Techniques for the interruption of tubal patency for female sterilisation.

BACKGROUND: This is an update of a review that was first published in 2002. Female sterilisation is the most popular contraceptive method worldwide. Several techniques exist for interrupting the patency of fallopian tubes, including cutting and tying the tubes, damaging the tube using electric current, applying clips or silicone rubber rings, and blocking the tubes with chemicals or tubal inserts. OBJECTIVES: To compare the different tubal occlusion techniques in terms of major and minor morbidity, failure rates (pregnancies), technical failures and difficulties, and women's and surgeons' satisfaction. SEARCH METHODS: For the original review published in 2002 we searched MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL). For this 2015 update, we searched POPLINE, LILACS, PubMed and CENTRAL on 23 July 2015. We used the related articles feature of PubMed and searched reference lists of newly identified trials. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing different techniques for tubal sterilisation, irrespective of the route of fallopian tube access or the method of anaesthesia. DATA COLLECTION AND ANALYSIS: For the original review, two review authors independently selected studies, extracted data and assessed risk of bias. For this update, data extraction was performed by one author (TL) and checked by another (RK). We grouped trials according to the type of comparison evaluated. Results are reported as odds ratios (OR) or mean differences (MD) using fixed-effect methods, unless heterogeneity was high, in which case we used random-effects methods. MAIN RESULTS: We included 19 RCTs involving 13,209 women. Most studies concerned interval sterilisation; three RCTs involving 1632 women, concerned postpartum sterilisation. Comparisons included tubal rings versus clips (six RCTs, 4232 women); partial salpingectomy versus electrocoagulation (three RCTs, 2019 women); tubal rings versus electrocoagulation (two RCTs, 599 women); partial salpingectomy versus clips (four RCTs, 3627 women); clips versus electrocoagulation (two RCTs, 206 women); and Hulka versus Filshie clips (two RCTs, 2326 women). RCTs of clips versus electrocoagulation contributed no data to the review.One year after sterilisation, failure rates were low (< 5/1000) for all methods.There were no deaths reported with any method, and major morbidity related to the occlusion technique was rare.Minor morbidity was higher with the tubal ring than the clip (Peto OR 2.15, 95% CI 1.22 to 3.78; participants = 842; studies = 2; I² = 0%; high-quality evidence), as were technical failures (Peto OR 3.93, 95% CI 2.43 to 6.35; participants = 3476; studies = 3; I² = 0%; high-quality evidence).Major morbidity was significantly higher with the modified Pomeroy technique than electrocoagulation (Peto OR 2.87, 95% CI 1.13 to 7.25; participants = 1905; studies = 2; I² = 0%; low-quality evidence), as was postoperative pain (Peto OR 3.85, 95% CI 2.91 to 5.10; participants = 1905; studies = 2; I² = 0%; moderate-quality evidence).When tubal rings were compared with electrocoagulation, postoperative pain was reported significantly more frequently for tubal rings (OR 3.40, 95% CI 1.17 to 9.84; participants = 596; studies = 2; I² = 87%; low-quality evidence).When partial salpingectomy was compared with clips, there were no major morbidity events in either group (participants = 2198, studies = 1). The frequency of minor morbidity was low and not significantly different between groups (Peto OR 7.39, 95% CI 0.46 to 119.01; participants = 193; studies = 1, low-quality evidence). Although technical failure occurred more frequently with clips (Peto OR 0.18, 95% CI 0.08 to 0.40; participants = 2198; studies = 1; moderate-quality evidence); operative time was shorter with clips than partial salpingectomy (MD 4.26 minutes, 95% CI 3.65 to 4.86; participants = 2223; studies = 2; I² = 0%; high-quality evidence).We found little evidence concerning women's or surgeon's satisfaction. No RCTs compared tubal microinserts (hysteroscopic sterilisation) or chemical inserts (quinacrine) to other methods. AUTHORS' CONCLUSIONS: Tubal sterilisation by partial salpingectomy, electrocoagulation, or using clips or rings, is a safe and effective method of contraception. Failure rates at 12 months post-sterilisation and major morbidity are rare outcomes with any of these techniques. Minor complications and technical failures appear to be more common with rings than clips. Electrocoagulation may be associated with less postoperative pain than the modified Pomeroy or tubal ring methods. Further research should include RCTs (for effectiveness) and controlled observational studies (for adverse effects) on sterilisation by minimally-invasive methods, i.e. tubal inserts and quinacrine.

