Carbetocin versus oxytocin with or without tranexamic acid for preventing postpartum hemorrhage in cesarean delivery: a randomized controlled trial

Abstract

Background

Postpartum hemorrhage (PPH) is a significant contributor to maternal morbidity, particularly following cesarean deliveries. Uterotonics, including oxytocin and carbetocin, are commonly used to prevent PPH. However, the comparative effectiveness of these agents when used in conjunction with tranexamic acid remains uncertain.

Aims

This study aims to evaluate the efficacy of carbetocin, oxytocin, and their combinations with tranexamic acid in mitigating intraoperative blood loss during cesarean deliveries.

Methods

In this randomized, double-blind, two-factorial trial, 200 women scheduled for cesarean sections were allocated into four groups (n = 50 each): carbetocin (100 µg), carbetocin combined with tranexamic acid, oxytocin (5 IU), and oxytocin combined with tranexamic acid. The interventions were administered intravenously immediately after delivery. The primary outcome was estimated intraoperative blood loss in the first 24 h, assessed through suction volume and gauze counts. Secondary outcomes included hematological parameters (hemoglobin, hematocrit) and hemodynamic changes (blood pressure, heart rate).

Results

The carbetocin group demonstrated significantly lower blood loss (629.0 ± 139.62 mL) compared to the oxytocin plus tranexamic acid group (712.7 ± 131.32 mL; p = 0.017). Post-hoc analysis revealed no significant difference in blood loss between the carbetocin and oxytocin-alone groups. Carbetocin also resulted in the smallest decreases in hematocrit (-2.01%) and hemoglobin (-0.99 g/dL), along with minimal changes in blood pressure (+ 1.60 mmHg systolic, + 3.42 mmHg diastolic). In contrast, the oxytocin groups exhibited greater hemodynamic fluctuations, characterized by significant reductions in blood pressure and increases in heart rate (p < 0.001). Significant differences in hematocrit, white blood cell count, and blood pressure changes were observed between the groups (p < 0.05). No significant differences in adverse effects were identified among the groups.

Conclusion

In this trial, carbetocin was associated with less blood loss than oxytocin combined with tranexamic acid and demonstrated a more favorable hemodynamic profile compared to oxytocin-based regimens. These findings suggest it may be considered a preferred uterotonic agent for the prevention of PPH in cesarean deliveries, though the role of tranexamic acid requires further clarification.

Introduction

Postpartum hemorrhage (PPH) is a leading cause of maternal mortality, responsible for 25–30% of maternal deaths globally, especially in low-resource settings [1]. Defined as blood loss > 500 mL after vaginal or > 1000 mL after cesarean delivery, primary PPH occurs within 24 h of birth, largely due to uterine atony (70–80% of cases) [2, 3].

The incidence of cesarean deliveries has risen globally due to factors such as increased maternal age, obesity, and various medical indications. This rise is associated with a higher risk of PPH compared to vaginal deliveries, underscoring the need for effective prophylactic interventions [4, 5]. Uterotonic agents, including oxytocin and carbetocin, play a crucial role in preventing PPH by promoting uterine contractions and reducing blood loss. However, their comparative efficacy, safety profiles, and optimal use in conjunction with other agents like tranexamic acid remain subjects of ongoing research [6].

Oxytocin, a synthetic nonapeptide, has long been the standard uterotonic for PPH prevention due to its rapid onset of action and wide availability [7]. It can be administered intravenously or intramuscularly to stimulate uterine smooth muscle contractions, thereby reducing postpartum bleeding. However, oxytocin’s short half-life (approximately 4–10 min) often necessitates continuous infusion or repeated dosing, complicating administration and increasing the risk of side effects such as hypotension and tachycardia [8]. These hemodynamic effects are particularly concerning during cesarean deliveries performed under regional anesthesia, where maintaining cardiovascular stability is critical [9]. Additionally, oxytocin’s efficacy may be diminished in high-risk populations, including women with obesity, multiple gestations, or prolonged labor, prompting the exploration of alternative agents [10].

Recently, carbetocin, a long-acting synthetic analogue of oxytocin, has emerged as a promising alternative for preventing PPH. With a half-life of approximately 40 min, carbetocin provides sustained uterine contractions, reducing the need for additional uterotonics or repeat dosing [11]. Its stability at room temperature makes it particularly suitable for low-resource settings where cold-chain storage for oxytocin may be unreliable [1]. Several studies have demonstrated that carbetocin is superior to oxytocin in reducing blood loss and the necessity for additional interventions during cesarean deliveries. For instance, Voon et al., conducted a meta-analysis of randomized controlled trials that revealed carbetocin significantly decreased intraoperative blood loss and the incidence of PPH compared to oxytocin [12]. Similarly, Abdelmegeed et al., reported reduced blood loss with carbetocin in women undergoing cesarean sections, attributing this advantage to its prolonged pharmacodynamic effect [13].

