Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile.

Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4(+) and CD8(+) T cells, with reductions not only in potentially deleterious IFN-γ and TNF-α production but also in IL-10 and IL-5. Conversely, production of IL-4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL-4. This was accompanied by reduced T-cell proliferation. Using fetal and viral antigen-specific CD8(+) T-cell clones, we confirmed that this as a direct, nonantigen-specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4(+) and CD8(+) T cells responded to progesterone in a dose-dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal-fetal interface. This characterization of how progesterone modulates T-cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss.

Investigating the effect of ethnicity on IVF outcome.

Success rates for IVF among women from different ethnic groups have been inconclusive. In this study, the relationship between ethnicity and IVF outcome was investigated. Results of a cohort study analysing 13,473 first cycles were compared with the results of meta-analysed data from 16 published studies. Adjustment was made for age, body-mass index, cause of infertility, duration of infertility, previous live birth, previous spontaneous abortion and number of embryos transferred. Black and South Asian women were found to have lower live birth rates compared with White women: Black versus White (OR 0.42 [0.25 to 0.70]; P = 0.001); South Asian versus White (OR 0.80 [0.65t o 0.99]; P = 0.04). Black women had significantly lower clinical pregnancy rates compared with White women (OR 0.41 [0.25 to 9 0.67]; P < 0.001). The meta-analysed results also showed that Black and South Asian women had statistically significant reduced odds of live birth (OR 0.62 [0.55 to 0.71); P < 0.001 and OR 0.66 [0.52 to 0.85); P = 0.001, respectively). Black and South Asian women seem to have the poorest outcome, which is not explained by the commonly known confounders. Future research needs to investigate the possible explanations for this difference and improve IVF outcome for all women.

The value of predicting restriction of fetal growth and compromise of its wellbeing: Systematic quantitative overviews (meta-analysis) of test accuracy literature.

BACKGROUND: Restriction of fetal growth and compromise of fetal wellbeing remain significant causes of perinatal death and childhood disability. At present, there is a lack of scientific consensus about the best strategies for predicting these conditions before birth. Therefore, there is uncertainty about the best management of pregnant women who might have a growth restricted baby. This is likely to be due to a dearth of clear collated information from individual research studies drawn from different sources on this subject. METHODS/DESIGN: A series of systematic reviews and meta-analyses will be undertaken to determine, among pregnant women, the accuracy of various tests to predict and/or diagnose fetal growth restriction and compromise of fetal wellbeing. We will search Medline, Embase, Cochrane Library, MEDION, citation lists of review articles and eligible primary articles and will contact experts in the field. Independent reviewers will select studies, extract data and assess study quality according to established criteria. Language restrictions will not be applied. Data synthesis will involve meta-analysis (where appropriate), exploration of heterogeneity and publication bias. DISCUSSION: The project will collate and synthesise the available evidence regarding the value of the tests for predicting restriction of fetal growth and compromise of fetal wellbeing. The systematic overviews will assess the quality of the available evidence, estimate the magnitude of potential benefits, identify those tests with good predictive value and help formulate practice recommendations.

Progesterone for the prevention of preterm birth: a critical evaluation of evidence.

A systematic review of the literature identified nine randomised trials that evaluated the effects of progestational agents in the prevention of preterm delivery. These studies were of variable quality. Meta-analyses showed reductions in delivery rates before 37 weeks (OR 0.42, 95% CI 0.31-0.57) and 34 weeks (OR 0.51, 95% CI 0.34-0.77) as well as in respiratory distress syndrome (OR 0.55, 95% CI 0.31-0.96) with progestational agents. A cumulative meta-analysis showed that the treatment benefit for the outcome of delivery before 37 weeks exceeded the conventional level of statistical significance in 1975 (p<0.01); by 1985, the p-value was <0.001, and by 2003, it was <0.0001. Another cumulative meta-analysis in which the studies were added to the pooled analysis by decreasing quality score showed significant benefit even when the analysis was limited to just the highest quality trials (OR 0.47, 95% CI 0.33, 0.66, p<0.0001). An exploration of the applicability of the effects across various baseline risks using a L'abbe plot found that the benefit was consistent across a range of risks. A comprehensive review of both trial and observational data on harm did not show any demonstrable evidence of harm to mother and baby. Women at high risk of preterm birth should be recommended progestational agent therapy.

Bias associated with delayed verification in test accuracy studies: accuracy of tests for endometrial hyperplasia may be much higher than we think!

