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Background: Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles., Objectives: To compare the effectiveness, and maternal and perinatal safety outcomes of IOL with vaginal misoprostol versus vaginal dinoprostone using individual participant data from randomised clinical trials., Search Strategy: The following databases were searched from inception to March 2023: CINAHL Plus, ClinicalTrials.gov, Cochrane Pregnancy and Childbirth Group Trial Register, Ovid Embase, Ovid Emcare, Ovid MEDLINE, Scopus and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)., Selection Criteria: Randomised controlled trials (RCTs), with viable singleton gestation, no language restrictions, and all published and unpublished data., Data Collection and Analysis: An individual participant data meta-analysis was carried out., Main Results: Ten of 52 eligible trials provided individual participant data, of which two were excluded after checking data integrity. The remaining eight trials compared low-dose vaginal misoprostol versus dinoprostone, including 4180 women undergoing IOL, which represents 32.8% of all participants in the published RCTs. Of these, 2077 were assigned to low-dose vaginal misoprostol and 2103 were assigned to vaginal dinoprostone. Compared with vaginal dinoprostone, low-dose vaginal misoprostol had a comparable rate of vaginal birth. Composite adverse perinatal outcomes did not differ between the groups. Compared with vaginal dinoprostone, composite adverse maternal outcomes were significantly lower with low-dose vaginal misoprostol (aOR 0.80, 95% CI 0.65-0.98, P = 0.03, I 2  = 0%)., Conclusions: Low-dose vaginal misoprostol and vaginal dinoprostone for IOL are comparable in terms of effectiveness and perinatal safety. However, low-dose vaginal misoprostol is likely to lead to a lower rate of composite adverse maternal outcomes than vaginal dinoprostone., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Aims: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations., Methods: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation., Results: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC 0-t and C max ratios were well within 2-fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC 0-t and C max ratios were well within 2-fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83)., Conclusion: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future., (© 2024 British Pharmacological Society.)

Background: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored., Objectives: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP., Search Strategy: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023., Selection Criteria: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications., Data Collection and Analysis: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology., Main Results: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I 2  = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I 2  = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I 2  = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I 2  = 0%; low-certainty evidence)., Conclusions: Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Vaginal progesterone therapy significantly reduces preterm birth (PTB) rates in those high-risk pregnancies with a sonographic short cervix (≤25 mm) and/or a history of spontaneous PTB. Cervical length (CL) is routinely measured at the midtrimester morphology scan; however, CL surveillance thereafter is not currently recommended. Progesterone's precise mechanism of action remains unknown, though if it indeed influences CL, shortening after treatment initiation could indicate therapeutic failure and risk of PTB., Aims: The aim was to explore the utility of serial transvaginal ultrasound (TVU) measurement of CL at 16, 19 and 22 weeks for predicting PTB in high-risk pregnancies prescribed progesterone therapy., Methods: A retrospective cohort study was conducted involving women who attended the King Edward Memorial Hospital PTB Prevention Clinic from 2015 to 2019 and were prescribed progesterone therapy. CL was measured at 16, 19 and 22 weeks by TVU. CL change across three time points was assessed using linear mixed models; then relationships between CL change between 16-19 and 19-22 weeks and PTB were analysed using logistic regression models., Results: Term birth was most likely when CL did not decrease across both time periods. The addition of 16-19 week decrease in CL to a model, including CL at 19 weeks alone, for predicting PTB increased sensitivity from 43.2 to 56.3%, specificity from 73.2 to 77.4%, and overall accuracy from 61.7 to 70.2%., Conclusion: For high-risk women prescribed vaginal progesterone therapy, serial measurement of the cervix at 16 and 19 weeks improves clinical ability to predict PTB from current recommendations of 19-week measurement alone., (© 2022 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Increasingly, births around the world are started artificially using medications or other methods. This process is known as induction of labour. As it becomes more common, methods are needed to meet the different clinical needs and birth preferences of women. Induction of labour typically includes a combination of the medication dinoprostone inserted into the vagina, artificial rupture of membranes ('releasing the waters'), and synthetic oxytocin (hormone given via a drip). This paper reviews some of the methods less commonly used for induction in the UK, namely a drug called misoprostol, which can be given orally or vaginally, and 'mechanical' methods, where labour is started by stretching the cervix (neck of the womb), most commonly with a soft silicone tube with a balloon near the tip, filled with water. Low-dose oral misoprostol tablets are now commercially available in the UK. Other methods for labour induction are not reviewed in detail in this paper. The evidence suggests mechanical induction of labour (using a balloon catheter) and misoprostol are both at least as safe and effective as using the standard drug, dinoprostone. There is evidence to suggest a balloon catheter may reduce the chance of serious negative outcomes for babies when compared with dinoprostone, and that giving low-dose oral misoprostol results in fewer caesarean births. Where possible and after informed consent, the method of induction of labour should be personalised to suit the individual woman, her clinical condition, and the setting in which she is giving birth. Local contexts and resources also need to be taken into account. To date, research into women's perspectives and experiences of induction of labour have been significantly lacking., (© 2022 John Wiley & Sons Ltd.)