Carbetocin’s favorable hemodynamic profile further enhances its attractiveness as a uterotonic agent. In contrast to oxytocin, which can induce transient hypotension and reflex tachycardia, carbetocin is associated with minimal cardiovascular disturbances, making it a safer choice for patients with preexisting conditions such as hypertension or valvular heart disease [14, 15]. Bekkenes et al., emphasized that carbetocin has a reduced impact on cardiac output compared to oxytocin, suggesting its potential advantages in high-risk cesarean deliveries [16]. However, the higher cost and limited availability of carbetocin in certain regions present significant barriers to its widespread adoption, underscoring the need for further research to validate its use over oxytocin [17].

Tranexamic acid, an antifibrinolytic agent, has garnered attention as an adjunct to uterotonics for the prevention of PPH. By inhibiting fibrinolysis, tranexamic acid stabilizes blood clots, thus reducing bleeding in surgical and obstetric contexts [3]. The World Health Organization recommends its use for the treatment of PPH; however, its prophylactic role in conjunction with uterotonics remains less clearly established [1]. A randomized trial compared the effects of carbetocin and oxytocin, both with and without tranexamic acid, during vaginal deliveries [18]. However, evidence regarding its effectiveness in cesarean deliveries is mixed, with some studies suggesting no additional benefit when tranexamic acid is combined with uterotonics [6]. Although rare, the potential for tranexamic acid to induce thromboembolism necessitates careful consideration of its prophylactic use [3].

Thus, incorporating tranexamic acid into uterotonic regimens represents a potentially valuable approach; however, its efficacy and safety in cesarean deliveries require further validation, particularly in direct comparison with different uterotonics [6]. This study aims to address these gaps by conducting a randomized, double-blind, factorial clinical trial comparing oxytocin, carbetocin, and their combinations with tranexamic acid in women undergoing cesarean delivery. The objectives include evaluating their efficacy in reducing intraoperative blood loss and assessing hematological parameters (e.g., hemoglobin, hematocrit) as well as hemodynamic stability (e.g., blood pressure, heart rate).

Methods

Trial design

This study was a randomized, double-blind, two-factorial clinical trial with a parallel-group design, conducted at Beheshti Hospital and Shabihkhani Maternity Center in Kashan, Iran. The trial utilized permuted block randomization with a 1:1:1:1 allocation ratio across four intervention groups. There were no modifications to the trial design after its initiation.

Participants

Eligible participants included women aged 18 years or older who were married, undergoing cesarean delivery, and willing to provide written informed consent. Exclusion criteria encompassed contraindications to the study medications (oxytocin, carbetocin, or tranexamic acid), known bleeding disorders, hypertension, recent use of nonsteroidal anti-inflammatory drugs, a history of severe anemia, allergies, recent blood transfusions, intraoperative adhesions, organ injuries during surgery (such as bladder or bowel), abnormal placental attachment, uterine incision extensions, preeclampsia, or high-risk pregnancies (including multiple gestation, polyhydramnios, grand multiparity [≥ 5], or macrosomia).

Participants were recruited from women presenting for delivery at the study sites. Following a comprehensive medical history and physical examination, baseline assessments were conducted, including vital signs, complete blood count (CBC), blood group, Rh factor, and blood pressure. A researcher-developed demographic questionnaire was used to collect data on age, parity, and other relevant variables. The clinical indications for cesarean delivery (e.g., previous cesarean, fetal malposition, maternal request, fetal distress) were also recorded.

Interventions

Participants were randomly assigned to one of four intervention groups:

• Group A: Carbetocin (100 µg, diluted in 10 mL of 0.9% normal saline) + placebo (10 mL of 0.9% normal saline).

• Group B: Carbetocin (100 µg, diluted in 10 mL of 0.9% normal saline) + tranexamic acid (500 mg, diluted in 10 mL of 0.9% normal saline).

• Group C: Oxytocin (30 IU, diluted in 10 mL of 0.9% normal saline) + placebo (10 mL of 0.9% normal saline).

• Group D: Oxytocin (30 IU, diluted in 10 mL of 0.9% normal saline) + tranexamic acid (500 mg, diluted in 10 mL of 0.9% normal saline).

