Sir, As part of his speeches, the Roman senator Cato the Elder frequently uttered “Carthago delenda est” (Carthage must be destroyed). Similarly, Lamont and colleagues frequently utter that the “wrong patients with the wrong diagnosis were given wrong antibiotics at the wrong gestational age.” We respect that Lamont and colleagues find it difficult to accept meta-analyses, which “cut a toe and a bit of a heel” to merge evidence from more publications, and we certainly cannot exclude the possibility that future research will change clinical practice. However, in contrast to Lamont and colleagues, we emphasize that not only statistical significance but also other aspects should be taken into consideration in the development of clinical recommendations (1). Using GRADE, we found that appreciable uncertainty exists regarding the magnitude of benefits from clindamycin treatment compared with the risks. Given that the relative risk reported in Figure 5 represents the truth (2), the number needed to treat was 45 bacterial vaginosis (BV)-positive pregnant women to avoid one spontaneous preterm delivery (sPTD) before gestational week 37. This relatively minor effect should especially be measured against the microbiological concerns for iatrogenic damage when clindamycin is administered to approximately 10–15% of Danish pregnant women. These concerns include resistance development of BV-associated bacteria, Clostridium difficile colitis, and yet unknown adverse effects to the microbiome (3). The major concern raised by Lamont and colleagues seems to relate to whether the intervention with clindamycin before 22 weeks’ gestation would significantly reduce the incidence of sPTD (4). We agree that had the cut-off been gestational week 22, then the difference in incidence of sPTD would have been statistically significant with respect to clindamycin. Regardless, according to GRADE, the overall level of evidence for the outcome sPTD was rated low for reasons given in Supporting Information Table 2 (2). Regarding the PREMEVA 1 study, we agree that the risk of bias may have increased since October 2014 when we conducted the literature search. At this time, the PREMEVA1 abstract had only been published for 10 months (5). We sent out official emails to the authors; however, none responded. We agree that it is worrisome that the PREMEVA1 study is not yet published and we, as Lamont and colleagues, can only speculate why. Could publication bias due to negative findings be disregarded? Finally, it should be emphasized that we cannot confirm from our analyses that treatment of BV reduces the rate of early preterm birth and low birthweight infants, nor could we find the evidence in the review and meta-analysis by Lamont et al. from 2011 (6). In conclusion, we do not agree that the concerns mentioned by Lamont and colleagues would change the clinical recommendations in the recent AOGS publication (2). The weak recommendation against clindamycin reflects that some experts might treat BV in pregnancy whereas the majority would not, as “weak recommendations for or against intervention are made when guideline authors believe that most informed people would choose the recommended course of action, but a substantial number would not.”

The article serves to review the literature on the human uterine cervix based on a new distension technology named functional luminal imaging probe. This technology was originally developed to study the biomechanical competence of the gastro-esophageal junction where it provides a geometric profile of the lumen during distension, which can be related to sensory data. We searched and reviewed publications on cervical distention from 2002. The functional luminal imaging probe technology has been used for studying the mechanical and mechano-sensory properties of the cervix in non-pregnant women. In early pregnant women and in term pregnant women, the technique provides geometric measurements from the whole cervical canal during distension, which changes dramatically during pregnancy. Furthermore, it has been demonstrated that the technique predicts the outcome of labor induction better than the Bishop score does. The functional luminal imaging probe technology has potential as a research tool as well as for clinical use in gynecology and obstetrics.

The article serves to review the literature on the human uterine cervix based on a new distension technology named functional luminal imaging probe. This technology was originally developed to study the biomechanical competence of the gastro-esophageal junction where it provides a geometric profile of the lumen during distension, which can be related to sensory data. We searched and reviewed publications on cervical distention from 2002. The functional luminal imaging probe technology has been used for studying the mechanical and mechano-sensory properties of the cervix in non-pregnant women. In early pregnant women and in term pregnant women, the technique provides geometric measurements from the whole cervical canal during distension, which changes dramatically during pregnancy. Furthermore, it has been demonstrated that the technique predicts the outcome of labor induction better than the Bishop score does. The functional luminal imaging probe technology has potential as a research tool as well as for clinical use in gynecology and obstetrics.

