Postpartum Hemorrhage in Humanitarian Settings: Heat-Stable Carbetocin and Tranexamic Acid Implementation Study in South Sudan

INTRODUCTION

Primary postpartum hemorrhage (PPH) is defined as excessive blood loss (≥ 500 mL after vaginal birth or ≥ 1000 mL after cesarean birth) within 24 hours.^[1] PPH contributes to over 25% of maternal deaths worldwide, primarily in low- and middle-income countries affected by fragility and humanitarian disasters.^[2]

Primary causes of PPH include uterine atony, trauma, retained placenta, tears, uterine rupture, clotting disorders, and uterine inversion.^[3] Active management of the third stage of labor (AMTSL) can prevent most PPH deaths.^[4] AMTSL includes prophylactic uterotonic use, delayed cord clamping, and controlled cord traction (if skilled attendants are available).^[4] Oxytocin (10 IU, IM/IV) is the preferred uterotonic in settings with multiple options but requires cold-chain storage.^[1,5] Heat-stable carbetocin (HSC), a long-acting oxytocin analog not requiring cold chain storage, is recommended for PPH prevention and was found cost-effective in reducing the number of PPH events and deaths as well as public healthcare system costs in India.^[6–8] Studies, including a 2018 trial by the World Health Organization (WHO), have shown HSC effectiveness and noninferiority to oxytocin in preventing PPH in low-income countries.^[9]

Prompt action is crucial for managing PPH.^[10] WHO recommends a multidisciplinary approach, including fluid replacement and additional uterotonic administration (following the initial dose for PPH prevention) as the primary interventions.^[1,5] Tranexamic acid (TXA), an antifibrinolytic agent, reduces bleeding risk in surgery and trauma.^[11,12] It does not require cold chain, is affordable ($1.30 per 1 g ampoule), and is readily available in hospitals.^[7] In obstetric care, TXA effectively controls bleeding in women with PPH regardless of the underlying cause.^[13]

A 2018 Cochrane Review by Gallos et al. found that oxytocin, misoprostol, ergometrine, and HSC were generally effective for PPH prevention, with HSC being potentially more effective than oxytocin without an increase in side effects.^[14] The review by Gallos et al. primarily relied on data from the 2018 trial by Widmer et al., which was conducted across 21 countries with varying income levels and in hospital settings.^[9,14] It aimed to compare HSC with oxytocin for PPH prevention. In another 2018 Cochrane Review by Shakur et al., prompt administration of intravenous TXA after the onset of bleeding was found to decrease primary PPH mortality in vaginal and cesarean births without raising thromboembolic risks.^[15] Additionally, in 2022, two scoping literature reviews highlighted the need for implementation research for PPH interventions, including HSC and TXA, in low-resource settings lacking cold chain systems.^[16,17]

We searched PubMed using the term “randomized controlled trial” combined with “postpartum,” “hemorrhage,” “vaginal,” and “carbetocin” or “tranexamic” for publications in English, focusing on trials in low-income countries (as defined by the World Bank) over the past ten years.^[18] We identified one trial since the 2022 scoping literature reviews—the E-MOTIVE trial (Early Detection of Postpartum Hemorrhage and Treatment), which took place in secondary-level hospitals in Kenya, Nigeria, South Africa, and Tanzania.^[19] E-MOTIVE aimed to test a package of interventions to identify and treat PPH. It found that detecting PPH early using a calibrated blood-collection drape and implementing bundled treatments (uterine massage, oxytocic drugs, TXA, intravenous fluids, examination, and intervention escalation) resulted in a reduced risk of severe PPH, laparotomy for bleeding, or bleeding-related death compared to standard care in women undergoing vaginal delivery.

Hence, there is a gap in the current evidence base, including in humanitarian and fragile settings such as South Sudan, detailing programmatic approaches to introduce HSC and TXA and enhance providers’ capacity to do so, particularly in nonhospital environments.

In light of this context, the overall aim of our implementation research was to investigate the influence of a capacity-strengthening package that includes HSC and TXA for PPH on the use of uterotonics (including HSC) for PPH prevention, detection, and use of uterotonics and TXA for PPH treatment in cold chain-challenged Basic Emergency Obstetric and Newborn Care (BEmONC) facilities. These facilities are often found in humanitarian settings. Our implementation research is based on the hypotheses that the package would enhance the quality of PPH care, integrate healthcare provider perspectives, align with national health policies, and address resource limitations, particularly in humanitarian and fragile contexts.

