Does Mid-trimester Cervical Length ≥ 25 mm Predict Preterm Birth in High-Risk Women?

Abstract

Objective

To assess pregnancy outcome along a continuum of cervical lengths ≥25 mm.

Study Design

Planned secondary analysis of a randomized cerclage trial of women with prior spontaneous preterm birth 17⁰–34^6/7 weeks. Outcomes of women who maintained cervical lengths ≥25 mm were analyzed. Women with cervical lengths <25 mm randomized to no cerclage comprised an internal comparison group.

Results

Of 1014 screened, 153 had cervical length <25mm, and 672 had cervical length ≥25 mm. Birth <35 weeks occurred in 16% of the ≥25 mm cohort. The relationship between cervical lengths ≥25 mm and birth gestational age was null (p=0.15). In the <25 mm group, progressively shorter cervical lengths predicted birth <35 weeks (p<0.001); this relationship was null in the ≥25 mm group (p=0.17).

Conclusion

The continuum of cervical lengths ≥25 mm measured between 16^0/7 and 22^6/7 weeks does not predict gestational length in women with prior spontaneous preterm birth.

A prior spontaneous preterm birth is one of the strongest historical predictors of recurrence, and sonographic evaluation of the cervix, especially shortened cervical length, has consistently been shown to be an effective predictor of preterm birth (1). Though not recommended for routine use in low-risk or unselected populations (2), cervical length screening appears to have the most clinical utility in high-risk populations (3, 4). Previous reports have described the association between shortened cervical length below a prescribed cutoff and the risk of preterm birth (4, 5, 6). The use of a 25 mm cutoff in the midtrimester has been utilized by investigators and clinicians to identify women at the highest risk of preterm birth. This cutoff threshold value is the lower 10^th percentile in both unselected (7) and high-risk (3) populations. The 25 mm threshold has also been utilized as the basis for cerclage intervention trials (8, 9, 10, 11)

Systematic reviews (4, 5, 6) confirm a consistent relationship between short cervix and earlier birth in various populations, but, using the native reports which populated the reviews, these investigators primarily sought to summarize and compare sensitivities, specificities and likelihood ratios for preterm birth at various cervical length and gestational age thresholds. None specifically evaluated the continuum of cervical lengths above a specified threshold for the prediction of preterm birth, as the outcomes of patients with longer cervical lengths were simply pooled in order to calculate the screening test characteristics. Iams and colleagues in the NICHD MFM units network (7) evaluated nearly 3000 unselected women at 24 weeks’ gestation and found increasing relative risks of preterm birth with cervical shortening using the upper quartile > 40 mm as the referent group; however, the trend in rates of preterm birth associated with cervical lengths above the 25 mm threshold was not formally evaluated.

To improve clinical decision making, patient selection for intervention trials and our understanding of the preterm birth syndrome (12), the risks of preterm birth associated with longer cervical lengths in high-risk women requires further characterization. Our null hypothesis was that the continuum of cervical lengths above a 25 mm cervical length threshold would not be associated with pregnancy duration in women with prior preterm birth.

METHODS

This is a planned secondary analysis of a randomized clinical trial performed by a consortium of 15 U.S. Centers between January, 2003 and November, 2007 (Owen, 2009). Multiparous women carrying a singleton and who had experienced at least one prior spontaneous preterm birth between 17^0/7 and 33^6/7 weeks’ gestation, confirmed by a review of the patient’s medical records, underwent serial vaginal sonographic assessment of cervical length. Exclusion criteria were fetal anomaly, planned history-indicated cerclage for a clinical diagnosis of cervical insufficiency, and clinically significant maternal-fetal complications. Other details of the study protocol are described elsewhere (11)

