New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline.

BACKGROUND: There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development. CONCLUSIONS: This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.

Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles.

BACKGROUND: The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols. CONCLUSIONS: This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.

Systematic review of shorter versus longer duration of bladder catheterization after surgical repair of urinary obstetric fistula.

BACKGROUND: Bladder catheterization duration after urinary obstetric fistula surgery varies widely. OBJECTIVE: To assess the effect of bladder catheterization duration after urinary obstetric fistula surgery. SEARCH STRATEGY: Medline, EMBASE, CINAHL, GIM, and POPLINE databases were searched, without language restrictions, using "obstetric urinary fistula" and "catheterization" from inception to September 30, 2017. SELECTION CRITERIA: Randomized controlled trials comparing shorter versus longer (>10 days) bladder catheterization after urinary obstetric fistula repair were included. DATA COLLECTION AND ANALYSIS: Data were extracted and meta-analyses were conducted. The GRADE system was used to assess evidence quality. MAIN RESULTS: Two unblinded non-inferiority trials (684 patients combined) were included. There were no differences between shorter and longer bladder catheterization in the risk of fistula repair breakdown either before (relative risk [RR] 1.14; 95% confidence interval [CI] 0.49-2.64) or after (RR 1.64; 95% CI 0.81-3.31) hospital discharge. Similarly, urinary infection (RR 5.18; 95% CI 0.25-107.44); urinary incontinence before (RR 1.15; 95% CI 0.54-2.43) or after (RR 1.16; 95% CI 0.62-2.18) discharge; urinary retention (RR 1.34; 95% CI 0.79-2.27); or extended hospital stay (RR 9.33; 95% CI 0.51-172.41) were not associated with duration of catheterization. Evidence quality was low or moderate. CONCLUSIONS: Shorter, compared to longer, bladder catheterization duration after urinary obstetric fistula surgery was not associated with significant outcome differences.

Accuracy of angiogenic biomarkers at ⩽20weeks' gestation in predicting the risk of pre-eclampsia: A WHO multicentre study.

OBJECTIVE: To assess the accuracy of angiogenic biomarkers to predict pre-eclampsia. DESIGN: Prospective multicentre study. From 2006 to 2009, 5121 pregnant women with risk factors for pre-eclampsia (nulliparity, diabetes, previous pre-eclampsia, chronic hypertension) from Argentina, Colombia, Peru, India, Italy, Kenya, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ⩽20, 23-27 and 32-35weeks' gestation (index tests, results blinded from carers). Women were monitored for signs of pre-eclampsia, diagnosed by systolic blood pressure ⩾140mmHg and/or diastolic blood pressure ⩾90mmHg, and proteinuria (protein/creatinine ratio ⩾0.3, protein ⩾1g/l, or one dipstick measurement ⩾2+) appearing after 20weeks' gestation. Early pre-eclampsia was defined when these signs appeared ⩽34weeks' gestation. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Pre-eclampsia was diagnosed in 198 of 5121 women tested (3.9%) of whom 47 (0.9%) developed it early. The median maternal serum concentrations of index tests were significantly altered in women who subsequently developed pre-eclampsia than in those who did not. However, the area under receiver operating characteristics curve at ⩽20weeks' gestation were closer to 0.5 than to 1.0 for all biomarkers both for predicting any pre-eclampsia or at ⩽34weeks' gestation. The corresponding sensitivity, specificity and likelihood ratios were poor. Multivariable models combining sEng with clinical features slightly improved the prediction capability. CONCLUSIONS: Angiogenic biomarkers in first half of pregnancy do not perform well enough in predicting the later development of pre-eclampsia.

Breakdown of simple female genital fistula repair after 7 day versus 14 day postoperative bladder catheterisation: a randomised, controlled, open-label, non-inferiority trial.

