Clinical trial NCT04733157
Conditions: Postpartum Hemorrhage
Keywords: Postpartum hemorrhage Tranexamic acid Caesarean section Prevent
Sponsor: University of Zimbabwe
Start date: 2021-03-23; Completion date: 2021-12-14
Enrollment: 1226 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study seeks to determine if the using tranexamic acid prophylactically at caesarean section will prevent postpartum haemorrhage which is a major cause of maternal mortality in Zimbabwe and globally.

Detailed description:
This trial will be an placebo-controlled, two-centre, randomized control trial with two parallel groups including 1,162 women who undergo elective or emergency caesarean deliveries at term. The study group will receive tranexamic acid (TXA) 1g intravenously at the onset of skin incision. There is normal saline placebo for the control group. The study and control groups will both receive the standard care offered at caesarean section including 5 IU of oxytocin intravenously on delivery of the baby. .

Arms: arm 1: The study group will receive TXA 1g intravenously at the onset of skin incision. arm 2: There is an equivalent volume of normal saline for the control group.
Interventions: intervention 1: Tranexamic acid injection intervention 2: Normal saline placebo
Intervention descriptions: intervention 1: Tranexamic 1g administered intravenously at the onset of skin incision at caesarean section intervention 2: 10ml of normal saline will be administered intravenously at onset of skin incision at caesarean section to the placebo group

Protocol documents:
Prot_SAP_000.pdf: 
Tranexamic acid versus no tranexamic acid for the prevention of postpartum 
haemorrhage among women undergoing elective caesarean section at two hospitals in 
Harare, Zimbabwe: a randomised controlled trial 
 
Study Identifier: NCT04733157 
 
Date: 16 January 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Tranexamic acid versus no tranexamic acid for the prevention of postpartum haemorrhage among 
women undergoing elective caesarean section at two hospitals in Harare, Zimbabwe: a randomised 
controlled trial 
 
CONTACT DETAILS 
Dr Chipo Gwanzura 
Senior Registrar - Department of Obstetrics and Gynaecology, College of Health Sciences, University of 
Zimbabwe 
Fogarty UCGHI GloCal Fellow 
0774718381 
chipo.gwanzura@gmail.com  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


INTRODUCTION 
Postpartum haemorrhage (PPH) is a significant cause of maternal mortality and is responsible for 25% of 
all maternal deaths globally(1).  Virtually all of these deaths (99%) occur in developing countries, with 66% 
occurring within Sub-Saharan Africa(2,3) . 
Uterotonics after birth are the only intervention that have been shown to be effective for PPH prevention, 
having demonstrated a 50% reduction in the incidence of PPH (3). Tranexamic acid (TXA) has been 
explored as a possible additional agent in PPH prevention (4).  
During an acute haemorrhage, both clot formation and clot breakdown (fibrinolysis) are necessary to 
achieve haemostasis. Fibrinolysis is the process by which tissue plasminogen activator enables plasmin to 
breakdown fibrin into fibrin degradation products. Antifibrinolytic agents, such as TXA, competitively 
inhibit lysine binding sites of the plasminogen molecule to stabilize fibrin levels and prevent fibrinolysis, 
thereby resulting in reduced blood loss (5).  Similarly, during placental separation, fibrinogen and fibrin are 
rapidly degraded, while, due to activation of the fibrinolytic system, plasminogen activators and fibrin 
degradation products increase. This activation can last six to ten hours postpartum, resulting in more 
bleeding (6).  
The use of TXA in obstetrics is gaining worldwide recognition, but its full potential is limited due to poor 
understanding on how to dose the drug, timing of administration, indications for use, and potential adverse 
effects profile (4). To date there is no definitive recommendation regarding the efficacy and safety of routine 
prophylactic TXA administration at delivery vaginal or caesarean delivery (4). 
STATEMENT OF THE PROBLEM 
PPH is a major cause of maternal mortality in Zimbabwe. PPH is the leading cause of maternal death, 
contributing 21 – 43% of maternal deaths within the provinces of Zimbabwe in 2018 based on the Maternal 
and Perinatal Death Surveillance and Response Report (7). According to the Zimbabwe Demographic 
Health Survey published in 2015, the MMR for Zimbabwe is estimated at 651 deaths per 100,000 births 
which is among the highest in the world (8) This makes fulfilling the third Sustainable Development Goal 