The interventions were administered intravenously over a period of two minutes by an anesthesia technician immediately following the delivery of the neonate. Identical syringes were prepared by a study coordinator who was not involved in patient care or outcome assessment. All participants received spinal anesthesia using standardized anesthetic agents. The surgical team -including obstetricians, midwives, nurses, and residents- remained consistent across all groups to minimize potential skill-related biases.

Outcomes

The primary outcome was intraoperative blood loss, which was estimated by summing the volume of suctioned blood and the blood absorbed by fully soaked gauzes (each gauze estimated to absorb approximately 40 mL). Secondary outcomes included postoperative vital signs (systolic and diastolic blood pressure and heart rate), postoperative CBC assessed six hours post-surgery, and adverse events such as fever (> 38 °C), chills, sweating, nausea, vomiting, headache, dizziness, and the need for uterine massage. Adverse events were managed with paracetamol for fever and headache, promethazine (25 mg) for nausea and vomiting, or pethidine (25 mg) for severe abdominal pain. Outcomes were recorded by a blinded resident using a standardized checklist.

Sample size

The sample size for this study was determined based on a previous investigation conducted by Shalaby et al., [18] which reported the mean blood loss associated with the administration of tranexamic acid combined with oxytocin compared to oxytocin alone. Using a confidence level of 90% (Z₁₋α/2 = 1.645) and a power of 90% (Z₁₋β = 1.282), the sample size formula utilized was:

This calculation indicated a minimum requirement of 45 participants per group. To accommodate potential participant attrition and ensure adequate resources, the sample size was increased to 60 participants per group, resulting in a total of 240 participants. Ultimately, 200 participants were recruited and randomized, which exceeded the calculated minimum requirement.

Randomization and allocation concealment

Permuted block randomization with block sizes of four was employed for sequence generation, facilitated by the Clinical Trial Randomization Tool software. A randomization table assigned participants to one of four groups (A, B, C, or D) based on their entry number. Allocation concealment was maintained through the use of sequentially numbered, opaque, sealed envelopes prepared by an independent statistician. The randomization sequence remained inaccessible to the investigators involved in participant enrollment.

Blinding

This trial employed a double-blind design. Participants, anesthesia technicians administering the interventions, residents assessing outcomes, and data analysts were all unaware of group assignments. The syringes containing the uterotonic agents and either tranexamic acid or placebo were identical in appearance and volume, and were prepared by a study coordinator who was not involved in any other trial activities.

Statistical analysis

Baseline characteristics were summarized using descriptive statistics, including frequencies, percentages, means, and standard deviations. The primary outcome, blood loss, was compared among groups using one-way analysis of variance (ANOVA). For significant ANOVA results, post-hoc comparisons were conducted using Tukey’s Honest Significant Difference (HSD) test. Secondary outcomes, including vital signs, complete blood count (CBC), and adverse events, were analyzed using either ANOVA or chi-square tests as appropriate. A two-sided p-value of less than 0.05 was deemed statistically significant. All analyses were performed using SPSS version 18. An intention-to-treat analysis was conducted, incorporating all randomized participants in their assigned groups regardless of adherence to the protocol. No interim analyses were planned or executed.

Ethical considerations

The study procedures complied with the Declaration of Helsinki and institutional guidelines. The study received approval from the Institutional Review Board of Kashan University of Medical Sciences (IR.KAUMS.MEDNT.REC.1402.285) and was registered in Iranian Registry of Clinical Trials (IRCT) with IRCT20240529061944N1, Registration date: 2024-06-14. Written informed consent was obtained from all participants after a thorough explanation of the study procedures, potential risks, and benefits. Participants were informed that they could withdraw from the study at any time without any impact on their care. To ensure data confidentiality, numerical codes were assigned to questionnaires and checklists. The principal investigator was responsible for managing any adverse events that arose during the study. Findings from the research were disseminated to the Research Center and published following peer review.

Results

Participant flow

Between April 2024-October 2025, a total of 200 pregnant women scheduled for cesarean sections at Beheshti Hospital and Shabihkhani Maternity Center in Kashan, Iran, were enrolled in the study. Participants were randomized equally into four intervention groups: Carbetocin, Carbetocin + Tranexamic Acid, Oxytocin, and Oxytocin + Tranexamic Acid, with 50 individuals assigned to each group. No participants were lost to follow-up, and all 200 were included in the intention-to-treat analysis. A flow diagram (Fig. 1) provides a visual representation of participant recruitment, randomization, and analysis.

Fig. 1.