IntroductionBacterial vaginosis (BV) is characterized by a dysbiosis of the vaginal microbiota with a depletion of Lactobacillus spp. In pregnancy, prevalence's between 7 and 30% have been reported depending on the study population and the definition. BV may be associated with an increased risk of spontaneous preterm delivery (sPTD). However, it is controversial whether or not BV-positive pregnant women will benefit from treatment to reduce the risk of sPTD. We could not identify any good-quality guideline addressing this issue. Consequently we aimed to produce this clinical recommendation based on GRADE.Material and methodsSystematic literature searches were conducted in the following databases: Guidelines International Network: G-I-N, Medline, Embase, The Cochrane Database of Systematic Reviews, Web of Science and from 1999 to 3 October 2014. Hence, nine guidelines, 34 reviews, 18 randomized controlled trials and 12 observational studies were included.ResultsThe GRADE quality of evidence was consistently low or very low, primarily because none of the risk ratios (RR) for the risk of sPTD at <37 weeks were statistically significant. Concerning treatment with metronidazole, RR was 1.11 (95% CI 0.93-1.34) in low-risk pregnancies and 0.96 (95% CI 0.78-1.18) in high risk pregnancies. Concerning treatment with clindamycin at any gestational age, the RR was 0.87 (95% CI 0.73-1.05).ConclusionThis systematic review gives a strong recommendation against treatment with metronidazole and a weak recommendation against treatment with clindamycin to reduce the sPTD rate in both high-risk and low-risk pregnancies with BV.

Bacterial vaginosis (BV) is characterized by a dysbiosis of the vaginal microbiota with a depletion of Lactobacillus spp. In pregnancy, prevalence's between 7 and 30% have been reported depending on the study population and the definition. BV may be associated with an increased risk of spontaneous preterm delivery (sPTD). However, it is controversial whether or not BV-positive pregnant women will benefit from treatment to reduce the risk of sPTD. We could not identify any good-quality guideline addressing this issue. Consequently we aimed to produce this clinical recommendation based on GRADE. Systematic literature searches were conducted in the following databases: Guidelines International Network: G-I-N, Medline, Embase, The Cochrane Database of Systematic Reviews, Web of Science and http://www.clinicaltrials.gov from 1999 to 3 October 2014. Hence, nine guidelines, 34 reviews, 18 randomized controlled trials and 12 observational studies were included. The GRADE quality of evidence was consistently low or very low, primarily because none of the risk ratios (RR) for the risk of sPTD at <37 weeks were statistically significant. Concerning treatment with metronidazole, RR was 1.11 (95% CI 0.93–1.34) in low-risk pregnancies and 0.96 (95% CI 0.78–1.18) in high risk pregnancies. Concerning treatment with clindamycin at any gestational age, the RR was 0.87 (95% CI 0.73–1.05). This systematic review gives a strong recommendation against treatment with metronidazole and a weak recommendation against treatment with clindamycin to reduce the sPTD rate in both high-risk and low-risk pregnancies with BV.

To give an overview of the methods available for biomechanical testing of the non-pregnant and pregnant uterine cervix in vivo. The following databases were searched. PubMed, Embase, and Cochrane Library. Additional studies were identified from reference lists. Only studies on in vivo biomechanical testing on both pregnant and non-pregnant women were included. Estimation of distensibility, compressibility, and biochemical composition of the uterine cervix. The distensibility methods evaluated a physiologic variable and might serve as a gold standard; however, they may never be clinically useful as they involve instrumentation of the cervical canal. The compression methods evaluated an unphysiological variable but despite that, they seemed to evaluate biologically relevant figures and were non-invasive. Of the methods evaluating the biomechanical properties indirectly, those based on ultrasound may be clinically useful. Other indirect methods only measured variables within the most superficial layer of the distal uterine cervix, so further studies are needed to evaluate whether these measurements reflect the entire organ. Both compression methods and indirect methods were similar or superior to the Bishop score and to cervical length measurements regarding prediction of spontaneous preterm delivery and successful induction of labor in small studies. The methods may have the potential to detect the biomechanical changes in the uterine cervix before the cervical length has shortened. The most promising methods need large-scale clinical testing regarding induction of labor and preterm delivery before they can be used in the clinic.