Sonologists underwent a uniform certification process by a single investigator (J.O.) to ensure uniformity in sonographic equipment, measurement technique, completion of study forms, and adherence to protocol. Specifics of this sonographic evaluation based on the technique of Iams have been previously described (7): the cervical length at each visit was measured along a closed endocervical canal, where minimal degrees of apparent dilation (i.e. echolucency along the entire canal) less than 5 mm were considered closed. Fundal pressure was also applied for 30 seconds by the sonologist as a provocative maneuver, and each scan included an evaluation period of at least 5 minutes to detect spontaneously occurring cervical shortening. The shortest cervical length for each examination that clearly displayed the internal and external cervical os with equivalent thickness of the anterior and posterior cervix was recorded as the cervical length, regardless of whether the measurement was obtained with pressure or was the result of spontaneous dynamic shortening. Managing physicians were masked to the results of the sonographic evaluations except in cases of complete placenta previa, oligohydramnios or fetal death.

The first sonographic assessment was scheduled in the gestational age window 16^0/7 to 21^6/7 weeks’ gestation. Subsequent evaluations were scheduled every 2 weeks. If the cervical length was observed to be 25–29 mm, scans were scheduled weekly. If on any evaluation the cervical length was < 25 mm, the woman became eligible for randomization to cerclage or to a no-cerclage group. Women with a cervical length that remained at least 25 mm at the final sonographic evaluation, scheduled to be no later than 22^6/7 weeks, were ineligible for randomization and comprised the ≥ 25 mm cohort. We also compared their outcomes to an internal control group of women who qualified for the trial based on a cervical length < 25 mm and were randomized to no cerclage. The protocol and consent forms received local institutional review board approval at all centers.

Categorical variables were analyzed with chi-square or the Mantel-Haenszel test of trend, while continuous variables were compared using a t-test or Wilcoxon rank-sum test. Linear regression modeled the association between 2 continuous variables. Differences in time to birth were assessed by Kaplan-Meier curves and the log-rank test. Multivariable Cox proportional hazard models considered possible confounders for time to birth. An alpha level of 0.05 was selected to represent statistical significance. Analyses were performed using SAS 9.2 (Cary, NC).

RESULTS

A total of 1014 eligible women gave consent and underwent their initial sonographic assessment of cervical length. From this cohort, we observed 318 (31%) who experienced cervical length shortening less than 25 mm. Sixteen patients did not consent to randomization, and 302 (95%) entered the randomized trial; 153 were assigned to the no-cerclage cohort. Of the 696 who underwent their initial scan and failed to shorten to < 25 mm, delivery outcomes were available in 672 (96.6%); these comprised the ≥ 25 mm cohort (Fig. 1). Selected characteristics of the 2 study cohorts are shown in Table 1. As anticipated, the cohorts differed with regard to several characteristics.

Figure 1. Flow of participants.

Table 1.

Characteristics

	< 25 mm (n = 153)	≥ 25 mm (n = 672)	p- value
Maternal age (y)	26.6 ± 5.1	26.7 ± 5.3	0.72
Number of prior births (n)	2 (1, 4)†	2 (1, 4)†	0.33
One or more prior induced abortion - no. (%)	25 (16)	62 (9)	0.01
Body mass index (kg/m2)	29.9 ± 7.5	28.7 ± 7.1	0.07
Race/ethnicity* - no. (%)			<0.00 01
Black (non-Hispanic)	93 (61)	217 (32)
White (non-Hispanic)	28 (18)	128 (19)
Hispanic	17 (11)	208 (92)
Asian	0 (0)	11 (2)
Other	15 (9.8)	108 (16)
Marital Status - no. (%)
Single/never married	99 (65)	337 (50)	0.002
Married	42 (27)	294 (44)
Divorced	10 (6.5)	36 (5.4)
Widowed	1 (0.7)	4 (0.6)
Other	1 (0.7)	1 (0.2)
Prior cerclage - no. (%)	12 (7.8)	17 (2.5)	0.001
Years of education (n)	11.9 ± 2.4	11.6 ± 4.4	0.35
Gestational age of qualifying birth (wks)	24.9 ± 4.7	26.8 ± 4.4	< 0.0001
Gestational age at first vaginal sonogram (wks)	17.4 ± 1.4	17.8 ± 1.4	0.002
Cervical length at first vaginal sonogram (mm)	29.5 ± 12.9	40.6 ± 10.1	< 0.0001
Gestational age at randomization or final sonogram (wks)	19.5 ± 2.0	21.3 ± 1.4	< 0.0001
Cervical length at randomization or final sonogram (mm)	19.5 ± 5.3	37.9 ± 8.2	< 0.0001
Total number of vaginal sonograms (N)	2 (1, 4)†	3 (1, 4)†	< 0.0001

