Efficacy of Tranexamic Acid in Preventing Postpartum Haemorrhage After Elective Caesarean Section
Phase: PHASE3
Conditions: Post Partum Hemorrhage
Sponsor: University of Zimbabwe

  
 
EFFICACY OF TRANEXAMIC ACID IN 
PREVENTING POSTPARTUM 
HAEMORRHAGE AFTER ELECTIVE 
CAESAREAN SECTION 
 
CLINICALTRIALS.GOV REGISTRATION 
NCT03463993 
 
STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
PRINCIPAL INVESTIGATOR 
DR CHIPO GWANZURA 
 
CO-INVESTIGATORS 
DR TAAZADZA NHEMACHEMA & PROFESSOR TSUNGAI CHIPATO 
 
 
DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY 
COLLEGE OF HEALTH SCIENCES 
UNIVERSITY OF ZIMBABWE 
30 June 2019 

i 
 
CONTENTS 
TABLE OF CONTENTS 
 
CONTENTS ...................................................................................................................................................... i 
TABLE OF CONTENTS .................................................................................................................................. i 
FIGURES ...................................................................................................... Error! Bookmark not defined. 
TABLES ........................................................................................................ Error! Bookmark not defined. 
ABBREVIATIONS ........................................................................................................................................... iii 
CHAPTER 1. INTRODUCTION ......................................................................................................................... 1 
1.1. 
POSTPARTUM HAEMORRHAGE .................................................................................................... 1 
1.1.1. 
THE SCALE OF THE PROBLEM OF POSTPARTUM HAEMORRHAGE ....................................... 1 
1.1.2. 
PREVENTION OF POSTPARTUM HAEMORRHAGE AT CAESAREAN SECTION ........................ 2 
1.2. 
TRANEXAMIC ACID ........................................................................................................................ 4 
1.2.1. 
RATIONALE OF USING THE DRUG AT CAESAREAN DELIVERY................................................ 4 
1.3. 
STATEMENT OF THE PROBLEM ..................................................................................................... 4 
1.4. 
RESEARCH QUESTION ................................................................................................................... 5 
CHAPTER 2. LITERATURE REVIEW ................................................................................................................. 6 
2.1. LITERATURE SEARCH STRATEGY ......................................................................................................... 6 
2.2. LITERATURE REVIEW .......................................................................................................................... 6 
2.2.1. CAESAREAN BIRTH INCREASES PPH RISK .................................................................................... 6 
2.2.2. CURRENT WHO RECOMMENDATIONS ........................................................................................ 6 
2.2.3. EVIDENCE ON USE OF TRANEXAMIC ACID IN OTHER SURGICAL CONTEXTS .............................. 7 
2.2.4. CURRENT EVIDENCE ON THE USE OF TRANEXAMIC ACID IN PREVENTING PPH ........................ 7 
2.3. 
JUSTIFICATION ............................................................................................................................ 11 
2.4. 
RESEARCH OBJECTIVES ............................................................................................................... 12 
CHAPTER 3. RESEARCH METHODS .............................................................................................................. 13 
1.1. 
RESEARCH DESIGN ...................................................................................................................... 13 
1.2. 
PARTICIPANTS ............................................................................................................................. 13 
1.3. 
STUDY SETTING ........................................................................................................................... 14 
1.4. 
SAMPLE SIZE ................................................................................................................................ 16 
1.5. 
RECRUITMENT AND ALLOCATION ............................................................................................... 17 

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1.6. 
RANDOMIZATION ........................................................................................................................ 17 
1.7. 
BLINDING..................................................................................................................................... 18 
1.8. 
INTERVENTION ............................................................................................................................ 18 
1.9. 
PHARMACY PLAN ........................................................................................................................ 19 
1.10. 
ASSESSMENT ........................................................................................................................... 20 
1.11. 
STATISTICAL METHODS ........................................................................................................... 22 
1.12. 
DATA MANAGEMENT .............................................................................................................. 23 
1.13. 
DATA CLEANING AND ENTRY .................................................................................................. 23 
1.14. 
OUTCOMES ............................................................................................................................. 23 
1.14.1. 
Primary Outcome ................................................................................................................ 23 
1.14.2. 
Secondary Outcomes .......................................................................................................... 23 
3.15. 
DATA REPORTING .................................................................................................................... 26 
3.16. 
INDEPENDENT DATA AND SAFETY MONITORING BOARD ...................................................... 26 
3.17. 
STOPPING RULES / DISCONTINUATION CRITERIA ................................................................... 26 
3.18. 
ETHICAL CONSIDERATIONS ..................................................................................................... 27 
3.19. 
TRIAL REGISTRATION .............................................................................................................. 28 
3.20. 
PROTOCOL ............................................................................................................................... 28 
REFERENCES ................................................................................................................................................ 29 
 
 
 

iii 
 
ABBREVIATIONS  
 
ACOG  
The American College of Obstetricians and Gynaecologists 
AIDS 
 
Acquired Immune Deficiency Syndrome 
AMCHA  
1-(aminomethyl)-cyclohexane-4-carboxylic acid 
AMTSL  
Active management of the third stage of labour 
ANW 
 
Antenatal Ward 
BMI 
 
Body Mass Index 
BNF 
 
British National Formulary 
BP 
 
Blood Pressure 
CI 
 
Confidence Interval 
CONSORT 
Consolidated Standards of Reporting Trials 
DSMB  
Data and Safety Monitoring Board 
EACA 
 
Epsilon-amino-caproic acid 
EBL 
 
Estimated blood loss 
EBV 
 
Estimated blood volume 
ELW 
 
Early Labour Ward 
FBC 
 
Full Blood Count 
FIGO 
 
International Federation of Gynaecologists and Obstetricians 
g 
 
gram 
Hb 
 
Haemoglobin 
HCT 
 
Haematocrit 
HMH 
 
Harare Maternity Hospital 
IM 
 
Intramuscularly  
IQR 
 
Interquartile range 
IU 
 
International Units 
 
 
 
