Kate Navaratnam

Labour induction with prostaglandins: a systematic review and network meta-analysis.

Objectives To assess the effectiveness and safety of prostaglandins used for labour induction. Design Systematic review with Bayesian network meta-analysis Data sources The Cochrane Pregnancy and Childbirth Group’s Database of Trials (which incorporates the results of a broad generic search for all pregnancy and postpartum trials). Sources included are CENTRAL, Medline, Embase, NHS Economic Evaluation Database, CINAHL, relevant journals, conference proceedings, and registries of ongoing trials. Eligibility criteria for selecting studies Randomised clinical trials of prostaglandin or prostaglandin analogues used for third trimester cervical ripening or labour induction versus placebo or no treatment, alternative prostaglandin dose or administration, or a different type of prostaglandin. We included studies recruiting women with a viable fetus, but had no other restrictions relating to indication for labour induction or language of publication. Outcomes assessed were serious neonatal morbidity (trialist defined) or perinatal death; serious maternal morbidity (trialist defined) or death; vaginal delivery not achieved within 24 hours, caesarean section, and uterine hyperstimulation with fetal heart rate changes. Results 280 randomised clinical trials were included (48 068 women) in the review. Maternal and neonatal mortality and serious morbidity were rarely reported and are summarized narratively. Unresolved inconsistency was observed for the hyperstimulation outcome. Relative to placebo, the odds of failing to achieve a vaginal delivery were lowest for vaginal misoprostol (≥50 µg) (odds ratio 0.06 (95% credible interval 0.02 to 0.12)), with a 39% absolute probability of event (95% credible interval 1% to 94%). Compared with placebo, odds of caesarean section were lowest for titrated oral misoprostol solution (<50 µg) (odds ratio 0.65 (0.49 to 0.83)), with an absolute probability of event of 15% (3% to 40%). Conclusions Low dose(<50 µg) titrated oral misoprostol solution had the lowest probability of caesarean section, whereas vaginal misprostol (≥50 µg) had the highest probability of achieving a vaginal delivery within 24 hours. These findings have important implications for a series of current national and international guidelines for induction of labour and future research in this area. Systematic review registration PROSPERO 2013:CRD42013005116

A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED)

AbstractBackground5% of first time pregnancies are complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful screening test exists; consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROvED Consortium members have pioneered a personalised medicine approach to identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The key objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia.Methods/DesignWe report the design of a multicentre, phase IIa clinical study aiming to recruit 5000 low risk primiparous women to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves maternal phlebotomy at 15 and 20 weeks’ gestation, with optional testing and biobanking at 11 and 34 weeks. Blood samples will be analysed using two innovative, proprietary prototype platforms; one metabolomic based and one proteomic based, both of which outperform current biomarker based screening tests at comparable gestations. Analytical and clinical data will be collated and analysed via the Copenhagen Trials Unit.DiscussionThe IMPROvED study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If ‘at risk’ patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROvED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome.Trial registrationTrial registration number NCT01891240 The IMPROvED project is funded by the seventh framework programme for Research and Technological development of the EU. http://www.fp7-improved.eu/

Low dose aspirin and pregnancy: how important is aspirin resistance?

Antiplatelet agents are pivotal for prevention of coronary artery disease and cerebrovascular disease worldwide. Individual patient data meta‐analysis indicates that low‐dose aspirin causes a 10% risk reduction in pre‐eclampsia for women at high individual risk. However, in the last 15 years it has emerged that a significant proportion of aspirin‐treated individuals exhibit suboptimal platelet response, determined biochemically and clinically, termed ‘aspirin non‐responsiveness’, ‘aspirin resistance’ and ‘aspirin treatment failure’. More recently, investigation of aspirin responsiveness has begun in pregnant women. This review explores the history and clinical relevance of ‘aspirin resistance’ applied to high‐risk obstetric populations.

Evaluation of agreement of placental growth factor (PlGF) tests and the soluble FMS-like tyrosine kinase 1 (sFlt-1)/PlGF ratio, comparison of predictive accuracy for pre-eclampsia, and relation to uterine artery Doppler and response to aspirin.

