A double-blind, randomized controlled trial to explore oral tranexamic acid as adjunct for the treatment for postpartum hemorrhage.

BACKGROUND: Oral tranexamic acid (TXA), if effective in reducing blood loss after delivery for women experiencing primary PPH, could be administered where parenteral administration is not feasible. This trial assessed the efficacy, safety, and acceptability of oral TXA when used as an adjunct to sublingual misoprostol to treat postpartum hemorrhage (PPH) following vaginal delivery. METHODS: From October 2016 to January 2018, women presenting at four hospitals in Senegal and Vietnam for vaginal delivery were screened for enrollment in the trial. Women diagnosed with postpartum hemorrhage (defined as blood loss ≥700 ml) were randomized to receive either oral TXA (1950 mg) or placebo in addition to 800 mcg sublingual misoprostol. Postpartum blood loss was measured using a calibrated drape. Blood loss for all PPH cases was recorded for 2 h after administration of the drugs. The primary outcome measure was the proportion of women with bleeding controlled with the trial regimen without recourse to further treatment. Secondary outcomes including the rate of severe PPH, mean/median blood loss, use of additional uterotonics and/or interventions side effects, and acceptability were also recorded. RESULTS: Of the 258 women who received treatment for PPH, 128 received placebo and misoprostol and 130 received TXA and misoprostol. The proportion of women who had active bleeding controlled with trial drugs alone and no additional interventions was similar in both groups: 77(60.2%) placebo; 74 (56.9%) TXA, p = 0.59). Use of other interventions to control bleeding, including uterotonics, did not differ significantly between groups. Median blood loss at PPH diagnosis was 700 ml in both groups. Uterine atony alone or in addition to another cause contributed to over 90% of PPH cases reported (92.2% placebo vs. 91.5% TXA), other causes included perineal and cervical lacerations and retained placenta. Reports of side effects and acceptability were similar in the two groups. CONCLUSION: Adjunct use of oral TXA with misoprostol to treat PPH resulted in similar clinical and acceptability outcomes when compared to treatment with misoprostol alone. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov, number NCT02805426. Registered on 3 September 2016.

Scaling up interventions: findings and lessons learned from an external evaluation of Niger's National Initiative to reduce postpartum hemorrhage.

BACKGROUND: Niger has one of the highest maternal mortality ratios in Sub Saharan Africa, of which postpartum hemorrhage is the leading cause. In 2014, Health and Development International and the Ministry of Health of Niger launched an initiative to introduce and scale-up three PPH interventions in health facilities nationwide: misoprostol, uterine balloon tamponade, and the non-pneumatic anti-shock garment. METHODS: A two-phase mixed-methods evaluation was conducted to assess implementation of the initiative. Health facility assessments, provider interviews, and household surveys were conducted in May 2016 and November 2017. RESULTS: All evaluation facilities received misoprostol prevention doses. However, shortages in misoprostol treatment doses, UBT kits, and NASG stock were documented. Health provider training increased while knowledge of each PPH intervention varied. Near-universal uterotonic coverage for PPH prevention and treatment was achieved and sustained throughout the evaluation period. Use of UBT and NASG to manage PPH was rare and differed by health facility type. Among community deliveries, fewer than 22% of women received misoprostol at antenatal care for self-administered prophylaxis. Among those who did, almost all reported taking the drugs for PPH prevention in each phase. CONCLUSIONS: This study is the first external evaluation of a comprehensive PPH program taking misoprostol, UBT, and NASG to national scale in a low resource setting. Although gaps in service delivery were identified, results demonstrate the complexities of training, managing stock, and implementing system-wide interventions to reach women in varying contexts. The experience provides important lessons for other countries as they develop and expand evidence-based programs for PPH care.

Sublingual misoprostol versus standard surgical care for treatment of incomplete abortion in five sub-Saharan African countries.