IV 
 
Intravenously 
JREC 
Joint Research and Ethics Committee for the University of Zimbabwe, College of Health 
Sciences and Parirenyatwa Group of Hospitals 

iv 
 
kg 
kilogram 
LFT 
 
Liver Function Test 
LW 
 
Labour Ward 
MCAZ  
Medicines Control Authority of Zimbabwe 
µg 
 
microgram 
mg 
 
milligram 
ml 
 
millilitre 
MMR  
Maternal Mortality Ratio 
MNMH  
Mbuya Nehanda Maternity Hospital 
MRCZ  
Medical Research Council of Zimbabwe 
mRNA  
messenger ribonucleic acid 
NICE 
 
National Institute of Health and Care Excellence 
NICU 
 
Neonatal Intensive Care Unit 
NNU 
 
Neonatal Unit 
PCW  
 
Post-caesarean section Ward 
PNA 
 
Postnatal ward A 
PNB 
 
Postnatal ward B 
PPH 
 
Postpartum Haemorrhage 
Pvt Ltd  
Private Limited 
RAMOS  
Reproductive Age Mortality Studies 
RCOG  
Royal College of Obstetricians and Gynaecologists 
RCT 
 
Randomized Controlled Trial 
RR 
 
Relative risk 
SD 
 
Standard deviation 
SDG 
 
Sustainable Development Goal 
SRMO  
Senior resident medical officer (intern) 
SHO 
 
Senior House Officer 
TRAAP   
Tranexamic Acid for Prevention of Postpartum haemorrhage 
TXA 
 
Tranexamic Acid 

v 
 
U&E 
 
Urea and Electrolytes 
WHO 
 
World Health Organization 
WMD  
Weighted mean difference 
WOMAN 
World Maternal Antifibrinolytic 
ZMPMS  
Zimbabwe Maternal and Perinatal Mortality Study 
 
 

1 
 
CHAPTER 1. INTRODUCTION 
1.1. 
POSTPARTUM HAEMORRHAGE 
1.1.1. THE SCALE OF THE PROBLEM OF POSTPARTUM HAEMORRHAGE 
 
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). At 546 per 100, 000 live births, the maternal mortality ratio 
(MMR) for the Sub-Saharan region is the highest in the world (2). This makes fulfilling the third Sustainable 
Development Goal (SDG3) a monumental task. Target 3.1 aims to decrease the worldwide MMR to less 
than 70 per 100,000 by 2030 by ending preventable maternal mortality (2). 
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 extremely high (4). However, these statistics are 
derived from the sisterhood method, an indirect method recommended by the World Health Organization 
(WHO) for developing countries. The costs of full surveillance programs in these countries would be 
expensive and unrealistic. The estimate may therefore not be accurate (5). PPH is the second most common 
cause of maternal death, contributing 14.4% of maternal deaths second to AIDS-defining conditions based 
on a Zimbabwean cross-sectional study in 2007 (6). It is important to note that this study was done 12 years 
ago and data collection was done using a facility birth survey as well as the Reproductive Age Mortality 
Studies (RAMOS) method, which made the estimate reliable (7). The update of this study will be available 
soon from the ongoing Zimbabwe Maternal and Perinatal Mortality Study (ZMPMS 2018-9). Given the 
magnitude of the problem of PPH in Zimbabwe, its prevention would go a long way in reducing the MMR 
in Zimbabwe. 

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Caesarean sections are associated with greater blood loss than vaginal deliveries. Worldwide there has 
been an increase in the caesarean section rate. This could increase the risk of morbidity and mortality 
from PPH especially among anaemic women (8).   PPH affects about 5% of all woman giving birth globally, 
3.9% of women after vaginal delivery and 6,4% of women after caesarean delivery, and it occurs in any 
setting (3, 9). PPH at caesarean section is frequently underestimated. It is documented as occurring in more 
than 5 - 10% of caesarean deliveries (10). The incidence of PPH in Zimbabwe is not known. In a retrospective 
descriptive study done at Mpilo Central Hospital in Bulawayo, the incidence was found to be 1.6%. This 
was low in comparison to 4.5%, in a low-resource hospital in Nigeria, 9% in Uganda, and 6.4% in a 
developed country, the Netherlands (11). 
It is not an effective health strategy to screen for high-risk women to deliver in specialized facilities as 
most women who succumb to PPH have no identifiable risk factor. Patients with risk factors for PPH 
however would do well to deliver in a facility that at least has access to blood and an operating theatre. 
What is efficacious is immediate access to quality care for all women giving birth. This includes providing 
adequate vital medications, stocks and equipment at any location to enable the delivery of first-line PPH 
management (12).  
Endeavours to prevent and decrease morbidity and mortality due to PPH by using interventions such as 
uterotonics and tranexamic acid (TXA), can assist in addressing the profound inequities in maternal and 
perinatal health globally (13). 
 