CONSORT chart illustrating the selection, evaluation, and follow-up process of participants

Baseline characteristics

The baseline demographic, clinical, and hemodynamic characteristics of the participants were comparable across all groups, with no statistically significant differences observed (Tables 1 and 2). The mean age of participants ranged from 29.22 to 30.78 years (p = 0.594), while the gravida count ranged from 2.28 to 2.48 (p = 0.794). The distribution of primary indications for cesarean delivery (e.g., previous cesarean, fetal malposition, maternal request, fetal distress) was similar across groups (p > 0.05). Baseline systolic blood pressure (SBP) values ranged from 112.40 to 115.70 mmHg (p = 0.300), and diastolic blood pressure (DBP) ranged from 73.88 to 77.50 mmHg (p = 0.321). However, heart rate exhibited significant variation (87.70–96.70 bpm, p < 0.001), with higher rates recorded in the Carbetocin and Carbetocin + Tranexamic Acid groups.

Table 1.

Baseline demographic and clinical characteristics

Parameter	Carbetocin (n = 50)	Carbetocin + TXA (n = 50)	Oxytocin (n = 50)	Oxytocin + TXA (n = 50)	P-value
Age (years)	30.38 ± 5.58	30.00 ± 5.86	30.78 ± 5.97	29.22 ± 6.19	0.594
Gravida	2.36 ± 0.80	2.28 ± 1.13	2.48 ± 1.18	2.32 ± 1.02	0.794
Live births	1.14 ± 0.76	0.94 ± 0.94	1.08 ± 0.75	0.92 ± 0.83	0.468
Stillbirths	0.04 ± 0.20	0.02 ± 0.14	0.08 ± 0.34	0.08 ± 0.27	0.541
Abortions	0.20 ± 0.40	0.36 ± 0.94	0.30 ± 0.61	0.32 ± 0.55	0.659
Primary Cesarean Indication	Previous CS: 22 (44%)	Previous CS: 20 (40%)	Previous CS: 24 (48%)	Previous CS: 21 (42%)	0.889
	Fetal Malposition: 15 (30%)	Fetal Malposition: 16 (32%)	Fetal Malposition: 14 (28%)	Fetal Malposition: 17 (34%)
	Other: 13 (26%)	Other: 14 (28%)	Other: 12 (24%)	Other: 12 (24%)

Data are presented as Mean ± SD or n (%). P-values for continuous variables (Age, Gravida, Live births, Stillbirths, Abortions) were calculated using one-way Analysis of Variance (ANOVA). The p-value for the categorical variable (Primary Cesarean Indication) was calculated using the Chi-square test

Table 2.

Baseline hemodynamic and hematological characteristics

Parameter	Carbetocin (n = 50)	Carbetocin + TXA (n = 50)	Oxytocin (n = 50)	Oxytocin + TXA (n = 50)	P-value
Systolic BP (mmHg)	112.60 ± 10.70	115.70 ± 12.37	112.40 ± 10.80	115.30 ± 10.42	0.300
Diastolic BP (mmHg)	73.88 ± 11.73	75.88 ± 12.47	76.60 ± 6.88	77.50 ± 7.97	0.321
Heart rate (bpm)	94.40 ± 9.67	96.70 ± 12.36	87.70 ± 10.21	89.30 ± 10.30	< 0.001
Hemoglobin (g/dL)	11.99 ± 1.03	12.04 ± 1.25	12.14 ± 1.29	11.96 ± 1.24	0.889
Hematocrit (%)	35.64 ± 3.11	36.07 ± 3.44	35.82 ± 3.82	35.23 ± 3.25	0.664
White blood cells (/mm³)	11,310 ± 3,511	11,438 ± 3,627	9,676 ± 4,293	8,996 ± 3,681	0.002
Platelets (/mm³)	200,960 ± 61,105	207,440 ± 62,595	205,300 ± 66,277	208,400 ± 74,454	0.946

Data are presented as Mean ± SD. P-values were calculated using one-way Analysis of Variance (ANOVA)

Primary outcome: blood loss

Intraoperative blood loss, the primary outcome of the study, varied significantly among the groups (p = 0.017). Post-hoc analysis using Tukey’s HSD test revealed that the carbetocin group had significantly lower blood loss than the oxytocin plus tranexamic acid group (p = 0.015). No other pairwise comparisons reached statistical significance. The mean blood loss was lowest in the Carbetocin group (629.0 ± 139.62 mL) and highest in the Oxytocin + Tranexamic Acid group (712.7 ± 131.32 mL) (Table 3).

Table 3.