Objective: To evaluate whether locally applied vaginal estrogen affects prolapse-associated complaints compared with placebo treatment in postmenopausal women prior to surgical prolapse repair., Design: Randomised, double-masked, placebo-controlled, multicentre study., Setting: Urogynaecology unit at the Medical University of Vienna and University Hospital of Tulln., Population: Postmenopausal women with symptomatic pelvic organ prolapse and planned surgical prolapse repair., Methods: Women were randomly assigned local estrogen cream or placebo cream 6 weeks preoperatively., Main Outcome Measures: The primary outcome was differences in subjective prolapse-associated complaints after 6 weeks of treatment prior to surgery, assessed with the comprehensive German pelvic floor questionnaire. Secondary outcomes included differences in other pelvic floor-associated complaints (bladder, bowel or sexual function)., Results: Out of 120 women randomised, 103 (86%) remained for the final analysis. After 6 weeks of treatment the prolapse domain score did not differ between the estrogen and the placebo groups (4.4 ± 0.19 versus 4.6 ± 0.19; mean difference, -0.21; 95% CI -0.74 to 0.33; P = 0.445). Multivariate analysis, including only women receiving the intervention, showed that none of the confounding factors modified the response to estradiol., Conclusions: These results demonstrate that preoperative locally applied estrogen does not ameliorate prolapse-associated symptoms in postmenopausal women with symptomatic pelvic organ prolapse., Tweetable Abstract: Preoperative local estrogen does not ameliorate prolapse-associated symptoms in postmenopausal women with pelvic organ prolapse., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Oral misoprostol is widely used for induction of labour (IOL) in developing countries because of its many advantages. However, limited data exist concerning its safety and efficacy when lower doses are used., Aim: To determine the safety and efficacy of a low-dose oral misoprostol regimen (commencing at 12 μg) compared to a standard-dose regimen (commencing at 25 μg) in Papua New Guinea (PNG) women undergoing IOL., Materials and Methods: This was an open-label non-inferiority randomised controlled trial conducted at a provincial hospital in PNG. Women with singleton pregnancies ≥36 weeks with cephalic presentation and a Bishops score of <6, requiring IOL were enrolled. Both regimens were incremented second-hourly to a maximum required dose within 24 h or until commencement of labour. The primary outcome was the proportion of women who delivered within 24 h of drug administration without any severe adverse events., Results: Of the 262 women induced (130 standard-dose vs 132 low-dose), rates of successful induction were high for both regimens (120/130 (92%) vs 118/132 (89%); P = 0.52). Fourteen women (11%) in the standard-dose regimen and 20 (15%) in the low-dose regimen had severe adverse events. There was no significant difference in the safety profile of the two regimens (106/130 (82%) vs 98/132 (74%); P = 0.18). The induction-to-delivery time was significantly shorter in the standard-dose arm (15.2 ± 8.7 h vs 18.0 ± 9.1 h; P = 0.01)., Conclusion: The standard-dose regimen for IOL has greater efficacy in reducing induction-to-delivery time compared to the low-dose regimen. There was no significant difference in the number of adverse events between the two regimens., (© 2021 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature., Design: A multicentre, randomised, open-label, equivalence trial and a meta-analysis., Setting: Tertiary referral hospitals in South Korea., Population: Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm)., Methods: Eligible women were screened and randomised at 16-22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α-hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237)., Main Outcome Measure: Preterm birth (PTB) before 37 weeks of gestation., Results: A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention-to-treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI -7.6 to 13.8%), which was within the equivalence margin of 15%. The meta-analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments., Conclusion: Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length., Tweetable Abstract: Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Background: Threatened miscarriage is a common complication of pregnancy. Results of randomised controlled trials on the efficacy of progestogen in the treatment of threatened miscarriage remain inconsistent., Objective: To investigate whether the use of progestogen is associated with improved event rate of live birth and other benefits in women with threatened miscarriage., Search Strategy: Ovid MEDLINE, Ovid Embase and Cochrane CENTRAL Register of Controlled Trials from their inception until 8 July 2019., Selection Criteria: Randomised controlled trials comparing progestogen with a placebo or no treatment for pregnancy outcomes in women with threatened miscarriage., Data Collection and Analysis: Two authors independently conducted data extraction and assessed study quality. We calculated risk ratios (RR) and 95% confidence intervals using the Mantel-Haenszel approach for dichotomous outcomes., Main Results: Ten trials with a total of 5056 participants were eligible for analysis. The use of progesterone increased the incidence of live birth (RR 1.07, 95% CI 1.00-1.15; P = 0.04; I 2  = 18%), with benefit only seen with the use of oral progestogen (RR 1.17, 95% CI 1.04-1.31; P = 0.008; I 2  = 0%) and not with vaginal progesterone (RR 1.04, 95% CI 1.00-1.08; P = 0.07; I 2  = 0%). Similarly, progestogen reduced the risk of miscarriage (RR 0.73, 95% CI 0.59-0.92), with benefit only seen with oral progestogen and not with vaginal progesterone., Conclusion: Progestogens may have benefits on live birth rate and miscarriage rate for women with threatened miscarriage. These benefits appear to be confined to the use of oral progestogen, and no statistically significant improvements were seen with vaginal progesterone., Tweetable Abstract: A meta-analysis of 10 trials found that progestogens increased live birth rates and reduced miscarriage rates for women with threatened miscarriage., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Objective: To investigate whether women using intravaginal progesterone suppositories for preterm birth prevention during pregnancy will have lower rates of group B streptococcus (GBS) colonisation at term, compared with women receiving intramuscular 17-alpha-hydroxyprogesterone caproate., Design: This was a retrospective observational cohort study of women who were prescribed a progestogen during their pregnancy for preterm birth prevention, and who delivered at term., Setting: A tertiary referral hospital in central Ohio., Population: Patients who were prescribed a progestogen during their pregnancy for preterm birth prevention between 2004 and 2017 were included in the study. Patients who delivered at <37 weeks of pregnancy, switched progestogen type during the pregnancy, or had a pessary or cerclage placed were excluded., Methods: Baseline characteristics were compared using Mann-Whitney U-test or Chi-square test as appropriate. The association between type of progestogen and GBS colonisation was assessed using bivariate and multivariable analyses., Main Outcome Measures: The primary outcome was GBS colonisation., Results: In all, 565 patients were included in the study, of whom 173 received intravaginal progesterone, and 392 17-alpha-hydroxyprogesterone caproate. Patients receiving intravaginal progesterone were less likely to be colonised with GBS (19.7 versus 28.1%). After adjustments for potential confounders were made in a multivariable logistic regression analysis, receiving intravaginal progesterone suppositories (adjusted odds ratio [OR] 0.61, 95% CI 0.39-0.95) was associated with reduced GBS colonisation., Conclusions: Intravaginal progesterone is associated with a decreased prevalence of rectovaginal GBS colonisation at term., Tweetable Abstract: Vaginal progesterone is associated with a lower incidence of rectovaginal GBS colonisation, compared with 17α-hydroxyprogesterone caproate., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Objective: To compare the World Health Organization (WHO) recommended orally administrated dosage of misoprostol (25 μg) with a vaginal slow-release (7 μg/hour) insert of misoprostol regarding time from induction to delivery and safety of the method., Design: Open label, Randomised controlled trial (RCT)., Setting: Delivery ward at a secondary referral hospital in Stockholm, Sweden, from 1 October 2016 to 21 February 2018., Population: One hundred and ninety-six primiparous women with singletons in cephalic presentation at ≥37 weeks of gestation and with a Bishop score of ≤4., Methods: Women were randomised to an oral solution of misoprostol (Cytotec ® n = 99) or vaginal slow-release misoprostol (Misodel ® [MVI] n = 97)., Main Outcome Measures: Primary outcome: time from induction to vaginal delivery., Secondary Outcomes: mode of delivery; proportion of vaginal deliveries within 24 hours (VD24); neonates with an Apgar score of <7 at 5 minutes; pH < 7.10; postpartum haemorrhage (PPH) of >1000 ml; hyperstimulation; and women's delivery experience (VAS)., Results: There was no difference in the time to delivery [corrected] (median 21.1 hours in the MVI group and 23.2 hours in the oral group; Kaplan-Mayer log rank P = 0.31). There was no difference regarding the proportion of VD24 (50.5 versus 55.7%, P = 0.16). Hyperstimulation with non-reassuring cardiotocography (CTG) was more common in the MVI group (14.4 versus 3.0%, P < 0.01). Terbutaline (Bricanyl ® ) was used more often for hyperstimulation in the MVI group (22.7 versus 4.0%, P < 0.01). There was no difference in the numbers of children admitted to the neonatal intensive care unit (NICU)., Conclusions: Vaginal delivery after induction of labour (IOL) with slow-release misoprostol did not result in a shorter time from induction to vaginal delivery, compared with oral misoprostol solution, but was associated with a higher risk for hyperstimulation and fetal distress. There were no differences in mode of delivery or neonatal outcome., Tweetable Abstract: IOL with MVI was similar to oral solution of misoprostol but hyperstimulation and fetal distress were more common., (© 2019 Royal College of Obstetricians and Gynaecologists.)

