Original Article
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Fetal Fibronectin versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy with or without 17-Hydroxyprogesterone Caproate C. Andrew Combs, MD, PhD1,2 Thomas J. Garite, MD1,3 Obstetrix Collaborative Research Network
Sunrise, Florida 2 Obstetrix Medical Group, San Jose, California 3 Department of Obstetrics and Gynecology, University of California, Irvine, California 4 Axistat, Inc., San Francisco, California
Anita Das, PhD4
for the
Address for correspondence C. Andrew Combs, MD, PhD, Obstetrix Medical Group, 900 E Hamilton Avenue #220, Campbell, CA 95008 (e-mail: [email protected]).
Am J Perinatol 2014;31:1023–1030.
Abstract
Keywords
► ► ► ►
fetal fibronectin cervical length twin pregnancy 17hydroxyprogesterone caproate ► preterm birth prediction
Objective The objective of this study was to compare cervicovaginal fetal fibronectin (FFN) versus transvaginal sonographic cervical length as predictors of preterm birth in twin pregnancy and to test whether 17-hydroxyprogesterone caproate (17OHPc) modifies the predictive value of FFN. Study Design Secondary analysis of a randomized trial of 17OHPc versus placebo in dichorionic-diamniotic twins, analyzing the subset with screening FFN (N ¼ 198) and/or cervical length (N ¼ 214) at 24 to 26 weeks of gestation. Results Positive FFN was found in 7%, cervical length 25 mm in 8%, and both positive FFN and cervical length 25 mm in 3%. Birth < 32, < 34, and < 37 weeks occurred in 8, 30, and 67%, respectively. In logistic regression analysis controlling for FFN, cervical length, prior preterm birth, and treatment group, positive FFN was significantly associated with birth < 30 and < 32 weeks (odds ratio 55.0 [95% confidence interval 5.2–582], 18.1 [3.3– 99], respectively, p < 0.001 for both) but cervical length 25 mm was not (odds ratio 0.1 [0.002–1.6], 0.6 [0.1–4.3]). Conclusion Positive FFN was stronger than cervical length 25 mm in predicting early preterm birth in twins, regardless of 17OHPc use. Treatment with 17OHPc did not appear to alter the predictive value of FFN.
Preterm birth occurs in 12% of pregnancies in the United States1 and is a major cause of perinatal morbidity and mortality.2 Considerable effort has been devoted to study risk factors for preterm birth, in part because patients with certain risk factors may benefit from targeted interventions to reduce the rate of preterm birth.3 Two such risk factors are history of
preterm birth in a prior pregnancy or short cervical length in the current pregnancy. For women with a history of a prior preterm birth, prophylactic treatment with 17-hydroxyprogesterone caproate (17OHPc) is recommended4,5 because it may significantly reduce the recurrence risk of preterm birth.6 For women with a short cervix identified by transvaginal sonography,7,8 treatment with vaginal micronized
received September 16, 2013 accepted after revision January 2, 2014 published online February 24, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1370342. ISSN 0735-1631.
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1 The Center for Research, Education, and Quality, Mednax, Inc.,
Kimberly Maurel, MSN1
FFN versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy progesterone is recommended4,5 because it may significantly reduce the risk of early preterm birth.9–11 Detection of fetal fibronectin (FFN) in cervicovaginal secretions is another risk factor for preterm birth. Several studies have found that FFN positivity is more strongly predictive of preterm birth than cervical length,12–15 history of prior preterm birth,12,13,16 or other current pregnancy risk factors.12,14 In a systematic review of 22 candidate predictors, only three tests had a positive likelihood ratio 5 for prediction of spontaneous preterm birth in asymptomatic women: cervicovaginal FFN, cervicovaginal prolactin, and cervical length.3 A recent report17 compared the test performance of FFN versus cervical length in predicting preterm birth in women with a history of prior preterm birth, all of whom were receiving prophylactic 17OHPc. In that study, cervical length was strongly predictive of recurrent preterm birth, but FFN was not. The authors hypothesized that 17OHPc treatment might have diminished the predictive value of FFN by downregulating inflammatory pathways involved in cervical ripening and preterm birth. The purpose of the present investigation was to determine whether prophylactic 17OHPc treatment affects the test performance of screening FFN and/or cervical length in predicting preterm birth in asymptomatic twin pregnancies.
Materials and Methods This is a secondary analysis of a multicenter, double-blind, randomized clinical trial of prophylactic 17OHPc for women with twin pregnancy. Details of the trial were reported previously.18 Briefly, consenting women with uncomplicated dichorionic-diamniotic twin pregnancy were enrolled at 15 to 23 weeks of gestation and randomly assigned to receive a weekly intramuscular injection of either 17OHPc (250 mg in 1 mL castor oil) or an identical appearing placebo (1 mL castor oil), continued until 34 weeks of gestation. The randomization was in a 2-to-1 ratio of 17OHPc-to-placebo. The 17OHPc was manufactured using current good manufacturing practices19 as specified in an Investigational New Drug application. Institutional review board approval for the trial was obtained at each participating site. The trial found no difference between the 17OHPc group and the placebo group in the rate of composite neonatal morbidity (primary outcome) or gestational age at delivery (secondary outcome).18 The trial protocol included a scheduled office visit at 24 to 26 weeks of gestation to perform an FFN test and to measure cervical length by transvaginal sonography. The purpose of this screening, stated a priori, was to generate exploratory data to evaluate the hypothesis that 17OHPc might be more effective or less effective in subgroups of women defined by cervical length or FFN. The FFN specimen was obtained according to the manufacturer’s instructions (placement of a sterile polyester swab into the posterior vaginal fornix during speculum exam and rotating for 10 seconds, Adeza Biomedical, Sunnyvale, CA) or according to an established protocol for “blind” placement of the vaginal swab without a speculum,20,21 depending on each American Journal of Perinatology
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provider’s customary practice. The swab was placed immediately into transport media and analyzed using the manufacturer’s TLiIQ system. The instrumentation reports results as either positive ( 50 ng/mL) or negative (< 50 ng/mL) depending on the concentration of FFN in the sample. Caregivers did not have access to FFN results which were obtained solely for research purposes. The cervical length measurement was obtained via transvaginal sonography after collection of the FFN specimen. The data collection form captured only the length of the undilated cervical canal, known as the “functional cervical length.”22 The value of cervical length and any other sonographic findings were reported to each patient’s caregivers. For the present analysis, we consider a short cervix to be cervical length 25 mm, but we did not specify any “cutoffs” or normal ranges as part of the trial. The protocol did not specify any particular management in the event a short cervix was found because there is no evidence-based intervention to improve pregnancy outcome after finding a short cervix in twin pregnancy. The use of vaginal progesterone was not permitted by the protocol. Descriptive statistics (mean and standard deviation for continuous variables, and count and percentage for categorical variables) were calculated for baseline characteristics. Statistical significance was tested using the Wilcoxon ranksum test and Fisher exact test, respectively. In an efficacy analysis of 17OHPc versus placebo, the relative risks and 95% confidence intervals (CIs) of birth < 32, < 34, and < 37 weeks of gestation were calculated in subgroups defined by FFN (positive or negative) and cervical length ( 25 or > 25 mm) and tested for statistical significance using Fisher exact test. Test characteristics, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated for the prediction of preterm birth by a positive FFN or cervical length 25 mm. Unadjusted (univariable) odds ratios and 95% CI were calculated for FFN, cervical length 25 mm, and history of prior preterm birth in predicting birth < 30, < 32, < 34, and < 37 weeks of gestation. A logistic regression analysis was conducted using FFN, cervical length 25 mm, prior preterm birth, and treatment group (17OHPc vs. placebo) as predictors of birth < 30, < 32, < 34, and < 37 weeks. We also tested for an interaction between FFN and treatment group. The p values < 0.05 were considered significant.
