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Cervical cerclage in women with short cervix did not greatly reduce the risk of early preterm birth
ARTICLE IN PRESS OBSTETRICS
Cervical cerclage in women with short cervix did not greatly reduce the risk of early preterm birth To MS, Alfirevic Z, HeathVCF,Cicero S,Chacho AM,Williamson PR, Nicolaides KH.Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004; 363:1849^53.
OBJECTIVE To determine if the insertion of a cervical suture could reduce three-fold the risk of early preterm delivery in women with a short cervix at midpregnancy.
DESIGN Multicentre, randomized, non-blinded, controlled trial. Allocation was by telephone to a central o⁄ce, using a computer-generated and blocked randomization scheme, strati¢ed by centre. The study had su⁄cient power to detect an absolute di¡erence of 17% in early preterm delivery rate.
SETTING Twelve hospitals in the UK, Brazil, Chile, South Africa, Slovenia, and Greece.
SUBJECTS A total of 253 women, mean age 30 years, who had a cervical length p15 (mean 9) mm on routine transvaginal ultrasonography at 22^24 weeks gestation of a singleton pregnancy. Previous delivery at 16^32 weeks was reported by 19% of women; 26% of women were primigravid. More than 47,000 women were screened and 470 (1%) were identi¢ed as having a shortened cervix.
INTERVENTION Randomization allocated 127 women to have insertion of a Shirodkar cervical suture under spinal anesthesia and 126 women to have expectant management. All women received prophylactic steroids at 26^28 weeks gestation. The
0021-9290/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ebobgyn.2004.12.010
suture was removed in the 37th week of pregnancy, unless earlier removal was indicated.
MAIN OUTCOME MEASURES Early preterm delivery (o33 weeks gestation), birthweight, perinatal death, major adverse neonatal outcome, maternal morbidity.
MAIN RESULTS Five women in the cerclage group did not receive cerclage and two women in the control group did have cerclage, but analysis was by intentionto-treat. Early preterm delivery occurred in 22% of the cerclage group, compared to 26% of the control group (p=0.44, relative risk (RR) 0.8, 95% CI 0.5^1.3).The mean (7SD) gestational age at delivery (36.474.7 vs 35.475.1 weeks, p=0.12), the mean birthweight (27697956 vs 25657956 g, p=0.09), and the median birthweight centile adjusted for gestational age (42 vs 37, p=0.10) were not signi¢cantly di¡erent in the two groups. There was no signi¢cant di¡erence between the cerclage and control groups in the proportions of women with preterm rupture of membranes (18 vs 15%, p=0.52), spontaneous labour (72 vs 83%, p=0.07), or cesarean delivery (26 vs 18%, p=0.14).Women in the cerclage group were more likely to report symptomatic vaginal discharge (6 vs 1%, p=0.04). There was no signi¢cant di¡erence between groups in the incidences of perinatal death (6 vs 8%, p=0.44) or serious neonatal morbidity.
CONCLUSION Cervical cerclage in women with a shortened cervix, identi¢ed on ultrasonographic screening at 22^24 weeks gestation, did not result in a three-fold reduction in the risk of early preterm delivery.