BACKGROUND: In low-resource settings, where abortion is highly restricted and self-induced abortions are common, access to post-abortion care (PAC) services, especially treatment of incomplete terminations, is a priority. Standard post-abortion care has involved surgical intervention but can be hard to access in these areas. Misoprostol provides an alternative to surgical intervention that could increase access to abortion care. We sought to gather additional evidence regarding the efficacy of 400 mcg of sublingual misoprostol vs. standard surgical care for treatment of incomplete abortion in the environments where need for economical non-surgical treatments may be most useful. METHODS: A total of 860 women received either sublingual misoprostol or standard surgical care for treatment of incomplete abortion in a multi-site randomized trial. Women with confirmed incomplete abortion, defined as past or present history of vaginal bleeding during pregnancy and an open cervical os, were eligible to participate. Participants returned for follow-up one week later to confirm clinical status. If abortion was incomplete at that time, women were offered an additional follow-up visit or immediate surgical evacuation. RESULTS: Both misoprostol and surgical evacuation are highly effective treatments for incomplete abortion (misoprostol: 94.4%, surgical: 100.0%). Misoprostol treatment resulted in a somewhat lower chance of success than standard surgical practice (RR = 0.90; 95% CI: 0.89-0.92). Both tolerability of side effects and women's satisfaction were similar in the two study arms. CONCLUSION: Misoprostol, much easier to provide than surgery in low-resource environments, can be used safely, successfully, and satisfactorily for treatment of incomplete abortion. Focus should shift to program implementation, including task-shifting the provision of post-abortion care to mid- and low- level providers, training and assurance of drug availability. TRIAL REGISTRATION: This study has been registered at clinicaltrials.gov as NCT00466999 and NCT01539408.

Treatment of post-partum haemorrhage with sublingual misoprostol versus oxytocin in women receiving prophylactic oxytocin: a double-blind, randomised, non-inferiority trial.

BACKGROUND: Oxytocin, the gold-standard treatment for post-partum haemorrhage, needs refrigeration, intravenous infusion, and skilled providers for optimum use. Misoprostol, a potential alternative, is increasingly used ad hoc for treatment of post-partum haemorrhage; however, evidence is insufficient to lend support to recommendations for its use. This trial established whether sublingual misoprostol is non-inferior to intravenous oxytocin for treatment of post-partum haemorrhage in women receiving prophylactic oxytocin. METHODS: In this double-blind, non-inferiority trial, 31 055 women exposed to prophylactic oxytocin had blood loss measured after vaginal delivery at five hospitals in Burkina Faso, Egypt, Turkey, and Vietnam (two secondary-level and three tertiary-level facilities). 809 (3%) women were diagnosed with post-partum haemorrhage and were randomly assigned to receive 800 mug misoprostol (n=407) or 40 IU intravenous oxytocin (n=402). Providers and women were masked to treatment assignment. Primary endpoints were cessation of active bleeding within 20 min and additional blood loss of 300 mL or more after treatment. Clinical equivalence of misoprostol would be accepted if the upper bound of the 97.5% CI fell below the predefined non-inferiority margin of 6%. All outcomes were assessed from the time of initial treatment. This study is registered with ClinicalTrials.gov, number NCT00116350. FINDINGS: All randomly assigned participants were analysed. Active bleeding was controlled within 20 min after initial treatment for 363 (89%) women given misoprostol and 360 (90%) given oxytocin (relative risk [RR] 0.99, 95% CI 0.95-1.04; crude difference 0.4%, 95% CI -3.9 to 4.6). Additional blood loss of 300 mL or greater after treatment occurred for 139 (34%) women receiving misoprostol and 123 (31%) receiving oxytocin (RR 1.12, 95% CI 0.92-1.37). Shivering (152 [37%] vs 59 [15%]; RR 2.54, 95% CI 1.95-3.32) and fever (88 [22%] vs 59 [15%]; 1.47, 1.09-1.99) were significantly more common with misoprostol than with oxytocin. Six women had hysterectomies and two women died. INTERPRETATION: Misoprostol is clinically equivalent to oxytocin when used to stop excessive post-partum bleeding suspected to be due to uterine atony in women who have received oxytocin prophylactically during the third stage of labour.

Postpartum infection, pain and experiences with care among women treated for postpartum hemorrhage in three African countries: A cohort study of women managed with and without condom-catheter uterine balloon tamponade.