BACKGROUND: To empirically evaluate bias in estimation of accuracy associated with delay in verification of diagnosis among studies evaluating tests for predicting endometrial hyperplasia. METHODS: Systematic reviews of all published research on accuracy of miniature endometrial biopsy and endometrial ultrasonography for diagnosing endometrial hyperplasia identified 27 test accuracy studies (2,982 subjects). Of these, 16 had immediate histological verification of diagnosis while 11 had verification delayed > 24 hrs after testing. The effect of delay in verification of diagnosis on estimates of accuracy was evaluated using meta-regression with diagnostic odds ratio (dOR) as the accuracy measure. This analysis was adjusted for study quality and type of test (miniature endometrial biopsy or endometrial ultrasound). RESULTS: Compared to studies with immediate verification of diagnosis (dOR 67.2, 95% CI 21.7-208.8), those with delayed verification (dOR 16.2, 95% CI 8.6-30.5) underestimated the diagnostic accuracy by 74% (95% CI 7%-99%; P value = 0.048). CONCLUSION: Among studies of miniature endometrial biopsy and endometrial ultrasound, diagnostic accuracy is considerably underestimated if there is a delay in histological verification of diagnosis.

Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review.

OBJECTIVE: To examine the effectiveness of aspirin in preventing perinatal death and preeclampsia in women with predisposing historical risk factors, such as previous history of preeclampsia, chronic hypertension, diabetes, and renal disease. DATA SOURCES: Searches were conductes in Medline, Embase, Cochrane Library, National Research Register, SCISEARCH, AND ISI Conference Proceedings without any language restrictions, using the following medical subject headings and text words: "aspirin," "antiplatelet*," "salicyl*," "acetylsalicyl*," "platelet aggregation inhibitors," "pre-eclamp*," "preeclamp*," and "hypertens*. METHODS OF STUDY SELECTION: We included all randomized trials that evaluated the effectiveness of aspirin compared with placebo or no treatment in women with predisposing historical risk factors and reported clinically relevant perinatal or maternal outcomes. Study selection, quality appraisal, and data extractions were performed independently and in duplicate.We identified 14 relevant trials, including a total of 12,416 women. Meta-analysis showed a significant benefit of aspirin therapy in reducing perinatal death (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.64, 0.96) and preeclampsia (OR 0.86, 95% CI 0.76, 0.96). Aspirin was also associated with a reduction in rates of spontaneous preterm birth (OR 0.86, 95% CI 0.79, 0.94), and an increase of 215 g in mean birth weight (weighted mean difference 215, 95% CI 90, 341). There was no increase in the risk of placental abruption with aspirin (OR 0.98, 95% CI 0.79, 1.21). Funnel plot analysis indicated that publication and related biases were unlikely (Egger test, P =.84). CONCLUSION: Aspirin reduces the risk of perinatal death and preeclampsia in women with historical risk factors. Given the importance of these outcomes and the safety and low cost of aspirin, aspirin therapy should be considered in women with historical risk factors.

The learning curve of selective salpingography and tubal catheterization.

OBJECTIVE: To determine the effect of increasing experience in fluoroscopically guided selective salpingography and tubal catheterization on radiation doses and screening times, thus establishing a learning curve for the procedure. DESIGN: Retrospective case note analysis. SETTING: IVF center of an academic teaching hospital. PATIENTS: Three hundred sixty-six patients with infertility seen over 3.5 years. INTERVENTION(S): Fluoroscopically guided selective salpingography and tubal catheterization. MAIN OUTCOME MEASURE(S): Reductions in radiation doses and screening times for different categories of selective salpingography and tubal catheterization, expressed as percentage reductions during the study period and reductions per 10 procedures. RESULT(S): During the study period, The median dose of radiation decreased by 62.6%-71.9%, and the median screening time declined by 61.5%-78.5%. Reductions per 10 procedures were 2.5%-4.2% and 2.7%-5%, respectively. CONCLUSION(S): Significant reductions in radiation doses and screening times start early in a clinical team's practice of selective salpingography and tubal catheterization and continue even as trainees are added to the pool of operators.

Diagnostic and therapeutic value of selective salpingography and tubal catheterization in an unselected infertile population.

