Effect on perinatal outcome of prophylactic antibiotics in preterm prelabor rupture of membranes: network meta-analysis of randomized controlled trials.

OBJECTIVES: Prophylactic antibiotics are recommended routinely for preterm prelabor rupture of membranes (PPROM), but there is an abundance of potential treatments and a paucity of comparative information. The aims of this network meta-analysis were to compare the efficiency of different antibiotic regimens on perinatal outcomes and to assess the quality of the current evidence. METHODS: This was a network meta-analysis of randomized controlled trials comparing prophylactic antibiotics, or regimens of antibiotics, with each other or with placebo/no treatment, in women with PPROM. MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, US Registry of Clinical Trials ( www.ClinicalTrials.gov) and gray literature sources were searched. The primary outcomes were neonatal mortality and chorioamnionitis; secondary outcomes included other measures of perinatal morbidity. Relative effect sizes were estimated using risk ratios (RR) and the relative ranking of the interventions was obtained using cumulative ranking curves. The quality of evidence for the primary outcomes was assessed according to GRADE guidelines, adapted for network meta-analysis. RESULTS: The analysis included 20 studies (7169 participants randomized to 15 therapeutic regimens). For the outcome of chorioamnionitis, clindamycin + gentamycin (network RR, 0.19 (95% CI, 0.05-0.83)), penicillin (RR, 0.31 (95% CI, 0.16-0.6)), ampicillin/sulbactam + amoxicillin/clavulanic acid (RR, 0.32 (95% CI, 0.12-0.92)), ampicillin (RR, 0.52 (95% CI, 0.34-0.81)) and erythromycin + ampicillin + amoxicillin (RR, 0.71 (95% CI, 0.55-0.92)) were superior to placebo/no treatment. Erythromycin was the only effective drug for neonatal sepsis (RR, 0.74 (95% CI, 0.56-0.97)). Clindamycin + gentamycin (RR, 0.32 (95% CI, 0.11-0.89)) and erythromycin + ampicillin + amoxicillin (RR, 0.83 (95% CI, 0.69-0.99)) were the only effective regimens for respiratory distress syndrome, whereas ampicillin (RR, 0.42 (95% CI, 0.20-0.92)) and penicillin (RR, 0.49 (95% CI, 0.25-0.96)) were effective in reducing the rates of Grade-3/4 intraventricular hemorrhage. None of the antibiotics appeared significantly more effective than placebo/no treatment in reducing the rates of neonatal death, perinatal death and necrotizing enterocolitis. No network RR could be estimated for neonatal intensive care unit admission. The overall quality of the evidence, according to GRADE guidelines, was moderate to very low, depending on the outcome and comparison. CONCLUSIONS: Several antibiotics appear to be more effective than placebo/no treatment in reducing the rate of chorioamnionitis after PPROM. However, none of them is clearly and consistently superior compared to other antibiotics, and most are not superior to placebo/no treatment for other outcomes. The overall quality of the evidence is low and needs to be updated, as microbial resistance may have emerged for some antibiotics, while others are underrepresented in the existing evidence. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Effect of long term aspirin use on the incidence of prostate cancer: A systematic review and meta-analysis.

BACKGROUND: Previous studies found divergent effects of aspirin use on prostate cancer incidence, potentially due to studies with short durations of aspirin use and insufficient adjustment for screening. METHODS: A systematic review on the association between aspirin use ≥3 years and incident prostate cancer was performed in accordance with the PRISMA and MOOSE criteria. RESULTS: In the cohort studies, aspirin use for at least 3 years was associated with a lower incidence rate of prostate cancer (Odds ratio (OR) 0.88, 95% CI 0.80-0.97). No protective association was established for the case-control studies (OR 0.92, 95% CI 0.68-1.23). Subgroup analysis of advanced and aggressive cancers showed a protective association (OR 0.82, 95% CI 0.71-0.94 and OR 0.75, 95% CI 0.61-0.97). CONCLUSION: This synthesis of observational studies suggests a potential protective association between long term aspirin use and incident prostate cancer. The current literature is highly heterogenous and suffers from inconsistent aspirin dose definition and measurement.

Genetic and non-genetic risk factors for pre-eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies.