OBJECTIVE: We aimed to determine the risk of postpartum infection and increased pain associated with use of condom-catheter uterine balloon tamponade (UBT) among women diagnosed with postpartum hemorrhage (PPH) in three low- and middle-income countries (LMICs). We also sought women's opinions on their overall experience of PPH care. METHODS: This prospective cohort study compared women diagnosed with PPH who received and did not receive UBT (UBT group and no-UBT group, respectively) at 18 secondary level hospitals in Uganda, Egypt, and Senegal that participated in a stepped wedge, cluster-randomized trial assessing UBT introduction. Key outcomes were reported pain (on a scale 0-10) in the immediate postpartum period and receipt of antibiotics within four weeks postpartum (a proxy for postpartum infection). Outcomes related to satisfaction with care and aspects women liked most and least about PPH care were also reported. RESULTS: Among women diagnosed with PPH, 58 were in the UBT group and 2188 in the no-UBT group. Self-reported, post-discharge antibiotic use within four weeks postpartum was similar in the UBT (3/58, 5.6%) and no-UBT groups (100/2188, 4.6%, risk ratio = 1.22, 95% confidence interval [CI]: 0.45-3.35). A high postpartum pain score of 8-10 was more common among women in the UBT group (17/46, 37.0%) than in the no-UBT group (360/1805, 19.9%, relative risk ratio = 3.64, 95% CI:1.30-10.16). Most women were satisfied with their care (1935/2325, 83.2%). When asked what they liked least about care, the most common responses were that medications (580/1511, 38.4%) and medical supplies (503/1511, 33.3%) were unavailable. CONCLUSION: UBT did not increase the risk of postpartum infection among this population. Women who receive UBT may experience higher degrees of pain compared to women who do not receive UBT. Women's satisfaction with their care and stockouts of medications and other supplies deserve greater attention when introducing new technologies like UBT.

Using misoprostol to treat postpartum hemorrhage in home deliveries attended by traditional birth attendants.

OBJECTIVE: To explore the clinical and programmatic feasibility of using 800 µg of sublingual misoprostol to prevent and treat postpartum hemorrhage (PPH) during home delivery. METHODS: The present double-blind randomized controlled trial included women who underwent home deliveries in Chitral district, Khyber Pakhtunkhwa province, Pakistan, after presenting at healthcare facilities during the third trimester of pregnancy between May 28, 2012, and November 27, 2014. Participants were randomized in a 1:1 ratio to receive either 800 µg of misoprostol or placebo sublingually if PPH was diagnosed, having previously received a prophylactic oral dose of 600 µg misoprostol. The primary outcome, hemoglobin decrease of 20 g/L or greater from pre- to post-delivery assessment, was compared on a modified intention-to-treat basis. RESULTS: There were 49 patients allocated to receive misoprostol and 38 allocated to receive placebo; the incidence of a 20 g/L decrease in hemoglobin was similar between the groups (20/43 [47%] vs 19/33 [58%], respectively; P=0.335). CONCLUSION: There was no significant difference in clinical outcomes between the two trial arms. ClinicalTrials.gov:NCT01485562.

Oxytocin via Uniject (a prefilled single-use injection) versus oral misoprostol for prevention of postpartum haemorrhage at the community level: a cluster-randomised controlled trial.

BACKGROUND: Access to injectable uterotonics for management of postpartum haemorrhage remains limited in Senegal outside health facilities, and misoprostol and oxytocin delivered via Uniject have been deemed viable alternatives in community settings. We aimed to compare the efficacy of these drugs when delivered by auxiliary midwives at maternity huts. METHODS: We did an unmasked cluster-randomised controlled trial at maternity huts in three districts in Senegal. Maternity huts with auxiliary midwives located 3-21 km from the closest referral centre were randomly assigned (1:1; via a computer-generated random allocation overseen by Gynuity Health Projects) to either 600 µg oral misoprostol or 10 IU oxytocin in Uniject (intramuscular), stratified by reported previous year clinic volume (deliveries) and geographical location (inland or coastal). Maternity huts that had been included in a previous study of misoprostol for prevention of postpartum haemorrhage were excluded to prevent contamination. Pregnant women in their third trimester were screened for eligibility either during community outreach or at home-based prenatal visits. Only women delivered by the auxiliary midwives in the maternity huts were eligible for the study. Women with known allergies to prostaglandins or pregnancy complications were excluded. The primary outcome was mean change in haemoglobin concentration measured during the third trimester and after delivery. This study was registered with ClinicalTrials.gov, number NCT01713153. FINDINGS: 28 maternity hut clusters were randomly assigned-14 to the misoprostol group and 14 to the oxytocin group. Between June 6, 2012, and Sept 21, 2013, 1820 women were recruited. 647 women in the misoprostol group and 402 in the oxytocin group received study drug and had recorded pre-delivery and post-delivery haemoglobin concentrations, and overall 1412 women delivered in the study maternity huts. The mean change in haemoglobin concentrations was 3·5 g/L (SD 16·1) in the misoprostol group and 2·7 g/L (SD 17·8) in the oxytocin group. When adjusted for cluster design, the mean difference in haemoglobin decreases between groups was not significant (0·3 g/L, 95% CI -8·26 to 8·92, p=0·71). Both drugs were well tolerated. Shivering was common in the misoprostol group, and nausea in the oxytocin group. Postpartum haemorrhage was diagnosed in one woman allocated to oxytocin, who was referred and transferred to a higher-level facility for additional care, and fully recovered. No other women were transferred. INTERPRETATION: In terms of effects on haemoglobin concentrations, neither oxytocin nor misoprostol was significantly better than the other, and both drugs were safe and efficacious when delivered by auxiliary midwives. The programmatic limitations of oxytocin, including short shelf life outside the cold chain, mean that misoprostol could be more appropriate for community-level prophylaxis of postpartum haemorrhage. FUNDING: Bill & Melinda Gates Foundation.

