Hanns Helmer

Promoter Elements and Transcription Factors Involved in Differentiation-Dependent Human Chorionic Gonadotrophin-α Messenger Ribonucleic Acid Expression of Term Villous Trophoblasts1

Differentiation of primary villous cytotrophoblasts into syncytia is associated with increasing production of α and β human CG subunits, which is predominantly governed at the level of messenger RNA expression. Here, we present a detailed study on the mechanisms involved in the differentiation-dependent regulation of the trophoblast-specific CGα gene promoter. Site-directed mutations in each of the five DNA-elements of the composite enhancer were performed to investigate the contribution of the individual regulatory sequences to the overall transcriptional activity of the promoter at two different stages of trophoblast in vitro differentiation. We show that deletion of one cyclic AMP response element (CRE) did not affect CGα promoter activity in cytotrophoblasts; however, it reduced transcription by 33% in differentiating cultures. Removal of both CREs almost abolished transcription at early and later stages of in vitro differentiation. Upon mutation the enhancer elements αACT, JRE, and CCAAT significantl...

Production of oxytocin receptor and cytokines in primary uterine smooth muscle cells cultivated under inflammatory conditions.

Objective: We studied the production of the oxytocin receptor and interleukins in human uterine smooth muscle cells cultured in vitro in the presence of cytokines that were shown to be elevated in gestational diseases such as intrauterine infections and chorioamnionitis. Methods: Human uterine smooth muscle cells were cultured in the absence or presence of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), or lipopolysaccharide (LPS). Additionally, cells were cultivated under hypoxic conditions (3.5% oxygen). After 6, 12, 24, and 48 hours of incubation, oxytocin receptor mRNA was measured from total RNA using quantitative, competitive reverse transcriptase-polymerase chain reaction. Secreted cytokines (IL-1β, IL-6, or IL-8) were quantitated from supernatants after 6, 12, 24, and 48 hours of stimulation by commercially available enzyme-linked immunosorbent assay. Results: In nonstimulated cultures basal secretion of IL-1β, IL-6, and IL-8 was detectable. Supplementation of IL-1β induced a statistically significant decrease in oxytocin receptor mRNA abundance, whereas IL-6, TNFα, LPS, or hypoxia did not significantly affect oxytocin receptor gene expression. The cytokines IL-1 and TNFα induced IL-6 and IL-8 release, whereas secretion of the two interleukins was not altered in the presence of LPS or hypoxia. Expression of IL-1β was not significantly induced under inflammatory or hypoxic culture conditions. Conclusion: The constitutive and cytokine-inducible expression of interleukins from uterine smooth muscle cells suggests that the myometrium may contribute to the overall production of inflammatory mediators in the uterus that are thought to govern term or infection-induced preterm labor. Down-regulation of the oxytocin receptor under IL-1β in myometrial cells may indicate that initiation and maintenance of labor could be partially limited under severe inflammatory conditions such as chorioamnionitis.

Intravesical instillation of oxybutynin in women with idiopathic detrusor instability: a randomised trial

Urinary incontinence is one of the most socially incapacitating problems affecting women. Frequency, urgency and urge incontinence have been found to increase with age. Yet, no underlying cause has been established for the detrusor instability encountered in most patients. Oxybutynin chloride is a tertiary amine with combined anti-cholinergic, muscle relaxant and local anaesthetic properties (Diokno & Lapides 1972). Oral oxybutynin chloride has a well documented therapeutic effect in patients with bladder instability. However, the high incidence of anti-cholinergic side effects (30 % to 80 %) often requires dosage reduction or discontinuation of treatment (Brendler et al. 1989). Therefore, alternatives to conventional pharmacological treatment of detrusor instability have been the object of various studies (Brendler et al. 1989; Greenfield & Fera 1991). Intravesical drug instillation may be one such alternative. The aim of this study was to evaluate the benefits and side effects of intravesical oxybutynin application in women with idiopathic detrusor instability by means of a randomised, placebo-controlled trial.

