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1.  ALIFE2 study: low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia - study protocol for a randomized controlled trial 
Trials  2015;16:208.
A large number of studies have shown an association between inherited thrombophilia and recurrent miscarriage. It has been hypothesized that anticoagulant therapy might reduce the number of miscarriages and stillbirth in these women. In the absence of randomized controlled trials evaluating the efficacy of anticoagulant therapy in women with inherited thrombophilia and recurrent miscarriage, a randomized trial with adequate power that addresses this question is needed. The objective of the ALIFE2 study is therefore to evaluate the efficacy of low-molecular-weight heparin (LMWH) in women with inherited thrombophilia and recurrent miscarriage, with live birth as the primary outcome.
Randomized study of LMWH plus standard pregnancy surveillance versus standard pregnancy surveillance alone.
Study population: pregnant women of less than 7 weeks’ gestation, and confirmed inherited thrombophilia with a history of 2 or more miscarriages or intra-uterine fetal deaths, or both.
Setting: multi-center study in centers from the Dutch Consortium of Fertility studies; centers outside the Netherlands are currently preparing to participate.
Intervention: LMWH enoxaparin 40 mg subcutaneously once daily started prior to 7 weeks gestational age plus standard pregnancy surveillance or standard pregnancy surveillance alone.
Main study parameters/endpoints: the primary efficacy outcome is live birth. Secondary efficacy outcomes include adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), fetal growth restriction, placental abruption, premature delivery and congenital malformations.
Safety outcomes include bleeding episodes, thrombocytopenia and skin reactions.
After an initial period of slow recruitment, the recruitment rate for the study has increased. Improved awareness of the study and acknowledgement of the need for evidence are thought to be contributing to the improved recruitment rates. We aim to increase the number of recruiting centers in order to increase enrollment into the ALIFE2 study.
The study website can be accessed via
Trial registration
The ALIFE2 study was registered on 19 March 2012 under registration number NTR3361
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0719-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4453290  PMID: 25947329
Recurrent miscarriage; Pregnancy complications; Fetal death; Thrombophilia; Anticoagulants; Aspirin; Low-molecular-weight-heparin
2.  Study protocol: differential effects of diet and physical activity based interventions in pregnancy on maternal and fetal outcomes—individual patient data (IPD) meta-analysis and health economic evaluation 
Systematic Reviews  2014;3:131.
Pregnant women who gain excess weight are at risk of complications during pregnancy and in the long term. Interventions based on diet and physical activity minimise gestational weight gain with varied effect on clinical outcomes. The effect of interventions on varied groups of women based on body mass index, age, ethnicity, socioeconomic status, parity, and underlying medical conditions is not clear. Our individual patient data (IPD) meta-analysis of randomised trials will assess the differential effect of diet- and physical activity-based interventions on maternal weight gain and pregnancy outcomes in clinically relevant subgroups of women.
Randomised trials on diet and physical activity in pregnancy will be identified by searching the following databases: MEDLINE, EMBASE, BIOSIS, LILACS, Pascal, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database. Primary researchers of the identified trials are invited to join the International Weight Management in Pregnancy Collaborative Network and share their individual patient data. We will reanalyse each study separately and confirm the findings with the original authors. Then, for each intervention type and outcome, we will perform as appropriate either a one-step or a two-step IPD meta-analysis to obtain summary estimates of effects and 95% confidence intervals, for all women combined and for each subgroup of interest. The primary outcomes are gestational weight gain and composite adverse maternal and fetal outcomes. The difference in effects between subgroups will be estimated and between-study heterogeneity suitably quantified and explored. The potential for publication bias and availability bias in the IPD obtained will be investigated. We will conduct a model-based economic evaluation to assess the cost effectiveness of the interventions to manage weight gain in pregnancy and undertake a value of information analysis to inform future research.
Systematic review registration
PROSPERO 2013: CRD42013003804
PMCID: PMC4228083  PMID: 25370505
Individual patient data meta-analysis; Diet and physical activity; Pregnancy; Weight gain
3.  Women’s groups practising participatory learning and action to improve maternal and newborn health in low-resource settings: a systematic review and meta-analysis 
Lancet  2013;381(9879):1736-1746.
Maternal and neonatal mortality rates remain high in many low-income and middle-income countries. Different approaches for the improvement of birth outcomes have been used in community-based interventions, with heterogeneous effects on survival. We assessed the effects of women’s groups practising participatory learning and action, compared with usual care, on birth outcomes in low-resource settings.