Techniques for the interruption of tubal patency for female sterilisation.

BACKGROUND: This is an update of a review that was first published in 2002. Female sterilisation is the most popular contraceptive method worldwide. Several techniques exist for interrupting the patency of fallopian tubes, including cutting and tying the tubes, damaging the tube using electric current, applying clips or silicone rubber rings, and blocking the tubes with chemicals or tubal inserts. OBJECTIVES: To compare the different tubal occlusion techniques in terms of major and minor morbidity, failure rates (pregnancies), technical failures and difficulties, and women's and surgeons' satisfaction. SEARCH METHODS: For the original review published in 2002 we searched MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL). For this 2015 update, we searched POPLINE, LILACS, PubMed and CENTRAL on 23 July 2015. We used the related articles feature of PubMed and searched reference lists of newly identified trials. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing different techniques for tubal sterilisation, irrespective of the route of fallopian tube access or the method of anaesthesia. DATA COLLECTION AND ANALYSIS: For the original review, two review authors independently selected studies, extracted data and assessed risk of bias. For this update, data extraction was performed by one author (TL) and checked by another (RK). We grouped trials according to the type of comparison evaluated. Results are reported as odds ratios (OR) or mean differences (MD) using fixed-effect methods, unless heterogeneity was high, in which case we used random-effects methods. MAIN RESULTS: We included 19 RCTs involving 13,209 women. Most studies concerned interval sterilisation; three RCTs involving 1632 women, concerned postpartum sterilisation. Comparisons included tubal rings versus clips (six RCTs, 4232 women); partial salpingectomy versus electrocoagulation (three RCTs, 2019 women); tubal rings versus electrocoagulation (two RCTs, 599 women); partial salpingectomy versus clips (four RCTs, 3827 women); clips versus electrocoagulation (two RCTs, 206 women); and Hulka versus Filshie clips (two RCTs, 2326 women). RCTs of clips versus electrocoagulation contributed no data to the review.One year after sterilisation, failure rates were low (< 5/1000) for all methods.There were no deaths reported with any method, and major morbidity related to the occlusion technique was rare.Minor morbidity was statistically significantly higher with the tubal ring than the clip (Peto OR 2.15, 95% CI 1.22 to 3.78; participants = 842; studies = 2; I² = 0%; high-quality evidence), as were technical failures (Peto OR 3.93, 95% CI 2.43 to 6.35; participants = 3476; studies = 3; I² = 0%; high-quality evidence).Major morbidity was significantly higher with the modified Pomeroy technique than electrocoagulation (Peto OR 2.87, 95% CI 1.13 to 7.25; participants = 1905; studies = 2; I² = 0%; low-quality evidence), as was postoperative pain (Peto OR 3.85, 95% CI 2.91 to 5.10; participants = 1905; studies = 2; I² = 0%; moderate-quality evidence).When tubal rings were compared with electrocoagulation, postoperative pain was reported significantly more frequently for tubal rings (OR 3.40, 95% CI 1.17 to 9.84; participants = 596; studies = 2; I² = 87%; low-quality evidence).When partial salpingectomy was compared with clips, there were no major morbidity events in either group (participants = 2198, studies = 1). The frequency of minor morbidity was low and not significantly different between groups (Peto OR 7.39, 95% CI 0.46 to 119.01; participants = 193; studies = 1, low-quality evidence). Although technical failure occurred more frequently with clips (Peto OR 0.18, 95% CI 0.08 to 0.40; participants = 2198; studies = 1; moderate-quality evidence); operative time was shorter with clips than partial salpingectomy (MD 4.26 minutes, 95% CI 3.65 to 4.86; participants = 2223; studies = 2; I² = 0%; high-quality evidence).We found little evidence concerning women's or surgeon's satisfaction. No RCTs compared tubal microinserts (hysteroscopic sterilisation) or chemical inserts (quinacrine) to other methods. AUTHORS' CONCLUSIONS: Tubal sterilisation by partial salpingectomy, electrocoagulation, or using clips or rings, is a safe and effective method of contraception. Failure rates at 12 months post-sterilisation and major morbidity are rare outcomes with any of these techniques. Minor complications and technical failures may be more common with rings than clips. Electrocoagulation may be associated with less postoperative pain than the modified Pomeroy or tubal ring methods. Further research should include RCTs (for effectiveness) and controlled observational studies (for adverse effects) on sterilisation by minimally-invasive methods, i.e. tubal inserts and quinacrine.