OBJECTIVE: To summarize evidence from the literature on genetic and non-genetic risk factors associated with pre-eclampsia (PE), assess the presence of statistical bias in the studies and identify risk factors for which there is robust evidence supporting their association with PE. METHODS: PubMed and ISI Web of Science were searched from inception to October 2016, to identify systematic reviews and meta-analyses of observational studies examining associations between genetic or non-genetic risk factors and PE. For each meta-analysis, the summary-effect size was estimated using random-effects and fixed-effects models, along with 95% CIs and the 95% prediction interval. Between-study heterogeneity was expressed using the I2 statistic, and evidence of small-study effects (large studies had significantly more conservative results than smaller studies) and evidence of excess significance bias (too many studies with statistically significant results) were estimated. RESULTS: Fifty-eight eligible meta-analyses were identified, which included 1466 primary studies and provided data on 130 comparisons of risk factors associated with PE, covering a wide range of comorbid diseases, genetic factors, exposure to environmental agents and biomarkers. Sixty-five (50%) associations had nominally statistically significant findings at P < 0.05, while 16 (12%) were significant at P < 10-6 . Sixty-five (50%) associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in 10 (8%) and 26 (20%) associations, respectively. The only non-genetic risk factor with convincing evidence for an association with PE was oocyte donation vs spontaneous conception, which had a summary odds ratio of 4.33 (95% CI, 3.11-6.03), was supported by 2712 cases with small heterogeneity (I2 = 26%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10) or excess of significance (P > 0.05). Of the statistically significant (P < 0.05) genetic risk factors for PE, only PAI-1 4G/5G (recessive model) polymorphism was supported by strong evidence for a contribution to the pathogenesis of PE. Eleven factors (serum iron level, pregnancy-associated plasma protein-A, chronic kidney disease, polycystic ovary syndrome, mental stress, bacterial and viral infections, cigarette smoking, oocyte donation vs assisted reproductive technology, obesity vs normal weight, severe obesity vs normal weight and primiparity) presented highly suggestive evidence for an association with PE. CONCLUSIONS: A large proportion of meta-analyses of genetic and non-genetic risk factors for PE have caveats that threaten their validity. Oocyte donation vs spontaneous conception and PAI-1 4G/5G polymorphism (recessive model) showed the strongest consistent evidence for an association with risk for PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

High miscarriage rate in women treated with Essure® for hydrosalpinx before embryo transfer: a systematic review and meta-analysis.

OBJECTIVES: Essure® has been tested as an alternative treatment for hydrosalpinx before embryo transfer (ET) in women undergoing assisted reproduction techniques. However, the persistence of a foreign body inside the uterine cavity might have a negative impact on the outcome of pregnancy. The present systematic review aimed at identifying, appraising and summarizing the available evidence regarding the effectiveness and safety of using Essure prior to ET for women with hydrosalpinx. METHODS: We searched for studies in PubMed, Scopus, CENTRAL, Web of Science and ClinicalTrials.gov and the reference lists of eligible studies. All studies including at least 10 women with hydrosalpinx who received Essure, any other intervention or no treatment prior to ET were considered eligible. Study selection, data extraction and evaluation of the risk of bias were performed independently by two authors. Study outcomes were miscarriage per clinical pregnancy, singleton preterm birth per singleton live birth and live birth/ongoing pregnancy and clinical pregnancy per ET. The pooled results for each outcome and intervention were summarized as proportions with their respective 95% CIs, using a random-effects model. RESULTS: Our electronic search of databases was performed on 7 November 2015, and 26 studies with 43 study arms were considered eligible: eight study arms evaluating Essure; seven assessing tubal aspiration; seven appraising effects of no treatment; 12 evaluating salpingectomy; two assessing tubal division; and seven evaluating tubal occlusion. When compared with women who had no intervention, women with Essure had a higher clinical pregnancy rate per ET (36% (95% CI, 0-43%) vs 13% (95% CI, 9-17%)). When compared with women who had other interventions, women with Essure had a higher miscarriage rate per clinical pregnancy (38% (95% CI, 27-49%) vs 15% (95% CI, 10-19%)). CONCLUSIONS: The available evidence suggests that, although Essure prior to ET in women with hydrosalpinx improves the chance of achieving a clinical pregnancy compared with no intervention, it is associated with a higher rate of miscarriage when compared with the other interventions. Although this evidence is based on observational studies, we believe that salpingectomy should be the first option for women who are eligible for videolaparoscopy. However, it is still premature to make recommendations for women who are not eligible for surgery, and randomized controlled trials are needed to clarify which is the best treatment alternative in such a scenario. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Nuchal translucency and major congenital heart defects in fetuses with normal karyotype: a meta-analysis.