The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90-100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapid-sampling microdialysis (1 sample/min) and high-performance liquid chromatography-tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non-dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5-s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5-s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: To study the tocolytic action of nifedipine combined with sildenafil citrate (SC) and if the combination is superior to nifedipine alone in inhibiting threatened preterm labour (PTL)., Design: Prospective randomised study., Setting: An Egyptian university hospital., Population: Women with threatened PTL who received either nifedipine with SC or nifedipine alone., Methods: Patients were randomly allocated to receive either (1) nifedipine 20 mg orally (stat dose), followed by 10 mg orally every 6-8 hours at the same time as vaginal administration of SC (25 mg at 8-hourly intervals) or (2) nifedipine alone. Medications were continued for 48-72 hours., Main Outcome Measures: The percentage of women who remained undelivered during hospitalisation., Results: From January 2015 to November 2016, 239 women were randomised. The baseline characteristics of participants were similar. Nifedipine combined with SC was associated with more women remaining undelivered (81.8 versus 68.6%; P = 0.018) during hospitalisation. Regarding secondary outcomes, the addition of SC was also associated with fewer deliveries within 7 days of admission (9.1 versus 20.3%; P = 0.014), prolonged latency (29 versus 7 days; P = 0.002), fewer admissions to neonatal intensive care units (31.4 versus 44.1%; P = 0.043), fewer very preterm deliveries (from 28 to <32 weeks, 20.7 versus 38.1%; P = 0.043), and increased neonatal birthweight (1900 versus 1500 g; P = 0.018)., Conclusions: Vaginal SC combined with nifedipine is an effective option for tocolytic therapy during threatened PTL., Tweetable Abstract: Vaginal SC enhances the tocolytic effect of nifedipine., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Background: Recent progesterone trials call for an update of previous syntheses of interventions to prevent preterm birth., Objectives: To compare the relative effects of different types and routes of administration of progesterone, cerclage, and pessary at preventing preterm birth in at-risk women overall and in specific populations., Search Strategy: We searched Medline, EMBASE, CINAHL, Cochrane CENTRAL, and Web of Science up to 1 January 2018., Selection Criteria: We included randomised trials of progesterone, cerclage or pessary for preventing preterm birth in at-risk singleton pregnancies., Data Collection and Analysis: We used a piloted data extraction form and performed Bayesian random-effects network meta-analyses with 95% credibility intervals (CrI), as well as pairwise meta-analyses, rating the quality of the evidence using GRADE., Main Results: We included 40 trials (11 311 women). In at-risk women overall, vaginal progesterone reduced preterm birth <34 (OR 0.43, 95% CrI 0.20-0.81) and <37 weeks (OR 0.51, 95% CrI 0.34-0.74), and neonatal death (OR 0.41, 95% CrI 0.20-0.83). In women with a previous preterm birth, vaginal progesterone reduced preterm birth <34 (OR 0.29, 95% CI 0.12-0.68) and <37 weeks (OR 0.43, 95% CrI 0.23-0.74), and 17α-hydroxyprogesterone caproate reduced preterm birth <37 weeks (OR 0.53, 95% CrI 0.27-0.95) and neonatal death (OR 0.39, 95% CI 0.16-0.95). In women with a short cervix (≤25 mm), vaginal progesterone reduced preterm birth <34 weeks (OR 0.45, 95% CI 0.24-0.84)., Conclusions: Vaginal progesterone was the only intervention with consistent effectiveness for preventing preterm birth in singleton at-risk pregnancies overall and in those with a previous preterm birth., Tweetable Abstract: In updated NMA, vaginal progesterone consistently reduced PTB in overall at-risk pregnancies and in women with previous PTB., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Background: There is a lack of consensus on the optimal dose and form of progesterone supplementation during frozen-thawed embryo transfer with hormone replacement therapy., Aims: We aim to identify the serum progesterone concentration on day 16 most likely to result in positive pregnancy outcomes., Materials and Methods: We undertook a retrospective study of 4582 women who underwent frozen embryo transfer with hormone replacement therapy, or natural frozen embryo transfer, over 14 years at a multi-site private in vitro fertilisation clinic. Embryos were 3-5 days of age at time of transfer. We extracted data on serum progesterone concentrations and outcomes, as well as dose and form of progesterone supplementation, from patient and pharmacy records., Results: Increased live birth rates for frozen embryo transfer with hormone replacement therapy were seen with day 16 serum progesterone concentrations >50 nmol/L (26.4% vs 11.3% for <50 nmol/L; adjusted odds ratio (OR) 3.14 (95% CI 2.21-4.48)). Similarly, a decreased pregnancy loss rate was seen in this group (14.3% vs 32.6% for ≤50 nmol/L; adjusted OR 0.26 (95% CI 0.12-0.58)). There was a positive correlation between live births and the number of progesterone doses per day (r = 0.119, P = 0.026) and day 16 progesterone concentrations (r = 0.128, P = 0.011)., Conclusion: Improved pregnancy outcomes are seen with day 16 serum progesterone concentrations >50 nmol/L. There is a statistically significant correlation between live births, number of progesterone doses per day and day 16 serum progesterone concentrations in this study., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Aims: A physiologically-based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring or film., Methods: A PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB. Literature reviews provided estimates for relevant physiological and physiochemical parameters. Drug concentration-time profiles were simulated in luminal fluids, vaginal tissue and plasma after administration of ring or film. Patient data were extracted from published clinical trials and used to test model predictions., Results: The DPV ring simulations tested the two dosing regimens and predicted PK profiles and area under the curve of luminal fluids (29 079 and 33 067 mg h l -1 in groups A and B, respectively) and plasma (0.177 and 0.211 mg h l -1 ) closely matched those reported (within one standard deviation). While the DPV film study reported drug concentration at only one time point per patient, our simulated profiles pass through reported concentration range., Conclusions: HIV is a major public health issue and vaginal microbicides have the potential to provide a crucial, female-controlled option for protection. The PBPK model successfully simulated realistic representations of drug PK. It provides a reliable, inexpensive and accessible platform where potential effectiveness of new compounds and the robustness of treatment modalities for pre-exposure prophylaxis can be evaluated., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: To evaluate the effect of adjuvants during intensive vaginal dilator therapy for functional and anatomical neovagina creation in women with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH)., Methods: This retrospective cohort study included 75 women with MRKH undergoing intensive vaginal dilator treatment between 2000 and 2014. One specialist nurse performed non-surgical vaginal dilation aided by adjuvants, during inpatient admissions for several dilation sessions per day. Following discharge, women continued dilation at home and were advised to attend fortnightly follow-up appointments., Results: Outcomes from 68 women were analysed. The median age of starting treatment was 18 years (range: 13-36). There was a mean of 3 days per admission (range 1-5) with a median of 10 dilation sessions per admission. Adjuvant treatment was used by 48/68 (71%) women: oestriol cream 29/68 (43%), 50:50 nitrous oxide and oxygen 44/68 (65%), diazepam 8/68 (12%), lidocaine ointment 26/68 (39%), paracetamol 35/68 (51%) and naproxen 2/68 (3%). There were no statistically significant