OBJECTIVE: To present diagnostic findings and fertility outcome after selective salpingography and tubal catheterization in an unselected infertile population. DESIGN: Cohort study. SETTING: Tertiary reproductive medicine unit. PATIENT(S): One hundred ten consecutive infertile women. No exclusion criteria were applied. Follow-up ranged from 16 to 54 months. INTERVENTION(S): Selective salpingography and tubal catheterization under fluoroscopic guidance as the primary test for the assessment of the fallopian tubes. MAIN OUTCOME MEASURE(S): Incidence of tubal disease at selective salpingography, therapeutic effectiveness of tubal catheterization, and fertility outcome after the procedure. RESULT(S): Tubal disease was present in 31.4% of the tubes examined. Of tubes proximally blocked at selective salpingography, 52.1% were found to be normal after tubal catheterization. Proximal tubal blockage (bilateral or unilateral) was detected in 34.8% of women. This was reduced to 5.5% after tubal catheterization. Spontaneous conceptions occurred in 21.9% of the women. In total, 36.2% conceived without IVF or ICSI. CONCLUSION(S): Selective salpingography and tubal catheterization can be useful as a primary tubal assessment tool in the investigation of infertility. In cases of proximal tubal blockage, an effective see-and-treat approach can be adopted. More research into the possible therapeutic benefits of the procedure is justified.

Instructions to authors for case reporting are limited: a review of a core journal list.

BACKGROUND: Case reports are frequently published in the health care literature, however advice on preparing such reports using the "instructions to authors" pages of journals is alleged to be limited. However, to our knowledge, this has not been formally evaluated. As roles of case reports may vary according to the case and the clinical specialities, one might expect the advice to authors to vary according to journal clinical grouping. METHODS: We surveyed the current advice available to authors of case reports from 'instructions to authors' pages of a core collection of 249 journals ('Hague' list). These were examined and compared for advice or recommendation on writing case reports. Of these, 163 (65%) published case reports and provided instructions on this publication type. Data were extracted on items of style and content of case reports, using a piloted data extraction form. RESULTS: Journals that published case reports were grouped into medical (n = 81, 50%), surgical (n = 38, 23%) and generic or multidisciplinary (n = 44, 27%) categories. There was a difference among the medical, surgical and generic or multidisciplinary journals in the maximum number of words and pages allowed but no difference in the number of figures, tables, references, authors, abstract or synopsis, indexing or key words and consent. Additionally, there was no statistically significant difference among the three different categories of journals regarding the content of the case reports. CONCLUSIONS: Of the journals reviewed, we found that 'instructions to authors' pages provided limited and varied information for preparing a case report. There is a need for consensus, and more consistent guidance for authors of case report.

Modification of the coaxial technique for selective salpingography with measurement of tubal perfusion pressures.

This article describes the use of the fallopotorque catheter system for transcervical selective salpingography and tubal catheterization under fluoroscopic guidance for the diagnosis and treatment of obstruction of the proximal Fallopian tube. The technique of tubal perfusion pressure assessment during the procedure, using the same catheter system, is also described. The relative advantages of this method of selective salpingography and tubal catheterization are then discussed in the background of previously described techniques.

Women's attitudes to HIV screening in pregnancy in an area of low prevalence.

OBJECTIVES: To identify factors that influence acceptance of the human immunodeficiency virus (HIV) screening test by pregnant women. DESIGN: Prospective survey using questionnaires. SETTING: An antenatal clinic at a tertiary referral hospital. POPULATION: 200 pregnant women of multiethnic origin residing in a low prevalence area. METHODS: Two hundred consecutive women attending the antenatal booking clinic were interviewed. We collected data on reasons for opting in or out and factors that could influence the rate of acceptance, such as ethnicity, age, parity, level of education, first language and marital or relationship status. MAIN OUTCOME MEASURES: Attitudes of pregnant women to HIV screening. The rate of acceptance of HIV screening was 160/200(80%). The most frequent reasons for opting in were the perceived benefits of screening (92/160, 58%) and the fact that the test is now routinely offered (87/160, 54%). The most frequent reason for refusal of screening was perceived low risk of HIV (27/40, 68%). Logistic regression analysis showed that ethnicity, age, parity and level of formal education did not play a role in influencing uptake of the test. However, women whose first language was English were more likely to opt in compared with those whose first language was not English (P = 0.016) and those who were married or in a stable relationship were more likely to opt in than those who were not (P < 0.001). CONCLUSION: We have not reached the national target of 90% in our region. This appears to be due to a combination of factors, the main one being a perception of low risk. Greater knowledge of the ease of transmission of HIV may alter this perception, which may improve acceptance of the test.

A systematic review of postgraduate teaching in evidence-based medicine and critical appraisal.