Continuous data are expressed as a mean ± 1 standard deviation except as noted.

^†Median and interdecile range

The rates of birth < 35 weeks were 42% in the < 25 mm internal comparison cohort and 16% in the ≥ 25 mm cohort (p < 0.0001). There was a non-significant association between cervical length (predictor variable) and birth gestational age in the ≥ 25 mm cohort using a linear regression model (p = 0.15). Figure 2 depicts the relationship between cervical length groups and birth < 35 weeks, both in the < 25 mm internal comparison cohort and also in the ≥ 25 mm cohort: the relationship between cervical length group and birth < 35 weeks in the < 25 mm internal comparison cohort, assessed with a test of trend, was statistically significant (p < 0.001) while the analogous comparison in the ≥ 25 mm cohort was not significant (p = 0.17). The mean gestational ages at birth were 26, 31, 33, and 35 weeks in the < 10 mm, 10–14 mm 15–19 mm and 20–24 mm groups respectively that comprised the internal control, no-cerclage cohort. The corresponding birth gestational ages in the failed-to-shorten cohort for cervical length groups 25–29 mm, 30–34 mm, 35–39 mm, 40–44 mm, 45–50 and ≥ 50 mm groups were, 37, 37, 37, 38, 38 and 38 weeks respectively.

Figure 2. Relationship between cervical length groups and birth < 35 weeks.

Rates of preterm birth < 35 weeks by cervical length group in both the < 25 mm, no-cerclage, internal comparison cohort and ≥ 25 mm, failed-to-shorten cohort

Finally, we chose to examine the relationship between cervical lengths near the 25 mm cutoff, i.e. 25–29 mm and longer cervical lengths of 30 mm or greater. As depicted in Figure 3, the Kaplan-Meier survival analysis, comparing the 25–29 mm and ≥ 30 mm subgroups and considering the event time to birth (i.e. percent undelivered), was statistically significant (log-rank test p = 0.02). However, in a multivariable Cox proportional hazards model, controlling for maternal race, age, cervical length at 1^st sonogram, gestational age at 1^st sonogram, cervical length at last sonogram, gestational age at last sonogram, and number of sonographic evaluations, the relationship between these 2 cervical length subgroups became once again, null (p = 0.38).

Figure 3. Kaplan-Meier survival curves of cervical length groups.

Probability of delivery across gestation in the ≥ 25 mm cohort, comparing women with cervical lengths 25–29 mm and those with cervical lengths 30 mm or greater.

COMMENT

In this large population of multiparous women, chosen to be homogeneous for the strongest historic risk factor for recurrent preterm birth, a mid-trimester cervical length threshold of 25 mm appeared to be a good, if imperfect discriminator of preterm birth risk. Although this cohort remained at increased risk for preterm birth < 35 weeks’ gestation (16%) compared to an unselected population (2.7%) (7), the continuum of cervical lengths at or beyond 25 mm had no appreciable impact on preterm birth risk or length of gestation as estimated with several different statistical models. Conversely, shorter lengths, as exemplified in the < 25 mm, no-cerclage cohort, clearly show the oft-demonstrated inverse relationship with preterm birth risk.