Evidence-based Obstetrics and Gynecology (2005) 7,15^16
15
ARTICLE IN PRESS Commentary This large multinational trial of cervical cerclage represents the largest cohort of women yet studied. Three similar randomized trials have been reported in the recent literature: the Dutch study (1995^2000),1 the Lehigh Valley study (1998 ^2003),2 and theThomas Jefferson University study (1998 ^2003)3.The sample size in the f|nal analysis of the LehighValley study (241) was similar to that of the present trial, but the Dutch and Thomas Jefferson studies were considerably smaller. The present trial included only singleton pregnancies, similar to the Dutch trial, while the other two studies both included multiple gestations. Of the four trials, the present trial had the highest proportion of subjects without historical risk factors, such as previous preterm birth, or gynecologic factors, such as prior cervical surgery, Mullerian anomalies, or DES exposure. This difference can be explained by the study design, in which women presenting for antenatal care were screened routinely. The present trial utilized a cervical length criterion of p1.5 cm, considerably shorter than the other trials, which utilized a cervical length of 2.5 cm or less. Approximately 94% of the women enrolled in the present trial had funneling associated with the cervical f|ndings, similar to the Lehigh Valley and Thomas Jefferson University studies, which enrolled exclusively women with a short cervix and funneling. The presence or absence of a funnel was unspecif|ed in the Dutch study. Short cervical length and the presence of a funnel are signif|cant risk factors for adverse perinatal outcome.4 Subjects in the present trial had a mean gestational age at enrollment of 23.5 weeks, signif|cantly higher than the mean of approximately 20 weeks in the three other trials. Early gestational age at entry has been associated with earlier delivery.The major effect of late gestational age at entry would be less perinatal mortality. With respect to medical therapy in the present trial, the women receiving cerclage were treated routinely with antibiotics and all women in both groups received steroids, but the use of tocolysis did not appear to be controlled.The Dutch study treated only the women receiving cerclage with antibiotics and indomethacin, but the LehighValley trial treated both groups.The use of antibiotics and tocolysis was not specif|ed in theThomas Jefferson study. None of these three other trials controlled the use of steroids. The use of antibiotics associated with cerclage has not been studied with respect to effect on perinatal outcome.Therefore, their use only in the cerclage group in the present study represents a confounding variable of unknown signif|cance.The use of tocolysis could also be a confounding factor; however, the authors found no signif|cant difference between groups in its rate of use postoperatively. The routine use of steroids for fetal lung maturation at 26 ^28 weeks gestational age for both groups is prudent, due to the increased risk of prematurity associated with these ultrasound f|ndings.The advanced gestational age achieved by the majority of neonates in the present trial is indicative of our inability to identify women destined to deliver preterm. The single braided tape cerclage suture utilized in the present trial was similar to that used in both the Dutch and Thomas Jef-
16
Evidence-based Obstetrics and Gynecology (2005) 7,15^16
ferson studies.Only the LehighValley study used a single non-absorbable, monof|lament tape. A recent study demonstrated that the choice of suture type probably does not affect perinatal outcome.5 The present trial utilized the Shirodkar technique for cerclage, whereas the three other randomized trials utilized the McDonald technique. Although, theoretically, the Shirodkar suture can be placed closer to the internal os, a recent study demonstrated that cerclage location has little or no clinical signif|cance, with respect to perinatal outcome.6 The present trial showed a minimal difference between groups in the mean gestational age at delivery, similar to theThomas Jefferson and Lehigh Valley studies. Only the small Dutch study concluded that cerclage improved perinatal outcome.With respect to perinatal death, there was no statistical difference between the cerclage and no-cerclage groups; the combined rate of 7% represents the lowest mortality rate of the four studies reviewed. The excellent overall perinatal outcome in both groups of this trial most likely reflects the high percentage of subjects without risk factors for preterm birth, the late gestational age at entry, and the excellent care provided to these women. These factors appear to have overcome the negative effect of the extremely short cervix (mean 0.9 cm) at enrolment. This study adds to the growing body of evidence that continues to question the clinical eff|cacy of cerclage placement in women with a short cervix demonstrated by transvaginal ultrasound in the second trimester.Until such time as a population can be def|ned that would benef|t from cerclage therapy, it should be considered as a procedure under investigation and certainly not as the standard of care. Orion A Rust, MD LehighValley Hospital and Health Network, Allentown PA, USA
Literature Cited 1. Althuisius SM, Dekker GA, Hummel P, et al.Final results of the cervical incompetence prevention randomized cerclage trial (CIPRACT): therapeutic cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001; 185:1106 ^12. 2. Rust O, Atlas R, Fischl S, et al. Does cerclage therapy improve perinatal outcome in patients with a history of previous preterm birth and cervical changes on second-trimester transvaginal ultrasound? Am J Obstet Gynecol 2003; 187:S58. 3. Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial. Am J Obstet Gynecol 2004; 191:1311^7. 4. Iams JD,Goldenberg RL, Meis PJ, et al.The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996; 334: 567^72. 5. Pereira L, Llevy C, Lewis D, et al. Effect of suture material on the outcome of emergent cerclage. Obstet Gynecol 2004; 103:35S. 6. Rust OA, Atlas RO, Meyn J, et al. Does cerclage location influence perinatal outcome? Am J Obstet Gynecol 2003; 189:1688 ^91.