Objective: To determine the stiffness of the pregnant uterine cervix in vivo.Method: Five women in early pregnancy and six women in late pregnancy were included. The EndoFlip is a 1-m-long probe with a 12-cm-long bag mounted on the tip. The tip of the probe was inserted into the cervical canal. Sensors spaced at 0.5-cm intervals along the probe were used to determine 16 serial cross-sectional areas of the bag. The diameter of the cervical canal could thereby be determined during inflation with up to 50 ml saline solution. Tissue stiffness was calculated from the geometric profiles and the pressure-strain elastic modulus (EP) at each sensor site. Three parts of the cervix were defined: the uterus-near part, the middle and the vaginal part. The EPmax was defined as the highest EP detected along the cervical canal.Results: The EPmax was always found in the middle part of the cervix. The median EPmax was 243 kPa (IQR, 67-422 kPa) for the early pregnant women and 5 kPa (IQR, 4-15 kPa) for those at term. In the early pregnant women the stiffness differed along the cervical length (p<0.05) whereas difference along the cervix was not found for late pregnant women. A positive correlation coefficient (Spearman's rho) was established between the EPs of the uterus-near and the middle part (0.84), between the vaginal and the middle part (0.81), and between the uterus-near and the vaginal part (0.85).Conclusion: This new method can estimate the stiffness along the cervical canal in vivo. This method may be useful in the clinical examination of the biomechanical properties of the uterine cervix.

Objective. To evaluate how the approximate Young's modulus of the uterine cervix assessed by quantitative sonoelastography in patients undergoing induction of labor is associated with the cervical dilation time and to evaluate the approximate Young's modulus as a predictor of prolonged cervical dilation time. Design. Cross-sectional study. Setting. Aarhus University Hospital, Aarhus, Denmark. Population. Term-pregnant women. Methods. A total of 49 term-pregnant women were included before induction of labor. The approximate Young's modulus of the anterior cervical lip was determined by the use of a reference cap applied on the end of the transvaginal transducer during sonoelastography. Main outcome measures. Cervical dilation time during active labor. Results. The approximate Young's modulus was associated with the cervical dilation time during active labor (R-log(2) = 0.24, p < 0.01) and predicted prolonged duration of cervical dilation time (>330 min) with the area under the receiver operating characteristic (ROC) curve of 0.71, sensitivity 74%, and specificity 69%. Equivalent figures for the Bishop's score were R-log(2) = 0.02 (p = 0.37), the area under the ROC curve 0.53, sensitivity 53%, and specificity 46%. For the cervical length measurements the corresponding results were: R-log(2) = 0.02, p = 0.35, area under the ROC curve 0.57, sensitivity 66% and specificity 54%. The intra-observer and inter-observer intraclass correlations were 88% and 58%, respectively, with quantitative elastography. Conclusions. The approximate Young's modulus is superior to the Bishop score and the cervical length measurements concerning the prediction of cervical dilation time and the risk of prolonged dilation time after induction of labor.

Background and aims: The course and outcome of pregnancy is closely correlated to change of biomechanical properties of the uterine cervix. The aim of this study was to build a non-linear, fiber reinforced mechanical model of the cervix for estimation of mechanical characteristics of the cervix in early- and term-pregnant women based on recordings of in vivo pressure and diameter by means of the Functional Luminal Imaging Probe (FLIP) technology.Materials and methods: Five early- and six term-pregnant women were examined with a FLIP probe. The bag on the probe was inserted into the cervical canal for concomitant measurement of diameters at 16 serial locations along the canal and the bag pressure. The bag was inflated to a maximum volume of 50 ml. A three-fiber-families model including isotropic elastin-dominated matrix and anisotropic collagen was introduced to describe the mechanical behavior of the cervical canal. The unknown geometric and mechanical parameters were calculated on the basis of the mid-cervical diameters and the intraluminal pressures during the inflation.Results: The wall thickness in the unloaded state (zero pressure applied) and mechanical properties of the matrix material (c) and collagens (c(1), c(2)) were estimated with good fits of the calculated intraluminal pressures to the FLIP recordings during the cervical canal distension. No significant difference in the wall thickness was found between the early- and term-pregnant women (10.3 +/- 0.8 mm vs. 11.7 +/- 2.2 mm, p = 0.30). The cervical matrix material and the collagen in the early-pregnant women were much stiffer than that in the term-pregnant women (p < 0.05).Conclusions: The cervical mechanical properties can be obtained from recorded pressure and diameter data in vivo via the established mechanical model. Matrix material and collagens of the cervix wall were remodeled during pregnancy. The mechanical model can be applied to other tubular visceral organs where concomitant measures of pressure and diameter can be obtained for better understanding diseases and their evolution or treatment. (C) 2014 Elsevier Ltd. All rights reserved.