differences for changes in vaginal parameters. Women receiving adjuvants had a median increase of 4.5 cm (0.5-7 cm) in neovaginal length compared with women not receiving adjuvants who had a median increase of 3.25 cm (0-7 cm) during intensive treatment. Women who received adjuvants tolerated more dilation sessions per day (10 vs 6.5 median sessions respectively) than those who did not (P < 0.001). Of those with documented length at discharge, 42/56 (75%) women had an anatomical neovagina of 7 cm or greater length., Conclusions: Vaginal dilation delivered by intensive treatment and supplemented by adjuvant treatments in a multi-disciplinary centre is a rapid and effective method for creation of a neovagina in women with MRKH., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Lasioglossins are a group of peptides with identified antimicrobial activity. The inhibitory effects of two synthetic lasioglossin derivatives, LLIII and D-isomeric variant LLIII-D, on morphological changes in Candida albicans in vitro and the effect of local administration of LLIII during experimental murine candidiasis were investigated. C. albicans blastoconidia were grown in the presence of lasioglossin LLIII or LLIII-D at concentrations of 11.5 μM and 21 μM, respectively, for 1, 2 and 3 days and their viability determined by flow cytometry using eosin Y staining. Morphological changes were examined by light and fluorescent microscopy. The Candida-inhibitory effect of daily intravaginal administration of 0.7 or 1.4 μg of LLIII was assessed in mice with experimentally-induced vaginal candidiasis. LLIII and LLIII-D lasioglossins exhibited candidacidal activity in vitro (>76% after 24 hr and >84% after 48 hr of incubation). After 72 hr incubation of Candida with low concentration of lasioglossins, an increase in viability was detected, probably due to a Candida antimicrobial peptides evasion strategy. Furthermore, lasioglossins inhibited temperature-induced morphotype changes toward hyphae and pseudohyphae with sporadic occurrence of atypical cells with two or enlarged nuclei, suggesting interference with mitosis or cytokinesis. Local application of LLIII reduced the duration of experimental candidiasis with no evidence of adverse effects. Lasioglossin LLIII is a promising candidate for development as an antimicrobial drug for treating the vaginal candidiasis., (© 2017 The Societies and John Wiley & Sons Australia, Ltd.)

Autoimmune progesterone dermatitis (APD) is a rare skin condition with a varying morphology, which appears on a monthly basis during the luteal phase of the menstrual cycle and resolves spontaneously with the endogenous decrease in progesterone during menses. We present the case of 39-year-old multiparous Caucasian woman with generalised, self-limited urticaria in her perimenstrual period. APD was diagnosed in light of the cyclical nature of the symptoms. An intradermal test with the administration of 0.5 mg/mL of medroxyprogesterone acetate showed a positive result. She started using vaginal hormonal contraceptive that paradoxically exacerbate the symptoms, which ceased after the removal of the device. An oral combined contraceptive was initiated instead, with complete resolution of the symptoms. We share the case because of the rarity of the situation, emphasising the importance of a multidisciplinary team for differential diagnosis and patient follow up., (© 2016 The Australasian College of Dermatologists.)

Background: About half of twin pregnancies deliver preterm, and it is unclear whether any intervention reduces this risk., Objectives: To assess the evidence for the effectiveness of progesterone, cerclage, and pessary in twin pregnancies., Search Strategy: We searched Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and ISI Web of Science, without language restrictions, up to 25 January 2016., Selection Criteria: Randomised controlled trials of progesterone, cerclage, or pessary for preventing preterm birth in women with twin pregnancies, without symptoms of threatened preterm labour., Data Collection and Analysis: Two independent reviewers extracted data using a piloted form. Study quality was appraised with the Cochrane Risk of Bias tool. We performed pairwise inverse variance random-effects meta-analyses., Main Results: We included 23 trials (all but three were considered to have a low risk of bias) comprising 6626 women with twin pregnancies. None of the interventions significantly reduced the risk of preterm birth overall at <34 or <37 weeks of gestation, or neonatal death, our primary outcomes, compared to a control group. In women receiving vaginal progesterone, the relative risk (RR) of preterm birth <34 weeks of gestation was 0.82 (95% CI 0.64-1.05, seven studies, I 2  36%), with a significant reduction in some key secondary outcomes, including very low birthweight (<1500 g, RR 0.71, 95% CI 0.52-0.98, four studies, I 2  46%) and mechanical ventilation (RR 0.61, 95% CI 0.45-0.82, four studies, I 2  22%)., Conclusion: In twin gestations, although no overarching intervention was beneficial for the prevention of preterm birth and its sequelae, vaginal progesterone improved some important secondary outcomes., Tweetable Abstract: Vaginal progesterone may be beneficial in twin pregnancies, but not 17-OHPC, cerclage, or pessary., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Background: Preterm birth (PTB) is the leading cause of infant death, but it is unclear which intervention is best to prevent it., Objectives: To compare progesterone, cerclage and pessary, determine their relative effects and rank them., Search Strategy: We searched Medline, EMBASE, CINAHL, Cochrane CENTRAL and Web of Science (to April 2016), without restrictions, and screened references of previous reviews., Selection Criteria: We included randomised trials of progesterone, cerclage or pessary for preventing PTB in women with singleton pregnancies at risk as defined by each study., Data Collection and Analysis: We extracted data by duplicate using a piloted form and performed Bayesian random-effects network meta-analyses and pairwise meta-analyses. We rated evidence quality using GRADE, ranked interventions using SUCRA and calculated numbers needed to treat (NNT)., Main Results: We included 36 trials (9425 women; 25 low risk of bias trials). Progesterone ranked first or second for most outcomes, reducing PTB < 34 weeks [odds ratio (OR) 0.44; 95% credible interval (CrI) 0.22-0.79; NNT 9; low quality], <37 weeks (OR 0.58; 95% CrI 0.41-0.79; NNT 9; moderate quality), and neonatal death (OR 0.50; 95% CrI 0.28-0.85; NNT 35; high quality), compared with control, in women overall at risk. We found similar results in the subgroup with previous PTB, but only a reduction of PTB < 34 weeks in women with a short cervix. Pessary showed inconsistent benefit and cerclage did not reduce PTB < 37 or <34 weeks., Conclusions: Progesterone was the best intervention for preventing PTB in singleton pregnancies at risk, reducing PTB < 34 weeks, <37 weeks, neonatal demise and other sequelae., Tweetable Abstract: Progesterone was better than cerclage and pessary to prevent preterm birth, neonatal death and more in network meta-analysis., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Ultrasound measurement of cervical length in the general population enables the identification of women at risk for spontaneous preterm delivery. Vaginal progesterone is effective in reducing the risk of preterm delivery in this population. This screening associated with treatment by vaginal progesterone is cost-effective. Universal screening of cervical length can therefore be considered justified. Nonetheless, this screening will not appreciably reduce the preterm birth prevalence: in France or UK, where the preterm delivery rate is around 7.4%, this strategy would make it possible to reduce it only to 7.0%. This small benefit must be set against the considerable effort required in terms of screening ultrasound scans., Tweetable Abstract: Universal ultrasound screening of cervical length is the inverse of Pareto's principle: a small benefit against a considerable effort., (© 2016 Royal College of Obstetricians and Gynaecologists.)