Results A total of 240 women participated in the trial, 160 in the 17OHPc group and 80 in the placebo group. Cervical length screening was performed in 214 women (89%) and FFN screening in 198 (83%). As shown in ►Table 1, those who had cervical length or FFN screening were similar to those who did not have screening in terms of baseline characteristics such as age, parity, and history of prior preterm birth. They were evenly distributed among the treatment groups (17OHPc vs. placebo) and had similar gestational age at delivery. Positive FFN was found in 7% of those screened (14 of 198) and cervical length 25 mm was found in 8% (18 of 214).
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FFN versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy
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Table 1 Characteristics of women who did or did not have screening Fetal Fibronectin Screening Screened (N ¼ 198)
Not screened (N ¼ 42)
Cervical Length Screening p Value
a
Screened (N ¼ 214)
Not screened (N ¼ 26)
p Valuea
Gestational age at screening (wk)
25.1 1.0
NA
NA
24.9 0.9
NA
NA
Maternal age (y)
34.1 5.9
33.8 7.1
0.790
31.2 6.1
33.4 6.7
0.632
Parity
0.8 1.0
0.9 1.1
0.711
0.8 1.0
0.8 1.2
0.782
Nulliparous
99 (50%)
20/41 (49%)
1.00
108 (51%)
12 (48%)
0.836
Prior preterm birth
26 (13%)
3/41 (7%)
0.432
29 (14%)
0 (0%)
0.052
Randomized to 17OHPc
129 (65%)
31 (73%)
0.368
141 (66%)
19 (73%)
0.517
Randomized to placebo
69 (35%)
11 (26%)
0.368
73 (34%)
7 (27%)
0.517
Gestational age at delivery (wk)
35.5 2.7
35.5 2.4
0.573
35.6 2.4
34.9 2.6
0.147
Among the 198 screened with FFN, preterm birth < 32 weeks occurred in 15 (8%), < 35 weeks in 59 (30%), and < 37 weeks in 134 (67%). Among the 214 screened with cervical length, preterm birth < 32 weeks occurred in 17 (8%), < 35 weeks in 63 (29%), and < 37 weeks in 140 (65%). Among the 188 women who had both screens performed, the mean gestational age at delivery was 32.7 4.3 weeks with both positive FFN and cervical length 25 mm (N ¼ 6), 32.2 4.5 weeks with positive FFN and cervical length > 25 mm (N ¼ 5), 34.8 1.62 weeks with negative FFN and cervical length 25 mm (N ¼ 10), and 35.8 2.1 weeks with negative
FFN and cervical length 25 mm (N ¼ 167, p ¼ 0.009 for the trend across categories, Kruskal–Wallis test). An analysis of the efficacy of 17OHPc for prevention of preterm birth in subgroups of women defined by FFN or cervical length is presented in ►Table 2. There was no significant difference between the 17OHPc and placebo groups in the rate of preterm birth at any gestational age in any subgroup. ►Table 3 shows the test performance characteristics of FFN and cervical length for prediction of preterm birth at various gestational ages. FFN generally outperformed cervical
Table 2 Efficacy of 17-hydroxyprogesterone caproate for prevention of preterm birth 17OHPc group
Placebo group
RR (95% CI)
p Valuea
7/119 (6%)
2/65 (3%)
1.91 (0.41–8.94)
0.496
FFN-negative subgroup Birth < 32 wk Birth < 34 wk
19/119 (16%)
7/65 (11%)
1.48 (0.66–3.34)
0.383
Birth < 37 wk
82/119 (69%)
40/65 (62%)
1.12 (0.89–1.41)
0.331
Birth < 32 wk
4/10 (40%)
2/4 (50%)
0.80 (0.23–2.76)
1.00
Birth < 34 wk
5/10 (50%)
3/4 (75%)
0.67 (0.29–1.54)
0.580
Birth < 37 wk
9/10 (90%)
3/4 (75%)
1.20 (0.66–2.19)
0.506
Birth < 32 wk
10/126 (8%)
3/70 (4%)
1.85 (0.53–6.51)
0.386
Birth < 34 wk
21/126 (17%)
8/70 (11%)
1.46 (0.68–3.12)
0.403
Birth < 37 wk
86/126 (68%)
39/70 (56%)
1.23 (0.96–1.56)
0.090
Birth < 32 wk
3/15 (20%)
1/3 (33%)
0.60 (0.09–3.99)
1.00
Birth < 34 wk
5/15 (33%)
1/3 (33%)
1.00 (0.17–5.77)
1.00
Birth < 37 wk
12/15 (80%)
3/3 (100%)
0.80 (0.62–1.03)
1.00
FFN-positive subgroup
CL > 25 mm subgroup
CL 25 mm subgroup
Abbreviations: CI, confidence interval; CL, cervical length; FFN, fetal fibronectin; 17OHPc, 17-hydroxyprogesterone caproate; RR, relative risk. Note: Data are N (%) or relative risk (95% CI). a Fisher exact test. American Journal of Perinatology
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Abbreviations: NA, not applicable; 17OHPc, 17-hydroxyprogesterone caproate. Note: Data are mean SD or N (%). None of the p values are significant (p > 0.05). a Fisher exact test for categorical variables or Wilcoxon rank-sum test for continuous variables.
FFN versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy
Combs et al.
