Tranexamic Acid for the Prevention of Obstetrical Hemorrhage After Cesarean

Conditions

Hemorrhage, Labor and Delivery, Obstetrical Complications

Keywords

Tranexamic Acid, Hemorrhage, Cesarean

Brief summary

A randomized placebo-controlled trial of 11,000 women to assess whether tranexamic acid as prophylaxis lowers the risk of postpartum hemorrhage in women undergoing a cesarean delivery.

Detailed description

Obstetrical hemorrhage is a common cause of maternal morbidity and mortality worldwide. The frequency and severity of hemorrhage is significantly higher after cesarean delivery than vaginal delivery. Recent evidence has emerged about the importance of the fibrinolytic pathway in the pathophysiology of hemorrhage in different clinical scenarios including trauma-associated bleeding, cardiovascular surgery, and obstetrical hemorrhage. Tranexamic acid (TXA) inhibits fibrinolysis and is used routinely to prevent hemorrhage in trauma cases and high risk surgeries. Randomized trials of TXA as a prophylaxis to prevent hemorrhage in cesarean delivery have been small and of mixed quality; however meta-analysis suggests that it is effective. This study is a randomized placebo-controlled trial of 11,000 women to assess whether tranexamic acid as prophylaxis lowers the risk of postpartum hemorrhage in women undergoing a cesarean delivery.

Luis D. Pacheco, Rebecca G. Clifton, George R. Saade, Steven J. Weiner, Samuel Parry et al. (19 authors)

New England Journal of Medicine2023-04-12105 citations

10.1056/nejmoa2207419

Tranexamic acid for the prevention of postpartum haemorrhage: the TAPPH-1 pilot randomized trial and lessons learned for trials in Canadian obstetrics

Asim Alam, Jon Barrett, Jeannie Callum, Lilia Kaustov, Shelly Au et al. (8 authors)

Scientific Reports2023-03-185 citations

10.1038/s41598-023-30947-8

Interventions

DRUGTranexamic Acid

A single dose of Tranexamic Acid (1 gram) in normal saline for a total of 50cc, administered intravenously immediately following umbilical cord clamping (or as soon as possible afterward)

DRUGPlacebo

50 cc normal saline administered intravenously immediately following umbilical cord clamping (or as soon as possible afterward)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

The patient nor the clinical staff will be aware of the treatment assignment. The TXA or placebo solutions will be prepared by the center research pharmacies.

Intervention model description

Participants will be randomized to receive either TXA (1 gram \[10cc\] mixed with 40 cc of normal saline) administered intravenously or a placebo control of 50 cc of normal saline administered intravenously

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

1. Scheduled or unscheduled cesarean delivery 2. Singleton or twin gestation

Exclusion criteria

1. Age less than 18 years 2. Transfusion or planned transfusion of any blood products during the current admission because the primary outcome is already pre-determined and the need for transfusion will be unrelated to perioperative hemorrhage 3. Recent diagnosis or history of venous thromboembolism or arterial thrombosis because TXA is a risk factor for thromboembolism, and its use is contraindicated 4. Known congenital or acquired thrombophilias, including antiphospholipid antibody syndrome, because of the increased risk of thrombosis 5. Seizure disorder (including eclampsia) because TXA is a GABA receptor antagonist, and its use has been associated with postoperative seizures 6. Serum creatinine 1.2 or higher or on dialysis, with renal disease, or a history of renal insufficiency, because TXA is substantially excreted by the kidney, and impaired renal function may increase the risk of toxic reactions. 7. Sickle cell disease, because of substantial use of perioperative transfusion unrelated to hemorrhage. Sickle cell trait is not an exclusion per se. 8. Autoimmune diseases such as lupus, rheumatoid arthritis, Sjogren's disease, and inflammatory bowel disease because of hypercoagulability and the increased risk of thrombosis or thromboembolism 9. Need for therapeutic dose of anticoagulation before delivery, because the risk of thrombosis may be increased with TXA 10. Treatment with clotting factor concentrates, because the risk of thrombosis may be increased with TXA 11. Presence of frank hematuria, because the risk of ureteral obstruction in those with upper urinary tract bleeding may be increased with TXA 12. Patient refusal of blood products because the primary outcome is then pre-determined 13. Receipt of TXA; or planned or expected use of TXA prophylaxis 14. Active cancer, because of risk of thromboembolism 15. Congestive heart failure requiring treatment, because of risk of thrombosis 16. History of retinal disease, because the risk of central retinal artery or vein obstruction may be increased with TXA 17. Acquired defective color vision or subarachnoid hemorrhage, since TXA is contraindicated 18. Hypersensitivity to TXA or any of the ingredients 19. No hemoglobin result available from the last 4 weeks, since it is necessary to measure the post-operative change in hemoglobin 20. Scheduled cesarean delivery and quota for scheduled deliveries already met. Quotas on the number of scheduled and unscheduled deliveries will be placed to ensure approximately equal distribution of scheduled and unscheduled cesarean deliveries. 21. Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, may be included. 22. Participating in another intervention study where the primary outcome includes postpartum bleeding or thromboembolism, or the study intervention directly affects postpartum bleeding or thromboembolism 23. Receipt of uterotonics, other than oxytocin, or planned or expected use of uterotonic prophylaxis 24. Symptomatic for COVID-19 infection within 14 days prior to delivery

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Maternal Death or Transfusion of Packed Red Blood Cells	by hospital discharge or by 7 days postpartum, whichever is sooner	Participants were monitored from delivery until hospital discharge or 7 days after delivery (postpartum), whichever is sooner. This is the number of mothers who died for any reason, or had a blood transfusion of 1 or more units (of packed red blood cells, including whole blood or cell saver).

