Cohort profile: Improved Pregnancy Outcomes via Early Detection (IMPROvED), an International Multicentre Prospective Cohort.

Background: Improved Pregnancy Outcomes via Early Detection (IMPROvED) is a multi-centre, European phase IIa clinical study. The primary aim of IMPROvED is to enable the assessment and refinement of innovative prototype preeclampsia risk assessment tests based on emerging biomarker technologies. Here we describe IMPROvED's profile and invite researchers to collaborate. Methods: A total of 4,038 low-risk nulliparous singleton pregnancies were recruited from maternity units in Ireland (N=1,501), United Kingdom (N=1,108), The Netherlands (N=810), and Sweden (N=619) between November 2013 to August 2017. Participants were interviewed by a research midwife at ~11 weeks (optional visit), ~15 weeks, ~20 weeks, ~34 weeks' gestation (optional visit), and postpartum (within 72-hours following delivery). Findings to date: Clinical data included information on maternal sociodemographic, medical history, and lifestyle factors collected at ~15 weeks' gestation, and maternal measurements, collected at each study visit. Biobank samples included blood, urine, and hair collected at each study visit throughout pregnancy in all units plus umbilical cord/blood samples collected at birth in Ireland and Sweden. A total of 74.0% (N=2,922) had an uncomplicated pregnancy, 3.1% (N=122) developed preeclampsia, 3.6% (N=143) had a spontaneous preterm birth, and 10.5% (N=416) had a small for gestational age baby. We evaluated a panel of metabolite biomarkers and a panel of protein biomarkers at 15 weeks and 20 weeks' gestation for preeclampsia risk assessment. Their translation into tests with clinical application, as conducted by commercial entities, was hampered by technical issues and changes in test requirements. Work on the panel of proteins was abandoned, while work on the use of metabolite biomarkers for preeclampsia risk assessment is ongoing. Future plans: In accordance with the original goals of the IMPROvED study, the data and biobank are now available for international collaboration to conduct high quality research into the cause and prevention of adverse pregnancy outcomes.

Foetal loss after chorionic villus sampling and amniocentesis in twin pregnancies: A multicentre retrospective cohort study.

OBJECTIVE: We aimed to determine foetal losses for DCDA and MCDA twins following transabdominal CVS or amniocentesis performed <22+0  weeks. METHODS: Retrospective cohort study conducted in the UK and Belgium 01/01/00-01/06/20. Cases with unknown chorionicity, monochorionic complications or complex procedures were excluded. Uncomplicated DCDA and MCDA twins without invasive procedures were identified as controls. We reported foetal losses <24+0  weeks and losses of genetically and structurally normal foetuses. RESULTS: Outcomes were compared for DCDA foetuses; 258 after CVS with 3406 controls, 406 after amniocentesis with 3390 controls plus MCDA foetuses, 98 after CVS with 1124 controls, and 160 after amniocentesis with 1122 controls. There were more losses <24+0  weeks with both procedures in DCDA (CVS RR 5.54 95% CI 3.38-9.08, amniocentesis RR 2.36 95% CI 1.22-4.56) and MCDA twins (CVS RR 5.14 95% CI 2.51-10.54, amniocentesis RR 7.01 95% CI 3.86-12.74). Losses of normal foetuses were comparable to controls (DCDA CVS RR 0.39 95% CI 0.05-2.83, DCDA amniocentesis RR 1.16 95% CI 0.42-3.22, MCDA CVS RR 2.3 95% CI 0.71-7.56, and MCDA amniocentesis RR 1.93 95% CI 0.59-6.38). CONCLUSIONS: This study indicates increased foetal losses for DCDA and MCDA twins following CVS and amniocentesis with uncertain risk to normal foetuses.

Platelet response to aspirin in UK and Irish pregnancy cohorts: a genome-wide approach.