Table 3 Test performance characteristics Sensitivity, % (95% CI)
Specificity, % (95% CI)
Positive predictive value, %(95% CI)
Negative predictive value, %(95% CI)
Positive likelihood ratio
Negative likelihood ratio
Prediction of birth < 30 wk FFN positive
50.0 (15.7–84.3)
94.7 (90.5–97.5)
28.6 (8.4–58.1)
97.8 (94.5–99.4)
9.43
0.53
CL 25 mm
22.2 (2.8–60.0)
92.2 (87.6–95.5)
11.1 (1.4–34.7)
96.4 (92.8–98.6)
2.85
0.84
Prediction of birth < 32 wk FFN positive
40.0 (16.3–67.7)
95.6 (91.6–98.1)
42.9 (17.7–71.1)
95.1 (90.9–97.7)
9.10
0.63
CL 25 mm
23.5 (6.8–49.9)
92.9 (88.4–96.1)
22.2 (6.4–47.6)
93.4 (88.9–96.4)
3.31
0.82
Prediction of birth < 34 wk FFN positive
23.5 (10.8–41.2)
96.3 (92.2–98.7)
57.1 (28.9–82.3)
85.9 (80.0–90.6)
6.35
0.79
CL 25 mm
17.1 (6.6–33.7)
93.3 (88.6–96.5)
33.3 (13.3–59.0)
85.2 (79.5–89.9)
2.55
0.89
Prediction of birth < 37 wk FFN positive
9.0 (4.7–15.1)
96.9 (89.2–99.6)
85.7 (57.2–98.2)
33.7 (26.9–41.0)
2.90
0.94
CL 25 mm
10.7 (6.1–17.1)
96.0 (88.6–99.2)
83.3 (58.6–96.4)
36.2 (29.5–43.4)
2.61
0.93
Abbreviations: CI, confidence interval; CL, cervix length; FFN, fetal fibronectin.
length in terms of superior sensitivity and positive likelihood ratios for predicting preterm birth at all gestational ages 34 weeks or less. ►Table 4 presents unadjusted (univariable) and adjusted (multivariable, logistic regression) analyses of various potential predictors for preterm birth, including FFN, cervical length, history of prior preterm birth, and treatment group (17OHPc or placebo). In the univariable analyses, positive FFN was more strongly associated with early preterm birth (higher odds ratios) than cervical length 25 mm, regardless of whether 17OHPc or placebo was given. The adjusted analysis shows that FFN was stronger than cervical length 25 mm as a predictor of early preterm birth. Indeed, after adjustment for the other variables, cervical length 25 mm had no significant association with preterm birth at any gestational age. Additional logistic regression models were tested that included the interaction of FFN with treatment group. However, we rejected these models because the interactions were far from statistical significance (p values of 0.963, 0.284, 0.248, and 0.671 for birth < 30, < 32, < 34, and < 37 weeks, respectively).
Comment We found that positive FFN at 24 to 26 weeks of gestation was stronger than cervical length 25 mm as a predictor of early preterm birth in twin pregnancy, regardless of whether 17OHPc or placebo was given. We found no evidence to support the hypothesis that 17OHPc treatment modifies the value of FFN as a predictor of preterm birth in twins. American Journal of Perinatology
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That is, we found no significant interaction between 17OHPc and FFN. There are several key differences between our study and the previous report that suggested that 17OHPc might modify the predictive value of FFN.17 The prior report included only women with singleton pregnancies, all of whom had a history of prior preterm birth, whereas we included only women with twin pregnancies, a few of whom had a prior preterm birth. The prior report involved serial screening of FFN and cervical length at various gestational ages from 22 to 32 weeks of gestation, whereas we performed only a single screen at 24 to 26 weeks. In the prior report, 17OHPc was continued until 36 weeks of gestation, compared with 34 weeks in our trial. Perhaps the most important difference is that the prior study included only women who had 17OHPc treatment, whereas we included women who were treated and women who were not. Of course, an untreated control group is essential for any determination as to whether 17OHPc treatment has an effect on FFN test performance. Strengths of our study include the moderately large sample size, the capture of detailed demographic and outcome data, and the prospective design with FFN and cervical length screening specified in the protocol of a closely monitored trial. Other strength is the inclusion of only dichorionicdiamniotic twins, which removes chorionicity as a potential confounding factor. Limitations include the relatively small number of women with positive FFN (14 women) or cervical length 25 mm (18 women), which limits our statistical power. Specifically, we have inadequate power to stratify the results between
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Table 4 Predictors of preterm birth Predictor
N
Birth < 30 wk
Birth < 32 wk
Birth < 34 wk
Birth < 37 wk
OR (95% CI)
OR (95% CI)
OR (95% CI)
OR (95% CI)
Unadjusted, 17OHPc group
Positive FFN
10
12.3 (2.3–66.1)a
10.7 (2.4–46)a
5.3 (1.4–20.0)a
4.1 (0.50–33)
CL 25 mm
15
3.1 (0.6–16.8)
2.9 (0.7–12.0)
2.5 (0.8–8.1)
1.9 (0.5–7.0)
Prior PTB
19
3.6 (0.8–15.3)
3.2 (0.9–11.1)
2.1 (0.7–6.2)
2.4 (0.7–8.7)
Unadjusted, placebo group
Positive FFN
4
NC
31.5 (2.8–315)a
24.9 (2.3–272.7)a
1.9 (0.2–19.0)
CL 25 mm
3
NC
11.2 (0.78–160)
3.9 (0.3–47.7)
NC
Prior PTB
10
NC
2.4 (0.2–25.7)
0.6 (0.1–5.7)
0.7 (0.2–3.0)
Unadjusted, both groups
Positive FFN
14
18.0 (3.9–82.7)a
14.6 (4.2–51)b
8.1 (2.6–25.3)b
3.0 (0.7–14.1)
2.9 (1.0–8.3)
2.8 (0.79–10.1)
1.6 (0.6–4.0)
1.4 (0.6–3.2)
CL 25 mm Prior PTB
Adjusted, both groupsc
18 29
3.4 (0.6–17.6) 4.6 (1.3–17.0)
4.0 (1.2–13.0) a b
a
2.9 (1.0–8.8) 18.1 (3.3–99.2)
b
Positive FFN
11
55.0 (5.2–582)
3.9 (1.0–16.4)
1.4 (0.3–7.7)
CL 25 mm
16
0.1 (0.002–1.6)
0.6 (0.1–4.3)
1.3 (0.3–5.2)
3.1 (0.6–15.5)
Prior PTB
26
15.2 (2.3–99.8)a
3.8 (1.0–14.2)a
1.4 (0.5–4.1)
1.3 (0.5–3.3)
17OHPc vs. Placebo
122
7.8 (0.5–136.0)
1.4 (0.4–5.09)
1.3 (0.6–3.1)
1.9 (0.8–2.3)
Abbreviations: CI, confidence interval; CL, cervical length; FFN, fetal fibronectin; NC, not calculated, odds ratio not defined because of cell(s) with 0 observations; OR, odds ratio; PTB, preterm birth; 17OHPc, 17-hydroxyprogesterone caproate. a p < 0.05. b p < 0.001, otherwise not significant (p > 0.05). c Logistic regression, adjusted for four predictors shown, includes only patients who had both FFN and cervical length screening.