The high prevalence of herpes simplex virus 2 (HSV-2) infections in humans necessitates the development of a safe and effective vaccine that will need to induce vigorous T-cell responses to control viral infection and transmission. We designed rAd-gD2, rAd-gD2ΔUL25, and rAd-ΔUL25 to investigate whether recombinant replication-defective adenoviruses vaccine could induce specific T-cell responses and protect mice against intravaginal HSV-2 challenge compared with FI-HSV-2. In the present study, recombinant adenovirus-based HSV-2 showed higher reductions in mortality and stronger antigen-specific T-cell responses compared with FI-HSV-2 and the severity of genital lesions in mice immunized with rAd-gD2ΔUL25 was significantly decreased by eliciting IFN-γ-secreting T-cell responses compared with rAd-gD2 and rAd-ΔUL25 groups. Our results demonstrated the immunogenicity and protective efficacy of recombinant adenovirus vaccines in acute HSV-2 infection following intravaginal challenge in mice., (© 2017 The Societies and John Wiley & Sons Australia, Ltd.)

Objective: To assess adverse event (AE) resolution, delivery mode and neonatal outcomes after misoprostol or dinoprostone vaginal insert (MVI or DVI) retrieval due to AE during induction of labour (IOL)., Design: Randomised, double-blind trial, EXPEDITE., Setting: Thirty five obstetric departments, USA., Population: Consisted of 1358 pregnant women with modified Bishop score ≤4 eligible for pharmacological IOL., Methods: Post hoc analysis., Main Outcome Measures: AEs prompting insert retrieval, times to AE resolution, delivery, delivery mode and neonatal intensive care unit (NICU) admissions., Results: 77/678 (11.4%) and 27/680 (4.0%) women had MVI and DVI retrieved due to AE, respectively (P < 0.001). The most common AEs prompting retrieval were uterine tachysystole with fetal heart rate (FHR) involvement and category II/III FHR pattern. Time to AE resolution varied for both treatments depending on the type of AE. For uterine tachysystole with FHR involvement, median resolution times were 1 hour 34.5 minutes (n = 36) and 8.5 minutes (n = 8) for MVI and DVI, respectively. Caesarean delivery occurred in a high proportion of women with insert retrieved due to AE (MVI: 44/77 (57.1%); DVI: 19/27 (70.4%)); the majority of caesareans were performed at least several hours after insert retrieval. Median times from retrieval to any delivery were not increased for women with insert retrieved due to AE. NICU admissions were 8/77 (10.4%) and 1/27 (3.7%) for MVI and DVI, respectively (P = 0.440)., Conclusions: AEs leading to insert retrieval were primarily uterine tachysystole with FHR involvement and category II/III FHR patterns. Insert retrieval due to an AE did not prolong time to delivery for either prostaglandin insert., Tweetable Abstract: Induction with prostaglandin vaginal inserts: outcomes following retrieval due to intrapartum adverse event., (© 2016 Ferring Pharmaceuticals. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Background: Medical management of miscarriage allows women to avoid the risks associated with surgical intervention. In 2011 the early pregnancy assessment service (EPAS) at the Royal Prince Alfred Hospital (RPAH) in Sydney, Australia introduced medical management of miscarriage with single-dose 800 μg vaginal misoprostol., Aims: We sought to investigate the impact of the introduction of medical management had on the proportion of women having surgery and conservative management and to examine the success and complication rates of medical management., Materials and Methods: We undertook a retrospective cohort study that included all women diagnosed with a miscarriage from 12 months prior to and 18 months after the introduction of medical management. Successful management was defined as the absence of retained products of conception or endometrial thickness less than 15 mm on ultrasound at two weeks. The change in management choices over time, the success rates and complication rates were measured., Results: Of 1102 women in the final analysis, 446 were in Group A (before medical management) and 656 in Group B (after medical management). Primary surgical procedures fell significantly for missed miscarriages from 68 to 48% (P < 0.001) and primary conservative management reduced for incomplete miscarriages (63-44%; P = 0.01). Overall 89 of 108 (82.4%) patients managed medically had a resolution within two weeks. One in ten presented with a complication., Discussion: The introduction of medical management led to a statistically significant reduction in the proportion of women undergoing primary surgical management of missed miscarriage. Success and complication rates were similar to other studies., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: The process of induction of labour (IOL) commonly involves cervical ripening, using mechanical or pharmacological methods. However, the optimum protocol of IOL remains undetermined., Aims: To report the maternal, neonatal and process outcomes for women being induced with a balloon catheter or prostaglandin E2 gel (PGE2)., Materials and Methods: Matched retrospective cohort study of women requiring IOL at term with a modified Bishop's score (MBS) <7. Those who underwent cervical ripening with a double balloon catheter were matched 1:1 for parity, indication and MBS score to those using PGE2 gel. The primary outcome measure was mode of birth., Results: After exclusions, data from 427 women induced with a balloon catheter were able to be matched to 427 women induced with PGE2 gel. Compared to women receiving PGE2 gel, those induced using a balloon catheter were more likely to have an unassisted vaginal birth (50.4% vs 42.9%; P = 0.028), a lower mean estimated blood loss (420 vs 481 mL; P = 0.028), a reduction in fetal acidaemia (2.4% vs 8.8%; P = 0.003) and a greater likelihood experiencing vaginal delivery within 24 h (33.7% vs 25.8%; P = 0.011)., Conclusion: Similar to findings in randomised controlled trials and meta-analyses of IOL methods, we observed more unassisted vaginal births, less blood loss, decreased fetal acidaemia, and a greater likelihood of vaginal delivery within 24 h, with use of balloon catheter as compared to PGE2 vaginal gel., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objectives: To compare the clinical effectiveness and cost-effectiveness of labour induction methods., Methods: We conducted a systematic review of randomised trials comparing interventions for third-trimester labour induction (search date: March 2014). Network meta-analysis was possible for six of nine prespecified key outcomes: vaginal delivery within 24 hours (VD24), caesarean section, uterine hyperstimulation, neonatal intensive care unit (NICU) admissions, instrumental delivery and infant Apgar scores. We developed a decision-tree model from a UK NHS perspective and calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit, and cost-effectiveness acceptability curves., Main Results: In all, 611 studies comparing 31 active interventions were included. Intravenous oxytocin with amniotomy and vaginal misoprostol (≥50 μg) were most likely to achieve VD24. Titrated low-dose oral misoprostol achieved the lowest odds of caesarean section, but there was considerable uncertainty in ranking estimates. Vaginal (≥50 μg) and buccal/sublingual misoprostol were most likely to increase uterine hyperstimulation with high uncertainty in ranking estimates. Compared with placebo, extra-amniotic prostaglandin E2 reduced NICU admissions. There were insufficient data to conduct analyses for maternal and neonatal mortality and serious morbidity or maternal satisfaction. Conclusions were robust after exclusion of studies at high risk of bias. Due to poor reporting of VD24, the cost-effectiveness analysis compared a subset