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Background: Focal abnormalities most commonly acquired within the uterine cavity include endometrial polyps (arising from the endometrium) and submucous fibroids (arising from the myometrium). These benign abnormalities can cause several problems, including abnormal uterine bleeding (AUB) and subfertility. Two-dimensional saline infusion sonography (2D SIS) is a minimally invasive test that can be used to diagnose these pathologies, but it is less accurate than hysteroscopy, which is a more invasive procedure by which an endoscope allows direct visualisation of the uterine cavity. Three-dimensional (3D) SIS appears to enhance sonographic visualisation within the uterine cavity, thereby offering a potentially more accurate minimally invasive diagnostic test., Objectives: Primary objectives • To evaluate the diagnostic accuracy of 3D SIS (index test 1) compared with 2D SIS for the diagnosis of focally growing lesions (presence or not) in women with AUB or subfertility, with hysteroscopy performed as the reference test. • To evaluate the diagnostic accuracy of 2D+3D SIS (index test 2) compared with 2D SIS for the diagnosis of focally growing lesions (presence or not) in women with AUB or subfertility, with hysteroscopy performed as the reference test. In this case, any abnormality on either modality was regarded as a positive result ('OR' approach). Secondary objectives • To evaluate the diagnostic accuracy of 3D SIS (index test 1) compared with 2D SIS according to type of abnormality and discrimination between uterine polyps and submucous fibroids in women with AUB or subfertility, with hysteroscopy and histology used as the reference.• To evaluate the diagnostic accuracy of 2D+3D SIS (index test 2) compared with 2D SIS according to type of abnormality and discrimination between uterine polyps and submucous fibroids in women with AUB or subfertility, with hysteroscopy and histology used as the reference., Search Methods: We searched the following databases: Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PubMed, Cochrane Gynaecology and Fertility Group (CGF) Specialised Register and CGFG Diagnostic Test Accuracy (DTA) Specialised Register, clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Screening reference lists of appropriate studies was also performed. We screened for eligibility all studies identified from inception until March 2016. We performed searches with no date or language restrictions., Selection Criteria: The population of interest consisted of premenopausal women with AUB or subfertility and postmenopausal women with AUB. Diagnostic test accuracy studies, randomised controlled trials (RCTs) and prospective cohort studies were eligible for inclusion if they evaluated the accuracy of both 2D SIS and 3D SIS for the diagnosis of acquired intracavitary abnormalities with hysteroscopy used as the reference standard. In light of the lack of data for 3D SIS, we also included studies that evaluated the accuracy of 3D SIS alone., Data Collection and Analysis: Two review authors read all potentially eligible references after performing a first screening by title and abstract (LLN and FJRH). They independently extracted data to construct 2×2 tables from eligible studies and assessed studies for methodological quality using the QUADAS-2 tool (revised tool for quality assessment of diagnostic accuracy studies). To describe and visually present results, we produced in RevMan forest plots showing pairs of sensitivity and specificity together with 95% confidence intervals from each study, as well as raw receiver operating characteristic (ROC) plots. We displayed paired analyses in an ROC plot by linking sensitivity-specificity pairs from each study by using a dashed line. To compare 3D SIS versus 2D SIS, we restricted analyses to studies that provided 2×2 tables for both tests and used the bivariate meta-analysis of sensitivity and specificity., Main Results: Thirteen studies (1053 women) reported the accuracy of 3D SIS for focal uterine abnormalities; 11 of these (846 women) were suitable for meta-analysis, and eight reported accuracy according to the type of focal abnormality. The design of the included studies seems applicable. The main problem involving the quality of included studies is insufficient reporting of study methods, resulting in unclear risk of bias for several of the quality domains assessed. Therefore, we considered the overall quality of the evidence as low. The summary estimate (11 studies reporting absence or presence of abnormality at 3D SIS) for sensitivity was 94.5% (95% confidence interval (CI) 90.6% to 96.9%) and for specificity 99.4% (95% CI 96.2% to 99.9%). Meta-analysis of the eight studies (N = 716) directly comparing 2D SIS versus 3D SIS showed summary sensitivity of 96.9% (95% CI 91.9% to 98.8%) and summary specificity of 99.5% (95% CI 96.1% to 100%) for 3D SIS. For 2D SIS, summary sensitivity was 90.9% (95% CI 81.2% to 95.8%) and summary specificity was 96.3% (95% CI 86.1% to 99.1%). The difference in accuracy between 2D SIS and 3D SIS was non-significant (P values of 0.07 for sensitivity and 0.10 for specificity)., Authors' Conclusions: Low-quality evidence suggests that 3D SIS may be very accurate in detecting intracavitary abnormalities. Meta-analysis revealed no statistically significant differences between 2D SIS and 3D SIS. Summary sensitivity and summary specificity are higher for 3D SIS, but margins of improvement are limited because 2D SIS is already very accurate. When the technology and appropriate expertise are available, 3D SIS offers an alternative to 2D SIS. Both 2D SIS and 3D SIS should be considered alternatives to diagnostic hysteroscopy when intracavitary pathology is suspected in subfertile women and in those with abnormal uterine bleeding.