Decentralizing postabortion care in Senegal with misoprostol for incomplete abortion.

OBJECTIVE: To expand access to postabortion care (PAC) services in Senegal by introducing misoprostol as a first-line treatment at the community level. METHODS: The present prospective study enrolled 481 women seeking treatment for incomplete abortion at 11 community health posts in Senegal between September 2011 and August 2012. Participants were given 400 µg of sublingual misoprostol and asked to return to the clinic 1 week later to confirm clinical status. At study completion, all women were asked to respond to a series of questions regarding their experience with this method. All care was provided by nurse midwives. RESULTS: All but three of the study women (99.4%; 474/477) had successful complete abortion after taking misoprostol. Almost all women were satisfied or very satisfied with the treatment (99.6%; 469/471), would select the method again if needed (98.9%; 465/470), and would recommend the method to a friend (99.8%; 468/469). CONCLUSION: The results provide further evidence that 400 µg of misoprostol is highly effective for first-line treatment of incomplete abortion. Furthermore, this regimen can be fully provided by nurse midwives, and can be easily and successfully introduced in community health settings where other methods of PAC may not previously have been available. Clinicaltrials.gov: NCT01939457.

Acceptability and feasibility of medical abortion with mifepristone and misoprostol in Nigeria.

OBJECTIVE: To examine the acceptability and feasibility of medical abortion in Nigeria. METHODS: In total, 250 women who were eligible for legal pregnancy termination with a gestational age of up to 63 days since last menstrual period were enrolled in Benin City and Zaria between May 2005 and October 2006. Participants received 200 mg of oral mifepristone in the clinic and then took 400 µg of oral misoprostol 2 days later-choosing to either return to the clinic or take it at home. Women returned 2 weeks later for an assessment of abortion status. RESULTS: The vast majority (96.3%) of women had successful complete abortions. Ultrasound was used to determine outcome in less than one-third (28.9%) of participants. Most women (83.2%) took the misoprostol at home. Almost all (96.2%) participants were satisfied or very satisfied with the abortion method. CONCLUSION: The introduction of medical abortion with mifepristone and misoprostol could greatly expand current method options and improve the quality of reproductive health care in Nigeria and other settings in which access to legal abortion services is limited.

Misoprostol as first-line treatment for incomplete abortion at a secondary-level health facility in Nigeria.

OBJECTIVE: To determine the feasibility of introducing misoprostol as first-line treatment for incomplete abortion at a secondary-level health facility. METHODS: An open-label prospective study was conducted in a secondary-level health facility in Nigeria. Eligible women diagnosed with incomplete abortion received 400-µg sublingual misoprostol as first-line treatment. Nurse-midwives took the lead in diagnosis, counseling, treatment, and assessment of final outcome. The primary outcome was the proportion of women who completed the abortion process. RESULTS: Complete evacuation was achieved in 83 of 90 (92.2%) eligible women. The most common adverse effects were abdominal pain/cramps (58 [64.4%]), heavy bleeding (21 [23.3%]), spotting (15 [16.7%]), and fever/chills (11 [12.2%]). More than 90% of women reported that the procedure was satisfactory, that pain and adverse effects were tolerable, and that bleeding was acceptable. Eighty-four (93.3%) and 86 (95.6%) women, respectively, would use the method in the future and recommend it to friends. CONCLUSION: Misoprostol is an effective, safe, and acceptable method for treating incomplete abortion. It can be successfully used as first-line treatment by nurse-midwives. Success rates over 90% are consistent with findings from previous studies in which drug administration was controlled solely by physicians.

Sublingual [corrected] misoprostol as first-line care for incomplete abortion in Burkina Faso.