Secondary

Measure	Time frame	Description
Number of Participants With Estimated Blood Loss Greater Than 1 Liter During Delivery	From skin incision to transfer from operating room, average of 1 hour	\[Major secondary outcome\] The surgeon or anesthesiologist estimated the blood loss during the delivery in milliliters, which was recorded in the anesthesia record and/or operative report
Number of Mothers Who Died or Had Thromboembolic Events (Venous or Arterial), Ischemic Stroke, Myocardial Infarction, New-onset Seizure Activity, or Were Admitted to the Intensive Care Unit for More Than 24 Hours	within 6 weeks postpartum	—
Number of Participants Who Were Transfused With Other Blood Products	within 7 days postpartum	This is the number of mothers who received during the first 7 days after delivery a transfusion of 1 or more units of fresh frozen plasma, cryoprecipitate, or platelets, or received any factor concentrates
Number of Participants Who Were Transfused With 4 or More Units of Packed Red Blood Cells	within 7 days postpartum	Participants were categorized according to the amount of packed red blood cells or whole blood transfused, either as 0 to 3 units, or 4 or more units
Number of Participants With a Thromboembolic Event (Venous or Arterial), Ischemic Stroke, or Myocardial Infarction	within 6 weeks postpartum	\[Key secondary outcome\] This is the number of mothers who experienced a thromboembolic event, ischemic stroke, or myocardial infarction during the 6 weeks after delivery.
Number of Participants With Seizure Activity That Was Not Seen Prior to Study Enrollment	within 6 weeks postpartum	This is the number of mothers who experienced seizure activity, confirmed by central review, whose onset is after enrollment
Number of Participants With Postpartum Infectious Complications	within 6 weeks postpartum	\[Key Secondary Outcome\] This is the number of mothers who experienced any of the following infectious complications in the 6 weeks after delivery: endometritis, surgical site infection, pelvic abscess
Number of Participants Who Were Treated With Uterotonics Other Than Oxytocin	within 48 hours postpartum	This is the number of mothers who were treated with uterotonics such as prostaglandins or methergine, but excluding oxytocin, from delivery through 48 hours after delivery.
Number of Participants Who Received Surgical or Radiologic Interventions to Control Bleeding and Related Complications	within 7 days postpartum	This is the number of mothers who required any of the following types of surgical procedures to control bleeding: laparotomy, evacuation of hematoma, hysterectomy, uterine packing, intrauterine balloon tamponade, interventional radiology
Change in Hemoglobin	from 4 weeks before delivery to 48 hours postpartum	\[Key secondary outcome\] Change in hemoglobin from the most recent measured before delivery to lowest measured in the 48 hours after delivery
Number of Participants Who Received Open Label TXA or Other Antifibrinolytic	within 7 days postpartum	This is the number of mothers who were treated with any amount of open-label TXA (not blinded study drug) or another antifibrinolytic (eg., Amicar)
Length of Stay	Until hospital discharge, an average of 3 days	Mother's length of stay from delivery to discharge
Number of Participants Who Received Treatments and Interventions in Response to Bleeding and Related Complications	within 7 days postpartum	\[Key secondary outcome\] This is the number of mothers who received treatments and interventions to control bleeding such as: uterotonics such as prostaglandins or methergine, but excluding oxytocin; open label TXA or other antifibrinolytics; transfusion of 1 or more units of fresh frozen plasma, cryoprecipitate, or platelets or administration of any factor concentrates; laparotomy, evacuation of hematoma, hysterectomy, uterine packing, intrauterine balloon tamponade, interventional radiology

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORRebecca Clifton, Ph.D.

The George Washington University Biostatistics Center

STUDY_DIRECTORMonica Longo, MD

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

STUDY_CHAIRLouis Pacheco, MD

UTMB

Participant flow

Recruitment details

We conducted this multicenter, randomized, controlled, double blinded trial at 31 hospitals. From March 2018 through July 2021, a total of 84,062 patients underwent screening for randomization. Of the 39,488 eligible patients, 11,000 provided informed consent and were randomized

Pre-assignment details

No participants were excluded after enrollment but before assignment to groups.