(SDG3) a monumental task. Target 3.1 of SDG3 aims to decrease the worldwide MMR to less than 70 per 
100,000 by 2030 by ending preventable maternal mortality (9). 
Caesarean birth rates have increased in developing countries to as high as 25 – 30% with an accompanying 
upward trend in the incidence of PPH (4). In a local unpublished thesis in 2017, virtually all of the 
peripartum hysterectomies were due to PPH, with the majority (67%) of the deliveries in these cases having 
occurred by caesarean section. 
The causes of PPH are related to abnormalities in one or more of four basic processes commonly described 
as the four T’s (tone, trauma, tissue and thrombin) (10). The most common reason for primary PPH is 
uterine atony (tone) accounting for about 80% of cases (10,11). Uterotonics are able to address problems 
with tone, but an adjunct would be required to address the other causes of PPH particularly trauma. 
Currently the public health sector is underfunded. The majority, 72%, of Zimbabweans are below the 
poverty datum line making them unable to bear the cost of their healthcare and blood products (12). 
At present, there is no clear consensus around the use of TXA for prevention of PPH. In 2017, an updated 
World Health Organisation (WHO) guideline recommended the use of TXA for the treatment of PPH 
regardless of the cause of bleeding (13). 
There is no similar guideline for the use of TXA in prevention of PPH and evidence is needed to inform 
such a recommendation for either or both vaginal and caesarean delivery. Unlike for treatment, to date there 
is no definitive recommendation regarding the efficacy and safety of routine prophylactic TXA 
administration for prevention of PPH(4).  
LITERATURE REVIEW 
Literature search strategy 
We updated the literature search of the review that was done between April 2017 and August 2020 for the 
pilot study. The initial literature search was directed at the quoted trials and references in the Cochrane 
review ‘Tranexamic acid for the prevention of postpartum haemorrhage’ by Sentilhes et. al. (1) 
Subsequently further articles were accessed after searching Google and PubMed in April 2017 using the 


search words ‘Tranexamic acid’ and ‘Tranexamic acid for prevention of PPH’, with a further search in 
August 2020. I identified articles on the use of Tranexamic acid, and its use in obstetrics.  
Literature review 
There is a significant interest among obstetricians in finding effective tools for managing blood loss during 
caesarean delivery, including the use of TXA prophylactically(4).  
Caesarean birth increases the risk of postpartum haemorrhage 
Caesarean section in itself increases the risk for PPH with an adjusted odds ratio of 7.54 (95% CI 4.11 – 
13.81), and it also increases the risk of uterine atony which is a leading cause of PPH (14).  
Current WHO recommendations 
WHO currently recommends the use of TXA for the treatment of PPH where oxytocin and other uterotonics 
fail to stop bleeding or if it is thought that the bleeding may be partly due to trauma, although WHO cautions 
that this is a weak recommendation supported by moderate-quality evidence(3) . 
Use of tranexamic acid as treatment for PPH 
The WOMAN Trial collaborators found that TXA reduces mortality due to bleeding in women with PPH 
after caesarean and vaginal births with no adverse effects or an increase in the incidence of thromboembolic 
events. In this trial, the effects of TXA as treatment of PPH on death, hysterectomy, and other relevant 
outcomes were reviewed. The WOMAN Trial completed in 2016 was one of the first trials to be performed 
that was adequately powered given the 20,060 participants. The participants received either 1g of TXA or 
placebo in addition to the usual care for PPH. The results showed a significant reduction in bleeding and 
laparotomy to control bleeding particularly when TXA was administered soon after the onset of PPH. 
However, TXA was not shown to prevent hysterectomy, as the decision to perform a hysterectomy is 
usually made after the onset of primary PPH (15) 
Use of tranexamic acid in preventing PPH at vaginal delivery 
The TRAAP (Tranexamic Acid for Preventing Postpartum haemorrhage after vaginal delivery), a 
multicentre randomized placebo-controlled trial, involved 4,079 women in labour with a planned vaginal 
delivery of a live baby at 35 weeks and greater. In this double-blind trial, in France, participants received 