Cervical cerclage in women with short cervix did not greatly reduce the risk of early preterm birth To MS, Alfirevic Z, HeathVCF,Cicero S,Chacho AM,Williamson PR, Nicolaides KH.Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004; 363:1849^53.
OBJECTIVE To determine if the insertion of a cervical suture could reduce three-fold the risk of early preterm delivery in women with a short cervix at midpregnancy.
DESIGN Multicentre, randomized, non-blinded, controlled trial. Allocation was by telephone to a central o⁄ce, using a computer-generated and blocked randomization scheme, strati¢ed by centre. The study had su⁄cient power to detect an absolute di¡erence of 17% in early preterm delivery rate.
SETTING Twelve hospitals in the UK, Brazil, Chile, South Africa, Slovenia, and Greece.
SUBJECTS A total of 253 women, mean age 30 years, who had a cervical length p15 (mean 9) mm on routine transvaginal ultrasonography at 22^24 weeks gestation of a singleton pregnancy. Previous delivery at 16^32 weeks was reported by 19% of women; 26% of women were primigravid. More than 47,000 women were screened and 470 (1%) were identi¢ed as having a shortened cervix.
INTERVENTION Randomization allocated 127 women to have insertion of a Shirodkar cervical suture under spinal anesthesia and 126 women to have expectant management. All women received prophylactic steroids at 26^28 weeks gestation. The
0021-9290/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ebobgyn.2004.12.010
suture was removed in the 37th week of pregnancy, unless earlier removal was indicated.
MAIN OUTCOME MEASURES Early preterm delivery (o33 weeks gestation), birthweight, perinatal death, major adverse neonatal outcome, maternal morbidity.
MAIN RESULTS Five women in the cerclage group did not receive cerclage and two women in the control group did have cerclage, but analysis was by intentionto-treat. Early preterm delivery occurred in 22% of the cerclage group, compared to 26% of the control group (p=0.44, relative risk (RR) 0.8, 95% CI 0.5^1.3).The mean (7SD) gestational age at delivery (36.474.7 vs 35.475.1 weeks, p=0.12), the mean birthweight (27697956 vs 25657956 g, p=0.09), and the median birthweight centile adjusted for gestational age (42 vs 37, p=0.10) were not signi¢cantly di¡erent in the two groups. There was no signi¢cant di¡erence between the cerclage and control groups in the proportions of women with preterm rupture of membranes (18 vs 15%, p=0.52), spontaneous labour (72 vs 83%, p=0.07), or cesarean delivery (26 vs 18%, p=0.14).Women in the cerclage group were more likely to report symptomatic vaginal discharge (6 vs 1%, p=0.04). There was no signi¢cant di¡erence between groups in the incidences of perinatal death (6 vs 8%, p=0.44) or serious neonatal morbidity.
CONCLUSION Cervical cerclage in women with a shortened cervix, identi¢ed on ultrasonographic screening at 22^24 weeks gestation, did not result in a three-fold reduction in the risk of early preterm delivery.