We did a systematic review and meta-analysis of randomised controlled trials undertaken in Bangladesh, India, Malawi, and Nepal in which the effects of women’s groups practising participatory learning and action were assessed to identify population-level predictors of effect on maternal mortality, neonatal mortality, and stillbirths. We also reviewed the cost-effectiveness of the women’s group intervention and estimated its potential effect at scale in Countdown countries.
Seven trials (119 428 births) met the inclusion criteria. Meta-analyses of all trials showed that exposure to women’s groups was associated with a 37% reduction in maternal mortality (odds ratio 0·63, 95% CI 0·32–0·94), a 23% reduction in neonatal mortality (0·77, 0·65–0·90), and a 9% non-significant reduction in stillbirths (0·91, 0·79–1·03), with high heterogeneity for maternal (I2=58·8%, p=0·024) and neonatal results (I2=64·7%, p=0·009). In the meta-regression analyses, the proportion of pregnant women in groups was linearly associated with reduction in both maternal and neonatal mortality (p=0·026 and p=0·011, respectively). A subgroup analysis of the four studies in which at least 30% of pregnant women participated in groups showed a 55% reduction in maternal mortality (0·45, 0·17–0·73) and a 33% reduction in neonatal mortality (0·67, 0·59–0·74). The intervention was cost effective by WHO standards and could save an estimated 283 000 newborn infants and 41 100 mothers per year if implemented in rural areas of 74 Countdown countries.
With the participation of at least a third of pregnant women and adequate population coverage, women’s groups practising participatory learning and action are a cost-effective strategy to improve maternal and neonatal survival in low-resource settings.
Wellcome Trust, Ammalife, and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Birmingham and the Black Country programme.
PMCID: PMC3797417  PMID: 23683640
4.  A comparison of clinical officers with medical doctors on outcomes of caesarean section in the developing world: meta-analysis of controlled studies 
Objective To review the effectiveness and safety of clinical officers (healthcare providers trained to perform tasks usually undertaken by doctors) carrying out caesarean section in developing countries compared with doctors.
Design Systematic review with meta-analysis.
Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, CINAHL, BioMed Central, the Reproductive Health Library, and the Science Citation Index (inception-2010) without language restriction.
Study selection Controlled studies.
Data extraction Information was extracted from each selected article on study characteristics, quality, and outcome data. Two independent reviewers extracted data.
Results Six non-randomised controlled studies (16 018 women) evaluated the effectiveness of clinical officers carrying out caesarean section. Meta-analysis found no significant differences between the clinical officers and doctors for maternal death (odds ratio 1.46, 95% confidence interval 0.78 to 2.75; P=0.24) or for perinatal death (1.31, 0.87 to 1.95; P=0.19). The results were heterogeneous, with some studies reporting a higher incidence of both outcomes with clinical officers. Clinical officers were associated with a higher incidence of wound infection (1.58, 1.01 to 2.47; P=0.05) and wound dehiscence (1.89, 1.21 to 2.95; P=0.005). Two studies accounted for confounding factors.
Conclusion Clinical officers and doctors did not differ significantly in key outcomes for caesarean section, but the conclusions are tentative owing to the non-randomised nature of the studies. The increase in wound infection and dehiscence may highlight a particular training need for clinical officers.
PMCID: PMC3272986  PMID: 21571914
5.  Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence 
Objectives To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment with levothyroxine on pregnancy outcomes in this group of women.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. We used a combination of key words to generate two subsets of citations, one indexing thyroid autoantibodies and the other indexing the outcomes of miscarriage and preterm birth.
Study selection Studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected in a two stage process. Two reviewers selected studies that met the predefined and explicit criteria regarding population, tests, and outcomes.
Data synthesis Odds ratios from individual studies were pooled separately for cohort and case-control studies with the random effects model.
Results 30 articles with 31 studies (19 cohort and 12 case-control) involving 12 126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12 566 women evaluated the association with preterm birth. Of the 31 studies evaluating miscarriage, 28 showed a positive association between thyroid autoantibodies and miscarriage. Meta-analysis of the cohort studies showed more than tripling in the odds of miscarriage with the presence of thyroid autoantibodies (odds ratio 3.90, 95% confidence interval 2.48 to 6.12; P<0.001). For case-control studies the odds ratio for miscarriage was 1.80, 1.25 to 2.60; P=0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P=0.01). Two randomised studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and meta-analysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03). One study reported on the effect of levothyroxine on the rate of preterm birth, and noted a 69% relative risk reduction (0.31, 0.11 to 0.90).