Safety concerns for the use of calcium channel blockers in pregnancy for the treatment of spontaneous preterm labour and hypertension: a systematic review and meta-regression analysis

Background. Calcium channel blockers (CCBs) are not licensed for use in pregnancy but are used without robust surveillance to treat hypertension in pregnancy and preterm labour. The objective of this study was to evaluate the fetomaternal safety of CCB in pregnancy by a quantitative systematic review. Methods. Medline (1996–2005), EMBASE (1996–2003), BIOSIS (1993–2003), Current contents (1995–2003), DERWENT DRUGFILE (1983–2003) and Cochrane Library (2005: issue 3). The number of women reporting an adverse event was used to compute a percentage of the total number of women in whom the occurrence of that event or confirmation of its absence was reported. Meta-regression with generalised estimation equations modelling explored reasons for heterogeneity, seeking factors that increased the rates of the most commonly reported adverse events. Findings. Of 269 relevant reports, including 5607 women, adverse fetomaternal events varied according to the total dose of nifedipine and study design. Adverse events were highest amongst women given more than 60 mg total dose of nifedipine [odds ratio (OR) 3.78, 95% confidence interval (CI) 1.27–11.2, p = 0.017] and in reports from case series compared to controlled studies (OR 2.45, 95% CI 1.17–5.15, p = 0.018). Interpretation. Adverse event rates generated from this study provide an evidence base for clinical guidelines and informed patient consent for CCB use in pregnancy.

The quality of nifedipine studies used to assess tocolytic efficacy: a systematic review

Abstract Objective: To assess the quality of studies of nifedipine used to treat spontaneous preterm labor. Design: A systematic review of study quality using a novel validity assessment tool, examining method-specific and topic-specific items in the domains of selection, performance and measurement biases. Data Sources: Medline (1996–2003), EMBASE (1996–2003), BIOSIS (1993–2003), Current Contents (1995–2003), DERWENT DRUGFILE (1983–2003), Cochrane Database of Systematic Reviews. Bibliographies of existing meta-analyses and systematic reviews of nifedipine as a tocolytic. Methods of Study Selection: Forty-five studies evaluating the effectiveness of nifedipine were identified. Data Extraction: Each study was assessed for 40 method-specific and topic-specific items of quality in duplicate using piloted data extraction forms. Disagreements between assessors were settled by consensus/arbitration. Data Synthesis: Very few of the studies complied with adequacy criteria of quality for either method-specific or topic-specific items. There was no improvement in quality over time. The quality of method-specific items was significantly poorer when compared with topic-specific items of quality overall (P<0.0001) and in the domains of selection bias (P<0.0001) and performance bias (P<0.0001). Conclusion: Studies of the effectiveness of nifedipine as a tocolytic are of poorer quality with respect to method-specific items than topic-specific items. These deficiencies should be highlighted in meta-analyses or systematic reviews which measure efficacy and should influence the generation of guideline statements or recommendations for the use of nifedipine as a tocolytic. A large randomized trial fulfilling the quality items is necessary to assess the real efficacy of nifedipine in preterm labor.

Fetal fibronectin as a predictor of spontaneous preterm birth : a European perspective

Preterm birth (PTB) is estimated to account for 6–10% of all births worldwide with 13 million PTBs occurring annually and 1 million resulting in death. The diagnosis of spontaneous preterm labor and accurate prediction of preterm delivery is notoriously difficult. Identification of effective risk assessment markers can potentially improve outcomes by enabling targeted therapy while allowing efficient use of resources and avoiding unnecessary interventions. Advances in perinatal medicine have not reduced PTB and effective measures that improve outcome are yet to be established. However, considerable progress has been made in the development of accurate methods (fetal fibronectin and cervical length assessment) to predict PTB in both symptomatic and asymptomatic high-risk women. The excellent negative predictive value of fFN has the ability to facilitate decision-making regarding admission, in utero transfer, administration of antenatal corticosteroids and/or tocolysis and has been shown to be cost-effective. This review describes the European perspective on the use of fFN and describes ongoing European clinical studies, which are appropriately designed with meaningful endpoints, which will undoubtedly facilitate a better understanding of test accuracy and cost-effectiveness within different populations.

