Cerclage placement in twin pregnancies with short or dilated cervix does not prevent preterm birth: a fragility index assessment

Abstract

ObjectiveThe effectiveness of preterm birth (PTB) prevention by cerclage placement in patients with twin pregnancies and a short or dilated cervix represents a clinical issue associated with marked uncertainty.1Berghella V. Roman A. Cerclage in twins: we can do better!.Am J Obstet Gynecol. 2014; 211: 5-6Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 2Saccone G. Rust O. Althuisius S. Roman A. Berghella V. Cerclage for short cervix in twin pregnancies: systematic review and meta-analysis of randomized trials using individual patient-level data.Acta Obstet Gynecol Scand. 2015; 94: 352-358Crossref PubMed Scopus (112) Google Scholar, 3Freegard G.D. Donadono V. Impey L.W.M. Emergency cervical cerclage in twin and singleton pregnancies with 0-mm cervical length or prolapsed membranes.Acta Obstet Gynecol Scand. 2021; 100: 2003-2008Crossref PubMed Scopus (1) Google Scholar, 4Li C. Shen J. Hua K. Cerclage for women with twin pregnancies: a systematic review and metaanalysis.Am J Obstet Gynecol. 2019; 220: 543-557.e1Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar A reanalysis of a systematic review and meta-analysis of randomized controlled trials (RCTs) concluded that cerclage placement in patients with twin gestations with a sonographic short cervix is associated with an increased risk of preterm birth and adverse perinatal outcomes.5Sanchez-Ramos L. The placement of a cerclage in patients with twin pregnancies and a short cervix is associated with increased risk of preterm birth and adverse perinatal outcome.Am J Obstet Gynecol. 2020; 222: 194-196Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Several systematic reviews and meta-analyses have reached similar conclusions.1Berghella V. Roman A. Cerclage in twins: we can do better!.Am J Obstet Gynecol. 2014; 211: 5-6Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar A more recent RCT, however, suggested that physical examination-indicated cerclage in twin pregnancies significantly decreased preterm birth at all gestational age cutoffs and reduced the risk of perinatal morbidity and mortality.6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google Scholar Given the importance placed on RCTs in the hierarchy of evidence to inform the development and conclusions of clinical obstetrical practice, we assessed the fragility of the RCT indicating the beneficial effects of cerclage placement in twin pregnancies with a short or dilated cervix.Study DesignRoman et al performed a multicenter RCT, aimed to determine whether physical examination-indicated cerclage reduced the incidence of preterm birth in patients with twin pregnancies and asymptomatic cervical dilation before 24 weeks of gestation.6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google Scholar The primary outcome was the incidence of spontaneous PTB at <34 weeks of gestation.We assessed the fragility index (FI) of the Roman et al trial using the method described by Walsh et al.7Walsh M. Srinathan S.K. McAuley D.F. et al.The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index.J Clin Epidemiol. 2014; 67: 622-628Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar The FI was calculated by changing the status of patients from a “non-event” to an “event” outcome in the treatment group with the smallest number of events until the P value (using the Fisher's exact test) exceeded .05. The FI score represents the number of patients responsible for the statistical significance of a trial finding, and it is an intuitive measure of the robustness of an RCT.ResultsRoman et al randomized and analyzed 30 patients (17 were allocated to the cerclage group, and 13 did not undergo cerclage; ultimately, 3 of these 30 individuals were excluded after randomization). The authors concluded that cerclage placement was associated with a statistically significant reduction in PTBs at all gestational age cutoffs (Table). Although cerclage placement was associated with a significant reduction in the primary outcome (relative risk [RR], 0.71; 95% confidence interval [CI], 0.52–0.96; P value, .05), the FI score was 0 to obtain a P value >.05 and was 2 to obtain a 95% CI that includes null).TableResults of effect estimates and their fragility assessment for the study of Roman et al6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google