Conclusion The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.
PMCID: PMC3089879  PMID: 21558126
6.  A multi-centre randomised controlled study of pre-IVF outpatient hysteroscopy in women with recurrent IVF implantation failure: Trial of Outpatient Hysteroscopy - [TROPHY] in IVF 
Reproductive Health  2009;6:20.
The success rate of IVF treatment is low. A recent systematic review and meta-analysis found that the outcome of IVF treatment could be improved in patients who have experienced recurrent implantation failure if an outpatient hysteroscopy (OH) is performed before starting the new treatment cycle. However, the trials were of variable quality, leading to a call for a large and high-quality randomised trial. This protocol describes a multi-centre randomised controlled trial to test the hypothesis that performing an OH prior to starting an IVF cycle improves the live birth rate of the subsequent IVF cycle in women who have experienced two to four failed IVF cycles.
Methods and design
Eligible and consenting women will be randomised to either OH or no OH using an internet based trial management programme that ensures allocation concealment and employs minimisation for important stratification variables including age, body mass index, basal follicle stimulating hormone level and number of previous failed IVF cycles. The primary outcome is live birth rate per IVF cycle started. Other outcomes include implantation, clinical pregnancy and miscarriage rates.
The sample size for this study has been estimated as 758 participants with 379 participants in each arm. Interim analysis will be conducted by an independent Data Monitoring Committee (DMC), and final analysis will be by intention to treat. A favourable ethical opinion has been obtained (REC reference: 09/H0804/32).
Trail Registration
The trial has been assigned the following ISRCTN number: ISRCTN35859078
PMCID: PMC2795733  PMID: 19958545
7.  Estimation of proteinuria as a predictor of complications of pre-eclampsia: a systematic review 
BMC Medicine  2009;7:10.
Proteinuria is one of the essential criteria for the clinical diagnosis of pre-eclampsia. Increasing levels of proteinuria is considered to be associated with adverse maternal and fetal outcomes. We aim to determine the accuracy with which the amount of proteinuria predicts maternal and fetal complications in women with pre-eclampsia by systematic quantitative review of test accuracy studies.
We conducted electronic searches in MEDLINE (1951 to 2007), EMBASE (1980 to 2007), the Cochrane Library (2007) and the MEDION database to identify relevant articles and hand-search of selected specialist journals and reference lists of articles. There were no language restrictions for any of these searches. Two reviewers independently selected those articles in which the accuracy of proteinuria estimate was evaluated to predict maternal and fetal complications of pre-eclampsia. Data were extracted on study characteristics, quality and accuracy to construct 2 × 2 tables with maternal and fetal complications as reference standards.
Sixteen primary articles with a total of 6749 women met the selection criteria with levels of proteinuria estimated by urine dipstick, 24-hour urine proteinuria or urine protein:creatinine ratio as a predictor of complications of pre-eclampsia. All 10 studies predicting maternal outcomes showed that proteinuria is a poor predictor of maternal complications in women with pre-eclampsia. Seventeen studies used laboratory analysis and eight studies bedside analysis to assess the accuracy of proteinuria in predicting fetal and neonatal complications. Summary likelihood ratios of positive and negative tests for the threshold level of 5 g/24 h were 2.0 (95% CI 1.5, 2.7) and 0.53 (95% CI 0.27, 1) for stillbirths, 1.5 (95% CI 0.94, 2.4) and 0.73 (95% CI 0.39, 1.4) for neonatal deaths and 1.5 (95% 1, 2) and 0.78 (95% 0.64, 0.95) for Neonatal Intensive Care Unit admission.
Measure of proteinuria is a poor predictor of either maternal or fetal complications in women with pre-eclampsia.
PMCID: PMC2670320  PMID: 19317889
8.  Tests for predicting complications of pre-eclampsia: A protocol for systematic reviews 
Pre-eclampsia is associated with several complications. Early prediction of complications and timely management is needed for clinical care of these patients to avert fetal and maternal mortality and morbidity. There is a need to identify best testing strategies in pre eclampsia to identify the women at increased risk of complications. We aim to determine the accuracy of various tests to predict complications of pre-eclampsia by systematic quantitative reviews.