of 20 interventions. There was considerable uncertainty in estimates, but buccal/sublingual and titrated (low-dose) misoprostol showed the highest probability of being most cost-effective., Conclusions: Future trials should be designed and powered to detect a method that is more cost-effective than low-dose titrated oral misoprostol., Tweetable Abstract: New study ranks methods to induce labour in pregnant women on effectiveness and cost., (© 2016 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Problem: The capacity of antigen-carrying vaccine nanoparticles (NPs) administered vaginally to stimulate local immune responses may be limited by the relatively low numbers of antigen-presenting cells (APCs) in the genital mucosa. Because inflammation is associated with increased susceptibility to sexually transmitted infections, we sought to increase APC numbers without causing inflammation., Method of Study: In this study, we evaluated intravaginal delivery of chemokines, growth factors, or synthetic adjuvants to expand APCs in reproductive tissues., Results: We found that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated expansion of CD11b+ dendritic cells (DCs) within 24 hr of intravaginal administration, with no effect on Langerhans cells or macrophages. Expansion of the CD11b+ DC population was not associated with increased inflammatory cytokine production, and these cells retained phagocytic function., Conclusion: Our data suggest that non-inflammatory expansion of mucosal APCs by intravaginal GM-CSF could be used as an adjuvanting strategy to potentiate the genital immune response to nanoparticulate mucosal vaccines., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To determine whether the use of vaginal progesterone in twin gestations with a cervical length (CL) of ≤2.5 cm is associated with a reduced risk of preterm delivery., Design: Retrospective cohort study., Setting: Tertiary-care medical centre in New York City., Population: Women with twin gestations undergoing sonographic cervical length screening., Methods: Women with twin gestations with a CL of ≤2.5 cm between 16 and 32 weeks of gestation, and who delivered at our centre between 2010 and 2013, were included. We evaluated the impact of vaginal progesterone on the risk of preterm delivery using a Cox proportional hazard model, adjusted for potential confounding factors. We then performed a propensity score analysis using inverse probability of treatment weights to account for treatment selection bias and confounding., Main Outcome Measure: Delivery prior to 35 weeks of gestation., Results: Of the 167 twin pregnancies analysed, 61 (35.7%) were treated with vaginal progesterone. The hazard ratio (HR) of delivery prior to 35 weeks of gestation in the vaginal progesterone group, compared with the no vaginal progesterone group, was 1.8 (95% confidence interval, 95% CI 1.5-3.1) in the unadjusted analysis, 1.4 (95% CI 0.7-3.2) following multivariable adjustment for confounding factors, and 1.5 (95% CI 1.1-2.3) using propensity score methods., Conclusion: Women with more risk factors for preterm delivery were more likely to be treated with vaginal progesterone. After statistically correcting for this with propensity score methods, we found that vaginal progesterone therapy in twin pregnancies with a CL ≤2.5 cm was associated with an increased risk of preterm delivery., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Background: The optimal dose of misoprostol for the induction of labour remains uncertain., Objectives: To compare the efficacy and safety of 25 versus 50 micrograms of intravaginal misoprostol tablets for the induction of labour and cervical ripening., Search Strategy: We performed electronic and manual searches to identify relevant randomised trials., Selection Criteria: The efficacy outcomes assessed were rates of vaginal delivery within 24 hours, delivery within one dose, and oxytocin augmentation, and interval to delivery. The safety outcomes assessed were incidences of tachysystole, hyperstimulation, caesarean delivery, cesarean delivery for non-reassuring fetal heart rate (FHR), operative vaginal delivery, abnormal 5-minute Apgar score, abnormal cord gas values, admission to a neonatal intensive care unit (NICU), and meconium passage., Data Collection and Analysis: Thirteen studies (1945 women) were included. Relative risk (RR) and 95% confidence intervals (CI) were calculated using fixed-effects and random-effects models., Main Results: We found that 25 micrograms was less efficacious, with lower rates of delivery after one dose (RR 0.59; 95% CI 0.39-0.88) and vaginal delivery within 24 hours (RR 0.88; 95% CI 0.79-0.96), and with increased rates of oxytocin augmentation (RR 1.54, 95% CI 1.36-1.75). We noted an improved safety profile with 25 micrograms, however, with decreased rates of tachysystole (RR 0.46; 95% CI 0.35-0.61), hyperstimulation (RR 0.5; 95% CI 0.31-0.78), caesarean deliveries for non-reassuring FHR (RR 0.67; 95% CI 0.52-0.87), NICU admissions (RR 0.63; 95% CI 0.4-0.98), and meconium passage (RR 0.65; 95% CI 0.45-0.96)., Conclusions: Although 50 micrograms of intravaginal misoprostol may be more efficacious, safety concerns make the 25-microgram dose preferable., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Objective: To evaluate the effectiveness of 200 mg of daily vaginal natural progesterone to prevent preterm birth in women with preterm labour., Design: Multicentre, randomised, double-blind, placebo-controlled trial., Setting: Twenty-nine centres in Switzerland and Argentina., Population: A total of 385 women with preterm labour (24(0/7) to 33(6/7) weeks of gestation) treated with acute tocolysis., Methods: Participants were randomly allocated to either 200 mg daily of self-administered vaginal progesterone or placebo within 48 hours of starting acute tocolysis., Main Outcome Measures: Primary outcome was delivery before 37 weeks of gestation. Secondary outcomes were delivery before 32 and 34 weeks, adverse effects, duration of tocolysis, re-admissions for preterm labour, length of hospital stay, and neonatal morbidity and mortality. The study was ended prematurely based on results of the intermediate analysis., Results: Preterm birth occurred in 42.5% of women in the progesterone group versus 35.5% in the placebo group (relative risk [RR] 1.2; 95% confidence interval [95% CI] 0.93-1.5). Delivery at <32 and <34 weeks did not differ between the two groups (12.9 versus 9.7%; [RR 1.3; 95% CI 0.7-2.5] and 19.7 versus 12.9% [RR 1.5; 95% CI 0.9-2.4], respectively). The duration of tocolysis, hospitalisation, and recurrence of preterm labour were comparable between groups. Neonatal morbidity occurred in 44 (22.8%) cases on progesterone versus 35 (18.8%) cases on placebo (RR: 1.2; 95% CI 0.82-1.8), whereas there were 4 (2%) neonatal deaths in each study group., Conclusion: There is no evidence that the daily administration of 200 mg vaginal progesterone decreases preterm birth or improves neonatal outcome in women with preterm labour., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Objective: To compare clinical outcomes from outpatient with inpatient cervical prostaglandin E2 ripening for low risk labour induction., Design: Randomised controlled trial., Setting: Two tertiary hospitals in Adelaide, Australia., Population: Women with uncomplicated term pregnancies, scheduled for induction of labour for reasons of post-dates or for social reasons., Methods: Eight hundred and twenty-seven women were randomised at induction decision to an outpatient or inpatient group. All women had CTG monitoring before and after vaginal PgE2 administration. The inpatient women were admitted and the outpatient group was discharged home overnight with instructions to return if labour established or rupture of