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Heat-stable sublingual oxytocin tablets as a potential needle-free approach for preventing postpartum hemorrhage in low-resource settings.

ABSTRACT: Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration. Using methods developed previously, we produced a robust FDT that maintained oxytocin stability at 40 °C, 75% relative humidity for 12 months. This formulation contains 9% sucrose, 1.5% (hydroxypropyl)methyl cellulose, 9% mannitol, 4% dextran, 1% carbomer, 1% sodium taurocholate, and 100 IU oxytocin. An in vitro study showed a >?30% reduction in tissue transepithelial electrical resistance after treatment with the oxytocin FDT, implying an increase in the permeability of the mucosal tissue to oxytocin. Anesthetized Yucatan miniature swine were administered a SL FDT, and blood was periodically collected for a pharmacokinetic study. Higher plasma concentrations were seen when larger SL doses were given. The maximum concentrations for SL and intramuscular doses in anesthetized pigs were 207 and 612 pg/mL, respectively. Whether the levels attained will be sufficient to elicit beneficial results in humans is yet to be determined. This study demonstrates the feasibility of our approach for developing a heat-stable oxytocin tablet that can be administered successfully via the SL route.

SUBMITTER: Zhu C

PROVIDER: S-EPMC5937893 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Heat-stable sublingual oxytocin tablets as a potential needle-free approach for preventing postpartum hemorrhage in low-resource settings.

Zhu Changcheng C Estrada Marcus M White Jessica J Lal Manjari M

Drug delivery and translational research 20180601 3

Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration. Using methods developed previously, we produced a ro ...[more]

PMID: 29435767

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Project description:BackgroundPostpartum hemorrhage (PPH) is a leading cause of maternal death in sub-Saharan Africa. Although the World Health Organization recommends use of oxytocin for prevention of PPH, misoprostol use is increasingly common owing to advantages in shelf life and potential for sublingual administration. There is a lack of data about the comparative efficacy of oxytocin and sublingual misoprostol, particularly at the recommended dose of 600 µg, for prevention of PPH during active management of labor.Methods and findingsWe performed a double-blind, double-dummy randomized controlled non-inferiority trial between 23 September 2012 and 9 September 2013 at Mbarara Regional Referral Hospital in Uganda. We randomized 1,140 women to receive 600 µg of misoprostol sublingually or 10 IU of oxytocin intramuscularly, along with matching placebos for the treatment they did not receive. Our primary outcome of interest was PPH, defined as measured blood loss ≥ 500 ml within 24 h of delivery. Secondary outcomes included measured blood loss ≥ 1,000 ml; mean measured blood loss at 1, 2, and 24 h after delivery; death; requirement for blood transfusion; hemoglobin changes; and use of additional uterotonics. At 24 h postpartum, primary PPH occurred in 163 (28.6%) participants in the misoprostol group and 99 (17.4%) participants in the oxytocin group (relative risk [RR] 1.64, 95% CI 1.32 to 2.05, p<0.001; absolute risk difference 11.2%, 95% CI 6.44 to 16.1). Severe PPH occurred in 20 (3.6%) and 15 (2.7%) participants in the misoprostol and oxytocin groups, respectively (RR 1.33, 95% CI 0.69 to 2.58, p = 0.391; absolute risk difference 0.9%, 95% CI -1.12 to 2.88). Mean measured blood loss was 341.5 ml (standard deviation [SD] 206.2) and 304.2 ml (SD 190.8, p = 0.002) at 2 h and 484.7 ml (SD 213.3) and 432.8 ml (SD 203.5, p<0.001) at 24 h in the misoprostol and oxytocin groups, respectively. There were no significant differences between the two groups in any other secondary outcomes. Women in the misoprostol group more commonly experienced shivering (RR 1.91, 95% CI 1.65 to 2.21, p<0.001) and fevers (RR 5.20, 95% CI 3.15 to 7.21, p = 0.005). This study was conducted at a regional referral hospital with capacity for emergency surgery and blood transfusion. High-risk women were excluded from participation.ConclusionsMisoprostol 600 µg is inferior to oxytocin 10 IU for prevention of primary PPH in active management of labor. These data support use of oxytocin in settings where it is available. While not powered to do so, the study found no significant differences in rate of severe PPH, need for blood transfusion, postpartum hemoglobin, change in hemoglobin, or use of additional uterotonics between study groups. Further research should focus on clarifying whether and in which sub-populations use of oxytocin would be preferred over sublingual misoprostol.Trial registrationClinicalTrials.gov NCT01866241 Please see later in the article for the Editors' Summary.