We included a < 25 mm internal comparison group to emphasize the disparity in the risk of preterm birth on either side of the 25 mm cervical length threshold. Not only is the rate of preterm birth < 35 weeks substantially higher (42% vs. 16%), but there was a strong correlation in the trend toward higher preterm birth rates in the < 25 mm group as the cervix shortens further; women with the shortest cervical lengths < 10 mm had > 90% chance of preterm birth < 35 weeks. An analogous trend in the continuum of risk was not observed in the ≥ 25 mm cohort (Figure 2). Not surprising is the observation that the 2 cohorts differed in several aspects, as shown in Table 1. Many of these characteristics, in addition to shorter cervical lengths, including Black race, abortion history and earlier gestational age of the prior (i.e. qualifying) preterm birth are themselves, well-known risk factors for preterm birth. That women in the ≥ 25 mm cohort underwent more sonograms and had their final sonogram at a later gestational age, is simply a reflection of their failure to shorten in the temporal scanning window.

Possible limitations to our study include that our observations were censored by trial design at 22^6/7 weeks gestation. Thus, it is possible that some women continued to experience cervical shortening after the observation window ended and that pathologic shortening was associated with some of the observed preterm births. Another explanation for the apparent increased preterm birth risk in this population who failed to demonstrate cervical shortening < 25 mm, is that some of these early births may have been due to other components of the preterm birth syndrome and that did not involve premature cervical shortening (Romero, 1994). Since we did not collect more detailed delivery information in the ≥ 25 mm cohort beyond date of delivery, we could not determine whether the preterm births were indicated or, if spontaneous, whether they were associated primarily with premature membrane rupture, labor or cervical insufficiency. However, by design, we specifically excluded women with known conditions that would put them at risk for maternal-fetal complications and indicated preterm birth. Of note, in the no-cerclage comparison cohort, the overall rate of preterm birth < 37 weeks was 59%, while the reported rate of indicated preterm birth only 4%. Thus we believe it is unlikely that, had we limited our analysis to spontaneous preterm birth in the failed-to-shorten cohort, our results would have been different. Similarly, we did not have information on ancillary preterm birth prevention strategies such as the use of progesterone (13), which may also have explained some of the observed variance in birth outcomes. Finally, as our null findings did not demonstrate an association between cervical lengths ≥ 25 mm and pregnancy duration, there was a concern about statistical power. From the observed data we determined that a sample of 672 women would have 80% power to detect a linear regression coefficient as small as 0.05, (considering birth gestational age as the dependent variable and cervical length as the predictor), if such a relationship actually exists. This would imply that for each additional mm of cervical length, mean gestational age would increase by 0.05 weeks. Our observed regression coefficient was 0.03, p = 0 .15.

One of the interesting clinical findings in this study is the 16% rate of preterm birth < 35 weeks in these 672 high-risk women whose mean earliest prior spontaneous preterm birth was 26.6 weeks. Women who fail to shorten to < 25 mm by 22^6/7 weeks can be reassured that the risk is low. Since ultrasound-indicated cerclage has been shown to improve pregnancy outcomes in women with prior spontaneous preterm birth and cervical length < 25 mm (11, 14), and since less than one third of these women experience cervical shortening < 25 mm (3, 11), we believe it is appropriate to screen women with a prior preterm birth history using serial sonography in order to limit history-indicated cerclage.

In summary, women at increased risk for recurrent preterm birth but who maintain a cervical length of at least 25 mm may still have an increased risk of recurrence. Nevertheless, whether a woman’s cervical length is near the threshold, or appreciably longer, her absolute risk appears to be stable. Whether this biologic relationship holds in other populations of women with no risk factor (e.g. nulliparas) or other historic risk factors cannot be estimated from our data. However, in women with prior spontaneous preterm birth, a cervical length threshold of 25 mm appears to be a clinically relevant discriminator of preterm birth risk. Further research initiatives may better define the pathways and mechanisms of preterm birth in women who fail to exhibit cervical shortening in the midtrimester. Future intervention trials in women with this preterm birth risk factor should consider using a cervical length threshold of 25 mm to identify the population at highest risk.