1g intravenously of TXA or placebo 2 minutes after delivery, after the initial routine intravenous dose of 
oxytocin. The use of TXA did not result in a significantly lower incidence of PPH compared to the use of 
placebo. The limitations of this trial were that the prenatal blood tests for measurement of the haemoglobin 
and haematocrit were mostly done in out-of-hospital laboratories without standardized timing, and the trial 
was underpowered to assess the effect on severe PPH of TXA (16). Also, in the context of this research, 
the trial looked at vaginal births as opposed to caesarean births. 
Use of tranexamic acid in preventing PPH at caesarean delivery 
Three recent large meta-analyses demonstrate that prophylactic TXA at the time of caesarean birth may be 
helpful in reducing blood loss and conferring secondary advantages(6,17,18). 
Table 1: Summary of recent meta-analyses on the use of TXA for the prevention of PPH during 
caesarean and vaginal delivery. 
STUDY 
# 
MOD 
BLOOOD LOSS > 1000ML 
TRANSFUSION 
VTE 
NOVIKOVA ET. AL. 
(2015) (17) 
12 
VD 
CD 
RR, 0.28 (95% CI, 0.06–1.36) 
RR, 0.43 (95% CI, 0.23–0.78)* 
RR, 0.33 (95% CI, 0.03–3.17) 
RR, 0.23 (95% CI, 0.10–0.54)* 
RR, 0.98 (95%CI, 0.14–6.78) 
SIMONAZZI ET. AL. 
(2016) (18) 
9 
CD 
RR, 0.42 (95% CI, 0.19–0.92)* 
RR, 0.33 (95% CI, 0.19–0.58)* 
RR, 0.98 (95%CI, 0.13–7.09 
WANG ET AL (2015)(6) 
11 
CD 
RR, 0.43 (95% CI, 0.20–0.92)* 
RR, 0.23 (95% CI, 0.10–0.57)* 
 
*Found to be significant, #-Number of trials, MOD-Mode of delivery, VD-Vaginal delivery, CD-caesarean delivery 
 
Simonazzi et. al. analysed 2345 caesarean deliveries. Compared with patients who did not receive TXA, 
the study group had significantly less blood loss, (−160.27; 95% CI, −224.63 to−95.92), a lower drop in 
haemoglobin (−0.61 g/dL; 95% CI, −1.04 to −0.18), and a lower incidence of PPH and severe PPH. They 
also had less need for additional uterotonics (4.2% vs 7.3%; RR, 0.54; 95% CI, 0.36–0.81). The percentage 
of patients requiring blood transfusion during or after caesarean delivery was significantly lower in the 
TXA group (1.9% vs 5.7%; RR,0.33; 95% CI, 0.19–0.58). The adverse outcomes showed no significant 
difference: 2 patients in the intervention group and 2 in the placebo group experienced thromboembolic 
events (Table 1). This study was unique in that it had broader inclusion criteria, including multiple gestation 
pregnancies, as well as both labouring and planned caesarean deliveries. However, clinical heterogeneity 


may have conflicted the results due to differences in TXA dosing, timing of intervention, and methods for 
measuring blood loss among the included studies (18).  
A widely referenced study by Wang et al is a large meta-analysis of 11 RCTs where TXA was administered 
before the start of scheduled caesarean deliveries. This study also showed that TXA intervention 
significantly reduced intraoperative blood loss during and after caesarean delivery without an increase in 
thromboembolic events; this reduction was similar for both 1 g dosing and weight-based TXA dosing 
regimens. Similar to the meta-analysis by Simonazzi et al, prophylactic TXA was associated with a lower 
incidence of PPH, a smaller drop in postpartum haemoglobin, and a reduced requirement for blood 
transfusion (6).  
A third large meta-analysis of prophylactic TXA use at the time of caesarean delivery, published as a 
Cochrane Review, produced similar outcomes to other large meta-analyses. For scheduled elective 
caesarean deliveries, TXA use was effective in reducing the incidence of PPH and blood transfusion 
requirements. As in other studies, gastrointestinal adverse effects, such as nausea and vomiting, were the 
most common adverse outcomes. Of note, the authors concluded that the studies were too small and 
underpowered to detect the effect of TXA on risk of maternal death or thromboembolism (17). 
Similar outcomes are described among small RCTs of TXA use before caesarean delivery (19–23). 
Currently ongoing is the TRAAP 2 trial which started on March 3, 2018, and is expected to be completed 
in 2020. The targeted sample size is 4,524, in a multicentre double-blind randomized placebo-controlled 
trial. One gram of TXA or placebo is administered intravenously, slowly over 30 – 60 seconds, after 
administration of uterotonic, after the cord is clamped, within 3 minutes after birth. The investigators will 
assess the incidence of PPH (blood loss exceeding 1,000ml) following caesarean delivery (24). 
In a local unpublished study conducted at Parirenyatwa and Sally Mugabe Central Hospitals, the pilot to 
this proposed study, the incidence of PPH was significantly lower in the TXA group compared to the control 
group in the per protocol analysis. The primary outcome occurred in 37(22.6%) of 164 women who received 
tranexamic acid and in 90 (31.4%) of the participants who did not receive tranexamic acid (p = 0.021).   