We performed extensive search in MEDLINE (1951–2004), EMBASE (1974–2004) and also will also include manual searches of bibliographies of primary and review articles. An initial search has revealed 19500 citations. Two reviewers will independently select studies and extract data on study characteristics, quality and accuracy. Accuracy data will be used to construct 2 × 2 tables. Data synthesis will involve assessment for heterogeneity and appropriately pooling of results to produce summary Receiver Operating Characteristics (ROC) curve and summary likelihood ratios.
This review will generate predictive information and integrate that with therapeutic effectiveness to determine the absolute benefit and harm of available therapy in reducing complications in women with pre-eclampsia.
PMCID: PMC2553049  PMID: 18694494
9.  Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis 
Alterations in waveforms in the uterine artery are associated with the development of pre-eclampsia and intrauterine growth restriction. We investigated the predictive accuracy of all uterine artery Doppler indices for both conditions in the first and second trimesters.
We identified relevant studies through searches of MEDLINE, EMBASE, the Cochrane Library and Medion databases (all records to April 2006) and by checking bibliographies of identified studies and consulting with experts. Four of us independently selected studies, extracted data and assessed study validity. We performed a bivariable meta-analysis of sensitivity and specificity and calculated likelihood ratios.
We identified 74 studies of pre-eclampsia (total 79 547 patients) and 61 studies of intrauterine growth restriction (total 41 131 patients). Uterine artery Doppler ultrasonography provided a more accurate prediction when performed in the second trimester than in the first-trimester. Most Doppler indices had poor predictive characteristics, but this varied with patient risk and outcome severity. An increased pulsatility index with notching was the best predictor of pre-eclampsia (positive likelihood ratio 21.0 among high-risk patients and 7.5 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 9.1) and severe (positive likelihood ratio 14.6) intrauterine growth restriction among low-risk patients.
Abnormal uterine artery waveforms are a better predictor of pre-eclampsia than of intrauterine growth restriction. A pulsatility index, alone or combined with notching, is the most predictive Doppler index. These indices should be used in clinical practice. Future research should also concentrate on combining uterine artery Doppler ultrasonography with other tests.
PMCID: PMC2263112  PMID: 18332385
10.  A three-arm randomised controlled trial comparing Gonadotrophin Releasing Hormone (GnRH) agonist long regimen versus GnRH agonist short regimen versus GnRH antagonist regimen in women with a history of poor ovarian response undergoing in vitro fertilisation (IVF) treatment: Poor responders intervention trial (PRINT) 
Reproductive Health  2007;4:12.
Poor response to ovarian stimulation with exogenous gonadotrophins occurs in 9–24% of women undergoing in vitro fertilisation (IVF) treatment, which represents an estimated 4000–10,000 women per year in the UK. Poor responders often have their treatment cycle cancelled because of expected poor outcome.
One treatment strategy that may influence outcome is the choice of pituitary suppression regimen prior to the initiation of ovarian stimulation. The three commonly used pituitary suppression regimens in IVF treatment are:
(1) the GnRH agonist long regimen,
(2) the GnRH agonist short regimen and
(3) the GnRH antagonist regimen.
A systematic review of randomised controlled trials of these pituitary suppression regimens has shown the evidence to be either inconclusive or inconsistent. We therefore designed a three arm randomised trial to evaluate the effectiveness of these regimens in women who had poor ovarian response in a previous IVF treatment cycle.
Consenting, eligible women will be randomised to one of the three regimens using an internet-based trial management programme that ensures allocation concealment and employs block randomisation and minimisation for prognostic variables. The primary outcome is the number of oocytes retrieved. Other outcomes include total dose of follicle stimulating hormone (FSH) used for ovarian stimulation, mature oocytes retrieved, embryos available for transfer, implantation rate and clinical pregnancy rate.
The sample size for this trial has been estimated as 102 participants with 34 participants in each of the three arms. Appropriate interim analysis will be conducted by a Data Monitoring and Ethics Committee (DMEC), and the final analysis will be by intention to treat.
Trial registration
PMCID: PMC2259311  PMID: 18163902
11.  Computer-based teaching is as good as face to face lecture-based teaching of evidence based medicine: a randomised controlled trial 
At postgraduate level evidence based medicine (EBM) is currently taught through tutor based lectures. Computer based sessions fit around doctors' workloads, and standardise the quality of educational provision. There have been no randomized controlled trials comparing computer based sessions with traditional lectures at postgraduate level within medicine.
This was a randomised controlled trial involving six postgraduate education centres in the West Midlands, U.K. Fifty five newly qualified foundation year one doctors (U.S internship equivalent) were randomised to either computer based sessions or an equivalent lecture in EBM and systematic reviews. The change from pre to post-intervention score was measured using a validated questionnaire assessing knowledge (primary outcome) and attitudes (secondary outcome).