The knowledge and skills needed for critical literature appraisal and evidence-based practice have not been covered in undergraduate education until recently. These educational needs are, therefore, often met through postgraduate education via courses, workshops and journal clubs. Previous reviews have generally considered postgraduates and undergraduates together. However, there is evidence that the effectiveness of educational interventions varies between postgraduates and undergraduates. In this study the authors therefore examine the effectiveness of evidence-based medicine and critical appraisal teaching at postgraduate level. A comprehensive search was conducted in MEDLINE, EMBASE, ERIC, CCTR, CDSR, DARE, HTA, Best Evidence and SCI. Seventeen studies were identified: two randomized trials, six controlled trials without randomization and nine before-and-after studies. The studies showed a significant improvement in knowledge, but not in attitude, skills or behaviour. However, to draw robust conclusions, well-designed trials are needed that focus on curriculum content and delivery as well as how outcomes are assessed.

Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with an indirect comparison of randomised trials.

OBJECTIVE: To explore the effectiveness of nifedipine compared with atosiban for tocolysis in preterm labour. DESIGN: A systematic review of randomised controlled trials with meta-analysis using adjusted indirect comparison. POPULATION: Six hundred and seventy-nine women recruited in nine randomised trials evaluating the effectiveness of nifedipine versus beta-agonists, and 852 women recruited in four trials of atosiban versus beta-agonists. There were no trials comparing nifedipine directly with atosiban. METHODS: We performed meta-analysis with a technique involving an adjusted indirect comparison between nifedipine and atosiban using beta-agonists as the common comparator. This approach preserves the benefit accrued by randomisation in the original comparisons. MAIN OUTCOME MEASURES: Reduction in neonatal respiratory distress syndrome and delay in delivery by 48 hours. RESULTS: Nifedipine tocolysis was associated with a significant reduction in respiratory distress syndrome compared with atosiban (OR 0.55, 95% CI 0.32-0.97). It also increased the number of women whose delivery was delayed by 48 hours (OR 1.20, 95% CI 0.73-1.95), although this result was not statistically significant. CONCLUSIONS: When indirectly compared with atosiban, nifedipine tocolysis is more effective. In the absence of a direct comparison, our analysis provides a way to explore the potential benefits of nifedipine versus atosiban.

Oxytocin antagonists for tocolysis in preterm labour -- a systematic review.

BACKGROUND: Oxytocin antagonists have been shown to inhibit uterine contractions and delay preterm delivery. Our objective was to examine the clinical effectiveness and safety of oxytocin antagonists for tocolysis in preterm labour. MATERIAL/METHODS: We searched MEDLINE, EMBASE, the Cochrane Controlled Trials Register and Science Citation Index using the following Medical Subject Headings and textwords: oxytocin (antagonists and inhibitors), atosiban, antocin, oxytocin antagonists, oxytocin receptor antagonists and oxytocin inhibitors. All randomised controlled trials that compared effectiveness and safety of atosiban with a placebo or another tocolytic in women with threatened or actual preterm labour were included. The primary outcome measure was the proportion of women undelivered by 48 hours from the commencement of treatment. RESULTS: Six articles met the inclusion criteria - two compared atosiban to placebo and four atosiban to a beta-agonist. Meta-analysis showed a significant increase in the proportion of women undelivered by 48 hours in women receiving atosiban compared to placebo (RR 1.13, 95%CI 1.02, 1.26). When compared with beta-agonists, atosiban increased the proportion of women undelivered by 48 hours, but this trend did not reach statistical significance (RR 1.07, 95%CI 0.98, 1.17). Side effect profile was substantially better for atosiban compared to beta-agonists. CONCLUSIONS: Oxytocin antagonists appear to be effective and safe for tocolysis in preterm labour.

The potential value of tubal perfusion pressures measured during selective salpingography in predicting fertility.

BACKGROUND: The value of tubal perfusion pressures assessed during selective salpingography and tubal catheterization in predicting fertility has not been investigated. METHODS: A total of 325 infertile women underwent selective salpingography and tubal catheterization. Pregnancy information was collected in 256 (78.7%). The 50th (300 mmHg) and 90th (500 mmHg) centiles of the tubal perfusion pressure distribution in women with normal tubes on selective salpingography were used as thresholds. Women were divided into three tubal perfusion pressure groups: good (both tubes <300, or one tube <300 and the other 300-500 mmHg), mediocre (both tubes 300-500, or one tube <300 and the other >500 mmHg) and poor (both tubes >500, or one tube > 500 and the other 300-500 mmHg). RESULTS: The pregnancy rate in the good perfusion pressure group was significantly higher than that in the poor perfusion pressure group, both when all non-IVF/ICSI first conceptions (P = 0.001) as well as when spontaneous first conceptions only were considered (P = 0.010). The pregnancy rate in the mediocre group lay between the good and the poor groups, though none of the comparisons reached statistical significance. CONCLUSIONS: Selective salpingography can provide additional diagnostic information in comparison with other tubal assessment tests. Tubal perfusion pressures may be predictive of future fertility.