A multi-center prospective cross-sectional and genome-wide association study (GWAS) recruited pregnant women taking low dose aspirin. Objectives were to (i) develop pregnancy-specific 95% reference intervals for a range of laboratory based platelet function tests (PFTs); (ii) select an optimal and acceptable PFT that reflected aspirin's COX-1 inhibition in women with confirmed aspirin adherence in pregnancy; and (iii) identify genomic variants that may influence pregnant women's platelet response to aspirin.The study included two independent cohorts of pregnant women. A range of PFTs and matched phenotyping with urinary 11-dehydrothromboxane B2 (11DTXB2) and nuclear magnetic resonance (NMR) spectroscopy detection of urinary salicyluric acid as a measure of aspirin adherence were performed. Genome-wide data was acquired from the UK Biobank Axiom® (Thermo Fisher Scientific). 11DTXB2 in combination with adherence testing with NMR salicyluric acid was an accurate and acceptable testing strategy for detecting biochemical aspirin responsiveness in pregnant women, with the provision of relevant reference ranges. GWAS meta-analysis found no significant single nucleotide polymorphisms in association with response to aspirin in pregnancy. Further evaluation in relation to effective dosing of aspirin in pregnancy and optimizing the benefits to specific subgroups should now be a priority for future research.

Anti-Infective Dosing in Special Populations: Pregnancy.

Substantial anatomical and physiological changes occur during pregnancy and labor, which impact on drug absorption, distribution, metabolism, and elimination. Reduced maternal concentrations may have a clinically important impact on the efficacy of anti-infectives for mother, fetus, and neonate, with potential dosing implications. However, there is a paucity of pregnancy-specific data examining this. Existing data on the pharmacokinetics of anti-infectives in pregnancy are summarized and evaluated, with emphasis on agents that are used in treatment of HIV, tuberculosis, malaria, and common bacterial infections. Limitations and challenges in achieving ideal study designs in pregnant populations are highlighted, and key quality considerations for the generation of the highest quality evidence are outlined. PubMed was searched for each chosen anti-infective. Pharmacokinetic studies which either compared pharmacokinetics from pregnant women against nonpregnant controls, or which assessed concentrations against a known minimum inhibitory concentration were included. Two independent reviewers extracted data from each study and appraised them using the 24-point ClinPK Checklist. The main finding was that there is a lack of published data for anti-infectives in pregnancy, despite their clinical importance. Of the studies identified, only those investigating cobicistat-boosted antiretroviral regimens firmly concluded that these should not be used in pregnancy. Most studies concluded either that further research was needed, or that there were significant pharmacokinetic differences between pregnant and nonpregnant participants which had uncertain clinical significance. Challenges in applying existing quality grading systems to these studies were noted, suggesting a development of a refined system for appraisal of pharmacokinetic studies in "special populations" may be warranted.

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.

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.

Aspirin non-responsiveness in pregnant women at high-risk of pre-eclampsia.

OBJECTIVES: Low-dose aspirin is recommended for prevention of pre-eclampsia in high-risk pregnant women. Current doses provide a conservative risk reduction and some individuals demonstrate 'aspirin non-responsiveness', with insufficient antiplatelet effects. We aimed to determine if aspirin non-responsiveness could be identified in women at high risk of pre-eclampsia and assess for potential associations with placentally-mediated adverse outcomes. STUDY DESIGN: Prospective cohort study. 180 women at high-risk of pre-eclampsia, by NICE criteria, prescribed 75 mg dispersible aspirin daily were recruited from antenatal clinics of Liverpool Women's Hospital between 17/01/14 and 31/03/16. Platelet function (Multiplate™ impedance aggregometry, VerifyNow™ and 11-dehydrothromboxane B2) and aspirin metabolites (nuclear magnetic resonance and liquid chromatography mass spectrometry) were assessed at 5 + 0-20 + 6 and 33 + 0-35 + 6 weeks. Pearson's chi-square test was used to assess for associations between longitudinal response to aspirin and (1) any pre-eclampsia (2) composite adverse placentally-mediated outcome (one, or combination of pre-eclampsia, placental abruption, IUGR and perinatal mortality). A Bonferroni correction was applied to correct for multiple analyses. RESULTS: 180 women were recruited, there were 4 withdrawals and no women were lost to follow-up. After 15 women delivered prior to the completion of follow-up, sufficient sample volumes for longitudinal platelet function and aspirin adherence testing were obtained from 156 women. There were no consistent aspirin non-responders in the cohort. 59% (n = 92) women exhibited normal response to aspirin, 34% (n = 53) variable response (switching response status between study visits) and in 7% (n = 11) response could not be determined as they exhibited lack of platelet response on a background of undetectable aspirin metabolites. There was no significant association between indeterminate or inconsistent (variable or indeterminate) response to aspirin and either pre-eclampsia (p = 0.59, p = 0.84) or composite outcome (p = 0.95, p = 0.65). CONCLUSIONS: When platelet function was assessed with COX-specific tests that measure the antiplatelet effects of low-dose aspirin and aspirin adherence is accurately accounted for aspirin non-responsiveness was not identified in pregnant women at high-risk of pre-eclampsia. Response to aspirin was not associated with placentally-mediated adverse outcomes. The high-degree of variable and indeterminate aspirin response indicates suboptimal adherence and/or dosing are more pressing factors to address to optimise aspirin effectiveness.