1.1.2. PREVENTION OF POSTPARTUM HAEMORRHAGE AT CAESAREAN SECTION 
There are various strategies employed to manage the third stage of labour to prevent excessive bleeding 
from the genital tract. For PPH prevention, the only intervention shown to be effective is the 

3 
 
administration of uterotonics (3). The World Health Organization recommends one of the following 
uterotonics during caesarean births: 
 
Oxytocin 10IU IM/IV 
 
Carbetocin 100µg IM/IV where it is cost effective to use it 
 
Misoprostol 400 or 600 µg orally 
 
Where hypertensive disorders have been safely excluded 
o Ergometrine/methylergometrine (200 μg, IM/IV)  
 
 
o Fixed-dose combination of oxytocin and ergometrine (5 IU/500 μg, IM) (3).  
Clinicians often extend prophylaxis where high-risk factors such as multiple pregnancy, fibroid uterus, 
and manual removal of the placenta are present. The prophylaxis includes infusions of 40IU of oxytocin 
in a crystalloid over 4 hours (27). The effectiveness of this has not been proven in randomized controlled 
trials. In addition, many patients who deliver at emergency caesarean section have been shown to have 
a loss of oxytocin receptors within the myometrium evidenced by the decrease in binding sites and very 
low mRNA concentrations (27). This could be the reason why there is likely to be more bleeding at 
emergency caesarean delivery. 
The Royal College of Obstetricians and Gynaecologists of the United Kingdom (RCOG) recommends 
practitioners to consider TXA (0.5 - 1.0g) in addition to oxytocin at caesarean delivery to prevent PPH (28). 
TXA was effective in decreasing the incidence of blood loss greater than 1,000 ml in women who had 
undergone caesarean section (relative risk (RR) 0.43, 95% confidence interval (CI) 0.23–0.78) in four 
studies with 1,534 women  (29). The authors of the Cochrane review, however, concluded that more studies 
needed to be done. TXA could, therefore, be added to the current uterotonic drugs given in the third stage 
of labour, particularly in women at high risk of PPH, for instance, those with multiple pregnancy, anaemia, 
placenta praevia and placental abruption (29). 

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1.2. 
TRANEXAMIC ACID  
1.2.1. RATIONALE OF USING THE DRUG AT CAESAREAN DELIVERY 
The chemical 1-(aminomethyl)- cyclohexane-4-carboxylic acid (AMCHA), commonly known as tranexamic 
acid, or the common trade name of Cyklokapron, or Lysteda, is a synthetic derivative of the amino acid 
lysine (30, 31). 
In the haemostatic process, the balance between the coagulation and fibrinolytic systems maintains an 
intact vascular system. Once damage occurs to a vessel, coagulation occurs rapidly to form a tight net of 
fibrin at the site. Concurrently the fibrinolytic system removes fibrin deposits that could cause vascular 
occlusion permanently once repair of the vessels has occurred. As a potent antifibrinolytic agent, TXA acts 
by blocking the lysine-binding sites on plasminogen molecules, thereby displacing them from fibrin, 
effectively competitively inhibiting the activation of plasminogen. It has the potential to enhance the 
patient’s haemostatic mechanisms. Consequently, clot breakdown is inhibited and bleeding is reduced (1). 
1.3. 
STATEMENT OF THE PROBLEM 
As is the case in other developing countries, PPH is a major cause of mortality in Zimbabwe. PPH is the 
second most common cause of maternal death, contributing 14.4% of maternal deaths second to AIDS-
defining conditions based on a Zimbabwean cross-sectional study in 2007(6). 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 extremely high (4). This makes fulfilling the third Sustainable Development Goal 
(SDG3) a monumental task. Target 3.1 aims to decrease the worldwide MMR to less than 70 per 100,000 
by 2030 by ending preventable maternal mortality (2). 
In confidential enquiries into maternal deaths in South Africa from 2005 to 2007, 383 maternal deaths 
due to PPH were reported with the majority considered preventable. Of the deaths, 17.5 % (67) were due 

5 
 
to uterine atony, where uterotonics would have been effective to control the bleeding, 21 % due to 
uterine rupture, 23% due to retained placenta, 0.02% due to uterine inversion, and 37% due to genital 
trauma including Caesarean section (29). Uterine atony contributed to a small proportion of the deaths. 
Therefore, attempts to address the problem should go beyond the use of uterotonic drugs.  
 
1.4. 
RESEARCH QUESTION 
Does intravenous Tranexamic Acid (TXA) 10mg/kg plus Oxytocin 5IU result in a lower incidence of primary 
postpartum haemorrhage compared to Oxytocin alone after elective caesarean section? 
 
 
 

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CHAPTER 2. LITERATURE REVIEW 
2.1. LITERATURE SEARCH STRATEGY 
Interest in the research topic was triggered after a review of the article published in the British Journal of 
Anaesthesia ‘Tranexamic acid for the prevention and treatment of postpartum haemorrhage’ (1). 
Therefore, the initial literature search was directed at the trials quoted and references listed in the 
systematic review article. Subsequently, further articles were accessed after searching Google and 
PubMed in April 2017 initially, and in 2019 using the search words ‘Tranexamic acid’ and ‘Tranexamic acid 
for the prevention of PPH’.  Relevant articles on the use of tranexamic acid and its use in obstetrics were 
identified. 
 
2.2. LITERATURE REVIEW 
2.2.1. CAESAREAN BIRTH INCREASES PPH RISK 
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 according to Ononge 
et. al. (39). In a local unpublished study in 2017, virtually all of the peripartum hysterectomies were due to 
PPH, with the majority (67%) of the deliveries being by been by caesarean section (40). 
 
2.2.2. 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 asserts that this is a weak recommendation supported by moderate-quality evidence (3, 12). 
 