Both groups were similar at baseline. Participants' improvement in knowledge in the computer based group was equivalent to the lecture based group (gain in score: 2.1 [S.D = 2.0] versus 1.9 [S.D = 2.4]; ANCOVA p = 0.078). Attitudinal gains were similar in both groups.
On the basis of our findings we feel computer based teaching and learning is as effective as typical lecture based teaching sessions for educating postgraduates in EBM and systematic reviews.
PMCID: PMC3225809  PMID: 17659076
12.  A hierarchy of effective teaching and learning to acquire competence in evidenced-based medicine 
A variety of methods exists for teaching and learning evidence-based medicine (EBM). However, there is much debate about the effectiveness of various EBM teaching and learning activities, resulting in a lack of consensus as to what methods constitute the best educational practice. There is a need for a clear hierarchy of educational activities to effectively impart and acquire competence in EBM skills. This paper develops such a hierarchy based on current empirical and theoretical evidence.
EBM requires that health care decisions be based on the best available valid and relevant evidence. To achieve this, teachers delivering EBM curricula need to inculcate amongst learners the skills to gain, assess, apply, integrate and communicate new knowledge in clinical decision-making. Empirical and theoretical evidence suggests that there is a hierarchy of teaching and learning activities in terms of their educational effectiveness: Level 1, interactive and clinically integrated activities; Level 2(a), interactive but classroom based activities; Level 2(b), didactic but clinically integrated activities; and Level 3, didactic, classroom or standalone teaching.
All health care professionals need to understand and implement the principles of EBM to improve care of their patients. Interactive and clinically integrated teaching and learning activities provide the basis for the best educational practice in this field.
PMCID: PMC1770917  PMID: 17173690
13.  Meta-DiSc: a software for meta-analysis of test accuracy data 
Systematic reviews and meta-analyses of test accuracy studies are increasingly being recognised as central in guiding clinical practice. However, there is currently no dedicated and comprehensive software for meta-analysis of diagnostic data. In this article, we present Meta-DiSc, a Windows-based, user-friendly, freely available (for academic use) software that we have developed, piloted, and validated to perform diagnostic meta-analysis.
Meta-DiSc a) allows exploration of heterogeneity, with a variety of statistics including chi-square, I-squared and Spearman correlation tests, b) implements meta-regression techniques to explore the relationships between study characteristics and accuracy estimates, c) performs statistical pooling of sensitivities, specificities, likelihood ratios and diagnostic odds ratios using fixed and random effects models, both overall and in subgroups and d) produces high quality figures, including forest plots and summary receiver operating characteristic curves that can be exported for use in manuscripts for publication. All computational algorithms have been validated through comparison with different statistical tools and published meta-analyses. Meta-DiSc has a Graphical User Interface with roll-down menus, dialog boxes, and online help facilities.
Meta-DiSc is a comprehensive and dedicated test accuracy meta-analysis software. It has already been used and cited in several meta-analyses published in high-ranking journals. The software is publicly available at .
PMCID: PMC1552081  PMID: 16836745
14.  What is the evidence that postgraduate teaching in evidence based medicine changes anything? A systematic review 
BMJ : British Medical Journal  2004;329(7473):1017.
Objective To evaluate the effects of standalone versus clinically integrated teaching in evidence based medicine on various outcomes in postgraduates.
Design Systematic review of randomised and non-randomised controlled trials and before and after comparison studies.
Data sources Medline, Embase, ERIC, Cochrane Library, DARE, HTA database, Best Evidence, BEME, and SCI.
Study selection 23 studies: four randomised trials, seven non-randomised controlled studies, and 12 before and after comparison studies. 18 studies (including two randomised trials) evaluated a standalone teaching method, and five studies (including two randomised trials) evaluated a clinically integrated teaching method.
Main outcome measures Knowledge, critical appraisal skills, attitudes, and behaviour.
Results Standalone teaching improved knowledge but not skills, attitudes, or behaviour. Clinically integrated teaching improved knowledge, skills, attitudes, and behaviour.
Conclusion Teaching of evidence based medicine should be moved from classrooms to clinical practice to achieve improvements in substantial outcomes.