Intraoperative blood loss and Post-Hoc pairwise comparisons

Group	Blood Loss (mL), Mean ± SD	Post-hoc p-value (vs. Carbetocin)
Carbetocin	629.0 ± 139.62	Reference
Carbetocin + Tranexamic Acid	649.8 ± 130.60	0.789
Oxytocin	670.6 ± 139.44	0.312
Oxytocin + Tranexamic Acid	712.7 ± 131.32	0.015
Overall p-value (ANOVA)		0.017

Data are presented as Mean ± SD. Between-group comparisons were performed using one-way Analysis of Variance (ANOVA) with Tukey’s Honest Significant Difference (HSD) test for post-hoc analysis

Hemodynamic and hematological parameters before and after intervention

Hemodynamic and hematological parameters were assessed before and after intervention across all four groups (Table 4). In the Carbetocin group, significant changes were noted in all parameters (P ≤ 0.048), except for systolic blood pressure (SBP) (P = 0.215). Specifically, diastolic blood pressure (DBP) increased while heart rate (HR), hemoglobin (Hb), hematocrit (Hct), and platelet counts decreased significantly (P = 0.000). The Carbetocin + Tranexamic Acid group did not show significant changes in SBP or DBP (P > 0.05), but significant alterations were observed in HR, white blood cell (WBC) count, Hb, Hct, and platelets (P = 0.000). Both the Oxytocin + Tranexamic Acid and Oxytocin groups exhibited significant changes across all parameters (P ≤ 0.001), including reductions in SBP and DBP.

Table 4.

Hemodynamic and hematological parameters before and after intervention in all study groups

Parameter	Group	Before Intervention	After Intervention	P-value
Systolic BP	Carbetocin	112.60 ± 10.70	114.20 ± 10.27	0.215
	Carbetocin + TXA	115.70 ± 12.37	114.10 ± 10.48	0.274
	Oxytocin + TXA	115.30 ± 10.42	108.80 ± 11.36	< 0.001
	Oxytocin	112.40 ± 10.80	107.70 ± 11.66	0.001
Diastolic BP	Carbetocin	73.88 ± 11.73	77.30 ± 7.37	0.048
	Carbetocin + TXA	75.88 ± 12.47	76.30 ± 7.68	0.827
	Oxytocin + TXA	77.50 ± 7.97	70.90 ± 7.54	< 0.001
	Oxytocin	76.60 ± 6.88	70.80 ± 7.91	< 0.001
Heart Rate	Carbetocin	94.40 ± 9.67	88.10 ± 7.35	< 0.001
	Carbetocin + TXA	96.70 ± 12.36	88.46 ± 14.27	< 0.001
	Oxytocin + TXA	89.30 ± 10.30	96.70 ± 11.55	< 0.001
	Oxytocin	87.70 ± 10.21	95.50 ± 10.80	< 0.001
Hemoglobin	Carbetocin	11.99 ± 1.03	11.00 ± 1.15	< 0.001
	Carbetocin + TXA	12.04 ± 1.25	10.89 ± 2.00	< 0.001
	Oxytocin + TXA	11.96 ± 1.24	10.71 ± 1.14	< 0.001
	Oxytocin	12.14 ± 1.29	10.86 ± 1.15	< 0.001
Hematocrit	Carbetocin	35.64 ± 3.11	33.63 ± 3.05	< 0.001
	Carbetocin + TXA	36.07 ± 3.44	33.34 ± 3.30	< 0.001
	Oxytocin + TXA	35.23 ± 3.25	33.63 ± 3.13	< 0.001
	Oxytocin	35.82 ± 3.82	34.06 ± 3.28	< 0.001
Platelets	Carbetocin	200,960 ± 61,105	170,860 ± 52,039	< 0.001
	Carbetocin + TXA	207,440 ± 62,595	172,120 ± 54,356	< 0.001
	Oxytocin + TXA	208,400 ± 74,454	176,940 ± 65,454	< 0.001
	Oxytocin	205,300 ± 66,277	166,560 ± 60,393	< 0.001

Data are presented as Mean ± SD. Within-group comparisons (Before vs. After) for each parameter were performed using Paired Samples T-tests

Hemodynamic and hematological changes

Post-intervention alterations in hemodynamic and hematological parameters were assessed both within and between the intervention groups (Table 5). Most parameters exhibited statistically significant changes from pre- to post-intervention within each group (p < 0.05), with the exception of systolic blood pressure in the Carbetocin group (p = 0.215) and the Carbetocin + Tranexamic Acid (TXA) group (p = 0.274), as well as diastolic blood pressure in the Carbetocin + TXA group (p = 0.827).

Table 5.