Abstract Objectives: The objective of this study is to evaluate agreement between PlGF and sFlt-1/PlGF ratio tests and compare their predictive accuracy for pre-eclampsia in high-risk women. Also, to examine for associations of abnormal PlGF or sFlt-1/PlGF ratio with abnormal uterine artery Doppler and platelet response to aspirin. Methods: Prospective cohort study, 150 pregnant women at high risk of pre-eclampsia prescribed 75 mg aspirin daily. Uterine artery Dopplers were assessed at 20+0–23+6 weeks. At 33+0–35+6 weeks platelet function aspirin metabolites, PlGF and the sFlt-1/PlGF ratio were measured. Outcome: Measures were all pre-eclampsia and pre-eclampsia requiring delivery prior to 37 weeks. Results: Overall percent agreement was 89.3% for PlGF tests but 74.7–78% for PlGF tests and the sFlt-1/PlGF ratio. AUCs were 0.70–0.75 for prediction of any pre-eclampsia and 0.92–0.99 for preterm pre-eclampsia. We found a significant association between abnormal PlGF or sFlt-1/PlGF ratio and abnormal uterine artery Doppler (χ2 5.47, p = .019), but no association with platelet response to aspirin (χ2 0.12, p = .913). There were no associations between suboptimal aspirin adherence and either abnormal angiogenic markers or uterine artery Dopplers (χ2 0.144, 0.038, p = .704, .846, respectively). Conclusions: There was good agreement between PlGF tests and limited agreement between PlGF tests and the sFlt-1/PlGF ratio. All tests have heightened predictive accuracy for preterm pre-eclampsia. Abnormal PlGF or sFlt-1/PlGF ratio relates to abnormal uterine artery Doppler but not platelet response to aspirin.

Does advanced operative obstetrics still have a place in contemporary practice

Purpose of review This article reviews recent significant contributions to the literature concerning advanced operative obstetric procedures used for rotational vaginal deliveries and their alternative, primary caesarean section. Recent findings Rising caesarean section rates are a global concern. Caesarean section in the second stage of labour is associated with high rates of maternal and fetal morbidity. Rotational vaginal deliveries may reduce the caesarean section rate without additional adverse effects on maternal and fetal outcomes. A recent national trainees’ survey highlighted that training in the management of operative birth in the second stage of labour, especially when there is malposition of the fetal head, is a priority. Summary There is a need for evidence-based guidelines, including standardized documentation of these advanced procedures. Training strategies for junior practitioners to acquire these skills and for experienced practitioners to maintain and disseminate their skills should be prioritized. The safety of rotational delivery methods versus primary caesarean section is likely to prove difficult to assess directly, in the context of a randomized controlled trial, but may be approximated via a national prospective audit.

Outcomes reported in trials of methods for the induction of labour

Background Labour inductions have increased steadily over the past two decades, with overall rates in many countries now exceeding 20% of all births. We have conducted a systematic review, network meta-analysis and cost-effectiveness analysis to determine which treatments for induction perform best on pre-specified safety and efficacy outcomes. This poster reports analysis of the outcomes reported in trials.

An unusual haemoperitoneum – secondary abdominal pregnancy

A 36-year-old amenorrhoeic patient presented with vague abdominal discomfort, and haemodynamic instability, a large haemoperitoneum was identified on transvaginal ultrasound. Ruptured tubal ectopic pregnancy was suspected. At laparotomy ruptured primary tubal ectopic pregnancy was identified, with 12–14 week secondary abdominal pregnancy implanted onto the omentum, confirmed by histopathology. Salpingo-oophrectomy with peritoneal washout was performed, and three units blood transfusion was required. The patient had an uneventful recovery to health.