We thank Fuchs, Pomorski and Zimmer for their positive responses to our article “Quantitative sonoelastography of the uterine cervix by interposition of a synthetic reference material” 1. We are glad that they see the clinical potential of our method. We are continuing our work with quantitative elastography and are developing a reference cap with less attenuation as well as a mechanical device to standardize the force applied on the uterine cervix during the elastography scan. Further, we are conducting a clinical study with the current reference cap of silicone and oil. We will take your advice about comparing the stiffness of the uterine cervix with the cervical length measurements obtained by conventional ultrasound. Again, we appreciate the valuable feedback that we will adopt in our future work.

ObjectiveTo give an overview of the methods available for biomechanical testing of the non-pregnant and pregnant uterine cervix in vivo.MethodsThe following databases were searched. PubMed, Embase, and Cochrane Library. Additional studies were identified from reference lists. Only studies on in vivo biomechanical testing on both pregnant and non-pregnant women were included.Main outcome measuresEstimation of distensibility, compressibility, and biochemical composition of the uterine cervix.ResultsThe distensibility methods evaluated a physiologic variable and might serve as a gold standard; however, they may never be clinically useful as they involve instrumentation of the cervical canal. The compression methods evaluated an unphysiological variable but despite that, they seemed to evaluate biologically relevant figures and were non-invasive. Of the methods evaluating the biomechanical properties indirectly, those based on ultrasound may be clinically useful. Other indirect methods only measured variables within the most superficial layer of the distal uterine cervix, so further studies are needed to evaluate whether these measurements reflect the entire organ. Both compression methods and indirect methods were similar or superior to the Bishop score and to cervical length measurements regarding prediction of spontaneous preterm delivery and successful induction of labor in small studies.ConclusionThe methods may have the potential to detect the biomechanical changes in the uterine cervix before the cervical length has shortened. The most promising methods need large-scale clinical testing regarding induction of labor and preterm delivery before they can be used in the clinic.

To evaluate how the approximate Young's modulus of the uterine cervix assessed by quantitative sonoelastography in patients undergoing induction of labor is associated with the cervical dilation time and to evaluate the approximate Young's modulus as a predictor of prolonged cervical dilation time. Cross-sectional study. Aarhus University Hospital, Aarhus, Denmark. Term-pregnant women. A total of 49 term-pregnant women were included before induction of labor. The approximate Young's modulus of the anterior cervical lip was determined by the use of a reference cap applied on the end of the transvaginal transducer during sonoelastography. Cervical dilation time during active labor. The approximate Young's modulus was associated with the cervical dilation time during active labor ( R 2 log = 0.24, p < 0.01) and predicted prolonged duration of cervical dilation time (>330 min) with the area under the receiver operating characteristic (ROC) curve of 0.71, sensitivity 74%, and specificity 69%. Equivalent figures for the Bishop's score were R 2 log = 0.02 ( p = 0.37), the area under the ROC curve 0.53, sensitivity 53%, and specificity 46%. For the cervical length measurements the corresponding results were: R 2 log = 0.02, p = 0.35, area under the ROC curve 0.57, sensitivity 66% and specificity 54%. The intra-observer and inter-observer intraclass correlations were 88% and 58%, respectively, with quantitative elastography. The approximate Young's modulus is superior to the Bishop score and the cervical length measurements concerning the prediction of cervical dilation time and the risk of prolonged dilation time after induction of labor.