BACKGROUND: Duration of bladder catheterisation after female genital fistula repair varies widely. We aimed to establish whether 7 day bladder catheterisation was non-inferior to 14 days in terms of incidence of fistula repair breakdown in women with simple fistula. METHODS: In this randomised, controlled, open-label, non-inferiority trial, we enrolled patients at eight hospitals in the Democratic Republic of the Congo, Ethiopia, Guinea, Kenya, Niger, Nigeria, Sierra Leone, and Uganda. Consenting patients were eligible if they had a simple fistula that was closed after surgery and remained closed 7 days after surgery, understood study procedures and requirements, and agreed to return for follow-up 3 months after surgery. We excluded women if their fistula was not simple or was radiation-induced, associated with cancer, or due to lymphogranuloma venereum; if they were pregnant; or if they had multiple fistula. A research assistant at each site randomly allocated participants 1:1 (randomly varying block sizes of 4-6; stratified by country) to 7 day or 14 day bladder catheterisation (via a random allocation sequence computer generated centrally by WHO). Outcome assessors were not masked to treatment assignment. The primary outcome was fistula repair breakdown, on the basis of dye test results, any time between 8 days after catheter removal and 3 months after surgery. The non-inferiority margin was 10%, assessed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01428830. FINDINGS: We randomly allocated 524 participants between March 7, 2012, and May 6, 2013; 261 in the 7 day group and 263 in the 14 day group. In the per-protocol analysis, ten (4%) of 250 patients had repair breakdown in the 7 day group (95% CI 2-8) compared with eight (3%) of 251 (2-6) in the 14 day group (risk difference 0·8% [95% CI -2·8 to 4·5]), meeting the criteria for non-inferiority. INTERPRETATION: 7 day bladder catheterisation after repair of simple fistula is non-inferior to 14 day catheterisation and could be used for management of women after repair of simple fistula with no evidence of a significantly increased risk of repair breakdown, urinary retention, or residual incontinence up to 3 months after surgery. FUNDING: US Agency for International Development.

Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys.

BACKGROUND: Rates of caesarean section surgery are rising worldwide, but the determinants of this increase, especially in low-income and middle-income countries, are controversial. In this study, we aimed to analyse the contribution of specific obstetric populations to changes in caesarean section rates, by using the Robson classification in two WHO multicountry surveys of deliveries in health-care facilities. The Robson system classifies all deliveries into one of ten groups on the basis of five parameters: obstetric history, onset of labour, fetal lie, number of neonates, and gestational age. METHODS: We studied deliveries in 287 facilities in 21 countries that were included in both the WHO Global Survey of Maternal and Perinatal Health (WHOGS; 2004-08) and the WHO Multi-Country Survey of Maternal and Newborn Health (WHOMCS; 2010-11). We used the data from these surveys to establish the average annual percentage change (AAPC) in caesarean section rates per country. Countries were stratified according to Human Development Index (HDI) group (very high/high, medium, or low) and the Robson criteria were applied to both datasets. We report the relative size of each Robson group, the caesarean section rate in each Robson group, and the absolute and relative contributions made by each to the overall caesarean section rate. FINDINGS: The caesarean section rate increased overall between the two surveys (from 26.4% in the WHOGS to 31.2% in the WHOMCS, p=0.003) and in all countries except Japan. Use of obstetric interventions (induction, prelabour caesarean section, and overall caesarean section) increased over time. Caesarean section rates increased across most Robson groups in all HDI categories. Use of induction and prelabour caesarean section increased in very high/high and low HDI countries, and the caesarean section rate after induction in multiparous women increased significantly across all HDI groups. The proportion of women who had previously had a caesarean section increased in moderate and low HDI countries, as did the caesarean section rate in these women. INTERPRETATION: Use of the Robson criteria allows standardised comparisons of data across countries and timepoints and identifies the subpopulations driving changes in caesarean section rates. Women who have previously had a caesarean section are an increasingly important determinant of overall caesarean section rates in countries with a moderate or low HDI. Strategies to reduce the frequency of the procedure should include avoidance of medically unnecessary primary caesarean section. Improved case selection for induction and prelabour caesarean section could also reduce caesarean section rates. FUNDING: None.

Non-inferiority of short-term urethral catheterization following fistula repair surgery: study protocol for a randomized controlled trial.

