidence of vomiting alone was analysed by 2 studies,[ and similar to the previous measures was higher in the TA treatment group than the control group (RR: 2.19, 95% CI: 1.56 – 3.07, P < .00001; Fig. 4C).

Figure 4

Adverse effects, tranexamic acid (TA) vs control groups. (A) nausea or vomiting, (B) nausea only, (C) vomiting only, (D) dizziness or (E) photopsia.

Adverse effects (dizziness and photopsia)

We analyzed 4 studies[ involving dizziness and 2[ including photopsia reports between patients treated with TA or control groups. There was no significant difference in the incidence of dizziness (RR: 1.28, 95% CI: 0.83 – 1.95, P = .26; Fig. 4D), or photopsia (RR: 1.00, 95% CI: 0.25 – 3.99, P = 1.00; Fig. 4E).

Discussion

After careful screening, 4 studies[ were included in the present meta-analysis. Similar to a previous meta-analysis,[ we found that TA treatment resulted in a lower total and postoperative blood loss. Interestingly, our meta-analysis with one more paper and much more patients also demonstrated that TA administration lead to higher occurrence of minor adverse effects including vomiting and nausea, but dizziness or photopsia, compared to control groups.

Li et al[ pointed out that their meta-analysis could not reach a definitive conclusion about the effect of TA usage on PPH number in vaginal delivery because the definition and criteria of obstetrical hemorrhage varies in different regions, which might cause a higher heterogeneity. In general, PPH is defined as loss of 500 mL of blood after vaginal birth.[ In our study, three included trials[ regarded PPH as over 500 mL while one used a 400 mL threshold.[ The addition of 1 more high-quality paper,[ including 3891 more patients, allowed us to reach the conclusion that TA is effective in reducing the occurrence of PPH.

Between 50% to 75% of mortality during childbirth worldwide is attributed to severe PPH,[ which for the purposes of this study we defined as blood loss that exceeds 1000 mL in 24 hours, based on previous studies.[ A published analysis that included only 2 trials[ with 559 patients failed to find statistical significance of TA treatment for severe PPH (P = .14), and our metaanalysis with 1 additional study had the same result.

Pregnancy carries an increased risk of deep venous thrombosis (DVT),[ which must be taken into account for any treatment that affects clotting. Several studies have found TA administration to be safe during surgery including for pregnant women.[ However, only 1 paper[ mirror those found by earlier studies that reported no increase in DVT after TA treatment in pregnant women. Moreover, physicians should be aware that TA can induce nausea and vomiting and take this into account when making decisions whether or not administer the treatment. It is our opinion that these adverse effects do not outweigh the potential benefits of decreased blood loss.

Though our results suggest TA is a safe treatment option to combat PPH, future studies need to determine whether lower dosages can achieve similar effects. In addition, more studies are needed on the effect TA administration has on neonates, though preliminary studies indicate it is potentially safe.[

We acknowledge that there exist several limitations to the present metaanalysis. First, only English or Chinese articles were obtained, and some of our analyses were conducted from the results of three or fewer studies. Thus, some of our conclusions may be based on relatively small numbers of patients when compared with others. Second, there was heterogeneity in some study characteristics, such as the dosage and duration of TA administration, different measures of blood loss, and so on. Finally, the influence of publication bias should be recognized.

In conclusion, TA treatment for vaginal delivery has been demonstrated to have substantial clinical efficacy resulting in reduced total/postoperative blood loss and fewer incidences of PPH. However, TA could lead to higher occurrences of minor adverse effects including vomiting and nausea other than dizziness and photopsia.

Author contributions

Conceptualization: Yimeng Xia, Qingsheng Xue.

Data curation: Brian B. Griffiths.

Formal analysis: Yimeng Xia, Brian B. Griffiths.

Investigation: Yimeng Xia.

Project administration: Qingsheng Xue.

Software: Yimeng Xia, Brian B. Griffiths.

Supervision: Qingsheng Xue.

Validation: Qingsheng Xue.

Writing – original draft: Yimeng Xia.

Writing – review and editing: Qingsheng Xue.