To develop a reference material that allows quantitative elastography of the uterine cervix using the calculation of the approximate tissue stiffness expressed as Young's modulus (N/mm 2 ). Further, to test the elastography equipment on phantoms from a clinical perspective regarding the distance dependence and the influence of a heterogeneous material. Methodological study. Aarhus University Hospital, Denmark. Six mid- and five full-term pregnant women. Reference caps and phantoms with Young's moduli between 0.07 and 0.40 N/mm 2 were made of silicone and oil. By using reference caps, the approximate Young's moduli of the cervixes were calculated from strain ratios obtained by elastography. Approximate Young's modulus of the cervix. The recordings of the phantoms revealed that the calculation of the approximate Young's moduli became unreliable at distances above 10–15 mm from the transducer. This was further increased for a phantom which included a soft layer imitating the cervical canal. The approximate Young's modulus obtained from the anterior cervical lip was 0.08 N/mm 2 in mid-term and 0.03 N/mm 2 in full-term pregnant women (Wilcoxon rank-sum test, p  =   0.01). The reference cap constitutes a promising tool for quantitative elastography of the anterior cervical lip. Figures obtained from the posterior cervical lip are less plausible due to the distance from the transducer and the heterogeneity introduced by the cervical canal. The method has the potential to be used to supplement cervical length assessment when evaluating women at risk of preterm delivery and when planning induction of labor.

Objective. To describe the effects and side-effects of the continuous use of oral contraceptives. Design. A review of articles concerning oral contraceptives taken continuously or in cycles with hormones taken for more than 21 days per cycle. Methods. We searched publications in PubMed and Embase. Randomized controlled trials were selected if possible, otherwise case–control studies or cohort studies with controls were chosen. A level of evidence as described by the Centre for Evidence Based Medicine (Oxford University, Oxford, UK) was assigned to all selected studies. Main outcome measures. Clinical and paraclinical effects and side-effects of oral contraceptives administered continuously. Results. The studies suggest that the endometrium is inactive during continuous use of oral contraceptives and the risk of endometrial hyperplasia is not increased. Numbers of bleeding days are halved with continuous use; however, spotting and irregular bleeding are more often seen in the beginning of use, decreasing with time. Hemostatic parameters and serum lipid and carbohydrate profiles in continuous and conventional users do not differ. Menstrual cycle-related symptoms are relieved better by continuous treatment. After surgery for endometriosis, the effect of continuously used oral contraceptives on the risk of recurrence of pain has been found to be less than that of gonadotropin-releasing hormone (GnRH) analogues, but better than the rate seen during conventional cyclic use. Conclusion. Oral contraceptives taken continuously or in long cycles seem to offer benefits with regard to menstrual symptoms and the recurrence of symptoms related to endometriosis. Long-term studies, comprising large groups of women, are lacking.

ObjectiveTo develop a reference material that allows quantitative elastography of the uterine cervix using the calculation of the approximate tissue stiffness expressed as Young's modulus (N/mm(2)). Further, to test the elastography equipment on phantoms from a clinical perspective regarding the distance dependence and the influence of a heterogeneous material.DesignMethodological study.SettingAarhus University Hospital, Denmark.PopulationSix mid- and five full-term pregnant women.MethodsReference caps and phantoms with Young's moduli between 0.07 and 0.40N/mm(2) were made of silicone and oil. By using reference caps, the approximate Young's moduli of the cervixes were calculated from strain ratios obtained by elastography.Main outcome measuresApproximate Young's modulus of the cervix.ResultsThe recordings of the phantoms revealed that the calculation of the approximate Young's moduli became unreliable at distances above 10-15mm from the transducer. This was further increased for a phantom which included a soft layer imitating the cervical canal. The approximate Young's modulus obtained from the anterior cervical lip was 0.08N/mm(2) in mid-term and 0.03N/mm(2) in full-term pregnant women (Wilcoxon rank-sum test, p=0.01).ConclusionThe reference cap constitutes a promising tool for quantitative elastography of the anterior cervical lip. Figures obtained from the posterior cervical lip are less plausible due to the distance from the transducer and the heterogeneity introduced by the cervical canal. The method has the potential to be used to supplement cervical length assessment when evaluating women at risk of preterm delivery and when planning induction of labor.