Newly independent in 2011, South Sudan grapples with severe maternal health issues and had the world’s highest maternal mortality ratio at 1223 deaths per 100,000 live births in 2020.^[2] Only 28% of births occurred in health facilities, and approximately 30% of married or in-union women in 2020 had unmet family planning needs.^[2,20,21] Merely 29% of women are literate as of 2019.^[21] With a population of 12.4 million, South Sudan shelters nearly 2.3 million Internally Displaced Persons (IDPs) and 308,000 refugees, constituting part of the 9.1 million people requiring humanitarian aid as of April 2023.^[22] Challenges in providing reproductive, maternal, neonatal, child, and adolescent health services stem from a scarcity of personnel, limited medical resources, and insufficient national funding.^[23] These hurdles are linked to the suspension of oil production in 2012, ongoing conflicts, governance deficiencies, a lack of accountability, and limited human resources, collectively resulting in inadequate healthcare and low service utilization.^[23]

METHODS

Stepwise Approach

All study sites followed the same sequence [Figure 1]: Step 1 (T1) involved a four-week routine care period (see below). This was followed by a six-month intervention design and training phase (T2). Step 2 (T2) featured a four-week intervention package with refresher training for facility providers but without HSC and TXA. Step 3 (T3) included an eight-week intervention package with HSC but no TXA. Step 4 (T4) included an eight-week intervention package with both HSC and TXA.

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Figure 1:

The four steps of the study, T1-T4. HSC: Heat-stable carbetocin, TXA: Tranexamic acid.

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RESULTS

DISCUSSION

Overall, our results showed that in humanitarian settings in South Sudan, where the availability of cold chain and cold storage is often unreliable, an HSC- and TXA-inclusive package of PPH prevention and treatment interventions that aimed at reinforcing providers’ capacity can change the trends in the type of uterotonic used for PPH prevention by replacing oxytocin with HSC, strengthen the visual diagnosis of PPH, and increase the uptake of TXA for PPH treatment. There was a momentary drop in oxytocin administration as treatment for women diagnosed with PPH coinciding with the introduction of prophylactic HSC. HSC was appropriately used for PPH prevention only and TXA was used appropriately for PPH treatment only.

To our understanding, our trial stands as one of the pioneering health implementation research studies at the primary care level conducted in South Sudan. Throughout the course of the study, we encountered various implementation challenges arising from the prevailing insecurity, characterized by intermittent intercommunal violence. This situation led to the displacement of communities into regions encompassed by our study sites, particularly Malakal, Bentiu, and Mingkaman. Adding to the complexity, severe flooding further exacerbated the circumstances. Given the dispersed nature of our study sites, we had to rely on air travel to commute between Juba and these locations. Due to the limited availability of flights and the occasional outbreaks of unrest and natural disasters, our WhatsApp-based Community of Practice proved invaluable in maintaining regular updates on the field situation, facilitating experience sharing, and promptly addressing any challenges that arose.

Uterotonic use for PPH prevention was already widespread at baseline, which is comparable to the results of the 2021 hospital-based EN-BIRTH study (Every Newborn Birth Indicators Research Tracking in Hospitals).^[29] This study found that >99% of women in Bangladesh, Nepal, and Tanzania received uterotonic for PPH prevention. Introducing HSC did not decrease, but increased the prevalence of uterotonic use. Once given the choice, providers replaced oxytocin with HSC in most cases. The uptake was higher than planned and led to a shortage of HSC in T4, explaining the drop in HSC use and the increase in oxytocin use from T3 to T4. HSC has a longer half-life than oxytocin and misoprostol. The concomitant use of HSC with other uterotonics, such as oxytocin or misoprostol, has not been extensively researched and should not be recommended.^[14] One study from Egypt examined the combination of oxytocin and carbetocin and observed an additive effect on preventing PPH during cesarean sections.^[30] There were rare cases of combined HSC use in our study (no serious side effects were reported). Future training and ongoing supportive supervision should reinforce the importance of not combining HSC with other uterotonics for PPH prevention and the continuous relevance of oxytocin for PPH treatment.