membranes occurred. Next morning, outpatient women were admitted for rupture of membranes or further ripening. After membrane rupture, both groups received routine care., Main Outcome Measures: Oxytocin use, maternal and fetal outcomes, and whether planned outpatient management was achievable., Results: There were no significant differences in oxytocin use (2.5% difference, CI-4.3 to 9.4), caesarean sections (-0.59% difference, CI-6.3 to 5.1), epidural use (1.5% difference, CI-5.1 to 8.2), vaginal delivery within 24 hours (-8.2% difference, CI-17.6 to 1.3) or labour complications. More than half of the randomised women did not receive the intervention as they laboured spontaneously, or did not require ripening. The post-hoc analysis of women who received ripening also indicated no statistically significant differences in the patterns or results, with the exception of outpatient women having a longer mean length of active labour (mean difference 66 minutes, CI 4-128 minutes). Outpatient women who received ripening were diagnosed more frequently with non-reassuring CTG monitoring and hyperstimulation, with less than half of the women going home and remaining home overnight., Conclusions: This study demonstrated no clinical advantage or disadvantage in prostaglandin E2 outpatient cervical ripening. Uterine stimulation following prostaglandins may preclude a woman from going home or remaining at home overnight and may not be the best agent for outpatient ripening., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Background: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB)., Objectives: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA)., Search Strategy: We searched international scientific databases, trial registration websites, and references of identified articles., Selection Criteria: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment., Data Collection and Analysis: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB., Main Results: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75)., Author's Conclusions: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Dinoprostone pessaries (DP) are widely used for cervical ripening, and while licensed for 12-h administration in Australia, 24-h use is also reported. We examined 396 consecutive women before and after a protocol change from 12-h to 24-h DP use to determine whether extended DP use decreases the need for additional mechanical cervical ripening. No significant difference in cervical ripening balloon (CRB) requirement or vaginal birth rates was detected, showing that prolonged DP use does not reduce subsequent use of CRB., (© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: To assess the economic consequences of labour induction with Foley catheter compared to prostaglandin E2 gel., Design: Economic evaluation alongside a randomised controlled trial., Setting: Obstetric departments of one university and 11 teaching hospitals in the Netherlands., Population: Women scheduled for labour induction with a singleton pregnancy in cephalic presentation at term, intact membranes and an unfavourable cervix; and without previous caesarean section., Methods: Cost-effectiveness analysis from a hospital perspective., Main Outcome Measures: We estimated direct medical costs associated with healthcare utilisation from randomisation to 6 weeks postpartum. For caesarean section rate, and maternal and neonatal morbidity we calculated the incremental cost-effectiveness ratios, which represent the costs to prevent one of these adverse outcomes., Results: Mean costs per woman in the Foley catheter group (n = 411) and in the prostaglandin E₂ gel group (n = 408), were €3297 versus €3075, respectively, with an average difference of €222 (95% confidence interval -€157 to €633). In the Foley catheter group we observed higher costs due to longer labour ward occupation and less cost related to induction material and neonatal admissions. Foley catheter induction showed a comparable caesarean section rate compared with prostaglandin induction, therefore the incremental cost-effectiveness ratio was not informative. Foley induction resulted in fewer neonatal admissions (incremental cost-effectiveness ratio €2708) and asphyxia/postpartum haemorrhage (incremental cost-effectiveness ratios €5257) compared with prostaglandin induction., Conclusions: Foley catheter and prostaglandin E2 labour induction generate comparable costs., (© 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.)

Background: The optimal dose of misoprostol to be used in the medical management of miscarriage before 13 weeks has not been resolved., Aim: To evaluate the effectiveness and side effect profile of two different dosages of misoprostol., Methods: A randomised controlled, equivalence study comparing 400 vs 800 μg misoprostol per vaginum (PV) on an outpatient basis. The allocated dose was repeated the next day if clinically the products of conception had not been passed. Complete miscarriage was evaluated using two methods: ultrasound criteria on Day 7 and the need for surgical management (clinical criteria). Equivalence was demonstrated if the 95% confidence interval [CI] of the observed risk difference between the two doses for complete miscarriage lay between -15.0 and 15.0%. Differences in side effects and patient satisfaction were evaluated using patient-completed questionnaires., Results: One hundred and fifty-eight women were allocated to receive 400 μg and 152 women to 800 μg misoprostol for the management of missed (91.3%) or incomplete (8.7%) miscarriage. The rate of induced complete miscarriage was equivalent using both ultrasound criteria (observed risk difference (ORD) -4.6%, 95% CI -12.8 to 3.7%; P = 0.313) and clinical criteria (ORD -5.6%, 95% CI -14.8 to 3.6%; P = 0.273). Following the 400 μg dose, the reported rate of fever/rigors was lower (ORD -15.6%, 95% CI -28.1 to -3.0%; P = 0.015), and more women reported their decision to undergo medical management as a good decision (ORD 15.2%, 95% CI 2.8 to 27.7%; P = 0.018)., Conclusion: Four hundred-microgram misoprostol PV can be recommended for the medical management of miscarriage on an outpatient basis., (© 2012 The Authors ANZJOG © 2012 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: Previous trials have shown little benefit for preventing preterm birth in twin pregnancies using 90-200 mg of daily vaginal natural progesterone. Higher doses have not been tested. Our aim was to determine the efficacy and safety of two different daily doses of vaginal natural progesterone (200 and 400 mg), compared with placebo, for preventing preterm birth in unselected twin pregnancies., Design: Randomised controlled double-blind multicentre trial (1:1:1)., Setting: The study was carried out in five university centres from Valencia, Murcia and Alicante (Spain)., Population: Women with dichorionic diamniotic twin pregnancies., Methods: The women self-inserted two vaginal pessaries daily, containing placebo (n = 96), 200 mg of natural progesterone (n = 97) or 400 mg of natural progesterone (n = 97), from 20 to 34 weeks of gestation or delivery. Randomisation was performed by an external centre. Data were analysed on an intention-to-treat basis., Main Outcome Measure: Preterm birth rate., Results: The baseline characteristics for placebo and progesterone groups were similar. Comparison of the three groups and analysis of progesterone-treated versus untreated women showed similar pregnancy and neonatal outcomes. The proportion of preterm and very preterm births, low birthweight, perinatal mortality and neonatal morbidity showed no differences between the three groups. Similar results were also obtained when comparing the 200- versus 400-mg progesterone groups. No serious adverse effects were encountered., Conclusions: Vaginal