Review question/objective

The quantitative objective is to identify the effectiveness of tranexamic acid on reducing blood loss in women undergoing cesarean section up to twenty four hours postoperatively.

Background

Postpartum hemorrhage

Postpartum hemorrhage (PPH) is the most common cause of mortality in low-income countries.1 Worldwide nearly one quarter of maternal deaths are due to PPH.1 The World Health Organization defines PPH as blood loss of 500 ml or greater in the first 24 hours after birth.1 PPH can also lead to significant morbidity associated with substantial blood loss, shock and end-organ dysfunction.1 The incidence of PPH following cesarean section is 5-10%.2 Common causes of PPH include uterine atony, abnormal placentation, uterine trauma and sepsis.2

Normal physiologic processes exist to prevent PPH such as an increase in blood volume, contraction of uterine muscle and clot formation. During pregnancy an increase in blood volume protects against hypovolemia and shock during the delivery period. During a normal delivery some blood loss is expected. Bleeding is primarily stopped by myometrial uterine contraction.4 Myometrial muscle fibers run in different directions and when the uterus contracts the muscle fibers compress blood vessels.4 In addition to the increase in blood volume and uterine contraction, clot formation helps to control blood loss during delivery. Pregnancy is considered a hypercoagulable state due to the presence of additional circulating clotting factors.5 When bleeding occurs during delivery, the activated clotting factors migrate to the site of bleeding and begin to coalesce with platelets to form a clot. When these normal processes fail, as in uterine atony or a clotting abnormality, treatment is needed to prevent PPH.

Recommended treatments for PPH following cesarean section include the use of uterotonics, like Oxytocin, and cord traction to remove the placenta.1 The use of uterotonics in PPH is primarily effective in treating PPH due to uterine atony. When uterine atony is not the cause of PPH, it is imperative to consider treatments other than uterotonics.

Antifibrinolytic therapy

During normal pregnancy fibrinolytic capacity is decreased because of increased levels of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and plasminogen activator inhibitor-2 (PAI-2) from the placenta.5 The increase of PAI-1 and PAI-2 helps to prevent excessive blood loss during labor. Despite these physiologic factors to prevent the breakup of blood clots, the body's clotting system exists in a balance that can become interrupted.

Antifibrinolytic agents commonly have been used to prevent and treat surgical blood loss in operating rooms. The administration of antifibrinolytics has dramatically changed patient morbidity and mortality, improved patient outcomes, and reduced the number of blood products required by patients. The use of antifibrinolytics has changed treatment plans from the reactive treatment mindset to the proactive prophylactic approach. Tranexamic acid (TXA) is an antifibrinolytic agent that chemically resembles the amino acid lysine and inhibits fibrinolysis by competing for the lysine binding site on plasminogen.6 The inhibition of fibrinolysis allows blood to clot and prevents further bleeding. Antifibrinolytic therapy is not routinely used during labor to prevent PPH. The World Health Organization recommends the use of TXA when uterotonics do not stop bleeding or when the bleeding is due to trauma.1 TXA if administered orally has a recommended loading dose of 15 mg/kg and a maintenance dose of 30 mg/kg every six hours.8

When administering antifibrinolytics, one concern is the potential for an increase in thromboembolic complications. The treatment goal of antifibrinolytics is to prevent the breakdown of blood clots. A legitimate concern is the possibility to cause an increased number of blood clots such as pulmonary, coronary or cerebral emboli. A Cochrane review that examined the effectiveness of antifibrinolytic agents in minimizing the need for a blood transfusion found that TXA did not increase the incidence of myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism.7

Why it is important to do this review

Postpartum hemorrhage is a significant cause of maternal morbidity and mortality. Prevention of PPH can contribute to achieving the United Nation's Millennium Development Goal of improving maternal health. A component of this goal is to reduce the maternal mortality rate by three quarters.9 Administration of antifibrinolytic therapy during the third stage of labor may help prevent PPH. The use of TXA has been shown to be a cost-effective therapy. One study examined the cost of TXA in elective surgical procedures compared to the need for a blood transfusion. Tranexamic acid decreased the number of blood transfusions required, thereby reducing the cost associated with increased blood transfusions.9 TXA can be beneficial in low-income countries where there is often no access to adequate blood transfusion therapies.10

Antifibrinolytic therapy may potentially reduce the amount of blood transfusions required. One benefit of decreased blood transfusions is a decreased risk of a transfusion reaction. Transfusion reactions can result in morbidity due to hemolytic transfusion reactions, septic transfusions, or transfusion-related acute lung injury.11 A potential benefit of antifibrinolytic therapy is to reduce the complications associated with blood transfusions.

A systematic review by Ferrer published in 2009 and which included three randomized controlled trials that compared TXA with no treatment found that TXA may reduce blood loss in PPH, but stated that the quality of evidence available was poor.12 In 2010, the Cochrane Collaboration published a review that included two randomized controlled trials. The review concluded that TXA decreases postpartum blood loss after vaginal births and cesarean section.13 The authors of this review suggest that further research is needed to confirm the safety and efficacy of antifibrinolytic therapy for preventing PPH. Since 2010, new randomized controlled trials on the use of antifibrinolytics in cesarean sections have been published. This study aims to include newly published literature to update the use of TXA in reducing postoperative blood loss.

Inclusion criteria

Types of participants

This review will consider studies that include women of any age undergoing cesarean section

Types of intervention(s)/phenomena of interest

This review will consider studies that evaluate administration of tranexamic Acid compared to administration of a placebo or no therapy.

Types of outcomes

This review will consider studies that include the following outcome measures: blood loss measured in milliliters within 24 hours postoperatively.

Secondary outcomes of interest will include side effects of tranexamic acid, maternal adverse events, neonatal adverse events, and changes in hemoglobin or hematocrit.

Types of studies

This systematic review will consider both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies for inclusion.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in the English language will be considered for inclusion in this review. Studies published from any date will be considered for inclusion in this review.

The databases to be searched include:

ClinicalKey

Cochrane Library

CINAHL

PubMed

Ovid

Elsevier Science Direct

EMBASE

Wiley Online Library

The search for unpublished studies will include:

MedNar

ProQuest

New York Academy of Medicine Grey Literature Report

Initial keywords to be used will be:

Antifibrinolytics OR tranexamic acid, h?emorrhage and cesarean section

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

Data extraction

Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.

Data synthesis

Quantitative data will, where possible be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Conflicts of interest

There are no existing conflicts of interest.

Acknowledgements

This review is a partial requirement for the doctoral degree in Nurse Anesthesia for Jaime Henry and Allison McFarland from Texas Christian University, Harris College of Nursing and Health Sciences, Fort Worth, Texas, USA.

References