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2.2.3. EVIDENCE ON USE OF TRANEXAMIC ACID IN OTHER SURGICAL CONTEXTS 
Regardless of the type of surgery (cardiac, orthopaedic, hepatic, urological, and vascular), in a systematic 
review of RCTs including 20,781 participants, TXA was shown to reduce the risk of transfusion of blood by 
39% [RR 0.61 (95% CI 0.54–0.69)], and the number of units transfused by 1.1 units (95% CI 0.64–1.59). The 
review also showed a statistically insignificant trend towards benefit on the need for re-laparotomy due 
to haemorrhage [RR 0.67 (95% CI 0.41–1.09)] (1). 
A meta-analysis of 129 RCTs evaluating the impact of TXA in the prevention of bleeding at elective surgery 
of 10,488 participants showed a reduction of the need for a blood transfusion by 38% [RR 0.62(95%CI 
0.58–0.65)]; regardless of the type of surgery (1). 
The administration of TXA reduced mortality in bleeding trauma patients in high-, middle-, and low-
income countries in the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-
2) trial (1). 
Treatment with TXA has also been shown to reduce by 26 – 54% (a material reduction) bleeding in women 
with menorrhagia(1). This suggests that TXA can reduce bleeding from the uterus even in low amounts in 
a non-surgical scenario. The latter provides evidence to support the hypothesis that TXA is useful for the 
prevention of PPH after vaginal and caesarean births. 
2.2.4. CURRENT EVIDENCE ON THE USE OF TRANEXAMIC ACID IN PREVENTING PPH 
In a randomized controlled trial (RCT) by Sujata and colleagues in 2016 of TXA among 60 parturients at 
increased risk of PPH undergoing elective or emergency caesarean delivery at a tertiary centre in India 
from August 2012 to April 2013, intravenous TXA 10mg/kg administered 10 minutes before skin incision 
significantly reduced the requirement for additional uterotonics within 24 hours (the primary outcome). 
Additional uterotonics were required in 23% of the patients assigned to TXA compared to 83% of patients 
given placebo (P<0.001). The trial, however, was small with only 60 participants, and anaesthetists were 
not blinded even though the patients and obstetricians were blinded to the interventions (41). 

8 
 
A Cochrane database review by Sentilhes et. al. in 2015 found 10 RCTs evaluating the use of TXA in 
preventing PPH after caesarean birth. In all except one, caesareans were elective. The 10 RCTs all 
reported that women who received TXA had significantly less blood loss without any change in blood 
pressure, pulse and respiratory rate, or thrombosis. However, all the studies had several limitations that 
included being single-centre trials, not having a placebo in three, eight not clearly stating the primary 
outcome, and some quasi-randomized (1). 
The two most reliable studies in the review are summarized.  
1. The first large double-blind RCT was reported by Gungorduk and colleagues in Turkey. The trial 
had an intention-to-treat analysis that included 660 women. This study had the most robust 
methodology. The primary outcome, estimated blood loss (EBL), was calculated by comparing 
the difference in haematocrits prior to and 48 hours after caesarean section. The reduction in 
bleeding at ceasarean delivery attributed to TXA was significant [mean 499.9 (SD 206.4) ml vs 
600.7 (215.7), P=0.001]. It also reduced the percentage of patients with blood loss more than 
1000 ml [2.1% vs 5.8%; RR 2.7] (95% CI 1.1–6.3), P=0.03], and the requirement for supplementary 
uterotonics [8.5% vs 14.5%; RR 1.7 (95% CI 1.1–2.6), P=0.02]. The study enrolled 88% of eligible 
patients and had no patients lost to follow-up. The findings suggest TXA may be beneficial in 
decreasing blood loss after caesarean delivery and haemorrhage (1, 38). 
2. In Egypt, a large (740 participants), open RCT was conducted by Abdel-Aleem and associates. The 
decrease in the average blood loss in the experimental group was statistically significant [241.61 
(SE 6.77) ml], compared to the control group [510.66 (SE 7.72) ml; weighted mean difference 
(WMD) - 269.0 (95% CI 288.6 to -249.5)]. When assessed 24 hours after the caesarean section, 
haemoglobin [- 0.48 (SD 0.87) vs -1.42 (1.16) g/dl, P=0.001] and haematocrit [-1.82% (SD 2.93) vs 
-4.30% (3.64), P=0.001] values had decreased less significantly in the TXA group compared to the 
control group. Nevertheless, the trial was not blinded and did not use a placebo (1). 

9 
 
Sentilhes and colleagues recommended adequately powered large multicentre RCTs as the quality of the 
evidence from the trials in their systematic review was unclear. They recommended interpreting the 
results with caution before the widespread use of TXA to prevent and treat PPH is recommended (1). 
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 (42). Also, in the context 
of this research, the trial looked at vaginal births as opposed to caesarean birth. 
Currently ongoing is the TRAAP 2 trial which started on March 3, 2018, and is expected to be complete on 
June 30, 2020. The targeted sample size is 4,524, in a multicentre double-blind randomized placebo-
controlled trial. One gram of TXA or placebo is being administered slowly over 30 – 60 seconds 
intravenously to the woman 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 (43).  
In a prospective RCT in Nepal published in 2019, a developing country like Zimbabwe, the use of 1g of TXA 
administered intravenously 10 minutes before caesarean section, was associated with a significantly lower 
blood loss intra- and post-operatively when compared to placebo (392.13 ml±10.06 vs 498.69 ml±15.87, 
respectively; p<0.001). However, the sample size of 160 was small, and the trial was not adequately 

10 
 
powered to reach conclusions on the incidence of thromboembolic complications, use of additional 
oxytocics, and the need for blood transfusion (44). 
The use of an intravenous dose of 15mg/kg 10 minutes before caesarean TXA combined with 100 µg of 
carbetocin intravenously after cutting the cord, and technical support (argon plasma coagulation) was 
noted to be effective in reducing haemorrhage around the time of surgery, duration of surgery, and 
postoperative stay in hospital in patients having repeat caesarean deliveries in a prospective cohort study 
in Ukraine that comprised 71 participants (45). This study, however, looked at the use of three different 
interventions, 2 medical, and one newer intervention in caesarean sections, argon plasma coagulation 
which is a non-contact thermal method of haemostasis currently being studied in Russia. The technology 
is known to produce prompt haemostasis, to decrease blood loss and pain as well as hospital stay, effects 
which may be difficult to attribute to TXA solely in this study (46).  
Uterine atony is the most common cause of PPH (13).  Uterotonics already address this as they have an 
effect on the myometrium. Their contractile effects close off the large spiral arteries pouring with blood 
from the placental bed. 40 – 70% of women with marked clotting disorders will not have PPH as the main 
mechanism for achieving haemostasis after childbirth is myometrial contraction compressing the uterine 
vessels rather than clotting. Clotting is the primary mechanism that would be useful where women have 
the deadly form of ongoing or delayed PPH. In this subgroup of women, bleeding is from spontaneous or 
iatrogenic lacerations to the genital tract, or trauma and they tend to bleed vaginally or into the abdomen. 
With its antifibrinolytic activity, TXA potentiates clotting thereby preventing PPH in this subset. This is the 
group of women who tend to collapse 1 – 3 hours after delivery from the deadly ooze. This subgroup of 
women is the group in which TXA was found to have the maximum effect in the WOMAN Trial (13). It 
follows, therefore, that women with iatrogenic trauma at caesarean section are also likely to benefit from 
this intervention. 