Simplifying oral misoprostol protocols for the induction of labour

Induction of labour is carried out worldwide for a broad range of maternal and fetal indications, so as to improve pregnancy outcomes. Oral misoprostol has been widely discussed as a method of labour induction. It is recommended for this indication by the World Health Organization (WHO), the International Federation of Gynecology and Obstetrics (FIGO), and the Society of Obstetricians and Gynaecologists of Canada (SOGC). A systematic review comparing misoprostol with Foley catheter and dinoprostone induction agents suggests that ‘Oral misoprostol for the induction of labour is safer than vaginal misoprostol and has the lowest rate of caesarean section’. A recently completed UK National Institute of Health Research (NIHR) funded network and cost-effectiveness analysis included 31 induction regimes evaluated in 611 trials with over 100 000 trial participants. Titrated low-dose oral misoprostol was identified as likely to be the most costeffective method, and also had a favourable safety profile. Sublingual or buccal misoprostol had significantly higher rates of hyperstimulation. This recent evidence is in contrast with the current National Institute for Health and Care Excellence (NICE) guidelines that do not recommend the use of misoprostol, citing that misoprostol is not labelled for labour induction, and that accurate concentrations and reliable drug delivery cannot be guaranteed given that low-dose formulations are not available. ‘Oral misoprostol’, however, is not a single entity and systematic reviewers have struggled to cope with the wide variation in protocols (Table 1). Published randomised trials have a wide variety of misoprostol doses (20–200 lg) and frequency of administration (1–6 hourly). Some protocols use a single dose for the whole induction period, whereas others escalate the dose until the desired effect is achieved. Some use misoprostol purely for cervical ripening and replace it with an oxytocin infusion once membrane rupture is feasible, whereas others use oral misoprostol continuously until delivery. But the variation doesn’t stop there. Until recently there was no commercially produced low-dose misoprostol tablet, and so clinicians developed their own ways of preparing and administering the intended dose. Some practitioners divided the small and notoriously crumbly 200or 100-lg tablets into fragments. Others made up 1-lg/ml solutions by dissolving tablets in tap water. It is only recently that commercially available 25-lg tablets have become available (Cipla, India; Azanta A/S, Denmark), but these are not yet widely available. Is there evidence to suggest that any of these protocols are superior? Subgroup analyses of some important clinical outcomes show a clear dose effect. For example, when comparing oral misoprostol with dinoprostone, the rate of hyperstimulation increases as the initial dose rises from 25 to 200 lg. It would therefore appear that there are safety benefits of using doses of 20–25 lg, even if they may result in a slower induction process. This is supported by a systematic review of just the studies that used 20–25 lg of oral misoprostol, which found lower caesarean section and lower hyperstimulation rates compared with standard induction methods. And whereas in previous studies researchers have been forced to either use cut 200-lg tablets or solution, high-quality 25-lg tablets are now available. Findings from a non-inferiority randomised controlled trial (RCT) of oral misoprostol 50mcg versus Foley catheter for induction of labour showed equivalent safety and effectiveness, whereas misoprostol tablets (25 lg) has recently been found to be more an effective than Foley catheter when given orally in a large Medical Research Council (MRC) labour induction study. The use of regimens in which misoprostol is given every 2 hours is supported by pharmacokinetic studies that show that oral misoprostol reaches its peak serum level within 30 minutes, but that its half-life is only 90 minutes as misoprostol acid is rapidly metabolised by the liver and

labour induction with prostaglandins: what works best? A systematic review, network meta-analysis and cost-effectiveness analysis

• A network meta-analysis (NMA) of randomised controlled trials (RCTs) was conducted comparing 12 different prostaglandins used for labour induction. Different methods were compared with each other and with no treatment or placebo. • Data were extracted for five key outcomes in terms of effectiveness and safety: serious neonatal morbidity or perinatal death, serious maternal morbidity or death, uterine hyperstimulation with fetal heart rate changes, failure to achieve vaginal delivery within 24 hours, and caesarean section. • Relative treatment effects are reported as posterior median odds ratios (OR) and 95% Credible Intervals (CrI). • The probability of each treatment being 1st, 2nd, 3rd, etc. most effective was calculated for each outcome. • All analysis were conducted within a Bayesian framework using OpenBUGS. LABOUR INDUCTION WITH PROSTAGLANDINS: WHAT WORKS BEST? A SYSTEMATIC REVIEW, NETWORK META-ANALYSIS AND COST-EFFECTIVENESS ANALYSIS Keeney E1, Welton NJ1, Dowswell T2, Dias S1, Medley N2, Jones L2, Navaratnam K2 , Alfirevic Z2 , Caldwell DM1