How important is aspirin adherence when evaluating effectiveness of low-dose aspirin?

Low-dose aspirin (LDA) is advocated for women at high-risk of pre-eclampsia, providing a modest, 10%, reduction in risk. Cardiology meta-analyses demonstrate 18% reduction in serious vascular events with LDA. Non-responsiveness to aspirin (sometimes termed aspirin resistance) and variable clinical effectiveness are often attributed to suboptimal adherence. The aim of this review was to identify the scope of adherence assessments in RCTs evaluating aspirin effectiveness in cardiology and obstetrics and discuss the quality of information provided by current methods. We searched MEDLINE, EMBASE and the Cochrane Library, limited to humans and English language, for RCTs evaluating aspirin in cardiology; 14/03/13-13/03/16 and pregnancy 1957-13/03/16. Search terms; 'aspirin', 'acetylsalicylic acid' appearing adjacent to 'myocardial infarction' or 'pregnancy', 'pregnant', 'obstetric' were used. 38% (25/68) of obstetric and 32% (20/62) of cardiology RCTs assessed aspirin adherence and 24% (6/25) and 29% (6/21) of obstetric and cardiology RCTs, respectively, defined acceptable adherence. Semi-quantitative methods (pill counts, medication weighing) prevailed in obstetric RCTs (93%), qualitative methods (interviews, questionnaires) were more frequent in obstetrics (67%). Two obstetric RCTs quantified serum thromboxane B2 and salicylic acid, but no quantitative methods were used in cardiology Aspirin has proven efficacy, but suboptimal adherence is widespread and difficult to accurately quantify. Little is currently known about aspirin adherence in pregnancy. RCTs evaluating aspirin effectiveness show over-reliance on qualitative adherence assessments vulnerable to inherent inaccuracies. Reliable adherence data is important to assess and optimise the clinical effectiveness of LDA. We propose that adherence should be formally assessed in future trials and that development of quantitative assessments may prove valuable for trial protocols.

Amniocentesis and chorionic villus sampling for prenatal diagnosis.

