Objective
To assess the accuracy of transvaginal sonographic cervical length (CL) in predicting spontaneous preterm birth in women with twin pregnancies.
Study Design
Systematic review and metaanalysis of predictive test accuracy.
Results
Twenty-one studies (16 in asymptomatic women and 5 in symptomatic women) with a total of 3523 women met the inclusion criteria. Among asymptomatic women, a CL ≤20 mm at 20-24 weeks’ gestation was the most accurate in predicting preterm birth <32 and <34 weeks’ gestation (pooled sensitivities, specificities, and positive and negative likelihood ratios of 39% and 29%, 96% and 97%, 10.1 and 9.0, and 0.64 and 0.74, respectively). A CL ≤25 mm at 20-24 weeks’ gestation had a pooled positive likelihood ratio of 9.6 to predict preterm birth <28 weeks’ gestation. The predictive accuracy of CL for preterm birth was low in symptomatic women.
Conclusion
Transvaginal sonographic CL at 20-24 weeks’ gestation is a good predictor of spontaneous preterm birth in asymptomatic women with twin pregnancies.
Despite advancing knowledge of the risk factors and mechanisms associated with preterm labor and delivery, the preterm birth rate has risen 36% in the United States during the last quarter century (from 9.4% in 1981 to 12.8% in 2006). This increase has been explained in part by a rise in the number of indicated preterm births in singleton gestations and preterm delivery of multiple pregnancies that occurred as a result of assisted reproductive technologies. Furthermore, the twin birth rate has risen 70% from 1980 (18.9 per 1000 live births) through 2006 (32.1 per 1000 live births).
In the United States, the rates of preterm birth <37 and <32 weeks of gestation for twin pregnancies (60.4% and 12.1%, respectively) were 5.4 and 7.6 times the rates for singleton pregnancies (11.1% and 1.6%, respectively). Overall, twin pregnancies comprise 15% of all preterm births accounting for a disproportionate share of preterm births. Therefore, there is an urgent need to develop cost-effective tests for the prediction of preterm birth in twin pregnancies. The ability to identify women at high risk for spontaneous preterm birth could allow for patients to undergo targeted interventions such as transfer to a tertiary care center, antenatal corticosteroid administration, and tocolysis, which might improve perinatal outcomes among twins. Previous reviews have suggested that transvaginal sonographic assessment of cervical length (CL) is an effective tool for predicting preterm birth, particularly in asymptomatic women or those at a higher risk of spontaneous preterm birth. However, these reviews largely evaluated the use of CL in singleton pregnancies. In addition, published studies on predictive accuracy of CL for preterm birth in twin pregnancies report conflicting conclusions on the value of this test.
The objective of this study was to assess the value of transvaginal sonographic CL for the prediction of spontaneous preterm birth in women with twin pregnancies through the use of formal methods for systematic reviews and metaanalytic techniques.
Materials and Methods
This systematic review was conducted following a prospectively prepared protocol and reported using recently recommended guidelines for systematic reviews of diagnostic test accuracy.
Literature search
Electronic searches, without language restrictions, were performed in the MEDLINE (January 1966-November 2009), EMBASE (January 1980-November 2009), CINAHL (January 1982-November 2009), LILACS (January 1982-November 2009), and Medion (January 1974-November 2009) databases to identify potentially eligible studies. We applied the following algorithm both in Medical Subject Headings and in free-text words in MEDLINE: {cervical length OR [(transvaginal OR vaginal OR cervix OR cervical) AND (ultrasound OR ultrasonography OR ultrasonographic OR sonography OR sonographic)]} AND (preterm OR premature). This search strategy was also used for the other databases, adjusted according to specific requirements for the particular electronic database. Proceedings of the Society for Maternal-Fetal Medicine and international meetings on preterm birth and twin or multiple pregnancy, reference lists of identified studies, textbooks, and previously published systematic reviews were also searched. In addition, we contacted experts in the field to obtain unpublished studies. All searches were conducted independently by 2 of the authors (A.C-A. and R.R.) and results were merged.
Inclusion criteria
Studies were included if they met the following minimal criteria: (1) a cohort or cross-sectional study that evaluated the accuracy of transvaginal sonographic CL measurement to predict spontaneous preterm birth in asymptomatic or symptomatic pregnant women with twin pregnancies; (2) the outcome measures included any category of spontaneous preterm birth <37 weeks of gestation; (3) the studies provided the necessary information to generate 2 × 2 tables; and (4) the women had no therapeutic intervention resulting from the test result. When a study based its results on mixed (singleton and twin) pregnancies, unless data for twins were extractable separately, it was not considered for inclusion in the review. In cases of duplicate publication we selected the most recent and complete versions and supplemented if additional information appeared in the other publications.