Combination of tocolytic agents for inhibiting preterm labour.

BACKGROUND: Preterm birth represents the single largest cause of mortality and morbidity for newborns and a major cause of morbidity for pregnant women. Tocolytic agents include a wide range of drugs that can inhibit labour to prolong pregnancy. This may gain time to allow the fetus to mature further before being born, permit antenatal corticosteroid administration for lung maturation, and allow time for intra-uterine transfer to a hospital with neonatal intensive care facilities. However, some tocolytic drugs are associated with severe side effects. Combinations of tocolytic drugs may be more effective over single tocolytic agents or no intervention, without adversely affecting the mother or neonate. OBJECTIVES: To assess the effects on maternal, fetal and neonatal outcomes of any combination of tocolytic drugs for the treatment of preterm labour when compared with any other treatment, no treatment or placebo. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2014) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials comparing a combination of tocolytic agents, administered by any route or any dose, for inhibiting preterm labour versus any other treatment (including other combinations of tocolytics or single tocolytics), no intervention or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study reports for eligibility, carried out data extraction and assessed risk of bias. MAIN RESULTS: Eleven studies met our inclusion criteria. Two studies did not report any outcome data relevant to the review, so the results of the review are based on nine trials that contributed data. Primary outcomes were perinatal mortality, serious maternal or infant outcomes, adverse drug reactions, birth before 48 hours of trial entry, birth before 34 weeks' gestation and preterm neonates delivered without a full course of antenatal steroids completed 24 hours before birth. The quality of evidence in included trials was mixed; only three of the trials were placebo controlled.The included trials examined seven different comparisons: intravenous (IV) ritodrine plus oral or IV magnesium (sulphate or gluconate) versus IV ritodrine alone (three trials, 231 women); IV ritodrine plus indomethacin suppositories versus IV ritodrine alone (one trial, 208 women); IV ritodrine plus vaginal progesterone versus IV ritodrine alone (one trial, 83 women); IV hexoprenaline sulphate plus IV magnesium hydrochloride versus IV hexoprenaline sulphate alone (one trial, 24 women); IV fenoterol plus oral naproxen versus IV fenoterol alone (one trial, 72 women); oral pentoxifylline plus IV magnesium sulphate plus IV fenoterol versus IV magnesium sulphate plus IV fenoterol (one trial, 125 women); and, IV terbutaline plus oral metoprolol versus IV terbutaline alone (one trial, 17 women). Few studies with small numbers of women were available for each comparison, hence very little data were pooled in meta-analysis. In all trials, not many of the primary outcomes were reported.Three trials examined intravenous (IV) ritodrine plus IV or oral magnesium (sulphate or gluconate) compared with IV ritodrine alone. One study, with 41 women, reported more adverse drug reactions in the group receiving the combined tocolytics (risk ratio (RR) 7.79, 95% confidence interval (CI) 1.11 to 54.80). Two trials reported discontinuation of therapy due to severe side effects (results were not combined due to high statistical heterogeneity, I² = 83%); one trial reported increased severe side effects in the group receiving IV ritodrine alone (RR 7.79, 95% CI 1.11 to 54.80, 41 women); in the other trial there was no clear difference between groups (RR 0.23, 95% CI 0.03 to 1.97, 107 women). Other primary outcomes were not reported.One trial assessed IV ritodrine plus indomethacin suppositories versus IV ritodrine alone. There were no significant differences between groups for perinatal mortality or serious neonatal morbidity. Results for other primary outcomes were not reported.There were no significant differences between groups receiving IV ritodrine plus vaginal progesterone compared with IV ritodrine alone for most outcomes reported, although the latency period (time from recruitment to delivery) was increased in the group receiving the combination of tocolytics.For other combinations of tocolytic agents, primary outcomes were rarely reported and for secondary outcomes results did not demonstrate differences between groups. AUTHORS' CONCLUSIONS: It is unclear whether a combination of tocolytic drugs for preterm labour is more advantageous for women and/or newborns due to a lack of large, well-designed trials including the outcomes of interest. There are no trials of combination regimens using widely used tocolytic agents, such as calcium channel blockers (nifedipine) and/or oxytocin receptor antagonists (atosiban). Further trials are needed before specific conclusions on use of combination tocolytic therapy for preterm labour can be made.

Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study.

BACKGROUND: We report the main findings of the WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS), which aimed to assess the burden of complications related to pregnancy, the coverage of key maternal health interventions, and use of the maternal severity index (MSI) in a global network of health facilities. METHODS: In our cross-sectional study, we included women attending health facilities in Africa, Asia, Latin America, and the Middle East that dealt with at least 1000 childbirths per year and had the capacity to provide caesarean section. We obtained data from analysis of hospital records for all women giving birth and all women who had a severe maternal outcome (SMO; ie, maternal death or maternal near miss). We regarded coverage of key maternal health interventions as the proportion of the target population who received an indicated intervention (eg, the proportion of women with eclampsia who received magnesium sulphate). We used areas under the receiver operator characteristic curves (AUROC) with 95% CI to externally validate a previously reported MSI as an indicator of severity. We assessed the overall performance of care (ie, the ability to produce a positive effect on health outcomes) through standardised mortality ratios. RESULTS: From May 1, 2010, to Dec 31, 2011, we included 314,623 women attending 357 health facilities in 29 countries (2538 had a maternal near miss and 486 maternal deaths occurred). The mean period of data collection in each health facility was 89 days (SD 21). 23,015 (7.3%) women had potentially life-threatening disorders and 3024 (1.0%) developed an SMO. 808 (26.7%) women with an SMO had post-partum haemorrhage and 784 (25.9%) had pre-eclampsia or eclampsia. Cardiovascular, respiratory, and coagulation dysfunctions were the most frequent organ dysfunctions in women who had an SMO. Reported mortality in countries with a high or very high maternal mortality ratio was two-to-three-times higher than that expected for the assessed severity despite a high coverage of essential interventions. The MSI had good accuracy for maternal death prediction in women with markers of organ dysfunction (AUROC 0.826 [95% CI 0.802-0.851]). INTERPRETATION: High coverage of essential interventions did not imply reduced maternal mortality in the health-care facilities we studied. If substantial reductions in maternal mortality are to be achieved, universal coverage of life-saving interventions need to be matched with comprehensive emergency care and overall improvements in the quality of maternal health care. The MSI could be used to assess the performance of health facilities providing care to women with complications related to pregnancy. FUNDING: UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP); WHO; USAID; Ministry of Health, Labour and Welfare of Japan; Gynuity Health Projects.

Umbilical vein injection for the routine management of third stage of labour.

BACKGROUND: Postpartum haemorrhage is among the biggest contributor to maternal mortality worldwide. Prevention of this condition includes routine use of uterotonic in the third stage of labour, which has been recommended throughout the world. Use of umbilical route to deliver this uterotonic after delivery of the baby has been proposed. Therapeutic use of this has been assessed, although routine (prophylactic) use of this has not been evaluated. OBJECTIVES: To compare, from the best available evidence, the effects of umbilical vein injection of a saline solution alone or with any uterotonic drug versus an alternative solution with or without any other uterotonic agent or expectant management or any other method for routine management of the third stage of labour, on maternal and perinatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2012) and reference lists of retrieved studies. SELECTION CRITERIA: We included all randomised controlled trials comparing the effects of umbilical vein injection of a saline solution alone or with any uterotonic drug versus any other alternative methods. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and trial quality. Two review authors extracted data. Data were checked for accuracy. MAIN RESULTS: We included nine studies involving 1118 women.We identified four comparisons. One comparison included six studies (which randomised 394 women) comparing umbilical vein injection of normal saline plus oxytocin versus that of normal saline, as well as three other comparisons, each of which includes one study. Comparing intraumbilical injection of normal saline plus oxytocin with intraumbilical injection of saline only, there was no evidence of difference in any of the relevant outcomes reported namely the number of women who required blood transfusion, the incidence of manual removal of placenta, blood loss, and length of the third stage of labour. Subgroup analyses by both total amount of solution administered and dose of oxytocin showed no evidence of difference. Other comparisons included only one study for each, and there was no relevant information available. AUTHORS' CONCLUSIONS: Routine use of oxytocin or any other uterotonics with normal saline via umbilical vein injection is not recommended until new evidence is available. Further research should be conducted to show effectiveness of oxytocin with normal saline via umbilical vein injection.