There was no significant difference in the intention-to-treat analysis. The results showed a trend towards 
efficacy of tranexamic acid in preventing postpartum haemorrhage (25).  
The available evidence suggests that routine TXA use before caesarean delivery may be a promising drug 
for the prevention of PPH, decreasing blood loss, and reducing the need for additional uterotonics and 
product transfusion with very mild adverse effects. However, the safest and most effective dosing, infusion 
rate, and timing of administration have yet to be determined (4).   
JUSTIFICATION 
TXA is already widely used in surgery to prevent clot breakdown to reduce blood loss (1). In the third stage 
of labour to prevent excessive bleeding, there are strong myometrial contractions that are potentiated by 
oxytocin; increased platelet action; as well as a massive release of coagulation factors with a concurrent 
increase in fibrinolysis. TXA can counter the fibrinolytic activity thereby facilitating coagulation (17).  Its 
actions would therefore potentiate the effect of uterotonics already in use in reducing blood loss at caesarean 
section.  
Early activation of fibrinolysis is common after trauma and is associated with increased mortality (26). 
Trauma triggers the release of tissue plasminogen activator, the enzyme that converts plasminogen to the 
fibrinolytic enzyme plasmin (27,28). Early activation of fibrinolysis is also recorded after childbirth. Within 
one hour of giving birth, the serum concentration of tissue plasminogen activator doubles, possibly because 
of tissue damage during childbirth; thereafter, the concentration falls (29). On the basis of results of clinical 
trials of PPH occurring during childbirth, tranexamic acid is recommended for the treatment of primary 
post-partum haemorrhage if uterotonics fail to control the bleeding or if the bleeding is thought to be due 
to trauma(15) 
TXA is cheap, already readily available, easily administered, easily stored (does not require refrigeration), 
and would be easy to add to routine protocols(30). It has the potential to reduce the number of deaths of 
mothers due to bleeding related to delivery and the undocumented consequences of the deaths on all the 
children who survive without a mother, husbands without their wives, and dependents without their 
breadwinners. 


Use of TXA for PPH prevention may also contribute to a reduction in blood product use, which is associated 
with multiple risks such as transfusion reactions, and transmission of blood-borne microorganisms that are 
not routinely screened for. Blood products are also expensive. While in Zimbabwe at present obstetric 
patients are receiving blood products at no cost, the cost is borne by the government. The majority of 
patients could not afford blood transfusion if charged, as only 30% of Zimbabweans are in formal 
employment and the majority (72.3%) are below the poverty datum line (31). A decrease in cost of blood 
transfusion would result in a cost saving of $125 per unit of packed red cells. Any savings would have 
important implications for the underfunded health system (11,32).  
PPH contributes to near-miss cases in addition to actual deaths, due to the serious complications that can 
occur as a consequence of serious PPH. These include adult respiratory distress syndrome, coagulopathy, 
shock, loss of fertility, and pituitary necrosis (Sheehan syndrome) (4). If PPH is prevented this could 
contribute towards reduced hospital stay, avoidance of expensive interventions for intractable PPH (such 
as hysterectomies and the need for blood products) and conserve our already strained resources.  
Prophylactic TXA use has been shown to produce a statistically significant decrease in postpartum blood 
loss; however, this may not convey clinical significance in terms of transfusion rates and maternal 
comorbidity from severe haemorrhage. Currently, there is no consensus regarding the optimal timing or 
dosing of prophylactic TXA for caesarean deliveries (33).  
In the light of the above, this research proposes to assess the efficacy of TXA in preventing PPH after 
caesarean delivery in a population large enough to be adequately powered to add to the current body of 
evidence. Also, there are no published RCTs, in Southern Africa reporting on TXA in obstetric patients. 
GOAL STATEMENT 
The aim of this study is to compare the effect of a low dose of TXA (1 g) at the time of skin incision during 
caesarean delivery together with prophylactic oxytocin administration, versus prophylactic oxytocin alone 
in an open label randomized clinical trial. 
 