Studies were excluded from the systematic review if they: (1) were case-control studies because these tend to overestimate the predictive or diagnostic accuracy of a test; (2) did not provide data on predictive estimates and sufficient information to calculate them could not be retrieved; or (3) they included women with cervical cerclage, previous cervical surgery, or premature rupture of membranes.
Studies deemed suitable were retrieved and reviewed independently by 2 authors (A.C-A. and R.R.) to determine inclusion. Disagreements were resolved by consensus.
Quality assessment
Methodological quality of included studies was assessed independently by 2 reviewers (A.C-A. and R.R.) using 4 of the 14 items of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. The remaining 10 QUADAS items were not used because they were not relevant to our review. Each item was scored as “yes,” “no,” or “unclear.”
The items of the QUADAS tool evaluated and their interpretation were as follows:
- 1
Representative spectrum of patients. This item was scored “yes” when pregnant women with twin pregnancies were consecutively selected in a prospective way. Convenience sampling, such as arbitrary recruitment or nonconsecutive recruitment, was scored as “no.”
- 2
Description of the test. This item was scored as “yes” if the study described sufficient details of the technique used for measuring CL such as plane in which images were obtained, anatomic references for the determination of CL, and number of measurements. If this information was not reported, then this item was scored as “no.”
- 3
Blinding of index test result. This item was scored “yes” if the study clearly stated that clinicians treating the patient did not have knowledge of the CL results. If this did not appear to be the case, this item was scored as “no.”
- 4
Reporting of study withdrawals. If there were withdrawals from the study, this item was scored as ”yes” if withdrawals were explained or if a flow diagram of study participants was reported. If it appeared that some of the participants did not complete the study and these patients were not accounted for, then this item was scored as “no.”
If there was insufficient information available to make a judgment of these items, then they were scored as “unclear.” Summary score estimating the overall quality of an article was not calculated because the interpretation of such summary scores is problematic and potentially misleading.
Discrepancies in quality assessment were resolved by discussion.
Data extraction
Data extraction was performed independently by 2 investigators (A.C-A. and R.R.) and recorded on a standardized form. There was no blinding of authorship. Information was extracted on study characteristics, study quality, and participant characteristics. With regard to transvaginal ultrasonography, we extracted data on the technique used for measuring CL, gestational age(s) at testing, and cutoff values used. Gestational age at testing was divided into 3 groups: <20, 20-24, and >24 weeks of gestation. For studies in which the reported gestational age at testing encompassed ≥2 of the groups, we classified them according to their mean gestational age at testing. For each study, for all reported cutoff values for CL, and for all categories of spontaneous preterm birth, we then extracted the number of true-positive, false-positive, true-negative, and false-negative results. When predictive accuracy data were not available, we recalculated them from the reported results.
Studies reporting on spontaneous preterm birth <35 weeks of gestation were considered with those reporting spontaneous preterm birth <34 weeks of gestation, as both these gestational ages have similar neonatal outcomes. In the same way, studies reporting spontaneous preterm birth <36 weeks of gestation were considered with those reporting spontaneous preterm birth <37 weeks of gestation. We extracted data separately for asymptomatic women and for women with threatened preterm labor.
Disagreements in data extraction were resolved by discussion among authors.
Statistical analysis
For both asymptomatic and symptomatic women, we synthesized data for spontaneous preterm birth at <34 and <37 weeks of gestation. In addition, for asymptomatic women we synthesized data for spontaneous preterm birth at <28 and <32 weeks of gestation.
Data extracted from each study were arranged in 2 × 2 contingency tables. When these tables contained cells for which the value was 0, we added 0.5 to those cells to allow for the calculation of variances. Sensitivity and specificity were calculated for each study and for all reported cutoff values. For asymptomatic women, we plotted sensitivities and specificities in receiver operating characteristic (ROC) plots according to the timing of transvaginal ultrasonography (20-24, and >24 weeks of gestation) and definition of spontaneous preterm birth as outcome measure (<28, <32, <34, and <37 weeks of gestation). We then constructed summary ROC curves for each outcome using a bivariate random effects approach and calculated area under the summary ROC curves with their corresponding 95% confidence intervals (CIs). This measure allows for comparison of the predictive accuracy of the test for different outcomes and cutoff values (2-sided P < .05 was considered to be statistically significant).