speculum versus blind-swab FFN techniques, based on lower “cutoff” values of cervical length (e.g., only 10 women had cervical length 20 mm), or based on individual centers. Another limitation is that some women were not screened, introducing the possibility of ascertainment bias. Even though we found no significant differences between those who were screened and those not screened (►Table 1), there may have been unknown differences between them that influenced the results. Another potential limitation is the lack of blinding of the cervical length measurements. It is possible that caregivers intervened in some way in response to the finding of a short cervix and that the intervention reduced the risk of preterm birth, thereby reducing or negating the predictive value of cervical length. However, we are unaware of any intervention that has been shown to reduce risk of preterm birth in twin pregnancy after a finding of short cervix. Vaginal micronized progesterone was not allowed in our protocol. Another limitation is the exclusion of monochorionic twins, which prevents us from making any conclusions about this group. A final limitation is inherent in the multicenter nature of the study. That is, there may have been between-center differences in the methods used for FFN collection, cervical length measurement, or other unknown factors. The principal reason why we included screening for FFN and cervical length in our trial was to explore whether the efficacy of 17OHPc might be better or worse in various subgroups based on screening results. The efficacy analysis, presented in ►Table 2, is tangential to the central thrust of the present report but is of interest nonetheless. Just as the overall trial found no effect of 17OHPc on the rate of preterm birth at any gestational age,18 we found no significant effect of 17OHPc on the rate of preterm birth in subgroups defined by cervical
length or FFN results. However, as implied by the relatively wide CIs in ►Table 2, our statistical power is limited in reaching a negative conclusion. Another trial of 17OHPc versus placebo for twins similarly found no effect of 17OHPc on the rate of preterm birth in the subgroup with a short cervix.23 Previous studies comparing cervical length and FFN as predictors of preterm birth have yielded contradictory results. In screening singleton pregnancies without symptoms of preterm labor, some studies have found that FFN is a stronger predictor of preterm birth12–15 and others have found that cervical length is a stronger predictor.24,25 Similar contradictions exist among studies of singleton pregnancies in which there are signs of preterm labor16,26–31 and among studies of asymptomatic twin pregnancies.32–37 In asymptomatic triplet pregnancies, cervical length and FFN were found to have similar test performance in predicting preterm birth.38 The reasons underlying these apparent contradictions are complex and likely include differences in patient selection (symptomatic vs. asymptomatic, singleton vs. multiple pregnancy, race/ethnicity, socioeconomic factors), gestational age at sampling, single-versus-serial measurements, end points (mean gestational age at delivery, various gestational age cutoffs, latency to delivery), study designs (evaluation of combined vs. sequential vs. contingent testing), and study quality. These and other issues have been extensively reviewed elsewhere.3,39 Our results do not imply that cervical length has no value in predicting preterm birth in twin pregnancy. In the univariable analysis, cervical length 25 mm was significantly associated with birth < 32 weeks, with an odds ratio of 4.0 (95% CI, 1.2–13.0). Further, cervical length 25 mm had a positive likelihood ratio between 2.55 and 3.31 for prediction American Journal of Perinatology
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Type of analysis, group
FFN versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy of preterm birth in every gestational age category studied (►Table 3). These values are similar to those reported in a recent meta-analysis of cervical length screening in asymptomatic twins pregnancies (cervical length 25 mm after 24 weeks of gestation had positive likelihood ratio 2.7, 2.3, and 1.8 for prediction of birth < 32, < 34, and < 37 weeks, respectively).40 Cervical length at 20 to 24 weeks may have better test performance (positive likelihood ratio 10.1, 9.0, and 4.4, respectively) than screening after 24 weeks.40 These results and our own suggest that cervical length may be useful if the FFN result is unknown, for example, because a valid FFN result cannot be obtained owing to recent intercourse, bleeding, pelvic examination, or transvaginal sonogram. Our results do suggest, however, that cervical length at 24 to 26 weeks of gestation adds little or nothing to the prediction of preterm birth in twin pregnancy if the FFN result is known. Twin pregnancies are at high risk of preterm birth, even the large majority with negative FFN and cervical length > 25 mm. In our series, these delivered at a mean gestational age of 35.8 weeks. This is comparable to a nationwide mean of 35.3 2.1 weeks among twins during the study period.41 Our results confirm some other studies in finding that positive FFN is stronger than cervical length as a predictor of early preterm birth in asymptomatic twin pregnancies,33,36 but this contradicts other studies.32,35 It will likely be impossible to reconcile the differences. For the time being, this is an academic question because, given the lack of a proven effective treatment after finding a short cervix or positive FFN in twin pregnancy, it is not currently recommended to screen asymptomatic twin pregnancies with these tests.4,5 This may change if future trials demonstrate that progestational agents or other interventions can reduce the risk of preterm birth in twin pregnancies complicated by short cervix or positive FFN. In that case, it may be important to know that 17OHPc treatment does not appear to substantially alter the predictive value of FFN.
Combs et al.