Objective  We assessed the influence of external factors on false-positive, false-negative, and invalid fibronectin results in the prediction of spontaneous delivery within 7 days. Methods  We studied symptomatic women between 24 and 34 weeks' gestational age. We performed uni- and multivariable logistic regression to estimate the effect of external factors (vaginal soap, digital examination, transvaginal sonography, sexual intercourse, vaginal bleeding) on the risk of false-positive, false-negative, and invalid results, using spontaneous delivery within 7 days as the outcome. Results  Out of 708 women, 237 (33%) had a false-positive result; none of the factors showed a significant association. Vaginal bleeding increased the proportion of positive fetal fibronectin (fFN) results, but was significantly associated with a lower risk of false-positive test results (odds ratio [OR], 0.22; 95% confidence intervals [CI], 0.12-0.39). Ten women (1%) had a false-negative result. None of the investigated factors was significantly associated with a significantly higher risk of false-negative results. Twenty-one tests (3%) were invalid; only vaginal bleeding showed a significant association (OR, 4.5; 95% CI, 1.7-12). Conclusion  The effect of external factors on the performance of qualitative fFN testing is limited, with vaginal bleeding as the only factor that reduces its validity., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: Threatened preterm labor (tPTL) is a complication of pregnancy. Identification of women and clinical definition differs between countries. This study investigated differences in tPTL and effectiveness of vaginal progesterone to prevent preterm birth (PTB) between two countries., Methods: Secondary analysis of a randomized controlled trial (RCT) from Argentina and Switzerland comparing vaginal progesterone to placebo in women with tPTL (n = 379). Cox proportional hazards analysis was performed to compare placebo groups of both countries and to compare progesterone to placebo within each country. We adjusted for baseline differences. Iatrogenic onset of labor or pregnancy beyond gestational age of interest was censored., Results: Swiss and Argentinian women were different on baseline. Risks for delivery <14 days and PTB < 34 and < 37 weeks were increased in Argentina compared to Switzerland, HR 3.3 (95% CI 0.62-18), 54 (95% CI 5.1-569) and 3.1 (95% CI 1.1-8.4). In Switzerland, progesterone increased the risk for delivery <14 days [HR 4.4 (95% CI 1.3-15.7)] and PTB <37 weeks [HR 2.5 (95% CI 1.4-4.8)], in Argentina there was no such effect., Conclusion: In women with tPTL, the effect of progesterone may vary due to population differences. Differences in populations should be considered in multicenter RCTs.