Mean hemodynamic and hematological changes Pre- and Post-Intervention across groups

Parameter	Carbetocin	Carbetocin + TXA	Oxytocin	Oxytocin + TXA	P-value (ANOVA)
Hemoglobin (g/dL)	-0.99 ± 0.75	-1.15 ± 1.81	-1.28 ± 0.76	-1.25 ± 0.75	0.559
Hematocrit (%)	-2.01 ± 1.58	-2.73 ± 1.77	-1.75 ± 2.09	-1.61 ± 2.12	0.018
Platelets (/mm³)	-30,100 ± 40,966	-35,320 ± 45,329	-38,740 ± 45,056	-31,460 ± 50,523	0.777
WBC (/mm³)	+ 2,018 ± 2,304	+ 2,406 ± 2,049	+ 3,310 ± 2,951	+ 3,606 ± 2,847	0.006
Systolic BP (mmHg)	+ 1.60 ± 9.00	-1.60 ± 10.22	-4.70 ± 9.82	-6.50 ± 11.79	0.001
Diastolic BP (mmHg)	+ 3.42 ± 11.90	+ 0.42 ± 13.49	-5.80 ± 7.85	-6.60 ± 10.17	< 0.001
Heart Rate (bpm)	-6.30 ± 6.99	-8.24 ± 12.45	+ 7.80 ± 10.70	+ 7.40 ± 11.66	< 0.001

Data are presented as Mean Change ± SD. Between-group comparisons of the mean change for each parameter were performed using one-way Analysis of Variance (ANOVA). For parameters with a significant ANOVA result (p < 0.05), Tukey’s Honest Significant Difference (HSD) test was used for post-hoc pairwise comparisons

Between-group comparisons yielded the following results:

• Hemoglobin (Hb): The Oxytocin group experienced the most significant mean reduction in Hb (-1.28 g/dL), while the Carbetocin group exhibited the least change (-0.99 g/dL); however, this difference was not statistically significant (p = 0.559).

• Hematocrit (HCT): A significant difference was identified (p = 0.018), with post-hoc tests indicating the reduction in the Carbetocin + TXA group was significantly greater than in the Oxytocin + TXA group (p = 0.021).

• White Blood Cell (WBC) Count: Significant differences between groups were observed (p = 0.006), with post-hoc tests showing the increase in the Oxytocin + TXA group was significantly greater than in the Carbetocin group (p = 0.008).

• Platelets: While reductions in platelet counts were noted across all groups, these differences were not statistically significant (p = 0.777).

• Systolic Blood Pressure (SBP): A significant difference was found (p = 0.001), with post-hoc analysis confirming the increase in the Carbetocin group was significantly different from the decrease in the Oxytocin + TXA group (p < 0.001).

• Diastolic Blood Pressure (DBP): This parameter also showed significant variation (p < 0.001), with post-hoc tests revealing the increase in the Carbetocin group was significantly different from the decreases in both the Oxytocin (p < 0.001) and Oxytocin + TXA (p < 0.001) groups.

• Heart Rate (HR): Significant differences were observed (p < 0.001), with post-hoc tests confirming the decreases in the carbetocin-based groups were significantly different from the increases in the oxytocin-based groups (all p < 0.01).

Adverse events

Adverse events were monitored throughout the study; however, they were not systematically documented in the original data collection. No serious adverse events, such as severe allergic reactions or thromboembolism, were reported. Minor adverse events, including nausea and headache, were managed according to established protocols.

Discussion

This randomized, double-blind, two-factorial clinical trial evaluated the efficacy of oxytocin, carbetocin, and their combinations with tranexamic acid in mitigating intraoperative blood loss during cesarean deliveries. The results revealed significant differences in blood loss, hematological parameters, and hemodynamic changes among the intervention groups. Notably, carbetocin exhibited the lowest mean blood loss (629.0 mL), while the combination of oxytocin and tranexamic acid resulted in the highest mean blood loss (712.7 mL). These findings contribute to the expanding evidence base regarding uterotonic agents for the prevention of PPH, a major contributor to maternal morbidity and mortality worldwide [1].

The primary outcome, intraoperative blood loss, was significantly lower in the carbetocin group compared to the oxytocin plus tranexamic acid group, as confirmed by post-hoc analysis (p = 0.015). This finding is consistent with multiple studies that have reported carbetocin’s superior efficacy in reducing blood loss during cesarean deliveries. For instance, Abdelmegeed et al., [13] found carbetocin to be more effective than oxytocin in decreasing intraoperative blood loss among women undergoing cesarean sections, attributing this advantage to carbetocin’s longer half-life and sustained uterotonic effect. Similarly, Voon et al., [12] conducted a meta-analysis of randomized controlled trials, concluding that carbetocin significantly reduced blood loss and the need for additional uterotonics compared to oxytocin in cesarean deliveries. The prolonged action of carbetocin, which maintains uterine tone for up to six hours compared to oxytocin’s shorter duration, likely explains its enhanced efficacy [11].