itan Hospital, San Jose, CA); Hugh Miller, MD, Diane Mercer, RN (Obstetrix Medical Group, Tucson Medical Center, Tucson, AZ); Cecilia Lyons, MD, Kenneth Chan, MD, James Kurtzman, MD, Christine Preslicka, RN, Marie McCann, LVN (Obstetrix Medical Group, Long Beach Memorial Medical Center, Long Beach, CA; Saddleback Memorial Medical Center, Laguna Hills, CA); David Luthy, MD, David Gorenberg, MD, Tina Lopez, RN, Dawn Artis, RN (Swedish Medical Center, Seattle, WA); Richard Porreco, MD, Greg Lindsay, MD, Kent Heyborne, MD, R. William Stettler, MD, Leslie Harden, PNNP, Maryanne Bruno, PNP, Gwen Dubois, RM, Marilyn Hall, CNM, Dian Lucero, PNNP (Obstetrix Medical Group, Presbyterian Saint Luke’s Hospital, Rose Medical Center, Denver, CO; Swedish Medical Center, Englewood, CO; Skyridge Medical Center, Lone Tree, CO); David Adair, MD, Lorrie Mason, NNP (Regional Obstetrical Consultants, Erlanger Medical Center, Chattanooga, TN); Manuel Porto, MD, Pamela Rumney, RNC (University of California Irvine Women’s Healthcare Group, Irvine, CA); Bannie Tabor, MD, Alaine McAfee, PNP, Mary Root, RN (Obstetrix Medical Group, Harris Methodist Fort Worth Hospital, Fort Worth, TX); George Lu, MD, Mary Jean Brown, RN (Obstetrix Medical Group, Saint Luke’s Hospital, Kansas City, MO); Neil Mandsager, MD, Amie Dawes, RN, Denise Cope, PNNP (Obstetrix Des Moines Perinatal Group, Mercy Medical Center, Des Moines, IA); Jon Rosnes, MD, Kristina Jones, RN (Obstetrix Medical Group, Baylor University Medical Center, Dallas, TX); Carolyn Kline, MD, Martin Walker, MD, Sally Ann deVitry Smith, RN (Obstetrix Medical Group, Evergreen Hospital, Kirkland, WA); and Donald Roberts, MD (University Perinatology, University Medical Center of Southern Nevada, Las Vegas, NV).
References 1 Martin JA, Hamilton BE, Ventura SJ, Osterman MJK, Wilson EC,
Acknowledgments The trial was funded by a research grant from the Center for Research, Education, and Quality, Mednax, Inc., Sunrise, FL. Fetal fibronectin test kits for this trial were donated by the manufacturer, Adeza Biomedical, Inc., Sunnyvale, CA. Dr. Combs, Dr. Garite, and Dr. Das have served on advisory boards for Hologic, Inc., Bedford, MA, which acquired Adeza in 2007, during the trial. Members of the Obstetrix Collaborative Research Network, in addition to the authors, were as follows: Alan Spitzer, MD, Sunrise, FL; James Thorp, MD, Pensacola, FL; Michael Gravett, MD, Seattle, WA; and Paul Meis, MD, Winston-Salem, NC (Data Safety and Monitoring Board, Center for Research, Education and Quality, Pediatrix Medical Group); Diana Abril, MS, CRM (Senior Clinical Coordinator, Gilbert, AZ); Richard Lee, MD, John Elliott, MD, Melissa Ingersoll, RN, Ana Bodea Braescu, MSN, MPH, RN (Obstetrix Medical Group, Phoenix Perinatal Associates, Banner Good Samaritan Hospital, Phoenix, AZ; Banner Desert Samaritan Hospital, Mesa, AZ); Kimberly Mallory, RN (Obstetrix Medical Group, Good SamarAmerican Journal of Perinatology
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gestation: relative risk of early preterm delivery. BJOG 2000; 107(10):1276–1281 McMahon KS, Neerhof MG, Haney EI, Thomas HA, Silver RK, Peaceman AM. Prematurity in multiple gestations: identification of patients who are at low risk. Am J Obstet Gynecol 2002;186(6): 1137–1141 Rizzo G, Capponi A, Arduini D, Lorido C, Romanini C. The value of fetal fibronectin in cervical and vaginal secretions and of ultrasonographic examination of the uterine cervix in predicting premature delivery for patients with preterm labor and intact membranes. Am J Obstet Gynecol 1996;175(5):1146–1151 Rozenberg P, Goffinet F, Malagrida L, et al. Evaluating the risk of preterm delivery: a comparison of fetal fibronectin and transvaginal ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1997;176(1, Pt 1):196–199 Gomez R, Romero R, Medina L, et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol 2005;192(2):350–359 Schmitz T, Maillard F, Bessard-Bacquaert S, et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labor. Am J Obstet Gynecol 2006;194(1):138–143 Tsoi E, Akmal S, Geerts L, Jeffery B, Nicolaides KH. Sonographic measurement of cervical length and fetal fibronectin testing in threatened preterm labor. Ultrasound Obstet Gynecol 2006;27(4): 368–372 Audibert F, Fortin S, Delvin E, et al. Contingent use of fetal fibronectin testing and cervical length measurement in women with preterm labour. J Obstet Gynaecol Can 2010;32(4):307–312 Goldenberg RL, Iams JD, Miodovnik M, et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The preterm prediction study: risk factors in twin gestations. Am J Obstet Gynecol 1996;175(4, Pt 1):1047–1053 Wennerholm U-B, Holm B, Mattsby-Baltzer I, et al. Fetal fibronectin, endotoxin, bacterial vaginosis and cervical length as predictors of preterm birth and neonatal morbidity in twin pregnancies. Br J Obstet Gynaecol 1997;104(12):1398–1404 Ruiz RJ, Fullerton J, Brown CEL. The utility of fFN for the prediction of preterm birth in twin gestations. J Obstet Gynecol Neonatal Nurs 2004;33(4):446–454 Gibson JL, Macara LM, Owen P, Young D, Macauley J, Mackenzie F. Prediction of preterm delivery in twin pregnancy: a prospective, observational study of cervical length and fetal fibronectin testing. Ultrasound Obstet Gynecol 2004;23(6):561–566 Fox NS, Saltzman DH, Klauser CK, Peress D, Gutierrez CV, Rebarber A. Prediction of spontaneous preterm birth in asymptomatic twin pregnancies with the use of combined fetal fibronectin and cervical length. Am J Obstet Gynecol 2009;201(3):313.e1–e5 DePlagne C, Maurice-Tison S, Coatleven F, Vandenbossche F, Horovitz J. Valeur predictive du couplage de la fibronectine a l’echographie du col chez les grossesses gemellaires. Gynecol Obstet Fertil 2013;41(5):289–296 Fox NS, Rebarber A, Roman AS, Klauser CK, Peress D, Saltzman DH. Combined fetal fibronectin and cervical length and spontaneous preterm birth in asymptomatic triplet pregnancies. J Matern Fetal Neonatal Med 2012;25(11):2308–2311 Smith V, Devane D, Begley CM, Clarke M, Higgins S. A systematic review and quality assessment of systematic reviews of fetal fibronectin and transvaginal length for predicting preterm birth. Eur J Obstet Gynecol Reprod Biol 2007;133(2):134–142 Conde-Agudelo A, Romero R, Hassan SS, Yeo L. Transvaginal sonographic cervical length for the prediction of spontaneous preterm birth in twin pregnancies: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203(2):128.e1––e12 Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Mathews TJ, Osterman MJ. Births: final data for 2008. Natl Vital Stat Rep 2010;59(1):1–73, 3–71 American Journal of Perinatology
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Fetal Fibronectin versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy with or without 17-Hydroxyprogesterone Caproate C. Andrew Combs, MD, PhD1,2 Thomas J. Garite, MD1,3 Obstetrix Collaborative Research Network
Sunrise, Florida 2 Obstetrix Medical Group, San Jose, California 3 Department of Obstetrics and Gynecology, University of California, Irvine, California 4 Axistat, Inc., San Francisco, California
Anita Das, PhD4
for the
Address for correspondence C. Andrew Combs, MD, PhD, Obstetrix Medical Group, 900 E Hamilton Avenue #220, Campbell, CA 95008 (e-mail: [email protected]).