BACKGROUND: A vaginal fistula is a devastating condition, affecting an estimated 2 million girls and women across Africa and Asia. There are numerous challenges associated with providing fistula repair services in developing countries, including limited availability of operating rooms, equipment, surgeons with specialized skills, and funding from local or international donors to support surgeries and subsequent post-operative care. Finding ways of providing services in a more efficient and cost-effective manner, without compromising surgical outcomes and the overall health of the patient, is paramount. Shortening the duration of urethral catheterization following fistula repair surgery would increase treatment capacity, lower costs of services, and potentially lower risk of healthcare-associated infections among fistula patients. There is a lack of empirical evidence supporting any particular length of time for urethral catheterization following fistula repair surgery. This study will examine whether short-term (7 day) urethral catheterization is not worse by more than a minimal relevant difference to longer-term (14 day) urethral catheterization in terms of incidence of fistula repair breakdown among women with simple fistula presenting at study sites for fistula repair service. METHODS/DESIGN: This study is a facility-based, multicenter, non-inferiority randomized controlled trial (RCT) comparing the new proposed short-term (7 day) urethral catheterization to longer-term (14 day) urethral catheterization in terms of predicting fistula repair breakdown. The primary outcome is fistula repair breakdown up to three months following fistula repair surgery as assessed by a urinary dye test. Secondary outcomes will include repair breakdown one week following catheter removal, intermittent catheterization due to urinary retention and the occurrence of septic or febrile episodes, prolonged hospitalization for medical reasons, catheter blockage, and self-reported residual incontinence. This trial will be conducted among 512 women with simple fistula presenting at 8 study sites for fistula repair surgery over the course of 24 months at each site. DISCUSSION: If no major safety issues are identified, the data from this trial may facilitate adoption of short-term urethral catheterization following repair of simple fistula in sub-Saharan Africa and Asia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01428830.

Misoprostol to prevent and treat postpartum haemorrhage: a systematic review and meta-analysis of maternal deaths and dose-related effects.

OBJECTIVE: To review maternal deaths and the dose-related effects of misoprostol on blood loss and pyrexia in randomized trials of misoprostol use for the prevention or treatment of postpartum haemorrhage. METHODS: We searched the Cochrane Controlled Trials Register and Pubmed, without language restrictions, for '(misoprostol AND postpartum) OR (misoprostol AND haemorrhage) OR (misoprostol AND hemorrhage)', and we evaluated reports identified through the Cochrane Pregnancy and Childbirth Group search strategy. Randomized trials comparing misoprostol with either placebo or another uterotonic to prevent or treat postpartum haemorrhage were checked for eligibility. Data were extracted, tabulated and analysed with Reviewer Manager (RevMan) 4.3 software. FINDINGS: We included 46 trials with more than 40,000 participants in the final analysis. Of 11 deaths reported in 5 trials, 8 occurred in women receiving >or= 600 microg of misoprostol (Peto odds ratio, OR: 2.49; 95% confidence interval, CI: 0.76-8.13). Severe morbidity, defined as the need for major surgery, admission to intensive care, organ failure or body temperature >or= 40 degrees C, was relatively infrequent. In prevention trials, severe morbidity was experienced by 16 of 10,281 women on misoprostol and by 16 of 10,292 women on conventional uterotonics; in treatment trials, it was experienced by 1 of 32 women on misoprostol and by 1 of 32 women on conventional uterotonics. Misoprostol recipients experienced more adverse events than placebo recipients: 8 of 2070 versus 5 of 2032, respectively, in prevention trials, and 5 of 196 versus 2 of 202, respectively, in treatment trials. Meta-analysis of direct and adjusted indirect comparisons of the results of randomized trials showed no evidence that 600 microg are more effective than 400 microg for preventing blood loss > 1000 ml (relative risk, RR: 1.02; 95% CI: 0.71-1.48). Pyrexia was more than twice as common among women who received > 600 microg rather than 400 microg of misoprostol (RR: 2.53; 95% CI: 1.78-3.60). CONCLUSION: Further research is needed to more accurately assess the potential beneficial and harmful effects of misoprostol and to determine the smallest dose that is effective and safe. In this review, 400 microg of misoprostol were found to be safer than > 600 microg and just as effective.