BACKGROUND: During pregnancy, fetal cells suitable for genetic testing can be obtained from amniotic fluid by amniocentesis (AC), placental tissue by chorionic villus sampling (CVS), or fetal blood. A major disadvantage of second trimester amniocentesis is that the results are available relatively late in pregnancy (after 16 weeks' gestation). Earlier alternatives are chorionic villus sampling (CVS) and early amniocentesis, which can be performed in the first trimester of pregnancy. OBJECTIVES: The objective of this review was to compare the safety and accuracy of all types of AC (i.e. early and late) and CVS (e.g. transabdominal, transcervical) for prenatal diagnosis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (3 March 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP; 3 March 2017), and reference lists of retrieved studies. SELECTION CRITERIA: All randomised trials comparing AC and CVS by either transabdominal or transcervical route. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included a total of 16 randomised studies, with a total of 33,555 women, 14 of which were deemed to be at low risk of bias. The number of women included in the trials ranged from 223 to 4606.Studies were categorized into six comparisons: 1. second trimester AC versus control; 2. early versus second trimester AC; 3. CVS versus second trimester AC; 4. CVS methods; 5. Early AC versus CVS; and 6. AC with or without ultrasound.One study compared second trimester AC with no AC (control) in a low risk population (women = 4606). Background pregnancy loss was around 2%. Second trimester AC compared to no testing increased total pregnancy loss by another 1%. The confidence intervals (CI) around this excess risk were relatively large (3.2% versus 2.3 %, average risk ratio (RR) 1.41, 95% CI 0.99 to 2.00; moderate-quality evidence). In the same study, spontaneous miscarriages were also higher (2.1% versus 1.3%; average RR 1.60, 95% CI 1.02 to 2.52; high-quality evidence). The number of congenital anomalies was similar in both groups (2.0% versus 2.2%, average RR 0.93, 95% CI 0.62 to 1.39; moderate-quality evidence).One study (women = 4334) found that early amniocentesis was not a safe early alternative compared to second trimester amniocentesis because of increased total pregnancy losses (7.6% versus 5.9%; average RR 1.29, 95% CI 1.03 to 1.61; high-quality evidence), spontaneous miscarriages (3.6% versus 2.5%, average RR 1.41, 95% CI 1.00 to 1.98; moderate-quality evidence), and a higher incidence of congential anomalies, including talipes (4.7% versus 2.7%; average RR 1.73, 95% CI 1.26 to 2.38; high-quality evidence).When pregnancy loss after CVS was compared with second trimester AC, there was a clinically significant heterogeneity in the size and direction of the effect depending on the technique used (transabdominal or transcervical), therefore, the results were not pooled. Only one study compared transabdominal CVS with second trimester AC (women = 2234). They found no clear difference between the two procedures in the total pregnancy loss (6.3% versus 7%; average RR 0.90, 95% CI 0.66 to 1.23, low-quality evidence), spontaneous miscarriages (3.0% versus 3.9%; average RR 0.77, 95% CI 0.49 to 1.21; low-quality evidence), and perinatal deaths (0.7% versus 0.6%; average RR 1.18, 95% CI 0.40 to 3.51; low-quality evidence). Transcervical CVS may carry a higher risk of pregnancy loss (14.5% versus 11.5%; average RR 1.40, 95% CI 1.09 to 1.81), but the results were quite heterogeneous.Five studies compared transabdominal and transcervical CVS (women = 7978). There were no clear differences between the two methods in pregnancy losses (average RR 1.16, 95% CI 0.81 to 1.65; very low-quality evidence), spontaneous miscarriages (average RR 1.68, 95% CI 0.79 to 3.58; very low-quality evidence), or anomalies (average RR 0.68, 95% CI 0.41 to 1.12; low-quality evidence). We downgraded the quality of the evidence to low due to heterogeneity between studies. Transcervical CVS may be more technically demanding than transabdominal CVS, with more failures to obtain sample (2.0% versus 1.1%; average RR 1.79, 95% CI 1.13 to 2.82, moderate-quality evidence).Overall, we found low-quality evidence for outcomes when early amniocentesis was compared to transabdominal CVS. Spontaneous miscarriage was the only outcome supported by moderate-quality evidence, resulting in more miscarriages after early AC compared with transabdominal CVS (2.3% versus 1.3%; average RR 1.73, 95% CI 1.15 to 2.60). There were no clear differences in pregnancy losses (average RR 1.15, 95% CI 0.86 to 1.54; low-quality evidence), or anomalies (average RR 1.14, 95% CI 0.57 to 2.30; very low-quality evidence).We found one study that examined AC with or without ultrasound, which evaluated a type of ultrasound-assisted procedure that is now considered obsolete. AUTHORS' CONCLUSIONS: Second trimester amniocentesis increased the risk of pregnancy loss, but it was not possible to quantify this increase precisely from only one study, carried out more than 30 years ago.Early amniocentesis was not as safe as second trimester amniocentesis, illustrated by increased pregnancy loss and congenital anomalies (talipes). Transcervical chorionic villus sampling compared with second trimester amniocentesis may be associated with a higher risk of pregnancy loss, but results were quite heterogeneous.Diagnostic accuracy of different methods could not be assessed adequately because of incomplete karyotype data in most studies.