Am J Perinatol 2014;31:1023–1030.
Abstract
Keywords
► ► ► ►
fetal fibronectin cervical length twin pregnancy 17hydroxyprogesterone caproate ► preterm birth prediction
Objective The objective of this study was to compare cervicovaginal fetal fibronectin (FFN) versus transvaginal sonographic cervical length as predictors of preterm birth in twin pregnancy and to test whether 17-hydroxyprogesterone caproate (17OHPc) modifies the predictive value of FFN. Study Design Secondary analysis of a randomized trial of 17OHPc versus placebo in dichorionic-diamniotic twins, analyzing the subset with screening FFN (N ¼ 198) and/or cervical length (N ¼ 214) at 24 to 26 weeks of gestation. Results Positive FFN was found in 7%, cervical length 25 mm in 8%, and both positive FFN and cervical length 25 mm in 3%. Birth < 32, < 34, and < 37 weeks occurred in 8, 30, and 67%, respectively. In logistic regression analysis controlling for FFN, cervical length, prior preterm birth, and treatment group, positive FFN was significantly associated with birth < 30 and < 32 weeks (odds ratio 55.0 [95% confidence interval 5.2–582], 18.1 [3.3– 99], respectively, p < 0.001 for both) but cervical length 25 mm was not (odds ratio 0.1 [0.002–1.6], 0.6 [0.1–4.3]). Conclusion Positive FFN was stronger than cervical length 25 mm in predicting early preterm birth in twins, regardless of 17OHPc use. Treatment with 17OHPc did not appear to alter the predictive value of FFN.
Preterm birth occurs in 12% of pregnancies in the United States1 and is a major cause of perinatal morbidity and mortality.2 Considerable effort has been devoted to study risk factors for preterm birth, in part because patients with certain risk factors may benefit from targeted interventions to reduce the rate of preterm birth.3 Two such risk factors are history of
preterm birth in a prior pregnancy or short cervical length in the current pregnancy. For women with a history of a prior preterm birth, prophylactic treatment with 17-hydroxyprogesterone caproate (17OHPc) is recommended4,5 because it may significantly reduce the recurrence risk of preterm birth.6 For women with a short cervix identified by transvaginal sonography,7,8 treatment with vaginal micronized
received September 16, 2013 accepted after revision January 2, 2014 published online February 24, 2014
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1370342. ISSN 0735-1631.
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1 The Center for Research, Education, and Quality, Mednax, Inc.,
Kimberly Maurel, MSN1
FFN versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy progesterone is recommended4,5 because it may significantly reduce the risk of early preterm birth.9–11 Detection of fetal fibronectin (FFN) in cervicovaginal secretions is another risk factor for preterm birth. Several studies have found that FFN positivity is more strongly predictive of preterm birth than cervical length,12–15 history of prior preterm birth,12,13,16 or other current pregnancy risk factors.12,14 In a systematic review of 22 candidate predictors, only three tests had a positive likelihood ratio 5 for prediction of spontaneous preterm birth in asymptomatic women: cervicovaginal FFN, cervicovaginal prolactin, and cervical length.3 A recent report17 compared the test performance of FFN versus cervical length in predicting preterm birth in women with a history of prior preterm birth, all of whom were receiving prophylactic 17OHPc. In that study, cervical length was strongly predictive of recurrent preterm birth, but FFN was not. The authors hypothesized that 17OHPc treatment might have diminished the predictive value of FFN by downregulating inflammatory pathways involved in cervical ripening and preterm birth. The purpose of the present investigation was to determine whether prophylactic 17OHPc treatment affects the test performance of screening FFN and/or cervical length in predicting preterm birth in asymptomatic twin pregnancies.
Materials and Methods This is a secondary analysis of a multicenter, double-blind, randomized clinical trial of prophylactic 17OHPc for women with twin pregnancy. Details of the trial were reported previously.18 Briefly, consenting women with uncomplicated dichorionic-diamniotic twin pregnancy were enrolled at 15 to 23 weeks of gestation and randomly assigned to receive a weekly intramuscular injection of either 17OHPc (250 mg in 1 mL castor oil) or an identical appearing placebo (1 mL castor oil), continued until 34 weeks of gestation. The randomization was in a 2-to-1 ratio of 17OHPc-to-placebo. The 17OHPc was manufactured using current good manufacturing practices19 as specified in an Investigational New Drug application. Institutional review board approval for the trial was obtained at each participating site. The trial found no difference between the 17OHPc group and the placebo group in the rate of composite neonatal morbidity (primary outcome) or gestational age at delivery (secondary outcome).18 The trial protocol included a scheduled office visit at 24 to 26 weeks of gestation to perform an FFN test and to measure cervical length by transvaginal sonography. The purpose of this screening, stated a priori, was to generate exploratory data to evaluate the hypothesis that 17OHPc might be more effective or less effective in subgroups of women defined by cervical length or FFN. The FFN specimen was obtained according to the manufacturer’s instructions (placement of a sterile polyester swab into the posterior vaginal fornix during speculum exam and rotating for 10 seconds, Adeza Biomedical, Sunnyvale, CA) or according to an established protocol for “blind” placement of the vaginal swab without a speculum,20,21 depending on each American Journal of Perinatology
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provider’s customary practice. The swab was placed immediately into transport media and analyzed using the manufacturer’s TLiIQ system. The instrumentation reports results as either positive ( 50 ng/mL) or negative (< 50 ng/mL) depending on the concentration of FFN in the sample. Caregivers did not have access to FFN results which were obtained solely for research purposes. The cervical length measurement was obtained via transvaginal sonography after collection of the FFN specimen. The data collection form captured only the length of the undilated cervical canal, known as the “functional cervical length.”22 The value of cervical length and any other sonographic findings were reported to each patient’s caregivers. For the present analysis, we consider a short cervix to be cervical length 25 mm, but we did not specify any “cutoffs” or normal ranges as part of the trial. The protocol did not specify any particular management in the event a short cervix was found because there is no evidence-based intervention to improve pregnancy outcome after finding a short cervix in twin pregnancy. The use of vaginal progesterone was not permitted by the protocol. Descriptive statistics (mean and standard deviation for continuous variables, and count and percentage for categorical variables) were calculated for baseline characteristics. Statistical significance was tested using the Wilcoxon ranksum test and Fisher exact test, respectively. In an efficacy analysis of 17OHPc versus placebo, the relative risks and 95% confidence intervals (CIs) of birth < 32, < 34, and < 37 weeks of gestation were calculated in subgroups defined by FFN (positive or negative) and cervical length ( 25 or > 25 mm) and tested for statistical significance using Fisher exact test. Test characteristics, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated for the prediction of preterm birth by a positive FFN or cervical length 25 mm. Unadjusted (univariable) odds ratios and 95% CI were calculated for FFN, cervical length 25 mm, and history of prior preterm birth in predicting birth < 30, < 32, < 34, and < 37 weeks of gestation. A logistic regression analysis was conducted using FFN, cervical length 25 mm, prior preterm birth, and treatment group (17OHPc vs. placebo) as predictors of birth < 30, < 32, < 34, and < 37 weeks. We also tested for an interaction between FFN and treatment group. The p values < 0.05 were considered significant.