ScholarOutcomeRR (95% CI)P valueFragility indexaTo obtain P value >0.05Fragility indexbTo obtain 95% CI that includes null.Fragility quotientNNT (95% CI)PTD <34 wk0.71 (0.52, 0.96).050203.4 (1.8–21.5)PTD <32 wk0.65 (0.46, 0.92).02130.075.7 (−32.5 to 2.6)PTD <28 wk0.49 (0.26, 0.89).02120.073.2 (−235.1 to 1.6)PTD <24 wk0.35 (0.16, 0.75).004340.133.2 (−235.1 to 1.6)CI, confidence interval; NNT, number needed to treat or harm; PTD, preterm delivery; RR, relative risk.Sanchez-Ramos. Fragility index assessment of cerclage placement in twin pregnancies with short or dilated cervix. Am J Obstet Gynecol 2022.a To obtain P value >0.05b To obtain 95% CI that includes null. Open table in a new tab ConclusionAn FI of 0 indicates a very fragile study, because it is not necessary to change a non-event to an event to achieve a nonsignificant P value in any participant group. This 0 FI can be explained by the difference in the statistical methods used for calculating the P values (ie, Wald test on the basis of the RR of the original study vs Fisher’s exact test). Similarly, an FI score of 2 indicates the number of additional events necessary to obtain a 95% CI that includes null. In addition, the results of a RCT should be viewed with suspicion if the number of patients who are lost to follow-up (N=3) is greater than the FI score. On the basis of these results, the importance of the RCT by Roman et al, is dubious. The findings of published systematic reviews and meta-analyses concluding that cerclage placement in twin pregnancies with a short or dilated cervix increases the risks of preterm birth and adverse perinatal outcomes represent our current best understanding of this intervention’s impact. ObjectiveThe effectiveness of preterm birth (PTB) prevention by cerclage placement in patients with twin pregnancies and a short or dilated cervix represents a clinical issue associated with marked uncertainty.1Berghella V. Roman A. Cerclage in twins: we can do better!.Am J Obstet Gynecol. 2014; 211: 5-6Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 2Saccone G. Rust O. Althuisius S. Roman A. Berghella V. Cerclage for short cervix in twin pregnancies: systematic review and meta-analysis of randomized trials using individual patient-level data.Acta Obstet Gynecol Scand. 2015; 94: 352-358Crossref PubMed Scopus (112) Google Scholar, 3Freegard G.D. Donadono V. Impey L.W.M. Emergency cervical cerclage in twin and singleton pregnancies with 0-mm cervical length or prolapsed membranes.Acta Obstet Gynecol Scand. 2021; 100: 2003-2008Crossref PubMed Scopus (1) Google Scholar, 4Li C. Shen J. Hua K. Cerclage for women with twin pregnancies: a systematic review and metaanalysis.Am J Obstet Gynecol. 2019; 220: 543-557.e1Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar A reanalysis of a systematic review and meta-analysis of randomized controlled trials (RCTs) concluded that cerclage placement in patients with twin gestations with a sonographic short cervix is associated with an increased risk of preterm birth and adverse perinatal outcomes.5Sanchez-Ramos L. The placement of a cerclage in patients with twin pregnancies and a short cervix is associated with increased risk of preterm birth and adverse perinatal outcome.Am J Obstet Gynecol. 2020; 222: 194-196Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Several systematic reviews and meta-analyses have reached similar conclusions.1Berghella V. Roman A. Cerclage in twins: we can do better!.Am J Obstet Gynecol. 2014; 211: 5-6Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar A more recent RCT, however, suggested that physical examination-indicated cerclage in twin pregnancies significantly decreased preterm birth at all gestational age cutoffs and reduced the risk of perinatal morbidity and mortality.6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google Scholar Given the importance placed on RCTs in the hierarchy of evidence to inform the development and conclusions of clinical obstetrical practice, we assessed the fragility of the RCT indicating the beneficial effects of cerclage placement in twin pregnancies with a short or dilated cervix. The effectiveness of preterm birth (PTB) prevention by cerclage placement in patients with twin pregnancies and a short or dilated cervix represents a clinical issue associated with marked uncertainty.1Berghella V. Roman A. Cerclage in twins: we can do better!.Am J Obstet Gynecol. 