 


RESEARCH QUESTION 
Does intravenous TXA 1g plus Oxytocin 10 IU result in a lower incidence of primary postpartum 
haemorrhage compared to Oxytocin 10 IU alone after caesarean section? 
OBJECTIVES  
1. To assess the effect of TXA (1g) on postpartum blood loss at caesarean delivery. 
2. To determine the potential adverse effects of intravenous TXA administered at caesarean section.   
PRIMARY OUTCOME 
Incidence of PPH, defined by a calculated estimated blood loss > 1000ml or a red blood cell transfusion up 
to day 2 postpartum 
Secondary Outcomes 
• 
Other outcome measures describing postpartum blood loss including 
o calculated blood loss, 
o visually estimated blood loss,  
o mean/median number of units of packed red blood cells transfused,  
o incidence of postpartum shock;  
o proportion of women requiring supplementary uterotonics,  
o incidence of postpartum transfusion,  
o incidence of emergency surgery for PPH including caesarean hysterectomies,  
o mean peripartum change in haemoglobin and haematocrit as well as haemoglobin drop > 2 g/dL,  
o transfer to intensive care unit (ICU),  
o or death from any cause. 
• 
To assess potential adverse effects of TXA: 
o Hemodynamic parameters,  
o adverse gastrointestinal events, renal, hepatic, and coagulation function,  
o and any venous or arterial thrombosis at any time during the woman’s postoperative course. 
 
 


METHODOLOGY 
Research design 
Open-label parallel randomized control trial. 
Target population 
Women undergoing caesarean sections at Sally Mugabe and Parirenyatwa Hospitals based on set inclusion 
and exclusion criteria. 
Inclusion criteria 
• 
Estimated gestational age of 37 weeks or more 
• 
Live intrauterine foetus 
• 
Elective or emergency caesarean delivery 
• 
Signed informed consent 
Exclusion criteria including any of the following factors or conditions identified prior to surgery 
• 
History of coagulopathies or conditions predisposing them to thromboembolic phenomena, 
• 
seizure history,  
• 
autoimmune disease,  
• 
placental abruption,  
• 
placenta praevia,  
• 
abnormally adherent placentae if identified on prenatal ultrasound,  
• 
eclampsia or HELLP syndrome,  
• 
known hypersensitivity to TXA,  
• 
planned general anaesthesia,  
• 
caesarean delivery for the second twin or second/third triplet(s) after vaginal birth of the first twin,  
• 
poor understanding of English/Shona languages,  
• 
those who have received anticoagulants in the week before delivery 
• 
persons-under-investigation for COVID-19 and confirmed COVID-19 positive women. 


Women will receive individual information in late pregnancy about the trial from obstetricians and 
midwives during antenatal clinic visits or from anaesthetists during the pre-caesarean visit, or both. Women 
may be pre-included (receive information and sign consent forms) for caesareans both before and during 
labour when the investigator considers that the woman is likely to have a caesarean delivery. The aim of 
pre-inclusion is to facilitate recruitment, particularly the recruitment of caesareans during labour, which 
may be decided upon and performed in emergency situations. Women recruited prior to emergency 
caesarean delivery (in labour) sign consent to have the caesarean section while in labour. We therefore 
consider that having received information about the trial during the antenatal period and on the labour ward, 
they will also be able to provide informed consent for inclusion into the trial at the same time. 
Study Setting  
The study will be performed at two tertiary institutions that are affiliated to the University of Zimbabwe 
that serve as referral centres for clinics located in Harare as well as district and provincial hospitals in the 
surrounding provinces: Sally Mugabe Central Hospital Maternity Unit and Parirenyatwa Group of Hospitals 
i.e. Mbuya Nehanda Maternity Hospital (MNMH). Most of these patients understand both English and 
Shona languages. 
Sample size 
The sample size has been calculated assuming a proportion of 2.1% PPH in the experimental group and 
5.8% (34) in the control group at 95% confidence interval and 90% power using the Fleiss formula giving 
a minimum sample size of 
 𝑛=
[Zα
2√(r + 1)p̅q̅ + Zβ√rp1q1 + p2q2]2
r(p1 −p2)2
 
𝑛=
[1.96√(1 + 1) × 0.0395 × 0.9605 + 1.28√0.021 × 0.979 + 0.058 × 0.942]
2
(0.021 −0.058)2
 
= 581 𝑝𝑒𝑟 𝑔𝑟𝑜𝑢𝑝 
Thus, total minimum sample size 𝑵 = 𝟏, 𝟏𝟔𝟐 women 
Where: n = sample size 
Zα = 1.96 at 95% confidence interval 


α = probability of a type I error (significance level) = 0.05 
β = probability of a type II error (1 – power of test) 
p₁ = proportion of PPH in the experimental group = 0.021 
p₂ = proportion of PPH in the control group = 0.058 
r = ratio of control group/population 2 to experimental group/population 1 
q = 1-p 
 