Results A total of 240 women participated in the trial, 160 in the 17OHPc group and 80 in the placebo group. Cervical length screening was performed in 214 women (89%) and FFN screening in 198 (83%). As shown in ►Table 1, those who had cervical length or FFN screening were similar to those who did not have screening in terms of baseline characteristics such as age, parity, and history of prior preterm birth. They were evenly distributed among the treatment groups (17OHPc vs. placebo) and had similar gestational age at delivery. Positive FFN was found in 7% of those screened (14 of 198) and cervical length 25 mm was found in 8% (18 of 214).
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Table 1 Characteristics of women who did or did not have screening Fetal Fibronectin Screening Screened (N ¼ 198)
Not screened (N ¼ 42)
Cervical Length Screening p Value
a
Screened (N ¼ 214)
Not screened (N ¼ 26)
p Valuea
Gestational age at screening (wk)
25.1 1.0
NA
NA
24.9 0.9
NA
NA
Maternal age (y)
34.1 5.9
33.8 7.1
0.790
31.2 6.1
33.4 6.7
0.632
Parity
0.8 1.0
0.9 1.1
0.711
0.8 1.0
0.8 1.2
0.782
Nulliparous
99 (50%)
20/41 (49%)
1.00
108 (51%)
12 (48%)
0.836
Prior preterm birth
26 (13%)
3/41 (7%)
0.432
29 (14%)
0 (0%)
0.052
Randomized to 17OHPc
129 (65%)
31 (73%)
0.368
141 (66%)
19 (73%)
0.517
Randomized to placebo
69 (35%)
11 (26%)
0.368
73 (34%)
7 (27%)
0.517
Gestational age at delivery (wk)
35.5 2.7
35.5 2.4
0.573
35.6 2.4
34.9 2.6
0.147
Among the 198 screened with FFN, preterm birth < 32 weeks occurred in 15 (8%), < 35 weeks in 59 (30%), and < 37 weeks in 134 (67%). Among the 214 screened with cervical length, preterm birth < 32 weeks occurred in 17 (8%), < 35 weeks in 63 (29%), and < 37 weeks in 140 (65%). Among the 188 women who had both screens performed, the mean gestational age at delivery was 32.7 4.3 weeks with both positive FFN and cervical length 25 mm (N ¼ 6), 32.2 4.5 weeks with positive FFN and cervical length > 25 mm (N ¼ 5), 34.8 1.62 weeks with negative FFN and cervical length 25 mm (N ¼ 10), and 35.8 2.1 weeks with negative
FFN and cervical length 25 mm (N ¼ 167, p ¼ 0.009 for the trend across categories, Kruskal–Wallis test). An analysis of the efficacy of 17OHPc for prevention of preterm birth in subgroups of women defined by FFN or cervical length is presented in ►Table 2. There was no significant difference between the 17OHPc and placebo groups in the rate of preterm birth at any gestational age in any subgroup. ►Table 3 shows the test performance characteristics of FFN and cervical length for prediction of preterm birth at various gestational ages. FFN generally outperformed cervical
Table 2 Efficacy of 17-hydroxyprogesterone caproate for prevention of preterm birth 17OHPc group
Placebo group
RR (95% CI)
p Valuea
7/119 (6%)
2/65 (3%)
1.91 (0.41–8.94)
0.496
FFN-negative subgroup Birth < 32 wk Birth < 34 wk
19/119 (16%)
7/65 (11%)
1.48 (0.66–3.34)
0.383
Birth < 37 wk
82/119 (69%)
40/65 (62%)
1.12 (0.89–1.41)
0.331
Birth < 32 wk
4/10 (40%)
2/4 (50%)
0.80 (0.23–2.76)
1.00
Birth < 34 wk
5/10 (50%)
3/4 (75%)
0.67 (0.29–1.54)
0.580
Birth < 37 wk
9/10 (90%)
3/4 (75%)
1.20 (0.66–2.19)
0.506
Birth < 32 wk
10/126 (8%)
3/70 (4%)
1.85 (0.53–6.51)
0.386
Birth < 34 wk
21/126 (17%)
8/70 (11%)
1.46 (0.68–3.12)
0.403
Birth < 37 wk
86/126 (68%)
39/70 (56%)
1.23 (0.96–1.56)
0.090
Birth < 32 wk
3/15 (20%)
1/3 (33%)
0.60 (0.09–3.99)
1.00
Birth < 34 wk
5/15 (33%)
1/3 (33%)
1.00 (0.17–5.77)
1.00
Birth < 37 wk
12/15 (80%)
3/3 (100%)
0.80 (0.62–1.03)
1.00
FFN-positive subgroup
CL > 25 mm subgroup
CL 25 mm subgroup
Abbreviations: CI, confidence interval; CL, cervical length; FFN, fetal fibronectin; 17OHPc, 17-hydroxyprogesterone caproate; RR, relative risk. Note: Data are N (%) or relative risk (95% CI). a Fisher exact test. American Journal of Perinatology
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Abbreviations: NA, not applicable; 17OHPc, 17-hydroxyprogesterone caproate. Note: Data are mean SD or N (%). None of the p values are significant (p > 0.05). a Fisher exact test for categorical variables or Wilcoxon rank-sum test for continuous variables.