11 
 
2.3. 
JUSTIFICATION 
 
TXA is already widely used in surgery to prevent clot breakdown to reduce blood loss. However, at present, 
there is little reliable evidence from randomized trials of the effectiveness of TXA in preventing PPH at 
caesarean section. 
Bleeding during and after caesarean section contributed the majority of deaths (34.9% i.e. 218 of 624 
deaths) due to obstetric haemorrhage in South Africa in the period 2014 – 2016, and has been quoted as 
a national emergency (47, 48). Therefore, TXA as an additional measure to reduce blood loss at caesarean 
delivery should be considered (48).   
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 (24).  Its actions would therefore potentiate the effect of uterotonics already in use in reducing 
blood loss at caesarean section. 
TXA is cheap, readily available, easily administered, easily stored (does not require refrigeration), and 
would be easy to add to routine protocols (29). See A in Error! Reference source not found.. It would 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 preventing PPH may contribute to the reduction of 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 

12 
 
patients would not afford it as only 30% of Zimbabweans are in formal employment and the majority 
(72.3%) are below the poverty datum line (49). A unit of packed cells that costs $120 ($335 in private 
hospitals), platelets $90 ($251), and fresh frozen plasma $90 ($251) means more resources can be 
diverted to other health service expenditures. Refer to B in Error! Reference source not found.. 
PPH contributes to near-miss cases due to the serious illness that can occur as a consequence that includes 
adult respiratory distress syndrome, coagulopathy, shock, loss of fertility, and pituitary necrosis (Sheehan 
syndrome) (14, 27). 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.  
In the light of the above, this research attempts to assess the efficacy of TXA in preventing PPH after 
caesarean delivery in a large enough population to be adequately powered to add to the current body of 
evidence, in Southern Africa where no regional studies have been done to assess TXA in obstetric patients.  
 
2.4. 
RESEARCH OBJECTIVES 
1. To determine the effect of TXA (10mg/kg) given intravenously 10 minutes prior to an elective 
caesarean section on postpartum blood loss. 
2. To determine the potential adverse effects of intravenous TXA given 10 minutes prior to elective 
caesarean section.   
 
 
 

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CHAPTER 3. RESEARCH METHODS 
1.1. 
RESEARCH DESIGN 
Open-label parallel randomized control trial in which women included in the trial were assigned either 
TXA or no TXA. No changes were made to the trial design after commencement. 
1.2. 
PARTICIPANTS 
The participants were women undergoing elective caesarean sections at Harare and Parirenyatwa 
Hospitals. 
Inclusion criteria 
 
Pregnant woman with signed informed consent*** 
 
Understand English and/or Shona 
 
Estimated gestational age of 38 weeks or more 
 
Requiring Elective Caesarean Section defined as caesarean section performed before onset of 
labour 
 
Live intrauterine foetus 
***The study enrolled participants who met the inclusion criteria including minors. Consent was 
sought from legally authorized representatives such as the parent or guardian where possible. Where 
this was not possible the pregnant participants who were under the age of 18 were considered 
emancipated minors by them having assumed adult responsibilities (becoming a mother) before 18 
years of age (50). 
Exclusion criteria 
Women with the following characteristics were excluded from the study: 
 
Placental Abruption 

14 
 
 
Emergency caesarean section 
 
Current or previous history of significant disease including heart disease, liver, renal disorders 
 
Known coagulopathy or history of deep venous thrombosis and/or pulmonary embolism, or 
arterial thrombosis (angina pectoris, myocardial infarction, stroke) 
 
History of epilepsy or seizures 
 
Autoimmune disease 
 
Sickle cell disease 
 
Intrauterine foetal demise 
 
Eclampsia/HELLP syndrome 
 
Administration of anticoagulants – clexane or antiplatelet agents in the week before delivery 
 
1.3. 
STUDY SETTING 
The trial was conducted at two tertiary institutions that are affiliated to the University of Zimbabwe. These 
serve as referral centres for 12 local authority clinics located in Harare as well as district and provincial 
hospitals in the surrounding provinces: Harare Central Hospital i.e. Harare Maternity Hospital (HMH) and 
Parirenyatwa Group of Hospitals i.e. Mbuya Nehanda Maternity Hospital (MNMH). Most of the patients 
understood at least one of either English or Shona languages. 
Located in the Southerton suburb, HMH is the referral centre for pregnant women mainly from the 
southern and western suburbs of Harare. The unit has an Antenatal Ward (ANW), Labour Ward (LW), Early 
Labour Ward (ELW), Post Natal Ward A (PNA) for patients after vaginal delivery and Post Natal Ward B 
(PNB) for patients post caesarean delivery. Babies with complications are admitted in the Neonatal Unit 
(NNU). 