The diagnosis of rupture of fetal membranes (ROM): a meta-analysis

Abstract Aim: The aim of this study was to compare the performance of tests based on the detection of insulin-like growth factor binding protein 1 (IGFBP-1) and placental α-microglobulin-1 (PAMG-1) in diagnosing rupture of fetal membranes (ROM) across different patient populations. Methods: A meta-analysis was conducted on prospective observational or cohort studies investigating ROM tests based on the detection of IGFBP-1 and PAMG-1 meeting the following criteria: (1) performance metrics calculated by comparing results to an adequate reference method; (2) sensitivity thresholds of the investigated tests matching those of the currently available tests; (3) study population, as a minimum, included patients between 25 and 37 weeks of gestation. Sensitivities, specificities, and diagnostic odds ratios were calculated. Results: Across all patient populations, the analyzed performance measures of the PAMG-1 test were significantly superior compared with those of the IGFBP-1 test. Of particular clinical relevance, PAMG-1 outperformed IGFBP-1 in the equivocal group, which comprised patients with uncertain rupture of membranes (sensitivity, 96.0% vs. 73.9%; specificity, 98.9% vs. 77.8%; PAMG-1 vs. IGFBP-1 tests, respectively). Conclusions: Compared with its performance in women with known membrane status, the accuracy of the IGFBP-1 test decreases significantly when used on patients whose membrane status is unknown. In this latter clinically relevant population, the PAMG-1 test has higher accuracy than the IGFBP-1 test.

The predictive value of quantitative fibronectin testing in combination with cervical length measurement in symptomatic women

BACKGROUND The combination of the qualitative fetal fibronectin test and cervical length measurement has a high negative predictive value for preterm birth within 7 days; however, positive prediction is poor. A new bedside quantitative fetal fibronectin test showed potential additional value over the conventional qualitative test, but there is limited evidence on the combination with cervical length measurement. OBJECTIVE The purpose of this study was to compare quantitative fetal fibronectin and qualitative fetal fibronectin testing in the prediction of spontaneous preterm birth within 7 days in symptomatic women who undergo cervical length measurement. STUDY DESIGN We performed a European multicenter cohort study in 10 perinatal centers in 5 countries. Women between 24 and 34 weeks of gestation with signs of active labor and intact membranes underwent quantitative fibronectin testing and cervical length measurement. We assessed the risk of preterm birth within 7 days in predefined strata based on fibronectin concentration and cervical length. RESULTS Of 455 women who were included in the study, 48 women (11%) delivered within 7 days. A combination of cervical length and qualitative fibronectin resulted in the identification of 246 women who were at low risk: 164 women with a cervix between 15 and 30 mm and a negative fibronectin test (<50 ng/mL; preterm birth rate, 2%) and 82 women with a cervix at >30 mm (preterm birth rate, 2%). Use of quantitative fibronectin alone resulted in a predicted risk of preterm birth within 7 days that ranged from 2% in the group with the lowest fibronectin level (<10 ng/mL) to 38% in the group with the highest fibronectin level (>500 ng/mL), with similar accuracy as that of the combination of cervical length and qualitative fibronectin. Combining cervical length and quantitative fibronectin resulted in the identification of an additional 19 women at low risk (preterm birth rate, 5%), using a threshold of 10 ng/mL in women with a cervix at <15 mm, and 6 women at high risk (preterm birth rate, 33%) using a threshold of >500 ng/mL in women with a cervix at >30 mm. CONCLUSION In women with threatened preterm birth, quantitative fibronectin testing alone performs equal to the combination of cervical length and qualitative fibronectin. Possibly, the combination of quantitative fibronectin testing and cervical length increases this predictive capacity. Cost-effectiveness analysis and the availability of these tests in a local setting should determine the final choice.

Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine

These guidelines are based upon most recent and updated evidence and they are adapted to a European perspective by an expert view of the problem. These guidelines are not intended to be a meta-anal...

Emerging issues over the choice of nifedipine, beta-agonists and atosiban for tocolysis in spontaneous preterm labour—a proposed systematic review by the International Preterm Labour Council

Department of Obstetrics and Gynaecology, University Hospital of Wales, Department of Obstetrics and Gynaecology, General Hospital, Medical University Clinics Vienna, Education Resource Centre, Birmingham Women’s Hospital, Birmingham, UK, Department of Obstetrics and Gynaecology, Northwick Park Hospital and Imperial College, London, UK, Perinatal Research F410, Womens Pavillion, Royal Victoria Hospital, Montreal, Quebec, Department of Obstetrics and Gynaecology, Glostrup University Hospital, Denmark, Maternité-Port Royal, Hopital Cochin, Université René Descartes, Paris, France, and Department of Obstetrics and Gynaecology, Virje universiteit Medical Center, Amsterdam