2014; 211: 5-6Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 2Saccone G. Rust O. Althuisius S. Roman A. Berghella V. Cerclage for short cervix in twin pregnancies: systematic review and meta-analysis of randomized trials using individual patient-level data.Acta Obstet Gynecol Scand. 2015; 94: 352-358Crossref PubMed Scopus (112) Google Scholar, 3Freegard G.D. Donadono V. Impey L.W.M. Emergency cervical cerclage in twin and singleton pregnancies with 0-mm cervical length or prolapsed membranes.Acta Obstet Gynecol Scand. 2021; 100: 2003-2008Crossref PubMed Scopus (1) Google Scholar, 4Li C. Shen J. Hua K. Cerclage for women with twin pregnancies: a systematic review and metaanalysis.Am J Obstet Gynecol. 2019; 220: 543-557.e1Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar A reanalysis of a systematic review and meta-analysis of randomized controlled trials (RCTs) concluded that cerclage placement in patients with twin gestations with a sonographic short cervix is associated with an increased risk of preterm birth and adverse perinatal outcomes.5Sanchez-Ramos L. The placement of a cerclage in patients with twin pregnancies and a short cervix is associated with increased risk of preterm birth and adverse perinatal outcome.Am J Obstet Gynecol. 2020; 222: 194-196Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Several systematic reviews and meta-analyses have reached similar conclusions.1Berghella V. Roman A. Cerclage in twins: we can do better!.Am J Obstet Gynecol. 2014; 211: 5-6Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar A more recent RCT, however, suggested that physical examination-indicated cerclage in twin pregnancies significantly decreased preterm birth at all gestational age cutoffs and reduced the risk of perinatal morbidity and mortality.6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google Scholar Given the importance placed on RCTs in the hierarchy of evidence to inform the development and conclusions of clinical obstetrical practice, we assessed the fragility of the RCT indicating the beneficial effects of cerclage placement in twin pregnancies with a short or dilated cervix. Study DesignRoman et al performed a multicenter RCT, aimed to determine whether physical examination-indicated cerclage reduced the incidence of preterm birth in patients with twin pregnancies and asymptomatic cervical dilation before 24 weeks of gestation.6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google Scholar The primary outcome was the incidence of spontaneous PTB at <34 weeks of gestation.We assessed the fragility index (FI) of the Roman et al trial using the method described by Walsh et al.7Walsh M. Srinathan S.K. McAuley D.F. et al.The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index.J Clin Epidemiol. 2014; 67: 622-628Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar The FI was calculated by changing the status of patients from a “non-event” to an “event” outcome in the treatment group with the smallest number of events until the P value (using the Fisher's exact test) exceeded .05. The FI score represents the number of patients responsible for the statistical significance of a trial finding, and it is an intuitive measure of the robustness of an RCT. Roman et al performed a multicenter RCT, aimed to determine whether physical examination-indicated cerclage reduced the incidence of preterm birth in patients with twin pregnancies and asymptomatic cervical dilation before 24 weeks of gestation.6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google Scholar The primary outcome was the incidence of spontaneous PTB at <34 weeks of gestation. We assessed the fragility index (FI) of the Roman et al trial using the method described by Walsh et al.7Walsh M. Srinathan S.K. McAuley D.F. et al.The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index.J Clin Epidemiol. 