15 
 
The northern and eastern suburbs are served by MNMH which is located in Avondale suburb. The unit has 
an ANW, a LW, Post Caesarean Section Ward (PCW) and a Postnatal Ward (PNW). Ill babies are admitted 
in the Neonatal Intensive Care Unit (NICU). 
There are five teams with 3 to 4 consultants each at MNMH and 5 teams at HMH each with 2 to 4 
consultants. MNMH delivers a total of 535 pregnancies per month while HMH delivers 1,335. On average 
60 elective and 250 emergency caesarean sections are done at HMH per month, while 80 elective and 210 
caesarean deliveries on average are done at MNMH. Refer to C in Error! Reference source not found.. 
Elective caesarean sections are performed by Senior House Officers and Registrars (including the principal 
investigator) mainly, with some cases performed by Senior Resident Medical Officers (in their second year 
of internship) or Consultants (usually in cases that have complications or serious concurrent 
medical/obstetric indications). 
 
 
 
 
 
 
 
 

16 
 
1.4. 
SAMPLE SIZE 
The sample size was calculated assuming a proportion of 2.1% PPH in the experimental group and 5.8% in 
the control group (38) at 95% confidence interval and 90% power using the Fleiss formula giving a minimum 
sample size of 
                         𝑛=
[Z஑/ଶඥ(r + 1)pതqത+ Zஒඥrpଵqଵ+ pଶqଶ]ଶ
r(pଵ−pଶ)ଶ
= ൣ1.96ඥ(1 + 1) × 0.0395 × 0.9605 + 1.28√0.021 × 0.979 + 0.058 × 0.942൧
ଶ
(0.021 −0.058)ଶ
 
                                    = 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 
 
 
 
 

17 
 
1.5. 
RECRUITMENT AND ALLOCATION 
Women who satisfied the inclusion criteria were provided with information about the trial in a language 
they understood by the researcher or research assistants. 
Informed consent was signed on the day before elective caesarean section. 
They were randomized to either the group that received TXA or the group which did not receive TXA. 
There was no blinding of staff or the patient. 
1.6. 
RANDOMIZATION 
A randomized allocation to study and control groups using computer-generated random numbers was 
done by the trial statistician. 
Equal numbers were randomly allocated to the two groups for the two hospitals.  
Based on the sample size the plan was for the statistician to prepare random numbers for 1,162 patients. 
Half of these numbers were labelled with A which represented the intervention 10mg/kg TXA and oxytocin 
5IU e.g. random number 4A, represented random number 4, allocated to group A. The other half had the 
extension B (control group) to receive Oxytocin 5IU only.  
The computer-generated numbers assigned the trial group and also a unique participant number. The 
numbered folded slips of paper were placed into sealed identical envelopes by the principal investigator. 
The sealed envelopes were kept in a box at each hospital in a locked-up room. At the beginning of the 
trial, TXA for 200 patients was available. The statistician therefore initially prepared random numbers for 
400 patients (200 with the extension A and 200 with the extension B), half of which were prepared for 
HMH (1 – 200) and the other half for MNMH (1 – 200). A further 106 were prepared when the 400 numbers 
were used up to make the total number recruited 506 during the initial trial period. 
The patients were enrolled by the principal investigator or the research assistants on the day before their 
scheduled caesarean section. Once they met the study criteria per the screening tool (see Error! 

18 
 
Reference source not found.), informed consent was obtained (Error! Reference source not found. &  
Error! Reference source not found.). The participant was asked to pick an envelope from the box. The 
envelope would then be opened by either the participant or the researcher.  
The study number would then be entered on the data collection tool as the study serial number. A unique 
study sticker labelled ‘Group A’/ ‘TXA’ or ‘Control’ would be attached to the patient’s notes. The data tool 
would then be inserted into the notes together with a prescription form if in group A for the attention of 
the theatre staff and anaesthetists. (Refer to Error! Reference source not found.). Only the data tool was 
attached to the control group patient’s notes. (Error! Reference source not found.). A list matching the 
serial number to the allocated group was compiled to match the original randomization. 
 
1.7. 
BLINDING 
There was no blinding after the sealed envelopes had been opened. After randomization, the participants 
and trial staff were aware of the trial group to which the patient had been allocated.  
A completely blinded trial would have required fully dedicated staff. Such a trial would have put pressure 
on already busy anaesthetists. However, there was an agreement from the departments that the TXA 
would be given according to the study protocol. 
 
1.8. 
INTERVENTION 
The participants in the intervention arm received TXA (10mg/kg) administered slowly over 5 minutes 
intravenously (iv) 10 minutes prior to skin incision and prophylactic oxytocin (5 IU iv) slow administration 
by the anaesthetists on delivery of the baby.  Participants in the control group received prophylactic 
oxytocin (5 IU iv) only on delivery of the baby. 5IU of Oxytocin were administered slowly intravenously as 
recommended by the WHO in 2012 (12).  Updated recommendations were then published by WHO in 2018 

19 
 
after ethical approvals had been obtained and came to the attention of the principal investigator after the 
initial planned period of data collection (1 January 2018 to 31 December 2018) recommending the use of 
10IU of oxytocin in the third stage. No change was made to the protocol during the data collection period 
(3).   All patients continued to receive 5IU of prophylactic oxytocin. 
TXA (10mg/kg) solution for injection from the vial was diluted with 100 – 200ml electrolyte solution such 
as Normal Saline, Ringers Lactate solution, dextrose/water for injection on the same day it was to be used 
by the anaesthetist at the dose prescribed.  Intravenous administration at a rate of 100mg or fraction 
thereof over at least 1 minute – usually at least 5 minutes for each patient was done. The administration 
was to be done at least 10 minutes before skin incision (32, 33, 37, 38). 
No additional prophylactic uterotonics were to be administered to the patient based on the anaesthetist’s 
or surgeon’s subjective preferences. Several local surgeons routinely add misoprostol for select cases at 
caesarean section. A recent local unpublished study conducted in 2017 concluded that adding misoprostol 
to the routine prophylactic oxytocin did not reduce the occurrence of PPH in patients undergoing low risk 
elective caesarean section (51). Therefore, additional uterotonics were to be administered only if clinically 
indicated. 
 