PMCID: PMC524555  PMID: 15514348
15.  Effectiveness of strategies incorporating training and support of traditional birth attendants on perinatal and maternal mortality: meta-analysis 
Objective To assess the effectiveness of strategies incorporating training and support of traditional birth attendants on the outcomes of perinatal, neonatal, and maternal death in developing countries.
Design Systematic review with meta-analysis.
Data sources Medline, Embase, the Allied and Complementary Medicine database, British Nursing Index, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, BioMed Central, PsycINFO, Latin American and Caribbean Health Sciences Literature database, African Index Medicus, Web of Science, Reproductive Health Library, and Science Citation Index (from inception to April 2011), without language restrictions. Search terms were “birth attend*”, “traditional midwife”, “lay birth attendant”, “dais”, and “comadronas”.
Review methods We selected randomised and non-randomised controlled studies with outcomes of perinatal, neonatal, and maternal mortality. Two independent reviewers undertook data extraction. We pooled relative risks separately for the randomised and non-randomised controlled studies, using a random effects model.
Results We identified six cluster randomised controlled trials (n=138 549) and seven non-randomised controlled studies (n=72 225) that investigated strategies incorporating training and support of traditional birth attendants. All six randomised controlled trials found a reduction in adverse perinatal outcomes; our meta-analysis showed significant reductions in perinatal death (relative risk 0.76, 95% confidence interval 0.64 to 0.88, P<0.001; number needed to treat 35, 24 to 70) and neonatal death (0.79, 0.69 to 0.88, P<0.001; 98, 66 to 170). Meta-analysis of the non-randomised studies also showed a significant reduction in perinatal mortality (0.70, 0.57 to 0.84, p<0.001; 48, 32 to 96) and neonatal mortality (0.61, 0.48 to 0.75, P<0.001; 96, 65 to 168). Six studies reported on maternal mortality and our meta-analysis showed a non-significant reduction (three randomised trials, relative risk 0.79, 0.53 to 1.05, P=0.12; three non-randomised studies, 0.80, 0.44 to 1.15, P=0.26).
Conclusion Perinatal and neonatal deaths are significantly reduced with strategies incorporating training and support of traditional birth attendants.
PMCID: PMC3228291  PMID: 22134967
16.  Accuracy of single progesterone test to predict early pregnancy outcome in women with pain or bleeding: meta-analysis of cohort studies 
Objective To determine the accuracy with which a single progesterone measurement in early pregnancy discriminates between viable and non-viable pregnancy.
Design Systematic review and meta-analysis of diagnostic accuracy studies.
Data sources Medline, Embase, CINAHL, Web of Science, ProQuest, Conference Proceedings Citation Index, and the Cochrane Library from inception until April 2012, plus reference lists of relevant studies.
Study selection Studies were selected on the basis of participants (women with spontaneous pregnancy of less than 14 weeks of gestation); test (single serum progesterone measurement); outcome (viable intrauterine pregnancy, miscarriage, or ectopic pregnancy) diagnosed on the basis of combinations of pregnancy test, ultrasound scan, laparoscopy, and histological examination; design (cohort studies of test accuracy); and sufficient data being reported.
Results 26 cohort studies, including 9436 pregnant women, were included, consisting of 7 studies in women with symptoms and inconclusive ultrasound assessment and 19 studies in women with symptoms alone. Among women with symptoms and inconclusive ultrasound assessments, the progesterone test (5 studies with 1998 participants and cut-off values from 3.2 to 6 ng/mL) predicted a non-viable pregnancy with pooled sensitivity of 74.6% (95% confidence interval 50.6% to 89.4%), specificity of 98.4% (90.9% to 99.7%), positive likelihood ratio of 45 (7.1 to 289), and negative likelihood ratio of 0.26 (0.12 to 0.57). The median prevalence of a non-viable pregnancy was 73.2%, and the probability of a non-viable pregnancy was raised to 99.2% if the progesterone was low. For women with symptoms alone, the progesterone test had a higher specificity when a threshold of 10 ng/mL was used (9 studies with 4689 participants) and predicted a non-viable pregnancy with pooled sensitivity of 66.5% (53.6% to 77.4%), specificity of 96.3% (91.1% to 98.5%), positive likelihood ratio of 18 (7.2 to 45), and negative likelihood ratio of 0.35 (0.24 to 0.50). The probability of a non-viable pregnancy was raised from 62.9% to 96.8%.
Conclusion A single progesterone measurement for women in early pregnancy presenting with bleeding or pain and inconclusive ultrasound assessments can rule out a viable pregnancy.
PMCID: PMC3460254  PMID: 23045257

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