Metaanalyses were performed using subgroups of studies with a similar gestational age at testing, cutoff values, and outcome measures to minimize clinical heterogeneity. Pooled estimates of sensitivity and specificity with 95% CIs were calculated using bivariate, random effects metaregression model. Thereafter, we derived likelihood ratios with 95% CIs from the pooled sensitivities and specificities for each outcome reported. Likelihood ratios indicate by how much a given test result raises or lowers the probability of having the disease and thus allow interpretation of the results for use in clinical practice. Likelihood ratios for a positive test result >10 and likelihood ratios for a negative test result <0.1 have been noted as providing convincing predictive evidence. Moderate prediction can be achieved with likelihood ratio values of 5-10 and 0.1-0.2, whereas those <5 and >0.2 would provide only minimal prediction. Likelihood ratios are more clinically meaningful than sensitivities or specificities because they are less likely to change with the prevalence of the disorder, they can be calculated for several levels of the test, and they can also be used in conjunction with pretest probability of disease to estimate the posttest probability of disease for individual patients.
Likelihood ratios generated from metaanalyses were used to determine posttest probabilities of spontaneous preterm birth <28, <32, <34, and <37 weeks of gestation for positive and negative CL results as follows:
Posttest probability of preterm birth = likelihood ratio × pretest probability/[1-pretest probability × (1-likelihood ratio)]
Estimates of pretest probabilities of spontaneous preterm birth <28, <32, <34, and <37 weeks of gestation were obtained from the global prevalence of these outcomes among included studies.
Heterogeneity of the results among studies was investigated through visual examination of forest plots of sensitivities and specificities, and ROC plots. In addition, heterogeneity was assessed by means of the quantity I 2 , which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. Statistical heterogeneity was defined as an I 2 statistic value of ≥50%. We explored potential sources of heterogeneity by performing metaregression analysis of subgroups as defined a priori: study setting (those conducted in North America vs Europe), sample size (<100 vs ≥100 in studies of asymptomatic women and <50 vs ≥50 in studies of symptomatic women), and study’s year of publication (<2000 vs ≥2000). In addition, we examined the impact of study quality on estimation of predictive accuracy according to individual quality items and according to an overall quality level incorporating these items (those that met all 4 methodological criteria vs <4).
We assessed publication and related biases visually by examining the symmetry of funnel plots and statistically by using the Egger regression test. P < .1 indicated significant asymmetry.
The bivariate models were fitted using the NLMIXED procedure (SAS 9.1 for Windows; SAS Institute Inc, Cary, NC). The summary ROC curves were constructed using Review Manager 5.0.21 (The Nordic Cochrane Centre, Copenhagen, Denmark). The remaining analyses were performed using SPSS, version 15.0 (SPSS Inc, Chicago, IL).
Results
The searches produced 1027 citations of which 314 were considered relevant ( Figure 1 ). In all, 293 studies were excluded, the main reasons being the inclusion of only singleton pregnancies (37%), not a test accuracy study (27%), and the lack of original data (24%). A total of 21 studies, including 3523 women with twin pregnancies, met the inclusion criteria of which 15 (3001 women) provided data for metaanalyses. Sixteen studies (3213 women) provided data on asymptomatic women and 5 studies (310 women) on women with symptoms of preterm labor. One of the included articles was an extended analysis of an initial study from which we extracted data for metaanalyses of CL ≤25 and ≤35 mm at 20-24 weeks of gestation to predict preterm birth <28 weeks of gestation. Six studies could not be included in the metaanalyses because the CL cutoff values used and outcome measures evaluated did not match those of other studies that provided data for metaanalyses. Predictive accuracy of CL for spontaneous preterm birth reported in studies not included in the metaanalyses is provided in the supplementary Appendix (available online at www.ajog.org ).
The main characteristics of studies included in the review are shown in Table 1 . Nine studies (43%) were performed in Europe, 8 (38%) in the United States, 2 in Israel, and 1 each in Egypt and the French West Indies. The sample size ranged from 18 28 to 1135 30 in asymptomatic women (median, 139) and from 26 to 105 35 in symptomatic women (median, 66). The range for outcome definitions was preterm birth at <28 to <37 weeks of gestation. Three studies provided data on preterm birth <28 weeks, 7 on preterm birth <32 weeks, 16 on preterm birth <34 or <35 weeks, and 8 on preterm birth <36 or <37 weeks. Five studies reported results using a CL cutoff value of 20 mm, 13 using 25 mm, 9 using 30 mm, and 8 using 35 mm. Among asymptomatic women, 3 studies reported data on CL at <20 weeks, 12 on CL at 20-24 weeks, and 8 on CL at >24 weeks.