1.9. 
PHARMACY PLAN 
Intravenous oxytocin 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 5IU 
oxytocin intravenously, administered slowly by the anaesthetist after delivery of the baby at HMH and 
MNMH. The cold chain is maintained up to the administration of the drug to the patient. 
TXA obtained for the study was purchased from Sky Pharmaceuticals (Tranexamic acid 0.1g/ml injection 
from Pfizer Laboratories, registration number: 75/10.4/574)) was kept in theatre. This was done to ensure 

20 
 
an uninterrupted supply of the drug for the trial. The TXA vials were kept in a lockable drug cupboard 
accessible to the sister-in-charge only, who would only dispense them to the anaesthetist on presentation 
of a study prescription form. A dispensing register for the TXA was kept in the same cupboard. Patient 
details and study number, amount of TXA dispensed and wasted were entered into the study register for 
accountability and to guard against abuse. Please refer to the detailed Pharmacy Plan in Error! Reference 
source not found.. 
 
1.10. ASSESSMENT 
Data were collected and recorded on the data collection tool. Any adverse event was to be reported on 
the MCAZ/MRCZ adverse event reporting form. 
Vital signs (heart rate, blood pressure, respiratory rate) were recorded before surgery, immediately after 
placental delivery, and 1 to 2 hours after birth. 
Full blood count (FBC), urea & electrolytes (U&E) and liver function tests (LFTs) were performed a day 
before delivery and on the second day after delivery. 
Estimated blood loss (EBL) was determined using the difference in haematocrit values taken before and 
48 hours after caesarean delivery according to the formula: 
 
= EBV × (Preoperative haematocrit – Postoperative haematocrit) 
Preoperative haematocrit 
Where EBV (estimated blood volume) in ml is equal to the woman’s weight in kg × 85 (38). 
 

21 
 
As haematocrit values were not consistently available, EBL was also determined using the haemoglobin 
(Hb) value using the Meunier’s formula BV × [(Hbi – Hbe)/(Hbe)], where BV is blood volume, Hbi is initial 
Hb, and Hbe is end Hb (52). 
Standard EBL based on visual estimates made by anaesthetist after assessment of patient’s linen and 
abdominal swabs was also recorded. 
The calculated method and visual estimation of blood loss were used in this study. Although visual 
estimation is the method used frequently by anaesthetists to estimate blood loss, it has been 
demonstrated as inaccurate in repeated studies. Its continued use in clinical practice is related to tradition 
and ease of use. This method was compared with the calculated method by Stafford et. al. who noted that 
these calculations could be inaccurate based on the hydration status of women, particularly related to 
intravenous loading conducted during regional anaesthesia (>90% had an epidural), or with pregnancy-
induced hypertension. They also acknowledged that maternal physiologic changes may alter the 
haematocrit changes. Plasma volume increases by on average 1.25 litres in all pregnant women, and all 
will undergo fluid changes post-delivery (23, 53, 54). In addition, all of the participants received intravenous 
fluids as they are surgical patients. Therefore, any effects on the haematocrit of the physiological changes 
or IV fluids happened in all the participants as the plasma volume changes were universal to all pregnant 
women. Secondly, we intended to do a subgroup analysis of women who had pregnancy-induced-
hypertension. Women with Eclampsia/HELLP syndrome were excluded from the study. As visual 
estimation is the method traditionally used at both hospitals, we used this together with the more 
objective calculated method for comparison to determine blood loss.  
Refer to Error! Reference source not found. for the patient flow in the study. 
 

22 
 
1.11. STATISTICAL METHODS 
Data analysis was conducted using Stata v15 (Stata Statistical Software: Release 15. College Station, TX: 
StataCorp LLC) following the CONSORT guidelines for reporting RCTs (55). 
The primary analysis compared women given a low dose of TXA (10mg/kg) administered 10 minutes 
before elective caesarean section with prophylactic oxytocin administration to those given prophylactic 
oxytocin alone.  
Baseline characteristics were compared between the groups to check the adequacy of randomization. 
Differences between patients lost to follow-up and included patients were also assessed. The intention-
to-treat analysis was followed. This is a statistical concept whereby every participant in the study is 
accounted for in the analysis according to the randomization treatment assignment regardless of whether 
there is noncompliance, protocol deviations, withdrawal from the study, and anything happens after 
randomization (56). 
 Categorical data were reported using frequencies and proportions while continuous data were 
summarized using means and standard deviations for normally distributed data, and medians and quartile 
range where data was not normally distributed. Comparisons for categorical data were done using the 
chi-square test or Fisher’s exact test when the sample size was small.  
For continuous data, the t-test was used to compare differences between the groups and the analysis of 
variance (ANOVA) was used for comparing more than two groups. Where data were not normally 
distributed, the nonparametric Kruskal Wallis test was used to compare differences in continuous 
outcome for more than two groups. The Mann-Whitney U test was used to compare two groups where 
data were not normally distributed. Effect estimates were presented with relative risk measures and 
associated 95% confidence intervals. Any subgroup analysis was conducted as the primary analysis. 

23 
 
An analysis was conducted after 506 participants had been recruited to check if there are any significant 
differences in adverse events in the two groups. 
 
1.12. DATA MANAGEMENT 
The researcher and assistants allocated the patient a study serial number. No identifiers were used. 
 