The prevalence of PPH tripled between T1 and T2–T4 to approximately 3%. The PPH refresher training, which occurred before T2, may have contributed to the increase. The training included a skill drills station, where providers had to visually estimate different amounts of bleeding using drapes tainted with red-colored juice and clotted liquid in a dish. Most providers underestimated blood loss, a phenomenon documented in the literature—with accuracy as low as 28% in a study in Thailand.^[31] Making trainees aware of their visual bias through short didactic and practical simulations effectively improves estimation and in our study, may have contributed to increased PPH detection.^[32] However, the resulting detection rate of approximately 3% remains below the PPH prevalence reported globally (6%) and in sub-Saharan Africa (11%).^[10] Calibrated drapes or other similar low-technology blood collection materials would be critical not only to document the incidence of PPH adequately but also to trigger detection and action in the treatment of PPH. Calibrated drapes were critical in the chain of PPH treatment measures illustrated in the 2023 E-MOTIVE study, which was based in referral hospitals.^[19] The feasibility of calibrated drapes and other blood collection materials should be further researched in humanitarian and lower maternity care settings.

Almost all women with PPH received TXA after its official introduction in T4, although the strength of this evidence is low due to the small sample size. The study sites received supplies of both HSC and TXA before T2 to minimize transportation and logistics costs related to the option of delivering TXA just before T4. We reminded providers to use TXA only in T4. As providers were already trained on TXA usage during the refresher training before T2 started, a few administered it to women with PPH during T2, a trend that decreased in T3 after a reminder of the study’s stepwise approach during supportive supervision. Nonetheless, the mistimed use of TXA in T2 allows us to learn two implementation lessons. First, providers will likely use life-saving medications such as TXA as soon as these are available, despite reminders to wait until the right time. Second, the use of TXA for PPH treatment before introducing HSC for PPH prevention appears to have no adverse effect on the trends of oxytocin use for either PPH prevention or in particular, PPH treatment. What happened to the latter in T3 once HSC was introduced came as a surprise with valuable insights for future scale-up efforts.

Oxytocin is a cornerstone in PPH treatment, which appears to be universally applied in T1 and T2 (even when TXA is used for treatment). The alarming and significant drop in its use down to 27% of women diagnosed with PPH during T3 coincided with the introduction of HSC. However, the credibility of this finding is limited by the relatively low number of PPH cases in the study. We searched for and did not identify similar phenomena published in the literature. This may be because most studies focused on the safety and efficacy of PPH medications, not on how using one affected other available treatment of the PPH management toolkit. Supportive supervision offered insights into providers’ confusion: as both HSC and oxytocin are uterotonics and should not be used prophylactically together, a number of staff thought that oxytocin could not be used to treat PPH if HSC was used beforehand for PPH prevention. Close monitoring dispelled this misconception and allowed a more systematic use of oxytocin for treatment, which increased again in T4.

Conclusion and Global Health Implications

Despite these limitations, implementing an HSC and TXA-inclusive PPH intervention package in humanitarian settings significantly increased women’s access to HSC for PPH prevention and TXA for PPH treatment. Based on the current evidence and increasing availability and affordability of HSC and TXA for PPH management in high-mortality countries, policymakers from low-resource settings have various strategies for introducing these medications to prevent and treat PPH. Such strategies depend on health service and cold chain gaps, needs, and opportunities at different levels of care. One such strategy is the one this implementation research identified in humanitarian cold chain system-challenged settings—our strategy does not just “parachute” HSC and TXA but integrates them into a package of interventions to enhance the quality of PPH care. Additionally, replacing prophylactic oxytocin of unknown quality with HSC could significantly unburden cold chain storage systems in low-resource settings. The widespread adoption of this approach could mitigate the challenges associated with transporting and storing oxytocin for PPH prevention. However, effective scale-up necessitates (i) continuous capacity development for skill enhancement and addressing staff turnover; (ii) ongoing supportive supervision to reinforce clinical practices and dispel misconceptions; (iii) close monitoring and evaluation with revised maternity registers, capturing essential PPH indicators; and (iv) enhancing cold chain for oxytocin quality assurance, as it remains vital for PPH treatment. While further research is needed to determine cost-effectiveness, the nature of the interventions and the emphasis on strengthening PPH quality of care in existing cold chain-challenged BEmONC facilities could accelerate reductions in maternal mortality ratio in high-burden countries hosting humanitarian crises.