progesterone therapy was generally well tolerated, but failed to prevent preterm births in unselected dichorionic diamniotic twin pregnancies. The 400-mg progesterone dose offered no advantages over the 200-mg regimen., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Background: Many misoprostol regimens have been used to treat early pregnancy loss as an alternative to surgical evacuation, with differing adverse event and success rates., Aims: This study sought to compare the effectiveness and adverse effects of 800 and 600 μg of misoprostol administered vaginally for the treatment of early pregnancy failure in an outpatient setting., Methods: A retrospective, observational study of 946 women with a missed miscarriage <12 weeks' gestation was performed: 487 women received 800 μg (group 1) and 459 women received 600 μg (group 2) of vaginal misoprostol every 24 h for two days. The first follow-up was seven days after treatment. Women were asked about symptoms, and a transvaginal ultrasound was performed. If an incomplete miscarriage or gestational sac was still found, then an additional dose of intravaginal misoprostol was prescribed, and a second follow-up visit was arranged for seven days later. Surgical evacuation was scheduled for women who did not wish to continue medical treatment after the first or second follow-up visit., Results: The total rate of complete miscarriage was 90.6% after 800 μg and 87.8% after 600 μg of intravaginal misoprostol. The percentage of women who underwent surgical evacuation after medical treatment was 9.4% for group 1 and 12.2% for group 2., Conclusions: Complete uterine evacuation after a missed miscarriage was effectively induced by both 600 and 800 μg of misoprostol. The overall success of medical treatment with intravaginal misoprostol demonstrates that the treatment is safe in an outpatient setting., (© 2011 The Authors. ANZJOG © 2011 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: To compare the effectiveness of prostaglandin E2 (dinopristone) vaginal gel versus vaginal tablets for the induction of labour at term., Design: Randomised controlled clinical trial., Setting:   University maternity hospital in London., Population: Pregnant women with cephalic presentation undergoing induction of labour after 37 weeks of gestation., Methods: Prostaglandin E2 vaginal tablets (3 mg) or vaginal gel (1 mg/ 2 mg) was administered at 6-hourly intervals until the cervix was suitable for amniotomy., Main Outcome Measures: Induction to delivery interval, in minutes; rate of failed induction of labour requiring caesarean delivery., Results: Eighty-two women received prostaglandin gel; 83 women received vaginal tablets. There were significant differences between the two treatment groups in the primary outcomes. The mean induction to delivery interval was significantly shorter in women who received the gel (1400 minutes, 690-2280 minutes, versus 1780 minutes, 960-2640 minutes; P = 0.03). The rate of failed induction of labour was significantly higher in women who received tablets (10.84 versus 1.22%; P = 0.01). Subanalysis showed that these differences were only representative of differences in the groups of primigravid women. There were no significant differences in any of the secondary outcomes, including the number of women who required syntocinon augmentation, the rate of uterine hyperstimulation, the need for epidural analgesia, meconium staining of liquor, the need for fetal blood sampling, or delivery by caesarean section. There were no differences in adverse maternal and neonatal outcomes., Conclusion: Prostaglandin E2 vaginal gel is superior to vaginal tablets for the induction of labour., (© 2011 Imperial College London BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.)

Background: There are a number of agents used for cervical ripening prior to the induction of labour. Two commonly used agents are intravaginal misoprostol and a transcervical Foley catheter., Objective: To review the evidence comparing misoprostol and transcervical Foley catheter placement for induction of labour, and perform a meta-analysis comparing these two induction agents., Search Strategy: We conducted database searches of PubMed, Embase, the Cochrane Library Database, and the ClinicalTrials.gov website. Bibliographies of all relevant articles were reviewed., Selection Criteria: Prospective, randomised trials comparing the use of intravaginal misoprostol and transcervical Foley catheter for the purpose of cervical ripening and induction of labour were included. We excluded studies in which the patients in these two intervention groups also received other induction agents concurrently, such as oral misoprostol, oxytocin, or other prostaglandins., Data Collection and Analysis: The primary outcomes selected were time to delivery, and the rates of caesarean section, uterine tachysystole, and chorioamnionitis. Random-effects generalised linear models with a poisson distribution and log link function were used to compare the two induction agents across the studies., Main Results: Nine studies (1603 patients) were identified as eligible to be included in this meta-analysis. There were no significant differences in the mean time to delivery (mean difference 1.08 ± 2.19 hours shorter for misoprostol, P = 0.2348), the rate of caesarean delivery (RR 0.991; 95% CI 0.768, 1.278), or in the rate of chorioamnionitis (RR 1.130; 95% CI 0.611, 2.089) between women who received misoprostol compared with transcervical Foley catheter. Patients who received misoprostol had significantly higher rates of tachysystole compared with women who received a transcervical Foley catheter (RR 2.844; 95% CI 1.392, 5.812)., Conclusions: Intravaginal misoprostol and transcervical Foley catheter have similar effectiveness as induction agents. Transcervical Foley catheter is associated with a lower incidence of tachysystole., (© 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.)

Background: The development of safe and effective techniques for second-trimester abortion (associated or not with fetal death) has become a major clinical challenge., Aims: To compare the efficacy and safety of sublingual versus vaginal misoprostol for mid-trimester pregnancy termination., Methods:  We conducted a meta-analysis of published randomised controlled trials that compared sublingual and vaginal routes. Primary outcome measures were complete abortion rate at 24 and 48 h and induction-abortion interval, and the secondary outcome measures were side effects and patients' preference for the route. Pooled risk ratios were calculated for categorical variables, and continuous variables were compared by means of weighted mean differences., Results:  Both routes' efficacy was similar following 24 h of treatment (pooled RR 1.04, 95% CI 0.93-1.7). Successful induction percentage after 24 h was significantly higher in nulliparous women with vaginal misoprostol (pooled RR 0.78; 95% CI 0.71-0.87). The efficacy after 48 h was significantly greater with vaginal misoprostol in the general population (pooled RR 0.96; 95% CI 0.93-0.99) and in nulliparous women (pooled RR 0.89; 95% CI 0.86-0.95). The sublingual route shortened the induction-fetal expulsion interval (WMD -4.54, 95% CI -8.03 to -1.05) and was the route preferred among women. No statistically significant differences between treatment groups were observed for placental retention or for any side effect except for fever, which was more common in the vaginal group., Conclusions:   Sublingual and vaginal misoprostol are safe and effective for mid-trimester pregnancy termination. The differences obtained between both routes probably do not have clinical consequences., (© 2011 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology © 2011 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)