Project description:Objectives: Subject to ethical constraints, real-world data are an important resource for evaluating treatment effects of medication use during pregnancy and the postpartum period. This study investigated whether motherwort injection, a traditional Chinese medicine preparation, was more effective than intramuscular (IM) oxytocin for preventing postpartum hemorrhage (PPH) in a real-world setting when intravenous (IV) oxytocin is administered. Methods: We conducted an active-controlled, propensity-score matched cohort study using an established pregnancy registry database. Women who underwent cesarean section and received IV oxytocin at the third stage of labor were included. We used an active-comparator design to minimize indication bias, in which we compared IM motherwort injection in the uterus versus IM oxytocin, both on top of IV oxytocin use. We applied 1:1 propensity-score matching (PSM) to balance patient baseline characteristics and used a logistic regression model to estimate treatment effect (i.e., risk difference (RD) and odds ratio (OR)) by using the counterfactual framework. The outcomes of interest were blood loss over 500 ml within 2 h after delivery (PPH, primary) and blood loss over 1,000 ml (severe PPH, secondary). We conducted four sensitivity analyses to examine the robustness of the results. Results: A total of 22,519 pregnant women underwent cesarean sections, among which 4,081 (18.12%) PPH and 480 (2.13%) severe PPH occurred. Among included women, 586 (2.60%) were administrated with IM motherwort injection, and 21,933 (97.40%) used IM oxytocin. After PSM, patient baseline characteristics were well balanced. Compared with IM oxytocin, the use of IM motherwort injection was associated with significantly lower risk of PPH (RD -25.26%, 95% CI -30.04% to -20.47%, p < 0.001; OR 0.25, 95% CI 0.18 to 0.32, p < 0.001) and severe PPH (RD -3.58%, 95% CI -5.87% to -1.30%, p < 0.001; OR 0.39, 95% CI 0.20 to 0.71, p < 0.002). Sensitivity analyses showed that the results were similar. Conclusion: With the use of data from a real-world setting, the findings consistently showed that among women undergoing cesarean section who had received IV oxytocin, the additional use of IM motherwort injection could achieve a lower risk of PPH as compared to the additional use of IM oxytocin. Our study suggested a paradigm for investigating the treatment effect of Chinese herbal medicine in the real-world practice setting.

Project description:Heat-stable carbetocin (HSC), a long-acting oxytocin analogue that does not require cold-chain transportation and storage, is effective in preventing postpartum haemorrhage (PPH) in vaginal and caesarean deliveries in tertiary-care settings. We aimed to identify literature documenting how it is implemented in resource-limited and lower-level maternity care settings to inform policies and practices that enable its introduction in these contexts. A rapid scoping review was conducted with an 8-week timeframe by two reviewers. MEDLINE, EMBASE, Emcare, the Joanna Briggs Institute Evidence-Based Practice Database, the Maternity and Infant Care Database, and the Cochrane Library were searched for publications in English, French, and Spanish from January 2011 to September 2021. Randomized and non-randomized studies examining the feasibility, acceptability, and health system considerations in low-income and lower-middle-income countries were included. Relevant data were extracted using pretested forms, and results were synthesized descriptively. The search identified 62 citations, of which 12 met the eligibility criteria. The review did not retrieve studies focusing on acceptability and health system considerations to inform HSC implementation in low-resource settings. There were no studies located in rural or lower-level maternity settings. Two economic evaluations concluded that HSC is not feasible in terms of cost-effectiveness in lower-middle-income economies with private sector pricing, and a third one found superior care costs in births with PPH than without. The other nine studies focused on demonstrating HSC effectiveness for PPH prevention in tertiary hospital settings. There is a lack of evidence on the feasibility (beyond cost-effectiveness), acceptability, and health system considerations related to implementing HSC in resource-constrained and lower-level maternity facilities. Further implementation research is needed to help decision-makers and practitioners offer an HSC-inclusive intervention package to prevent excessive bleeding among pregnant women living in settings where oxytocin is not available or of dubious quality.

Project description:IntroductionLow- and middle-income countries (LMICs) are committed to achieving the Sustainable Development Goal 3.1 to reduce maternal mortality. The Ministry of Health and Family Welfare of India recommends prophylactic uterotonic administration to every woman following delivery to reduce the risk of postpartum hemorrhage (PPH), as PPH is the leading cause of maternal mortality in LMICs, including India. In 2018, the World Health Organization first recognized heat-stable carbetocin for PPH prevention. Governments are now considering its introduction into their public health systems.MethodsA decision-tree model was developed from the public healthcare system perspective to compare the value of heat-stable carbetocin versus oxytocin and misoprostol among women giving birth in public sector healthcare facilities in India. The model accounted for differences in PPH risk and costs based on mode of delivery and healthcare setting, as well as provider behavior to mitigate quality concerns of oxytocin. Model outcomes for each prophylactic uterotonic included the number of PPH events, DALYs due to PPH, deaths due to PPH, and direct medical care costs. The budget impact was estimated based on projected uterotonic uptake between 2022-2026.ResultsCompared to oxytocin, heat-stable carbetocin avoided 5,468 additional PPH events, 5 deaths, and 244 DALYs per 100,000 births. Projected direct medical costs to the public healthcare system were lowered by US $171,700 (₹12.8 million; exchange rate of ₹74.65 = US$1 from 2 Feb 2022) per 100,000 births. Benefits were even greater when compared to misoprostol (7,032 fewer PPH events, 10 fewer deaths, 470 fewer DALYs, and $230,248 saved per 100,000 births). In the budget impact analysis, India's public health system is projected to save US$11.4 million (₹849 million) over the next five years if the market share for heat-stable carbetocin grows to 19% of prophylactic uterotonics administered.ConclusionsHeat-stable carbetocin is expected to reduce the number of PPH events and deaths, avoid more DALYs, and reduce costs to the public healthcare system of India. Greater adoption of heat-stable carbetocin for the prevention of PPH could advance India's efforts to achieve its maternal health goals and increase efficiency of its public health spending.

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Heat-stable sublingual oxytocin tablets as a potential needle-free approach for preventing postpartum hemorrhage in low-resource settings.

Publications

Heat-stable sublingual oxytocin tablets as a potential needle-free approach for preventing postpartum hemorrhage in low-resource settings.

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