Objective. To describe the effects and side-effects of the continuous use of oral contraceptives. Design. A review of articles concerning oral contraceptives taken continuously or in cycles with hormones taken for more than 21 days per cycle. Methods. We searched publications in PubMed and Embase. Randomized controlled trials were selected if possible, otherwise casecontrol studies or cohort studies with controls were chosen. A level of evidence as described by the Centre for Evidence Based Medicine (Oxford University, Oxford, UK) was assigned to all selected studies. Main outcome measures. Clinical and paraclinical effects and side-effects of oral contraceptives administered continuously. Results. The studies suggest that the endometrium is inactive during continuous use of oral contraceptives and the risk of endometrial hyperplasia is not increased. Numbers of bleeding days are halved with continuous use; however, spotting and irregular bleeding are more often seen in the beginning of use, decreasing with time. Hemostatic parameters and serum lipid and carbohydrate profiles in continuous and conventional users do not differ. Menstrual cycle-related symptoms are relieved better by continuous treatment. After surgery for endometriosis, the effect of continuously used oral contraceptives on the risk of recurrence of pain has been found to be less than that of gonadotropin-releasing hormone (GnRH) analogues, but better than the rate seen during conventional cyclic use. Conclusion. Oral contraceptives taken continuously or in long cycles seem to offer benefits with regard to menstrual symptoms and the recurrence of symptoms related to endometriosis. Long-term studies, comprising large groups of women, are lacking.

OBJECTIVE:To conduct a literature search for selected biomarkers on preterm delivery and estimate their likelihood ratios (LR).DESIGN:Structured review.POPULATION:Low and high-risk populations and women with symptoms of preterm delivery. METHODS. Publications were identified in PubMed.MAIN OUTCOME MEASURES:LR on selected biomarkers for preterm delivery.RESULTS:In asymptomatic women with low risk of preterm delivery, the following biomarkers gave major shifts in probability (LR above 5): twins (LR+ 10), Ureaplasma urealyticum in amniotic fluid (LR+ of 10), cervical length <25mm (LR+ 6), salival estriol (LR+ 5) and various combined tests. In asymptomatic women with high risk of preterm delivery, short cervical length (LR+ 11, LR- 0.7), high serum tumor necrosis factor-alpha (LR+ 10, LR- 0.6) gave major shifts in probability. In women with symptoms of preterm delivery, major shifts in probability can be obtained from the following amniotic fluid biomarkers: high matrix metalloproteinase-8 (LR+ 23, LR- 0.6), Ureaplasma urealyticum (LR+ 19, LR- 0.8), high interleukin (IL)-6 (LR+ 9, LR- 0.2), IL-8 (LR+10, LR- 0.2) and tumor necrosis factor-alpha (LR+ 8, LR- 0.4). In serum IL-6 (LR+ 12, LR- 0.2), Cluster of Differentiation 163 (LR+9, LR-0.8) and various combined tests. Vaginal fetal fibronectin (LR+ 3 and LR- 0.5) and short cervical length (LR+ 2, LR- 0.3) gave LRs of some importance (LR below 5).CONCLUSION:Several biomarkers have been identified for assessment of risk of preterm delivery. Their clinical relevance depends on the efficacy of the interventions which can be offered to these patients.

Objective. To study maternal serum interleukin-17 (IL-17) during normal pregnancy and evaluate the association with preterm delivery. Design. Prospective study. Setting. Aarhus University Hospital, Denmark. Population. Three cohorts: (a) low-risk cohort of 1,069 women who had serum drawn in weeks 12 and 19, (b) subgroup of the low-risk cohort, consisting of 40 women, who had serum drawn at 12, 19, 26, 33 and 39 weeks of gestation and (c) a symptomatic cohort of 93 women admitted with symptoms of preterm delivery at a gestational age of 24 + 0 weeks to 33 + 6 weeks. Methods. Serum IL-17 determined by an in-house developed multiplex sandwich immunoassay. Main outcome measures. Preterm delivery <37 +0 weeks gestation. Results. Serum IL-17 did not change during normal pregnancy. At admission to hospital, women with preterm contractions had significantly decreased serum IL-17 as compared with normal pregnancies (median <4 [interquartile ranges, IQR, <4–10 pg/ml] vs. 174 pg/ml [IQR, 92 – 485 pg/ml]); this difference was enhanced and highly significant for women delivering preterm versus term (median <4 [IQR, <4–7.9 pg/ml] vs. median 6.0 [IQR, <4–221 pg/ml]; p- value 0.03). Serum IL-17 was also lower in women with preterm prelabor rupture of membranes. A slightly, but not statistically significant decrease was found in weeks 12 and 19 in low-risk women who subsequently delivered preterm. Conclusion. Maternal serum IL-17 may be involved in preterm delivery.