Elective cervical cerclage for prevention of preterm birth: a systematic review.

BACKGROUND: Elective cervical cerclage has been purported to prevent spontaneous preterm birth. We present a systematic review to determine the effectiveness of cervical cerclage in preventing spontaneous preterm birth before 34 weeks' gestation. METHODS: Searches were conducted in MEDLINE, EMBASE, Cochrane Library, and Science Citation Index to identify randomized trials published between 1966 and 2002. All randomized trials that evaluated the effectiveness of elective cerclage compared with no cerclage in women who were at risk of preterm birth before 34 weeks' gestation were included for analysis. Quality assessment and data extraction were performed in duplicate. RESULTS: There were seven relevant trials, comprising 2354 women. Meta-analysis was inappropriate because of large differences in the quality of the studies. However, in the largest single trial of good quality, cerclage was shown to prevent birth before 34 weeks' gestation. In this single study the reported number to be treated to prevent one additional preterm birth before 34 weeks was 24 women (95% CI: 10-61). The results of other trials were consistent with the finding of the largest trial. Data on complications were sparse and inconclusive. CONCLUSION: Our systematic review shows that elective cervical cerclage has a significant effect in preventing spontaneous preterm birth before 34 weeks' gestation. Further research should focus on identification and quantification of possible complications, and of risk factors and tests that identify high-risk women who would benefit most from cerclage.

Accuracy of sperm-cervical mucus penetration tests in evaluating sperm motility in semen: a systematic quantitative review.

BACKGROUND: Our objective was to determine the accuracy of in-vitro sperm penetration into cervical mucus or substitutes in evaluating sperm motility in semen. METHODS: This was a systematic quantitative review of test accuracy studies. The Cochrane library (2000:4), Medline (1966-2001), Embase (1988-2001) and SciSearch (1981-2001) were searched, in addition to manual searches of conference papers and bibliographies of known primary and review articles. Primary studies measuring in-vitro sperm penetration into cervical mucus, or substitutes (i.e. sperm-mucus penetration test, SMPT) and comparing results with sperm motility in semen were included. RESULTS: There were 18 primary diagnostic studies published in 17 papers, involving a total of 2580 samples. Fourteen primary diagnostic tests used vanguard distance as diagnostic criteria (SMPT(vd)) and the pooled likelihood ratio (LR) for positive (LR+) and negative (LR-) tests were 2.29 (1.82-2.87) and 0.52 (0.44-0.63) respectively. Four studies used diagnostic criteria based directly or indirectly on swim-up sperm count per high power field (SMPT(sc)) instead. Their pooled LR+ and LR- were 5.24 (3.36-8.18) and 0.15 (0.06-0.39) respectively. CONCLUSIONS: SMPT(vd) has a low accuracy in the evaluation of sperm motility in semen. However, SMPT(sc) was found to be more accurate. This method of using sperm concentration, instead of vanguard distance, as diagnostic criteria of in-vitro SMPT has potential as a useful laboratory-based sperm function test.

Long-term fertility prognosis following selective salpingography and tubal catheterization in women with proximal tubal blockage.

BACKGROUND: The possibility of conception following selective salpingography and tubal catheterization is believed to decline sharply a few months after the procedure. This observation may be due to the relatively small number of patients and short follow-up of previous studies. Furthermore, couples with other causes of infertility apart from proximal tubal blockage have usually been excluded. METHODS: Survival analysis of conceptions of 218 consecutive infertile women with proximal tubal blockage who underwent selective salpingography and tubal catheterization was performed. There were no exclusion criteria. Follow-up ranged from 16 to 56 months. RESULTS: A total of 47.2% of spontaneous conceptions and 43.2% of all conceptions, apart from those achieved by IVF or ICSI treatments, occurred after the first 12 months following selective salpingography and tubal catheterization. The decline in the possibility of pregnancy during the study period (conception hazard rate) was only minimal. CONCLUSIONS: In a population of infertile women with proximal tubal blockage, a significant proportion of conceptions occur after the first 12 months following selective salpingography and tubal catheterization. The presence of any additional causes of infertility in the couple should not be regarded as an absolute contraindication to the procedure.