OBJECTIVE: To explore 400-µg sublingual misoprostol as primary treatment in lower-level facilities with no previous experience providing postabortion care. METHODS: Women presenting with incomplete abortion were offered a single dose of 400-µg sublingual misoprostol. Incomplete abortion was defined as uterine size consistent with fewer than 12 weeks of gestation, open cervical os, and reports of past or present history of vaginal bleeding. Women returned to the clinic 1 week after misoprostol administration for follow-up. At that time, they were discharged if the uterine evacuation was a success or were offered a second follow-up visit or surgical completion if still incomplete. RESULTS: One-hundred women received misoprostol; outcome data were unavailable for 1 woman. Complete uterine evacuation was achieved for 97 (98.0%) women. Satisfaction was high, with nearly all women indicating that they were "satisfied" (n=57 [57.6%]) or "very satisfied" (n=41 [41.4%]) with their experience. Adverse effects were considered "tolerable" by 72 of 97 (74.2%) women. Ninety-seven of 99 (98.0%) participants indicated that they would choose misoprostol for incomplete abortion care in the future and 95 of 97 (97.9%) stated that they would recommend it to a friend. CONCLUSION: Misoprostol is a viable option for treatment of incomplete abortion at mid-level facilities.

Oral misoprostol as an alternative to surgical management for incomplete abortion in Ghana.

OBJECTIVE: To investigate whether 600-µg oral misoprostol is an effective alternative to manual vacuum aspiration (MVA) for the treatment of incomplete abortion. METHODS: From June 16, 2004, to July 20, 2005, 230 women of reproductive age presenting with incomplete abortion were randomized in an open-label trial to either 600-µg oral misoprostol or MVA for the treatment of incomplete abortion. RESULTS: Regardless of the assigned method, more than 98% of participants experienced complete uterine evacuation following initial treatment. Efficacy, acceptability, and satisfaction ratings were similar and high for both methods. CONCLUSION: 600-µg oral misoprostol is a safe, effective, and acceptable alternative to MVA for the treatment of incomplete abortion.

Comparing two early medical abortion regimens: mifepristone+misoprostol vs. misoprostol alone.

BACKGROUND: Nonsurgical abortion methods have the potential to improve access to high-quality abortion care. Until recently, availability and utilization of mifepristone medical abortion in low-resource countries were restricted due to the limited availability and perceived high cost of mifepristone, leading some providers and policymakers to support use of misoprostol-only regimens. Yet, this may not be desirable if misoprostol-only regimens are considerably less effective and ultimately more costly for health care systems. This study sought to document the differences in efficacy between two nonsurgical abortion regimens. STUDY DESIGN: This double-blind randomized placebo-controlled trial enrolled women with gestational ages up to 63 days seeking early medical abortion from August 2007 to March 2008 at a large tertiary hospital in Ho Chi Minh City, Vietnam. Eligible consenting women received either (1) two doses of 800 mcg buccal misoprostol 24 h apart or (2) 200 mg mifepristone and 800 mcg buccal misoprostol 24 h later. Participants self-administered all study drugs and returned to the hospital for follow-up 1 week later. The trial is registered at ClinicalTrials.gov as NCT00680394. RESULTS: Four hundred women were randomized to either misoprostol-only (198) or mifepristone+misoprostol (202). Complete abortion occurred for 76.2% (n=147) of women allocated to misoprostol-only vs. 96.5% (n=194) of those given mifepristone+misoprostol (RR 0.79, 95% CI 0.73-0.86). Ongoing pregnancy was documented for 16.6% (32) of misoprostol-only users and 1.5% (3) of mifepristone+misoprostol users (1.62, 0.68-3.90). Side effects were generally similar for both groups, although significantly more women allocated to misoprostol-only reported diarrhea. CONCLUSIONS: Mifepristone+misoprostol is significantly more effective than use of misoprostol-alone for early medical abortion. The number of ongoing pregnancies documented with misoprostol-only warranted an early end of the trial after unblinding of the study at interim analysis. Policymakers should advocate for greater access to mifepristone. Future research should prioritize misoprostol-only regimens with shorter dosing intervals.

Two routes of administration for misoprostol in the treatment of incomplete abortion: a randomized clinical trial.

BACKGROUND: This study was conducted to compare the safety, effectiveness and acceptability of 400 mcg sublingual misoprostol and 600 mcg oral misoprostol for treatment of incomplete abortion. STUDY DESIGN: We used an open-label randomized controlled trial conducted from July 2005 to August 2006 in a large tertiary level maternity hospital in Antananarivo, Madagascar, and a large tertiary level hospital in Chisinau, Moldova. Three hundred consenting women seeking treatment for clinically diagnosed incomplete abortion with uterine size