Randomization 
A randomized allocation to study and control groups using computer-generated random numbers will be 
prepared by the trial statistician. 
Pharmacy Plan 
Oxytocin iv is dispensed weekly from the pharmacy to theatre, where it is stored in a refrigerator in the 
custody of the sister in charge. All patients undergoing caesarean delivery routinely receive 10IU oxytocin 
iv, administered slowly by the anaesthetist after delivery of baby at Sally Mugabe Hospital Maternity Unit 
and Mbuya Nehanda Maternity Hospital. Cold chain will be maintained up to the administration of drug to 
the patient. 
TXA obtained for the study will be kept in theatre. This is to ensure an uninterrupted supply of the drug for 
the study. The TXA vials will be kept in theatre in a locked drug cupboard accessible to the researcher and 
research assistants at the authorization of the sister in charge. A dispensing register for the drugs will be 
kept together with the drugs. Patient details and study number, amount of TXA dispensed and wasted will 
be entered into the study register for accountability and to guard against abuse. 
Intervention 
The participants in the intervention arm will receive generally from the anaesthetist or nurse anaesthetist 
TXA (1g), administered slowly (over 30 – 60seconds) at the time of skin incision. Participants in both the 
intervention arm and control group will receive the routine prophylactic 10 IU oxytocin intravenously at 
birth of the baby. All other aspects of management of the caesarean section will be identical in both arms 
(34). 


Other aspects of the caesarean delivery 
• 
The surgical team will decide on the administration of additional uterotonics and the management of 
PPH, in a manner consistent with local guidelines. In particular, the use of TXA for the treatment of 
PPH will be allowed and left to the practitioner’s discretion according to the hospital protocol. 
• 
Because the surgeon’s level of experience may affect estimated blood loss during or after a caesarean 
delivery, the obstetrician’s experience, categorized as senior resident medical officer, senior house 
officer, junior registrar, senior registrar or consultant will be recorded (34). 
Assessment 
Data will be collected and recorded on the data collection tool. Any adverse event will to be reported on 
the IRB adverse event reporting form.  
Primary outcome measure 
Estimated blood loss (EBL) will be determined using haematocrit, haemoglobin, and visual estimates. 
Calculated estimated blood loss = estimated blood volume × (preoperative haematocrit – postoperative 
haematocrit) / preoperative haematocrit. Where estimated blood volume (mL) = weight (kg) × 85).  
The calculation is an objective measure to estimate blood loss because of the inaccuracy of other methods 
used to determine blood loss and caesarean delivery(35).  
Preoperative haematocrit will be determined on the day before elective caesarean or on the day of 
emergency caesarean delivery. Postoperative haematocrit will be the haematocrit obtained by blood 
sampling at D2 (on the second morning after caesarean section). If haematocrit is not available at D2, then 
haematocrit at D3 will be considered; if it is also missing, then the postpartum haematocrit closest to D2 in 
the absence of transfusion will be considered (36,37). 
All women who receive RBC transfusion for PPH between delivery and D2 postpartum are defined to have 
PPH and meet the criteria for the primary outcome. Calculated blood loss is impossible to determine for 
these women. Moreover, women only rarely receive an RBC transfusion for a blood loss less than 1000 ml. 
As a marker of significant maternal morbidity, RBC transfusion is considered equivalent or superior to 
blood loss greater than 1000 mL(25). 


Although visual estimation is the method used frequently by anaesthetists to estimate blood loss, it has been 
demonstrated as inaccurate in repeated studies. The estimate of blood loss is affected by amniotic fluid as 
well. Its continued use in clinical practice is likely related to tradition and it being easily used. We will also 
take note of the visual estimate made by the anaesthetist, and by the operating surgeon, as this is the method 
used locally(6,38)(39) 
Secondary outcome measures 
Describing postpartum blood loss 
1. Clinical 
a. Visually estimated blood loss 
b. proportion of women requiring supplementary uterotonic treatment 
c. incidence of postpartum transfusion  
d. mean number of RBC units transfused 
e. incidence of emergency surgery for PPH including caesarean hysterectomies 
f. incidence of hypovolemic shock related to PPH as determined by assessing BP and pulse 
g. incidence of transfer to ICU 
h. incidence of maternal death from any cause 
i. 
length of hospital stay. 
2. Laboratory 
a. incidence of calculated blood loss > 500 mL and > 1500 mL 
b. mean total calculated blood loss 
c. mean peripartum change in haemoglobin (difference between haemoglobin before delivery and at 
D2) 
d. Haemoglobin drop > 2 g/dL (between haemoglobin before delivery and at D2) (34). 
Describing adverse events 
1. Clinical 
a. Hemodynamic parameters (heart rate, blood pressure) 15, 30, 45, 60, and 120 min after delivery 