OBJECTIVE: To pool published data regarding the sensitivity and specificity of nuchal translucency (NT) in the diagnosis of major congenital heart defects (CHDs) in fetuses with normal karyotype. METHODS: MEDLINE and Scopus searches using combinations of the terms 'nuchal' and 'cardiac*' were complemented by perusal of references of the retrieved articles and an additional automated search using the 'search for related articles' function on PubMed. Only fetuses with normal karyotype and major CHDs were analyzed. Weighted estimates were made and summary receiver-operating characteristics curves were constructed. RESULTS: The analysis included 20 studies (205 232 fetuses; 537 cases with major CHDs). The pooled sensitivity and specificity of NT > 95(th) centile for diagnosis of major CHDs was 44.4% (95% CI, 39.5-49.5) and 94.5% (95% CI, 94.4-94.6), respectively. The pooled sensitivity and specificity of NT > 99(th) centile was 19.5% (95% CI, 15.9-23.5) and 99.1% (95% CI, 99.1-99.2), respectively. For the subgroup of studies in which NT was measured by Fetal Medicine Foundation-certified operators, the pooled sensitivity and specificity of NT > 95(th) centile was 45.6% (95% CI, 39.6-51.7) and 94.7% (95% CI, 94.6-94.9), respectively. The corresponding estimates for NT > 99(th) centile were 21.0% (95%CI, 16.5-26.1) and 99.2% (95% CI, 99.2-99.3). The pooled positive likelihood ratio for NT > 99(th) centile was 30.5 (95% CI, 24.3-38.6). There was high across-studies heterogeneity for most estimates. CONCLUSION: Approximately 44% of chromosomally normal fetuses with CHDs have NT > 95(th) centile and 20% have NT > 99(th) centile. However, there is high heterogeneity across studies, which largely remains even in subgroup analyses of studies of apparently similar design, potentially indicating the presence of some residual unidentified bias.

Perinatal outcome in women treated with progesterone for the prevention of preterm birth: a meta-analysis.

OBJECTIVE: To quantify the effect on perinatal outcome in women treated with progesterone for the prevention of preterm birth. METHODS: MEDLINE and SCOPUS searches, including references of the retrieved articles and additional automated search using the 'search for related articles' PubMed function, were used. Randomized controlled trials assigning women at risk for preterm birth to progesterone or placebo were included (both singleton and multiple pregnancies). Outcomes were neonatal and perinatal death, respiratory distress syndrome (RDS), retinopathy, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) Grade 3-4, sepsis, admission to the neonatal intensive care unit (NICU) and composite adverse outcome. RESULTS: Sixteen studies (singletons, n = 7; twins, n = 7; triplets, n = 2) were included in the meta-analysis. For singleton pregnancies, progesterone reduced the rates of neonatal death (risk ratio (RR) 0.487 (95% CI, 0.290-0.818)), RDS (RR 0.677 (95% CI, 0.490-0.935)), NICU admission (RR 0.410 (95% CI, 0.204-0.823)) and composite adverse outcome (RR 0.576 (95% CI, 0.373-0.891)). No favorable effect was observed in twins; in fact, progesterone was associated with increased rates of perinatal death (RR 1.551 (95% CI, 1.014-2.372)), RDS (RR 1.218 (95% CI, 1.038-1.428)) and composite adverse outcome (RR 1.211 (95% CI, 1.029-1.425)). No significant effect was observed in triplet pregnancies. CONCLUSION: Progesterone administration in singleton pregnancies at risk for preterm birth improves perinatal outcomes, but may actually have adverse effects in multiple pregnancies.

Neurodevelopmental outcome of fetuses with increased nuchal translucency and apparently normal prenatal and/or postnatal assessment: a systematic review.