Participants by arm

Arm	Count
Tranexamic Acid Tranexamic Acid for intravenous administration Tranexamic Acid: A single dose of Tranexamic Acid (1 gram) in normal saline for a total of 50cc, administered intravenously immediately following umbilical cord clamping (or as soon as possible afterward)	5,525
Placebo Normal saline for intravenous administration Placebo: 50 cc normal saline administered intravenously immediately following umbilical cord clamping (or as soon as possible afterward)	5,470
Total	10,995

Baseline characteristics

Characteristic	Tranexamic Acid	Placebo	Total
Age, Continuous	30.1 years STANDARD_DEVIATION 5.8	30.1 years STANDARD_DEVIATION 5.8	30.1 years STANDARD_DEVIATION 5.8
Preoperative Hemoglobin <8g/dL	10 Participants	26 Participants	36 Participants
Race/Ethnicity, Customized Asian	218 Participants	193 Participants	411 Participants
Race/Ethnicity, Customized Hispanic	1636 Participants	1642 Participants	3278 Participants
Race/Ethnicity, Customized Non-Hispanic Black	1334 Participants	1310 Participants	2644 Participants
Race/Ethnicity, Customized Non-Hispanic White	2170 Participants	2159 Participants	4329 Participants
Race/Ethnicity, Customized Other, unknown, or more than one race or ethnic group	167 Participants	166 Participants	333 Participants
Sex: Female, Male Female	5525 Participants	5470 Participants	10995 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	26 / 5,529	32 / 5,471
other Total, other adverse events	593 / 5,529	647 / 5,471
serious Total, serious adverse events	82 / 5,529	70 / 5,471

Outcome results

Primary

Number of Participants With Maternal Death or Transfusion of Packed Red Blood Cells

Participants were monitored from delivery until hospital discharge or 7 days after delivery (postpartum), whichever is sooner. This is the number of mothers who died for any reason, or had a blood transfusion of 1 or more units (of packed red blood cells, including whole blood or cell saver).

Time frame: by hospital discharge or by 7 days postpartum, whichever is sooner

Population: Of 5529 participants, 4 were enrolled in the study for a second pregnancy in the tranexamic acid group and out of 5471 participants, 1 was enrolled for a second pregnancy in the placebo group. Since participants were only permitted to be enrolled in the study one time, only the first pregnancy was included in the analysis.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Tranexamic Acid	Number of Participants With Maternal Death or Transfusion of Packed Red Blood Cells	201 Participants
Placebo	Number of Participants With Maternal Death or Transfusion of Packed Red Blood Cells	233 Participants

p-value: 0.1995.26% CI: [0.74, 1.07]Other (Log-binomial regression model)

Secondary

Change in Hemoglobin

\[Key secondary outcome\] Change in hemoglobin from the most recent measured before delivery to lowest measured in the 48 hours after delivery

Time frame: from 4 weeks before delivery to 48 hours postpartum

Population: Only those with both hemoglobin measurements before and after delivery are included. Additionally, 5 enrolled for a second pregnancy (4 in the tranexamic acid group and 1 in the placebo group) only included the result from the first enrolled pregnancy (when available) since participants were only permitted to be enrolled in the study one time.

Arm	Measure	Value (MEAN)	Dispersion
Tranexamic Acid	Change in Hemoglobin	-1.8 grams per deciliter	Standard Error 1.1
Placebo	Change in Hemoglobin	-1.9 grams per deciliter	Standard Error 1.1

Secondary

Length of Stay

Mother's length of stay from delivery to discharge

Time frame: Until hospital discharge, an average of 3 days

Population: Of 5529 participants, 4 were enrolled in the study for a second pregnancy in the tranexamic acid group and out of 5471 participants, 1 was enrolled for a second pregnancy in the placebo group. Since participants were only permitted to be enrolled in the study one time, only the first pregnancy was included in the analysis.

Arm	Measure	Value (MEDIAN)
Tranexamic Acid	Length of Stay	3 days
Placebo	Length of Stay	3 days

Secondary

Number of Mothers Who Died or Had Thromboembolic Events (Venous or Arterial), Ischemic Stroke, Myocardial Infarction, New-onset Seizure Activity, or Were Admitted to the Intensive Care Unit for More Than 24 Hours

Time frame: within 6 weeks postpartum

Population: Participants who received study medication are included according to the treatment received; only those with follow-up through 6 weeks postpartum are included. Additionally, 5 enrolled for a second pregnancy (4 in the tranexamic acid group and 1 in the placebo group) only included the result from the first enrolled pregnancy (when available) since participants were only permitted to be enrolled in the study one time.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Tranexamic Acid	Number of Mothers Who Died or Had Thromboembolic Events (Venous or Arterial), Ischemic Stroke, Myocardial Infarction, New-onset Seizure Activity, or Were Admitted to the Intensive Care Unit for More Than 24 Hours	35 Participants
Placebo	Number of Mothers Who Died or Had Thromboembolic Events (Venous or Arterial), Ischemic Stroke, Myocardial Infarction, New-onset Seizure Activity, or Were Admitted to the Intensive Care Unit for More Than 24 Hours	32 Participants

Secondary

Number of Participants Who Received Open Label TXA or Other Antifibrinolytic

This is the number of mothers who were treated with any amount of open-label TXA (not blinded study drug) or another antifibrinolytic (eg., Amicar)