b. the occurrence of potential mild adverse effects of TXA in the operating room: 
i. nausea 
ii. vomiting 
iii. sensation of rings or spots of light in visual field 
iv. dizziness 
c. the occurrence of potential severe adverse effects of TXA during the hospital stay and up to discharge 
i. deep vein thrombosis, if the diagnosis is confirmed by Doppler ultrasound 
ii. pulmonary embolism, if the diagnosis is confirmed by radiological examination 
iii. myocardial infarction 
iv. seizure 
v. renal failure requiring dialysis 
d. any other unexpected adverse events 
Data Management 
The researcher and assistants will allocate each patient codes. No identifiers will be used. Any data collected 
will be stored in an office accessible only to the researcher and research assistants, as well as on a password-
protected laptop computer. 
data cleaning and entry 
Completed questionnaires will be checked for validity, accuracy and completeness by the principal 
investigator before data entry into the computer.  
Statistical methods and data reporting 
Data analysis and reporting will be guided by the Consolidated Standards of Reporting Trials (CONSORT) 
and will be done by the researchers with the assistance of the statistician. (34). 
The women’s demographic characteristics and standard risk factors for PPH will be compared between the 
two groups.  


The main analysis of the primary and secondary outcomes will be performed in the modified intention-to-
treat (ITT) population, defined as women who undergo randomization and have a caesarean delivery 
(except if they withdraw consent or are deemed ineligible after randomization).  
We will also analyse two separate per-protocol populations: women from the modified ITT population 
receiving a uterotonic and TXA (as specified in the protocol) (per-protocol group 1); the other will include 
women from the modified ITT population receiving a uterotonic and then tranexamic acid or no TXA in 
the 10min after delivery (per-protocol group 2; for a situation more consistent with routine clinical practice). 
The baseline characteristics of the trial participants, the management of the third stage of labour, and 
protocol adherence will be compared by descriptive statistics. 
Quantitative variables will be expressed, as appropriate, as means with standard deviations (and compared 
by Student’s t-test) or as medians with interquartile ranges (compared by the Wilcoxon rank-sum test). Chi-
square or Fisher’s exact tests will be used, as appropriate, to compare categorical variables. The effects of 
TXA will be expressed as relative risks with 95% confidence intervals for categorical outcomes and as 
mean differences with 95% confidence intervals for quantitative outcomes. The results will also be 
expressed as absolute risk differences with 95% confidence intervals for binary outcomes. 
Two specified subgroup analyses will examine the primary outcome in subgroups of women at high risk of 
PPH. The subgroups will include women who undergo a caesarean during labour and those who are at risk 
for PPH according to a composite definition (having at least one risk factor with an odds ratio of 3 or greater 
in the literature (34) history of any of PPH, hypertensive disorder of pregnancy, multiple pregnancy, or 
caesarean during labour). Moreover, prespecified subgroup analyses will examine the secondary outcomes 
in the subgroup of women who undergo a caesarean during labour. We will use the Benjamini–Hochberg 
procedure to adjust for multiple comparisons of secondary outcomes or subgroups (34). A statistical test 
may be significant by chance but in reality, not significant. The Benjamini-Hochberg method is used to 
control for this false discovery rate in statistical tests. Statistical analysis will be conducted using Stata v16. 
Feasibility  


Prior to the COVID 19 pandemic HMH delivered 1,335 pregnancies while a total of 535 pregnancies per 
month were delivered at MNMH. On average 60 elective and 250 emergency caesarean sections were done 
at HMH per month, while 80 elective and 210 caesarean deliveries on average are done at MNMH. Based 
on a review of the theatre delivery records during the period from April 2020 to August 2020 an average of 
154 emergency caesarean sections were done monthly at MNMH, while an average of 149 emergency cases 
were done at HMH. During this COVID period an average of 303 caesarean sections are being done per 
month. About 90% of these meet the inclusion criteria. Assuming a participation rate of 50% of these, an 
inclusion period of 8 months should make it possible to recruit 1,162 participants. Given that the lockdown 
conditions are being eased, with staff returning after industrial action, and that the hospitals are slowly 
reintroducing antenatal clinics, there should be an increase in caesarean sections (elective and emergency) 
across both institutions which may allow us to reach the targeted number in a shorter time period. 
Impact of COVID-19 
Coronavirus disease 2019 (COVID-19) has led to the deadliest pandemic observed in over 100 years (40). 
Healthcare workers and potentially researchers in obstetric wards are at a particularly increased risk for 
occupational exposure due to long periods of interaction with patients during labour, patient care involving 
multiple team members, the unpredictable occurrence of sudden obstetrical emergencies with their potential 
for unanticipated intubations in women undergoing labour and delivery. Presence on an obstetrical ward 
presents a real risk for infection to the research team (41). 
At the point of recruitment, the researcher and team will employ a combination of standard contact and 
droplet precautions, with further precautions undertaken during aerosol-generating procedures such as 
recruitment of patients in labour (42).  
The standard precautions are used to prevent or minimize transmission at all times. These include hand 
hygiene, appropriate use of personal protective equipment (PPE), safe handling of sharps, respiratory 
hygiene, occupational health and injection safety (42). 
Transmission-based precautions – droplet or contact include: 
• 
hand hygiene which is the most essential aspect 