OBJECTIVES: To systematically review and, when feasible, pool, published data regarding the prevalence of childhood neurodevelopmental delay in fetuses with increased first-trimester nuchal translucency (NT), normal karyotype and absence of structural defects or identifiable syndromes. METHODS: MEDLINE and SCOPUS searches using combinations of the terms 'nuchal translucency' AND 'outcome*' were complemented by perusal of the references of the retrieved articles and an additional automated search using the 'search for related articles' PubMed function. Only children with a normal karyotype and no structural defects or syndromic abnormalities were included in the analysis. Between-studies heterogeneity was assessed using the I(2) statistic. RESULTS: The total prevalence of developmental delay in all 17 studies was 28/2458 (1.14%; 95% CI, 0.79-1.64; I(2) = 57.6%). Eight studies (n = 1567) used NT > 99(th) centile as the cut-off; 15 children (0.96%; 95% CI, 0.58-1.58%) were reported as having developmental delay (I(2) = 72.2%). Four studies (n = 669) used the 95(th) centile as the cut-off for increased NT; seven children (1.05%; 95% CI, 0.51-4.88%) were reported as having developmental delay (I(2) = 29.2%). Five studies used 3.0 mm as the cut-off for increased NT; the pooled rate of developmental delay was six of 222 children (2.70%; 95% CI, 1.24-5.77%; I(2) = 0.0%). CONCLUSION: The rate of neurodevelopmental delay in children with increased fetal NT, a normal karyotype, normal anatomy and no identifiable genetic syndromes does not appear to be higher than that reported for the general population. More large-scale, prospective case-control studies would be needed to enhance the robustness of the results.

First-trimester ductus venosus screening for cardiac defects: a meta-analysis.

BACKGROUND: Heart defects are the most common congenital abnormalities. OBJECTIVE: We aimed to evaluate in a meta-analysis the screening performance of abnormal ductus venosus (DV) Doppler waveform for detection of congenital heart disease (CHD) in chromosomally normal fetuses. SEARCH STRATEGY: Studies were retrieved from a search of MEDLINE, ISI, SCOPUS and EMBASE (from 1999 to March 2011) using the keywords 'ductus venosus', 'DV', 'chromosomal abnormalities', 'congenital heart disease' and 'nuchal translucency'. SELECTION CRITERIA: We considered all studies that examined the diagnostic performance of DV in the first trimester for CHD in chromosomally normal fetuses. We included studies that were limited to fetuses with increased nuchal translucency (NT), normal NT, and studies that examined fetuses regardless of NT status. DATA COLLECTION AND ANALYSIS: Seven studies (n = 50,354) regardless of the NT status, nine studies (n = 2908) with increased NT and seven studies (n = 47,610) with normal NT were included in the meta-analysis. We drew hierarchical summary receiver operating characteristic (HSROC) curves using the parameters of the fitted models. MAIN RESULTS: In populations including participants regardless of NT status, the summary sensitivity and specificity of DV for detecting CHD were 50 and 93%, respectively. In participants with increased NT, the summary sensitivity and specificity were 83 and 80%, and in those with normal NT, they were 19 and 96%, respectively. AUTHORS' CONCLUSIONS: The estimated performance of DV assessment for detection of CHD in chromosomally normal fetuses can be considered in evaluating the potential use and limitations of this screening test.

Transvaginal cervical length measurement for prediction of preterm birth in women with threatened preterm labor: a meta-analysis.

OBJECTIVES: To integrate data on the performance of cervical length measurement for the prediction of preterm birth in symptomatic women. METHODS: MEDLINE, SCOPUS and manual searches for studies with transvaginal ultrasound measurement of the cervical length in symptomatic women were carried out. Random effects models were used for data integration, and pooled test estimates of sensitivity, specificity, and positive and negative likelihood ratios (LR+ and LR-) were calculated along with their 95% CIs. RESULTS: Twenty-eight studies fulfilled the selection criteria. For birth within 1 week from presentation, the pooled sensitivity, specificity, LR+ and LR- of cervical length < 15 mm were 59.9% (95% CI, 52.7-66.8%), 90.5% (95% CI, 89.0-91.9%), 5.71 (95% CI, 3.77-8.65) and 0.51 (95% CI, 0.33-0.80), respectively. The same estimates for studies with presentation at or before 34 + 0 weeks were 71.0% (95% CI, 60.6-79.9%), 89.8% (95% CI, 87.4-91.9%), 5.19 (95% CI, 2.29-11.74) and 0.38 (95% CI, 0.11-1.34), respectively. For prediction of birth before 34 weeks, the pooled sensitivity, specificity, LR+ and LR- of cervical length < 15 mm were 46.2% (95% CI, 34.8-57.8%), 93.7% (95% CI, 90.7-96.0%), 4.31 (95% CI, 2.73-6.82) and 0.63 (95% CI, 0.38-1.04), respectively. There was considerable heterogeneity across studies in most estimates. CONCLUSIONS: Measurement of cervical length in symptomatic women can detect a significant proportion of those who will deliver within 1 week and help to rationalize their management. The considerable heterogeneity across studies may be indicative of methodological flaws, which either were not reported at all or were under-reported.