1.13. DATA CLEANING AND ENTRY 
Completed questionnaires were checked for validity, accuracy and completeness by the principal 
investigator before data entry into the computer by the research assistant  
  
1.14. OUTCOMES  
1.14.1. Primary Outcome  
1. Incidence of PPH defined by blood loss equal to or exceeding 1,000 ml following elective 
caesarean section 
 
Based on calculated estimates. 
1.14.2. Secondary Outcomes 
1. Incidence of PPH defined by blood loss equal to or exceeding 1000 ml following elective caesarean 
section  
 
Based on visual estimation 
2. Estimated blood loss during caesarean section 
 
Based on visual estimate of blood loss and calculated estimates 
3. Need for blood transfusion 
 
Mean or median number of units of red blood cells transfused up to day 2 postpartum 
4. Use of additional uterotonics (such as oxytocin infusion or prostaglandins) 

24 
 
 
Number of participants who required additional uterotonics 
5. Incidence of emergency surgical interventions for PPH up to day 2 post-surgery 
6. Mean change in HCT up to day 2 post-surgery 
 
Difference between the HCT on the day before surgery and day 2 post-surgery  
7. Mean peripartum change in haemoglobin up to day 2 post-surgery 
 
Difference between the haemoglobin on the day before surgery and at day 2 post-delivery 
8. Duration of mother’s hospital stay 
9. TXA side effects 
 
number of participants with headache, anaphylaxis, nausea, diarrhoea, dizziness, fatigue, 
nasal sinus complaints, transient visual disturbances, abdominal pain, complaints of 
feeling faint, reported by anaesthetists and theatre staff [time frame: up to discharge 
from the recovery ward on day of surgery] 
 
number of participants with deep venous thrombosis, pulmonary embolism, myocardial 
infarction, or any thrombotic event confirmed by laboratory investigations up to day 2 
post-surgery 
 
number of participants with seizures up to day 2 post-surgery 
 
number of participants with renal failure (defined by the need for dialysis) up to day 2 
post-surgery 
 
number of participants with hypotension reported by anaesthetists and theatre staff 
[time frame: up to discharge from the recovery ward on day of surgery] 
 
Vital signs before surgery 
 Heart rate before surgery 
 Systolic BP before surgery 
 Diastolic BP before surgery 

25 
 
 
Vital signs after placental delivery 
 Heart rate after delivery of the placenta 
 Systolic BP after delivery of the placenta 
 Diastolic BP after delivery of the placenta 
 
Post-caesarean delivery creatinine (mg/dL) 
 
Postoperative urea g/L 
 
Postoperative aspartate transaminase (IU/L) 
 
Postoperative alanine transaminase (IU/L) 
 
Postoperative total bilirubin (IU/L) 
10. Neonatal outcomes 
 
Birth weight in grams determined on the date of delivery 
 
Apgar scores at 1 and 5 minutes on the date of delivery 
 
Reason for admission to NNU/NICU [time frame: up to discharge from NNU/NICU] 
 
Number of neonates with neonatal jaundice determined clinically [time frame: up to 
discharge from NNU/NICU] 
 
Number of neonates with thromboembolic events determined clinically [time frame: up 
to discharge from NNU/NICU] 
 
Number of neonates who died [time frame: up to the day of discharge of the mother] 
 
 
 

26 
 
3.15. DATA REPORTING 
The study is reported according to the Consolidated Standards of Reporting Trials (CONSORT) which 
ensures that RCTs are reported in a standardized manner internationally and that all study participants 
are accounted for clearly and transparently (55). 
 
3.16. INDEPENDENT DATA AND SAFETY MONITORING BOARD  
An Independent Data and Safety Monitoring Board (DSMB) was established for the study comprising of 3 
individuals: Professor S. Rusakaniko (Statistician), Dr M. Madziyire (Obstetrician & Gynaecologist), and Dr 
T. Marere (Obstetrician & Gynaecologist). 
The DSMB was established to assess at intervals the progress of the clinical trial, the safety data, and the 
critical efficacy endpoints, and to recommend to the sponsors and researchers whether to continue, 
modify, or stop the trial. The DSMB reviewed the analysis prepared for this report. 
  
3.17. STOPPING RULES / DISCONTINUATION CRITERIA 
If at any stage during the trial the principal investigator, co-investigators (supervisors), DSMB, or ethical 
authorities were satisfied that having due regard to the initial risks, discomforts or other adverse effects 
caused to persons taking part in the trial, it was in the public interest to stop or suspend the trial, the trial 
would be stopped or suspended immediately. The DSMB or ethical authorities would notify the 
investigator in writing accordingly. Ethical authorities, as well as the hospital authorities, would be notified 
accordingly by the investigator. 
 
 
 

27 
 
3.18. ETHICAL CONSIDERATIONS 
Approval to conduct the study and to use the hospital records of patients was sought and obtained from 
the following: 
Table 1 Ethical approvals 
Ethical Body
Approval Number
Harare Hospital Research and Ethics Committee
HCHEC 300817/61
Joint Research and Ethics Committee (JREC) at 
Parirenyatwa Group of Hospitals 
JREC/239/17
Medical Research Council of Zimbabwe (MRCZ)
MRCZ/B/1386
Medicines Control Authority of Zimbabwe (MCAZ)
B/279/5/35/2018
 
Refer to Error! Reference source not found.. 
Participants were requested to provide written informed consent. Refer to Error! Reference source not 
found. and Error! Reference source not found.. Participants were given full disclosure of the nature of 
the study, the risks, benefits and alternatives. They were given an opportunity to ask questions. No 
participant was coerced into participation. Participants were assured that no punitive implication or denial 
of service would be encountered if they did not agree to enter the trial and were permitted at any time 
to withdraw their participation. Women in the study were not given any material benefits. 
The researcher liaised with the team managing the patient to continue the usual care even when the 
patient was not willing to enter or withdrew their participation. The patient was free to communicate 
with the researcher if they felt they did not get due treatment. The study used only coded numbers with 
no personal identifiers to ensure confidentiality. 

28 
 
 
3.19. TRIAL REGISTRATION 
The trial was registered on clinicaltrials.gov NCT03463993. 
 
3.20. PROTOCOL 
The full trial protocol can be accessed at: 
The Department of Obstetrics and Gynaecology, University of Zimbabwe College of Health Sciences,  
P.O. Box A178, Avondale, Harare, Zimbabwe 
 
 
 
 
 
 
 

29 
 
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