Umbilical vein injection for management of retained placenta.

BACKGROUND: If a retained placenta is left untreated, there is a high risk of maternal death. However, manual removal of the placenta is an invasive procedure with serious complications of haemorrhage, infection or genital tract trauma. OBJECTIVES: To assess the use of umbilical vein injection (UVI) of saline solution alone or with oxytocin in comparison either with expectant management or with an alternative solution or other uterotonic agent for retained placenta. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2011). SELECTION CRITERIA: Randomized trials comparing UVI of saline or other fluids, with or without oxytocics, either with expectant management or with an alternative solution or other uterotonic agent, in the management of retained placenta. DATA COLLECTION AND ANALYSIS: Two review authors assessed the methodological quality of the studies and extracted the data. MAIN RESULTS: We included 15 trials (1704 women). The trials were of variable quality. Compared with expectant management, UVI of saline solution alone did not show any significant difference in the incidence of manual removal of the placenta (risk ratio (RR) 0.99; 95% confidence interval (CI) 0.84 to 1.16). UVI of oxytocin solution compared with expectant management showed no reduction in the need for manual removal (RR 0.87; 95% CI 0.74 to 1.03).Oxytocin solution compared with saline solution alone showed a reduction in manual removal of the placenta, but this was not statistically significant (RR 0.91; 95% CI 0.82 to 1.00). When only high-quality studies were assessed, there was no statistical difference (RR 0.92; 95% CI 0.83 to 1.01). We detected no differences in any of the other outcomes.UVI of oxytocin solution compared with UVI of plasma expander showed no statistically significant difference in the outcomes assessed by the only one small trial included. Prostaglandin solution compared with saline solution alone was associated with a statistically significant lower incidence in manual removal of placenta (RR 0.42; 95% CI 0.22 to 0.82) but we observed no difference in the other outcomes evaluated. Prostaglandin plus saline solution showed a statistically significant reduction in manual removal of placenta when compared with oxytocin plus saline solution (RR 0.43; 95% CI 0.25 to 0.75), and we also observed a small reduction in time from injection to placental delivery (mean difference -6.00; 95% CI -8.78 to -3.22). However, there were only two small trials contributing to this meta-analysis. AUTHORS' CONCLUSIONS: UVI of oxytocin solution is an inexpensive and simple intervention that could be performed while placental delivery is awaited. However, high-quality randomized trials show that the use of oxytocin has little or no effect. Further research into the optimal timing of manual removal and into UVI of prostaglandins or plasma expander is warranted.

Techniques for the interruption of tubal patency for female sterilisation.