Conversely, the combination of oxytocin with tranexamic acid resulted in the highest blood loss observed in our study, which contrasts with some previous findings. For example, a randomized trial during vaginal deliveries reported that combining tranexamic acid with oxytocin reduced blood loss compared to oxytocin alone [18]. This discrepancy may be attributed to variations in delivery mode (cesarean versus vaginal), patient populations, or dosing regimens. Tranexamic acid, an antifibrinolytic agent, is known to decrease bleeding by inhibiting fibrinolysis; however, its synergistic effect with uterotonics may differ based on surgical factors or baseline fibrinolytic activity [3]. We hypothesize that in the context of a cesarean delivery, where surgical bleeding is a major component, the vasodilatory effect of a rapid oxytocin bolus may transiently outweigh the hemostatic benefit of tranexamic acid, or that TXA’s effect is less pronounced when hyperfibrinolysis is not the primary driver of bleeding. The increased blood loss observed in the oxytocin plus tranexamic acid group in our study necessitates further investigation, as it may reflect context-specific factors such as surgical techniques or patient characteristics.

Carbetocin’s performance in our trial is particularly noteworthy given its consistent efficacy across diverse populations, including high-risk groups. For instance, Behery et al., [10] demonstrated carbetocin’s superiority over oxytocin in obese nulliparous women undergoing emergency cesarean deliveries, while Ibrahim et al., [14] reported similar findings in hypertensive women. These studies suggest that carbetocin’s pharmacodynamic profile may confer advantages in complex clinical scenarios, potentially due to its stability and reduced requirement for repeated dosing compared to oxytocin [1].

Secondary outcomes, including changes in hematocrit, white blood cell count, blood pressure, and heart rate, revealed significant differences among the groups. The carbetocin group demonstrated the smallest reductions in hematocrit (-2.01%) and hemoglobin (-0.99 g/dL), indicating a better preservation of red blood cell mass. This finding is consistent with the work of Bonus et al., [4] who reported that carbetocin was associated with lower rates of additional uterotonic use and blood transfusions, thereby indirectly supporting its role in minimizing hematological compromise. Conversely, the carbetocin plus tranexamic acid group exhibited the largest reduction in hematocrit (-2.73%), which may reflect either increased intraoperative bleeding or hemodilution effects; however, the clinical significance of this difference warrants further investigation.

Notable hemodynamic changes were also observed, with the carbetocin group exhibiting the smallest variations in systolic (+ 1.60 mmHg) and diastolic (+ 3.42 mmHg) blood pressure, alongside a decrease in heart rate (-6.30 bpm). In contrast, the oxytocin-containing groups experienced significant reductions in blood pressure and increases in heart rate. These results align with findings from Bahr et al., [8] and Rabow et al., [9] who reported that carbetocin possesses a more favorable hemodynamic profile than oxytocin during cesarean delivery under regional anesthesia. The rapid bolus administration of oxytocin is known to induce transient hypotension and tachycardia due to vasodilation and reflex sympathetic activation [7]. In contrast, carbetocin’s slower onset and prolonged action appear to mitigate these adverse effects, making it a safer option for patients with cardiovascular comorbidities, such as those with stenotic valvular heart disease [15].

The significant increase in white blood cell count observed across all groups, particularly in the oxytocin plus tranexamic acid group (+ 3,606/mm³), likely reflects a stress response to surgical intervention rather than a direct pharmacological effect. This observation is supported by Balki et al., [19] who noted similar leukocytosis following cesarean deliveries, attributing it to perioperative inflammation. Additionally, platelet count reductions were uniformly observed across all groups, with no significant differences between them (p = 0.777), suggesting that neither the uterotonics nor tranexamic acid significantly impacts platelet dynamics in this context.