Dose calculation and verification of intensity modulation generated by dynamic multileaf collimators.

While the development of inverse planning tools for optimizing dose distributions has come to a level of maturity, intensity modulation has not yet been widely implemented in clinical use because of problems related to its practical delivery and a lack of verification tools and quality assurance (QA) procedures. One of the prerequisites is a dose calculation algorithm that achieves good accuracy. The purpose of this work was twofold. A primary-scatter separation dose model has been extended to account for intensity modulation generated by a dynamic multileaf collimator (MLC). Then the calculation procedures have been tested by comparison with carefully carried out experiments. Intensity modulation is being accounted for by means of a 2D (two-dimensional) matrix of correction factors that modifies the spatial fluence distribution, incident to the patient. The dose calculation for the corresponding open field is then affected by those correction factors. They are used in order to weight separately the primary and the scatter component of the dose at a given point. In order to verify that the calculated dose distributions are in good agreement with measurements on our machine, we have designed a set of test intensity distributions and performed measurements with 6 and 20 MV photons on a Varian Clinac 2300C/D linear accelerator equipped with a 40 leaf pair dynamic MLC. Comparison between calculated and measured dose distributions for a number of representative cases shows, in general, good agreement (within 3% of the normalization in low dose gradient regions and within 3 mm distance-to-dose in high dose gradient regions). For absolute dose calculations (monitor unit calculations), comparison between calculation and measurement reveals good agreement (within 2%) for all tested cases (with the condition that the prescription point is not located on a high dose gradient region).

The 'equivalent wedge' implementation of the Varian Enhanced Dynamic Wedge (EDW) into a treatment planning system.

The purpose of this work was to establish procedures for the implementation of the Varian Enhanced Dynamic Wedge into a treatment planning system (TPS), based as much as possible on simple theoretical considerations and already available data. A method is presented for the calculation (rather than measurement) of off-axis relative wedge transmission curves that are required by the TPS for relative dose calculations. We also present a method for absolute dose (monitor unit) calculations, based on the calculation of an effective wedge factor on the prescription point. A simple formula has been derived for the calculation of the effective wedge factor for the most general case, i.e. an arbitrary effective wedge angle, field size and prescription point. Relative dose calculations have been verified by measurements performed on a Varian Clinac 2300C/D linear accelerator, for 6 MV and 20 MV photon energies. Monitor unit calculations have also been verified experimentally for several cases such as symmetric and asymmetric fields with prescription on the collimator axis or on the geometrical centre of the asymmetric field. The presented technique provides results within 2% for both relative and absolute dose calculations for clinically relevant cases.

[Use of a multileaf collimator for the production of intensity-modulated beams]. / Utilisation d'un collimateur multilames pour la production de faisceaux modulés en intensité.

In external radiotherapy, the use of intensity modulated fields has been proposed for tissue and non-homogeneity compensation or for the generation of conformal dose distributions. Multileaf collimators can be employed dynamically for the modulation of the X-ray field in two dimensions. Efficient dynamic collimation became possible due to advances in computer and linear accelerator technology. It presents a number of advantages over conventional methods such as the use of compensators. We have developed a program which calculates, from a given intensity distribution, the motion of the MLC leaves as a function of monitor units, and we have applied it on a Varian linear accelerator with a 40 pair multileaf collimator. The analysis of the experimental results demonstrates the feasibility and the potential of the method.