• 
PPE which consists of gloves, gown, and a medical mask 
• 
Safe waste management (42). 
Aerosol-generating procedures include women in labour. Precautions while recruiting and consenting 
women in labour include: 
• 
Researchers wearing PPE – gloves, gown, fit-tested particulate respirator (N95 respirator) and eye-
protection (goggles or face shield) 
• 
Interviews in adequately ventilated rooms (42). 
We will review the screening questionnaire for COVID-19 that is part of the standard triage form at our 
healthcare facilities. We will not recruit persons under investigation (PUI) or confirmed COVID-19 positive 
women. This is largely because of the knowledge gaps that currently exist as well as the potential for 
increased thrombotic events in COVID-19 patients which would potentially exacerbate or mask the 
potential adverse effects of TXA.  High levels of d-dimers have been reported with 28-day mortality in 
patients with infection or sepsis. Contributory mechanisms include systemic pro-inflammatory cytokine 
responses that are mediators of atherosclerosis directly contributing to plaque rupture through local 
inflammation, induction of procoagulant factors, and haemodynamic changes, which predispose to 
ischaemia and thrombosis. In addition, angiotensin converting enzyme 2, the receptor for SARS-CoV-2, is 
expressed on myocytes and vascular endothelial cells, so there is at least theoretical potential possibility of 
direct cardiac involvement by the virus (43).  
Independent Data and Safety Monitoring Board  
An Independent Data and Safety Monitoring Board (DSMB) has been established for the study comprising 
of 3 individuals: Professor S. Rusakaniko (Statistician) [DSMB chair], Dr M. Madziyire (Obstetrician & 
Gynaecologist), and Dr T. Marere (Obstetrician & Gynaecologist). 
 


The DSMB has been established to assess at intervals the progress of the clinical trial, the safety data, and 
the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop the 
trial. 
Stopping Rules / Discontinuation Criteria 
If at any stage during the trial the principal investigator, co-investigators (supervisors), DSMB, or ethical 
authorities are satisfied that having due regard to the initial risks, discomforts or other adverse effects caused 
to persons taking part in the trial it is in the public interest to stop or suspend the trial, the trial shall be 
stopped or suspended immediately. The DSMB or ethical authorities will notify the investigator in writing 
accordingly. Ethical authorities as well as the hospital authorities will be notified accordingly as well by 
the investigator. 
ETHICAL CONSIDERATIONS 
Approval to conduct the study and to use the hospital records of patients shall be sought from the 
following: 
1. Parirenyatwa Group of Hospitals  
2. Sally Mugabe Central Hospital Research and Ethics Committee 
3. Medical Research Council of Zimbabwe (MRCZ) 
4. Medicines Control Authority of Zimbabwe (MCAZ)  
Participants will be requested to provide informed consent shall be sought from all the participants. 
Women in the study will receive full disclosure of the nature of the study, the risks, benefits and 
alternatives. They will be given an opportunity to ask questions. No participant will be coerced into 
participation. Participants will be assured that no punitive implication or denial of service shall be 
encountered in the event she declines and that at any time she can decide to withdraw her participation.  
The researcher will liaise with the team managing the patient to continue the usual care even when the 
patient is not willing or withdraws participation. The patient will be free to communicate with the researcher 
if she feels she did not get due treatment. The study shall only use coded numbers with no personal 
identifiers to ensure confidentiality. 


Timeline 
The clinical trial will run over 12 months. The initial four months will be used to obtain ethical approval 
for study. Approximately six months will be spent recruiting study participants and collecting and entering 
data. With the help of a bioinformatician I will analyse the data in preparation for dissemination in the last 
two months of the study. 
BUDGET AND SPONSORSHIP 
This project is supported by the Fogarty International Centre and the National Institute of Mental Health of 
the National Institutes of Health (NIH) under Award Number D43TW009343 and the University of 
California Global Health Institute (UCGHI).  
 
 
 


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