Evidence-based Obstetrics and Gynecology (2005) 7,15^16
15
ARTICLE IN PRESS Commentary This large multinational trial of cervical cerclage represents the largest cohort of women yet studied. Three similar randomized trials have been reported in the recent literature: the Dutch study (1995^2000),1 the Lehigh Valley study (1998 ^2003),2 and theThomas Jefferson University study (1998 ^2003)3.The sample size in the f|nal analysis of the LehighValley study (241) was similar to that of the present trial, but the Dutch and Thomas Jefferson studies were considerably smaller. The present trial included only singleton pregnancies, similar to the Dutch trial, while the other two studies both included multiple gestations. Of the four trials, the present trial had the highest proportion of subjects without historical risk factors, such as previous preterm birth, or gynecologic factors, such as prior cervical surgery, Mullerian anomalies, or DES exposure. This difference can be explained by the study design, in which women presenting for antenatal care were screened routinely. The present trial utilized a cervical length criterion of p1.5 cm, considerably shorter than the other trials, which utilized a cervical length of 2.5 cm or less. Approximately 94% of the women enrolled in the present trial had funneling associated with the cervical f|ndings, similar to the Lehigh Valley and Thomas Jefferson University studies, which enrolled exclusively women with a short cervix and funneling. The presence or absence of a funnel was unspecif|ed in the Dutch study. Short cervical length and the presence of a funnel are signif|cant risk factors for adverse perinatal outcome.4 Subjects in the present trial had a mean gestational age at enrollment of 23.5 weeks, signif|cantly higher than the mean of approximately 20 weeks in the three other trials. Early gestational age at entry has been associated with earlier delivery.The major effect of late gestational age at entry would be less perinatal mortality. With respect to medical therapy in the present trial, the women receiving cerclage were treated routinely with antibiotics and all women in both groups received steroids, but the use of tocolysis did not appear to be controlled.The Dutch study treated only the women receiving cerclage with antibiotics and indomethacin, but the LehighValley trial treated both groups.The use of antibiotics and tocolysis was not specif|ed in theThomas Jefferson study. None of these three other trials controlled the use of steroids. The use of antibiotics associated with cerclage has not been studied with respect to effect on perinatal outcome.Therefore, their use only in the cerclage group in the present study represents a confounding variable of unknown signif|cance.The use of tocolysis could also be a confounding factor; however, the authors found no signif|cant difference between groups in its rate of use postoperatively. The routine use of steroids for fetal lung maturation at 26 ^28 weeks gestational age for both groups is prudent, due to the increased risk of prematurity associated with these ultrasound f|ndings.The advanced gestational age achieved by the majority of neonates in the present trial is indicative of our inability to identify women destined to deliver preterm. The single braided tape cerclage suture utilized in the present trial was similar to that used in both the Dutch and Thomas Jef-
16
Evidence-based Obstetrics and Gynecology (2005) 7,15^16
ferson studies.Only the LehighValley study used a single non-absorbable, monof|lament tape. A recent study demonstrated that the choice of suture type probably does not affect perinatal outcome.5 The present trial utilized the Shirodkar technique for cerclage, whereas the three other randomized trials utilized the McDonald technique. Although, theoretically, the Shirodkar suture can be placed closer to the internal os, a recent study demonstrated that cerclage location has little or no clinical signif|cance, with respect to perinatal outcome.6 The present trial showed a minimal difference between groups in the mean gestational age at delivery, similar to theThomas Jefferson and Lehigh Valley studies. Only the small Dutch study concluded that cerclage improved perinatal outcome.With respect to perinatal death, there was no statistical difference between the cerclage and no-cerclage groups; the combined rate of 7% represents the lowest mortality rate of the four studies reviewed. The excellent overall perinatal outcome in both groups of this trial most likely reflects the high percentage of subjects without risk factors for preterm birth, the late gestational age at entry, and the excellent care provided to these women. These factors appear to have overcome the negative effect of the extremely short cervix (mean 0.9 cm) at enrolment. This study adds to the growing body of evidence that continues to question the clinical eff|cacy of cerclage placement in women with a short cervix demonstrated by transvaginal ultrasound in the second trimester.Until such time as a population can be def|ned that would benef|t from cerclage therapy, it should be considered as a procedure under investigation and certainly not as the standard of care. Orion A Rust, MD LehighValley Hospital and Health Network, Allentown PA, USA
Literature Cited 1. Althuisius SM, Dekker GA, Hummel P, et al.Final results of the cervical incompetence prevention randomized cerclage trial (CIPRACT): therapeutic cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001; 185:1106 ^12. 2. Rust O, Atlas R, Fischl S, et al. Does cerclage therapy improve perinatal outcome in patients with a history of previous preterm birth and cervical changes on second-trimester transvaginal ultrasound? Am J Obstet Gynecol 2003; 187:S58. 3. Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial. Am J Obstet Gynecol 2004; 191:1311^7. 4. Iams JD,Goldenberg RL, Meis PJ, et al.The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996; 334: 567^72. 5. Pereira L, Llevy C, Lewis D, et al. Effect of suture material on the outcome of emergent cerclage. Obstet Gynecol 2004; 103:35S. 6. Rust OA, Atlas RO, Meyn J, et al. Does cerclage location influence perinatal outcome? Am J Obstet Gynecol 2003; 189:1688 ^91.