The findings of this study have significant implications for clinical practice, particularly in contexts where the prevention of PPH is crucial. Carbetocin’s efficacy in reducing blood loss while causing minimal hemodynamic disturbance positions it as a preferred first-line agent for preventing PPH during cesarean deliveries, especially among high-risk groups such as women with twin pregnancies or obesity [20, 21]. Its single-dose administration simplifies management compared to the continuous infusion required for oxytocin, thereby reducing nursing workload and the potential for dosing errors [17]. However, the higher cost of carbetocin may limit its accessibility in low-resource settings, where oxytocin remains the standard treatment. Nonetheless, in contexts with high rates of PPH, the cost-effectiveness of carbetocin may justify its use [1, 17]. The suboptimal performance of the oxytocin plus tranexamic acid combination in this study raises questions about its routine prophylactic application, as it may lead to increased blood loss in certain cases [3]. Therefore, clinicians should consider tailoring its use to patients with coagulopathy or elevated fibrinolytic activity, pending further research to elucidate its role across various healthcare systems.

Strengths of this study include its randomized, double-blind, factorial design, which minimized bias and allowed for the simultaneous evaluation of two key interventions. The comprehensive assessment of both efficacy (blood loss, hematology) and safety (hemodynamics) outcomes provides a holistic view of the interventions. Furthermore, the study directly addresses a gap in the literature regarding the combined use of tranexamic acid with different uterotonics in the cesarean setting.

Despite its strengths, this study has several limitations. Firstly, the sample size of 200 participants was relatively modest, which may have restricted the power to detect smaller differences between groups, particularly regarding secondary outcomes such as changes in hemoglobin levels (p = 0.559). Larger trials, such as those conducted by Balogun et al., [22] have reported more pronounced differences in hematological outcomes. Secondly, the study did not systematically document adverse events. Although no serious adverse events were recorded, it is essential to quantify minor events (e.g., nausea, headache) to fully evaluate safety [23]. Thirdly, a significant baseline difference in heart rate (p < 0.001) may have influenced post-intervention hemodynamic outcomes, although randomization should have minimized this effect. Future studies should consider employing stratified randomization to balance such variables.

The method used for measuring blood loss, which relied on suction volumes and gauze counts, is inherently prone to estimation errors, as highlighted in previous studies [6]. Utilizing more precise measurement techniques, such as gravimetric methods, could improve accuracy. Additionally, conducting the study in a single region may limit the generalizability of the findings to diverse populations with varying risks of PPH [24]. Finally, the absence of long-term follow-up restricts insights into delayed outcomes, such as PPH occurring beyond the intraoperative period or late hemodynamic effects [16].

Future research should prioritize larger, multicenter trials to confirm the relative efficacy of carbetocin and clarify the role of tranexamic acid when used in conjunction with uterotonics. Studies conducted in low-resource settings are particularly necessary to evaluate the cost-effectiveness and feasibility of carbetocin [17]. Investigating optimal dosing regimens, as explored by McDonagh et al., [25] could further refine the application of carbetocin. Furthermore, trials that incorporate advanced blood loss measurement techniques and long-term follow-up would provide a more comprehensive understanding of strategies for preventing PPH [6]. Lastly, examining the efficacy of carbetocin in specific high-risk groups, such as women with cardiac conditions or those experiencing multiple gestations, could inform personalized treatment approaches [15, 26].

Conclusion

This trial demonstrates that carbetocin was associated with significantly less blood loss than oxytocin combined with tranexamic acid during cesarean deliveries while maintaining a favorable hemodynamic profile. When considering the full pattern of results, carbetocin-based regimens appear advantageous over oxytocin-based ones. These findings support the use of carbetocin as a preferred uterotonic for preventing PPH, particularly in high-risk cesarean cases. However, the increased blood loss associated with the oxytocin plus tranexamic acid combination highlights the need for careful consideration when using this approach. While this study contributes valuable insights to the existing literature, its limitations emphasize the necessity for larger and more diverse trials to optimize PPH prevention strategies. Addressing these gaps will enhance maternal safety and improve outcomes in obstetric care.

Authors’ contributions

All authors read and approved the final manuscript. All authors take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

Thanks to financial support, guidance, and advice from the “Kashan University of Medical Sciences”.

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Data availability

The data used in this study are available from the corresponding author on request.

Declarations

Ethics approval and consent to participate

The study procedures complied with the Declaration of Helsinki and institutional guidelines. The study received approval from the Institutional Review Board of Kashan University of Medical Sciences (IR.KAUMS.MEDNT.REC.1402.285) and was registered in Iranian Registry of Clinical Trials (IRCT) with IRCT20240529061944N1, Registration date: 2024-06-14. Written informed consent was obtained from all participants after a thorough explanation of the study procedures, potential risks, and benefits. Participants were informed that they could withdraw from the study at any time without any impact on their care. To ensure data confidentiality, numerical codes were assigned to questionnaires and checklists. The principal investigator was responsible for managing any adverse events that arose during the study. Findings from the research were disseminated to the Research Center and published following peer review.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.