| Study, year | Country | No. of women | Inclusion criteria | Exclusion criteria | Gestational age at testing, wk | Cervical length cutoff, mm | Outcome |
|---|---|---|---|---|---|---|---|
| Asymptomatic women | |||||||
| Goldenberg et al, 1996 | United States | 147 | Twins | Cervical cerclage, placenta previa, major fetal anomaly | 24, 28 | 25 | Preterm birth <32, <35, and <37 wk |
| Imseis et al, 1997 | United States | 85 | Twins | Cervical cerclage | 24-26 | 35 | Preterm birth <34 wk |
| Wennerholm et al, 1997 | Sweden | 101 | Twins | Not reported | 24-34 | 33 | Preterm birth <35 and <37 wk |
| Grisaru-Granovsky et al, 1998 | Canada | 38 | Twins, triplets, quadruplets | Not reported | 18-29 (mean, 25) | 30 | Preterm birth <34 wk |
| Yang et al, 2000 | United States | 65 | Twins | Cervical cerclage, placenta previa, or bleeding | 18-26 (91% at <24 wk) | 25, 30, 35 | Preterm birth <32 and <35 wk |
| Guzman et al, 2000 | United States | 131 | Twins | Cervical cerclage | 15-20, 21-24, 25-28 | 20 | Preterm birth <28,<30, <32, and <34 wk |
| Soriano et al, 2002 | Israel | 44 | Twins | Not reported | 18-24 (mean, 22.7) | 35 | Preterm birth <34 wk |
| Vayssière et al, 2002 | France | 251 | Twins | Cervical cerclage, placenta previa, major fetal anomaly, twin-twin transfusion syndrome, premature rupture of membranes | 21-23, 26-28 | 25, 30 | Preterm birth <32 and <35 wk |
| Gibson et al, 2004 | United Kingdom | 91 | Twins | Fetal anomaly, twin-twin transfusion syndrome | 18, 24, 28, and 32 | 25, 22 | Preterm birth <35 wk |
| Sperling et al, 2005 | Denmark and Sweden | 383 | Twins | Cervical cerclage, prior conization | 23 | 20, 25, 30, 35 | Preterm birth <28,<32, <33, <34, and <35 wk |
| Fait et al, 2005 | Israel | 18 | Triplets reduced to twins | Cervical cerclage | 15.9 ± 0.3 | 35 | Preterm birth <33 wk |
| Arabin et al, 2006 | The Netherlands | 153 | Twins | Not reported | 20-25 | 25, 30 | Preterm birth <36 wk |
| To et al, 2006 | United Kingdom | 1135 | Twins | Cervical cerclage, major fetal abnormalities, premature rupture of membranes, monochorionic twins with severe twin-twin transfusion syndrome | 22-24 | 5-55 a | Preterm birth <30, <32, and <34 wk |
| Klein et al, 2008 | Austria | 223 | Twins | Not reported | 20-25 | 25, 30, 35 | Preterm birth <34 wk |
| Aboulghar et al, 2009 | Egypt | 193 | Twin ICSI pregnancies | Cervical cerclage | Mean, 20 | 38 | Preterm birth <34 wk |
| Fox et al, 2009 | United States | 155 | Twins | Monoamniotic twins, fetal aneuploidy, major fetal abnormalities | 22-24, 25-32 | 20, 25, 35 | Preterm birth <28,<32, <34, and <37 wk |
| Women with symptoms of preterm labor | |||||||
| Crane et al, 1997 | Canada | 26 | Twins, regular uterine contractions with cervical changes (dilatation, effacement, or change in consistency) | Active vaginal bleeding, placenta previa, premature rupture of membranes, cervical cerclage, stillbirth, cervical dilatation >3 cm | 23-33 | 25, 30 | Preterm birth <34 and <37 wk |
| Persutte et al, 2000 | United States | 105 | Twins, spontaneous onset of labor and vaginal delivery | Not reported | 20-32 | 25 | Preterm birth <37 wk |
| Vendittelli et al, 2001 | French West Indies | 26 | Twins, uterine contractions on external tocodynamometry at least 1 every 10 min and/or with changes in manual cervical effacement or dilatation | Cervical dilatation >3 cm, premature rupture of membranes, cervical cerclage, active vaginal bleeding, placenta previa, stillbirth, fetal malformation | 18-36 | 25 | Preterm birth <37 wk |
| Fuchs et al, 2004 | Germany, United Kingdom | 87 | Twins, painful and regular uterine contractions | Cervical dilatation >3 cm, cervical cerclage, premature rupture of membranes | 24-36 | 25 | Delivery within 7 d of testing |
| Gonzalez et al, 2004 | France | 66 | Twins, regular uterine contractions with cervical changes (effacement of at least 50% or dilatation of at least 1 finger) | Cervical cerclage, maternal or fetal disorder contraindicating continuation of pregnancy | <34 | 20, 30 | Preterm birth <34 and <37 wk |
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