2014; 67: 622-628Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar The FI was calculated by changing the status of patients from a “non-event” to an “event” outcome in the treatment group with the smallest number of events until the P value (using the Fisher's exact test) exceeded .05. The FI score represents the number of patients responsible for the statistical significance of a trial finding, and it is an intuitive measure of the robustness of an RCT. ResultsRoman et al randomized and analyzed 30 patients (17 were allocated to the cerclage group, and 13 did not undergo cerclage; ultimately, 3 of these 30 individuals were excluded after randomization). The authors concluded that cerclage placement was associated with a statistically significant reduction in PTBs at all gestational age cutoffs (Table). Although cerclage placement was associated with a significant reduction in the primary outcome (relative risk [RR], 0.71; 95% confidence interval [CI], 0.52–0.96; P value, .05), the FI score was 0 to obtain a P value >.05 and was 2 to obtain a 95% CI that includes null).TableResults of effect estimates and their fragility assessment for the study of Roman et al6Roman A. Zork N. Haeri S. et al.Physical examination-indicated cerclage in twin pregnancy: a randomized controlled trial.Am J Obstet Gynecol. 2020; 223: 902.e1-902.e11Abstract Full Text Full Text PDF Scopus (31) Google ScholarOutcomeRR (95% CI)P valueFragility indexaTo obtain P value >0.05Fragility indexbTo obtain 95% CI that includes null.Fragility quotientNNT (95% CI)PTD <34 wk0.71 (0.52, 0.96).050203.4 (1.8–21.5)PTD <32 wk0.65 (0.46, 0.92).02130.075.7 (−32.5 to 2.6)PTD <28 wk0.49 (0.26, 0.89).02120.073.2 (−235.1 to 1.6)PTD <24 wk0.35 (0.16, 0.75).004340.133.2 (−235.1 to 1.6)CI, confidence interval; NNT, number needed to treat or harm; PTD, preterm delivery; RR, relative risk.Sanchez-Ramos. Fragility index assessment of cerclage placement in twin pregnancies with short or dilated cervix. Am J Obstet Gynecol 2022.a To obtain P value >0.05b To obtain 95% CI that includes null. Open table in a new tab Roman et al randomized and analyzed 30 patients (17 were allocated to the cerclage group, and 13 did not undergo cerclage; ultimately, 3 of these 30 individuals were excluded after randomization). The authors concluded that cerclage placement was associated with a statistically significant reduction in PTBs at all gestational age cutoffs (Table). Although cerclage placement was associated with a significant reduction in the primary outcome (relative risk [RR], 0.71; 95% confidence interval [CI], 0.52–0.96; P value, .05), the FI score was 0 to obtain a P value >.05 and was 2 to obtain a 95% CI that includes null). CI, confidence interval; NNT, number needed to treat or harm; PTD, preterm delivery; RR, relative risk. Sanchez-Ramos. Fragility index assessment of cerclage placement in twin pregnancies with short or dilated cervix. Am J Obstet Gynecol 2022. ConclusionAn FI of 0 indicates a very fragile study, because it is not necessary to change a non-event to an event to achieve a nonsignificant P value in any participant group. This 0 FI can be explained by the difference in the statistical methods used for calculating the P values (ie, Wald test on the basis of the RR of the original study vs Fisher’s exact test). Similarly, an FI score of 2 indicates the number of additional events necessary to obtain a 95% CI that includes null. In addition, the results of a RCT should be viewed with suspicion if the number of patients who are lost to follow-up (N=3) is greater than the FI score. On the basis of these results, the importance of the RCT by Roman et al, is dubious. The findings of published systematic reviews and meta-analyses concluding that cerclage placement in twin pregnancies with a short or dilated cervix increases the risks of preterm birth and adverse perinatal outcomes represent our current best understanding of this intervention’s impact. An FI of 0 indicates a very fragile study, because it is not necessary to change a non-event to an event to achieve a nonsignificant P value in any participant group. This 0 FI can be explained by the difference in the statistical methods used for calculating the P values (ie, Wald test on the basis of the RR of the original study vs Fisher’s exact test). Similarly, an FI score of 2 indicates the number of additional events necessary to obtain a 95% CI that includes null. In addition, the results of a RCT should be viewed with suspicion if the number of patients who are lost to follow-up (N=3) is greater than the FI score. On the basis of these results, the importance of the RCT by Roman et al, is dubious. The findings of published systematic reviews and meta-analyses concluding that cerclage placement in twin pregnancies with a short or dilated cervix increases the risks of preterm birth and adverse perinatal outcomes represent our current best understanding of this intervention’s impact.