BACKGROUND: Female sterilisation is the most popular contraceptive method worldwide. Several techniques are described in the literature, however only few of them are commonly used and properly evaluated. OBJECTIVES: To compare the different tubal occlusion techniques in terms of major and minor morbidity, failure rates (pregnancies), technical failures and difficulties, and women's and surgeons' views. SEARCH STRATEGY: Originally MEDLINE and The Cochrane Controlled Trials Register were searched. For the 2010 update, searches of Popline, Lilacs, Pubmed and The Cochrane Controlled Trials Register were performed. Reference lists of identified trials were searched. SELECTION CRITERIA: All randomised controlled trials comparing different techniques for tubal sterilisation, regardless of the route of Fallopian tube access or the method of anaesthesia. DATA COLLECTION AND ANALYSIS: Trials under consideration were evaluated for methodological quality and appropriateness for inclusion. Nine relevant studies were included and the results were stratified in five groups: tubal ring versus clip, modified Pomeroy versus electrocoagulation, tubal ring versus electrocoagulation, modified Pomeroy versus Filshie clip and Hulka versus Filshie clip. Results are reported as odds ratio for dichotomous outcomes and weighted mean differences for continuous outcomes. MAIN RESULTS: Tubal ring versus clip: Minor morbidity was higher in the ring group (Peto OR 2.15; 95% CI 1.22, 3.78). Technical difficulties were found less frequent in the clip group ( Peto OR 3.87; 95% CI 1.90, 7.89). There was no difference in failure rates between the two groups (Peto OR 0.70; 95% CI 0.28, 1.76). Pomeroy versus electrocoagulation: Women undergoing modified Pomeroy technique had higher major morbidity than those with the electrocoagulation technique (Peto OR 2.87; 95% CI 1.13, 7.25). Postoperative pain was more frequent in the Pomeroy group (Peto OR 3.85; 95% CI 2.91, 5.10). Tubal ring versus electrocoagulation: Post operative pain was more frequently reported in the tubal ring group. No pregnancies were reported. Pomeroy versus Filshie clip: In the only trial comparing the two interventions only one pregnancy was reported in the Pomeroy group after follow-up for 24 months. No differences were found when comparing Hulka versus Filshie clip in the only study that compared these two devices. AUTHORS' CONCLUSIONS: Electrocoagulation was associated with less morbidity including post-operative pain when compared with the modified Pomeroy and tubal ring methods, despite the risk of burns to the small bowel. The small sample size and the relative short period of follow-up in these studies limited the power to show clinical or statistical differences for rare outcomes such as failure rates. Aspects such as training, costs and maintenance of the equipment may be important factors in deciding which method to choose.

Accuracy of diagnostic tests to detect asymptomatic bacteriuria during pregnancy.

OBJECTIVE: A dipslide is a plastic paddle coated with agar that is attached to a plastic cap that screws onto a sterile plastic vial. Our objective was to estimate the diagnostic accuracy of the dipslide culture technique to detect asymptomatic bacteriuria during pregnancy and to evaluate the accuracy of nitrate and leucocyte esterase dipslides for screening. METHODS: This was an ancillary study within a trial comparing single-day with 7-day therapy in treating asymptomatic bacteriuria. Clean-catch midstream samples were collected from pregnant women seeking routine care. Positive and negative likelihood ratios and sensitivity and specificity for the culture-based dipslide to detect and chemical dipsticks (nitrites, leukocyte esterase, or both) to screen were estimated using traditional urine culture as the "gold standard." RESULTS: : A total of 3,048 eligible pregnant women were screened. The prevalence of asymptomatic bacteriuria was 15%, with Escherichia coli the most prevalent organism. The likelihood ratio for detecting asymptomatic bacteriuria with a positive dipslide test was 225 (95% confidence interval [CI] 113-449), increasing the probability of asymptomatic bacteriuria to 98%; the likelihood ratio for a negative dipslide test was 0.02 (95% CI 0.01-0.05), reducing the probability of bacteriuria to less than 1%. The positive likelihood ratio of leukocyte esterase and nitrite dipsticks (when both or either one was positive) was 6.95 (95% CI 5.80-8.33), increasing the probability of bacteriuria to only 54%; the negative likelihood ratio was 0.50 (95% CI 0.45-0.57), reducing the probability to 8%. CONCLUSION: A pregnant woman with a positive dipslide test is very likely to have a definitive diagnosis of asymptomatic bacteriuria, whereas a negative result effectively rules out the presence of bacteriuria. Dipsticks that measure nitrites and leukocyte esterase have low sensitivity for use in screening for asymptomatic bacteriuria during gestation. CLINICAL TRIAL REGISTRATION: ISRCTN, isrctn.org, 1196608 LEVEL OF EVIDENCE: II.