Short versus Standard Mifepristone and Misoprostol Regimen for Second- and Third-Trimester Termination of Pregnancy for Fetal Anomaly.

BACKGROUND: Termination of pregnancy requires a 48-hour 'window' between mifepristone and misoprostol. Shorter durations have been used in first-trimester termination, but there are few data available in later termination for fetal anomaly. MATERIAL AND METHODS: We reviewed all terminations for fetal anomaly at ≥13 weeks from May 2013 to May 2014. Cases were managed using a short (≤12 h) or standard (≥36 h) mifepristone-to-misoprostol interval. RESULTS: Two hundred and twenty women underwent a termination of pregnancy for fetal anomaly during the study period, of which 119 were included for analysis. Sixty-six (55%) women were managed according to the short regimen and 53 (45%) women with the standard regimen. The short regimen resulted in a shorter mifepristone-to-delivery interval but was less likely to result in delivery within 12 h of misoprostol. Delivery rates at 24 h were equivocal. There was no difference in blood loss, vaginal delivery rates, complications or bed nights. The short regimen did require more doses of misoprostol. Feticide or previous uterine scar had no effect on outcomes. DISCUSSION: There was no significant difference in clinical outcome for women managed with a short (≤12 h) or a standard (≥36 h) regimen for medical termination of pregnancy for fetal anomaly, suggesting that either regimen could be offered.

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.

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.

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

BACKGROUND: 5% 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/DESIGN: We 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. DISCUSSION: The 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 REGISTRATION: Trial registration number NCT01891240The IMPROvED project is funded by the seventh framework programme for Research and Technological development of the EU. http://www.fp7-improved.eu/

Aromatase inhibitors for uterine fibroids.

BACKGROUND: Uterine fibroids, also called uterine leiomyomas or myomas, are the most common benign tumours in women of reproductive age. Albeit generally benign, uterine fi broids can have a major impact on women's health and quality of life by contributing to abnormal uterine bleeding and causing pelvic pressure symptoms (such as increased urinary frequency, pelvic pain and constipation). Traditional treatments for symptomatic fi broids include a variety of surgical techniques. However, because of the high recurrence rate, as well as possible pain and infertility caused by the formation of postoperative adhesions, this approach may not be advisable. Safer and more effective medical therapy has long been awaited. Both in vitro studies and clinical trials have suggested that use of the aromatase inhibitors (AIs), a class of anti-oestrogens, might inhibit fi broid growth, thereby eliminating the need for surgery. OBJECTIVES: To evaluate the effectiveness and safety of aromatase Inhibitors (AIs) in women with uterine fibroids. SEARCH METHODS: We searched the following databases (from inception to August 21, 2013): Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL and PsycINFO. In addition, the reference lists of included trials were searched, and experts in the field were contacted. SELECTION CRITERIA: Randomised controlled trials (RCTs) in women of reproductive age comparing the effects of any AI versus placebo, no treatment or any medical treatment/surgery were included. DATA COLLECTION AND ANALYSIS: Selection of eligible trials, assessment of trial quality and data extraction were performed independently by two review authors. If data were available, we planned to calculate odds ratios (ORs) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CIs). MAIN RESULTS: Only one trial involving 70 participants was included. This trial did not report our primary review outcome (relief of symptoms of fibroids). The only secondary review outcomes reported by this trial were adverse effects (hot flushes) and reduction in fibroid size. Significantly fewer women reported hot flushes in the letrozole group than in the GnRHa group (0/33 vs 26/27, P < 0.05). Use of letrozole reduced fibroid volume by 46% and use of a gonadotrophin-releasing hormone (GnRH) agonist (GnRHa) by 32% after 12 weeks of treatment; these proportions were not significantly different. The included trial did not report data on fibroid volume in a form that permitted calcuation of an odds ratio. Morevoer it was unblinded and included only 60/70 women in analysis. AUTHORS' CONCLUSIONS: Evidence is insufficient to support the use of AI drugs in the treatment of women with uterine fibroids.

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.