Background: Preterm birth is a major cause of neonatal mortality and morbidity. As preventive strategies are largely ineffective, threatened preterm labor is a frequent problem that affects approximately 10 % of pregnancies. In recent years, risk assessment in these women has incorporated cervical length measurement and fetal fibronectin testing, and this has improved the capacity to identify women at increased risk for delivery within 14 days. Despite these improvements, risk for preterm birth continues to be increased in women who did not deliver after an episode of threatened preterm labor, as indicated by a preterm birth rate between 30 to 60 % in this group of women. Currently no effective treatment is available. Studies on maintenance tocolysis and progesterone have shown ambiguous results. The pessary has not been evaluated in women with threatened preterm labor, however studies in asymptomatic women with a short cervix show reduced rates of preterm birth rates as well as perinatal complications. The APOSTEL VI trial aims to assess the effectiveness of a cervical pessary in women who did not deliver within 48 h after an episode of threatened preterm labor., Methods/design: This is a nationwide multicenter open-label randomized clinical trial. Women with a singleton or twin gestation with intact membranes, who were admitted for threatened preterm labor, at a gestational age between 24 and 34 weeks, a cervical length between 15 and 30 mm and a positive fibronectin test or a cervical length below 15 mm, who did not deliver after 48 h will be eligible for inclusion. Women will be allocated to a pessary or no intervention (usual care). Primary outcome is preterm delivery < 37 weeks. Secondary outcomes are amongst others a composite of perinatal morbidity and mortality. Sample size is based on an expected 50 % reduction of preterm birth before 37 weeks (two-sided test, α 0.05 and β 0.2). Two hundred women with a singleton pregnancy need to be randomized. Analysis will be done by intention to treat., Discussion: The APOSTEL VI trial will provide evidence whether a pessary is effective in preventing preterm birth in women who did not deliver 48 h after admission for threatened preterm labor and who remain at high risk for preterm birth., Trial Registration: Trial is registered at the Dutch Trial Register: http://www.trialregister.nl , NTR4210, date of registration: October 16th 2013.

Objective: Cervical length (CL) is associated with the risk of preterm birth (PTB) in multiple pregnancies. However, the position of CL within the pathophysiological pathway of PTB is unclear, and it is unknown which factors are predictive for CL. This study aims to investigate whether in twin pregnancies baseline maternal and obstetrical characteristics are potential indicators for CL, to improve insight in the pathophysiological pathway of PTB., Study Design: Secondary analysis of data on twin pregnancies and CL measurement between 16 and 22 weeks. A set of 10 potential indicators, known to be associated with an increased risk of PTB and/or which have a plausible mechanism resulting in a change of CL were selected. We used multivariable linear regression with backward selection to identify independent indicators for CL., Results: A total of 1,447 women with twin pregnancies were included. Mean CL was 43.7 (±8.9) mm. In multivariable analysis, age (0.27 mm/y; 95% confidence interval [CI] 0.16 to 0.39), use of assisted reproductive technologies (ART) (-1.42 mm, 95% CI -2.6 to -0.25), and having delivered at term in a previous pregnancy (1.32 mm, 95% CI 0.25 to 2.39) were significantly associated with CL., Conclusion: This study shows that in twin pregnancies, age, use of ART and having delivered term in a previous pregnancy has an association with CL., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer, accounting for nearly 30% of all paediatric cancers and 80% of childhood leukaemias. Polymorphisms in folate-related genes may influence the susceptibility to childhood ALL. This review summarizes the results of 14 studies that focussed on the relationship between folate-related gene polymorphisms and the susceptibility to ALL and that fulfilled certain quality criteria. The total group consisted of 729 children and 1821 adults or non age-defined patients. The results of different studies sometimes contradict each other, for which there are several possible explanations. This includes an influence of the type of population studied, because there was a difference between Asian and European study results. Based on several studies, it is plausible that polymorphisms in the MTHFR gene, 677C>T and 1298A>C, are associated with a decreased susceptibility to childhood ALL in non-Asian populations. Polymorphisms in other folate related genes (MTRR, MTR [MS], TYMS [TS], SLC19A1 [RFC1], NNMT, and SHMT1) are less clearly associated with susceptibility to ALL, and the number of included studies on this subject in this review is limited. Further investigations on the relevance of these polymorphisms need to be performed. In general, it is clear that susceptibility to (childhood) ALL is partly related to constitutional differences in folate gene polymorphisms.