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Table 3 Test performance characteristics Sensitivity, % (95% CI)
Specificity, % (95% CI)
Positive predictive value, %(95% CI)
Negative predictive value, %(95% CI)
Positive likelihood ratio
Negative likelihood ratio
Prediction of birth < 30 wk FFN positive
50.0 (15.7–84.3)
94.7 (90.5–97.5)
28.6 (8.4–58.1)
97.8 (94.5–99.4)
9.43
0.53
CL 25 mm
22.2 (2.8–60.0)
92.2 (87.6–95.5)
11.1 (1.4–34.7)
96.4 (92.8–98.6)
2.85
0.84
Prediction of birth < 32 wk FFN positive
40.0 (16.3–67.7)
95.6 (91.6–98.1)
42.9 (17.7–71.1)
95.1 (90.9–97.7)
9.10
0.63
CL 25 mm
23.5 (6.8–49.9)
92.9 (88.4–96.1)
22.2 (6.4–47.6)
93.4 (88.9–96.4)
3.31
0.82
Prediction of birth < 34 wk FFN positive
23.5 (10.8–41.2)
96.3 (92.2–98.7)
57.1 (28.9–82.3)
85.9 (80.0–90.6)
6.35
0.79
CL 25 mm
17.1 (6.6–33.7)
93.3 (88.6–96.5)
33.3 (13.3–59.0)
85.2 (79.5–89.9)
2.55
0.89
Prediction of birth < 37 wk FFN positive
9.0 (4.7–15.1)
96.9 (89.2–99.6)
85.7 (57.2–98.2)
33.7 (26.9–41.0)
2.90
0.94
CL 25 mm
10.7 (6.1–17.1)
96.0 (88.6–99.2)
83.3 (58.6–96.4)
36.2 (29.5–43.4)
2.61
0.93
Abbreviations: CI, confidence interval; CL, cervix length; FFN, fetal fibronectin.
length in terms of superior sensitivity and positive likelihood ratios for predicting preterm birth at all gestational ages 34 weeks or less. ►Table 4 presents unadjusted (univariable) and adjusted (multivariable, logistic regression) analyses of various potential predictors for preterm birth, including FFN, cervical length, history of prior preterm birth, and treatment group (17OHPc or placebo). In the univariable analyses, positive FFN was more strongly associated with early preterm birth (higher odds ratios) than cervical length 25 mm, regardless of whether 17OHPc or placebo was given. The adjusted analysis shows that FFN was stronger than cervical length 25 mm as a predictor of early preterm birth. Indeed, after adjustment for the other variables, cervical length 25 mm had no significant association with preterm birth at any gestational age. Additional logistic regression models were tested that included the interaction of FFN with treatment group. However, we rejected these models because the interactions were far from statistical significance (p values of 0.963, 0.284, 0.248, and 0.671 for birth < 30, < 32, < 34, and < 37 weeks, respectively).
Comment We found that positive FFN at 24 to 26 weeks of gestation was stronger than cervical length 25 mm as a predictor of early preterm birth in twin pregnancy, regardless of whether 17OHPc or placebo was given. We found no evidence to support the hypothesis that 17OHPc treatment modifies the value of FFN as a predictor of preterm birth in twins. American Journal of Perinatology
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That is, we found no significant interaction between 17OHPc and FFN. There are several key differences between our study and the previous report that suggested that 17OHPc might modify the predictive value of FFN.17 The prior report included only women with singleton pregnancies, all of whom had a history of prior preterm birth, whereas we included only women with twin pregnancies, a few of whom had a prior preterm birth. The prior report involved serial screening of FFN and cervical length at various gestational ages from 22 to 32 weeks of gestation, whereas we performed only a single screen at 24 to 26 weeks. In the prior report, 17OHPc was continued until 36 weeks of gestation, compared with 34 weeks in our trial. Perhaps the most important difference is that the prior study included only women who had 17OHPc treatment, whereas we included women who were treated and women who were not. Of course, an untreated control group is essential for any determination as to whether 17OHPc treatment has an effect on FFN test performance. Strengths of our study include the moderately large sample size, the capture of detailed demographic and outcome data, and the prospective design with FFN and cervical length screening specified in the protocol of a closely monitored trial. Other strength is the inclusion of only dichorionicdiamniotic twins, which removes chorionicity as a potential confounding factor. Limitations include the relatively small number of women with positive FFN (14 women) or cervical length 25 mm (18 women), which limits our statistical power. Specifically, we have inadequate power to stratify the results between
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Table 4 Predictors of preterm birth Predictor
N
Birth < 30 wk
Birth < 32 wk
Birth < 34 wk
Birth < 37 wk
OR (95% CI)
OR (95% CI)
OR (95% CI)
OR (95% CI)
Unadjusted, 17OHPc group
Positive FFN
10
12.3 (2.3–66.1)a
10.7 (2.4–46)a
5.3 (1.4–20.0)a
4.1 (0.50–33)
CL 25 mm
15
3.1 (0.6–16.8)
2.9 (0.7–12.0)
2.5 (0.8–8.1)
1.9 (0.5–7.0)
Prior PTB
19
3.6 (0.8–15.3)
3.2 (0.9–11.1)
2.1 (0.7–6.2)
2.4 (0.7–8.7)
Unadjusted, placebo group
Positive FFN
4
NC
31.5 (2.8–315)a
24.9 (2.3–272.7)a
1.9 (0.2–19.0)
CL 25 mm
3
NC
11.2 (0.78–160)
3.9 (0.3–47.7)
NC
Prior PTB
10
NC
2.4 (0.2–25.7)
0.6 (0.1–5.7)
0.7 (0.2–3.0)
Unadjusted, both groups
Positive FFN
14
18.0 (3.9–82.7)a
14.6 (4.2–51)b
8.1 (2.6–25.3)b
3.0 (0.7–14.1)
2.9 (1.0–8.3)
2.8 (0.79–10.1)
1.6 (0.6–4.0)
1.4 (0.6–3.2)
CL 25 mm Prior PTB
Adjusted, both groupsc
18 29
3.4 (0.6–17.6) 4.6 (1.3–17.0)
4.0 (1.2–13.0) a b
a
2.9 (1.0–8.8) 18.1 (3.3–99.2)
b
Positive FFN
11
55.0 (5.2–582)
3.9 (1.0–16.4)
1.4 (0.3–7.7)
CL 25 mm
16
0.1 (0.002–1.6)
0.6 (0.1–4.3)
1.3 (0.3–5.2)
3.1 (0.6–15.5)
Prior PTB
26
15.2 (2.3–99.8)a
3.8 (1.0–14.2)a
1.4 (0.5–4.1)
1.3 (0.5–3.3)
17OHPc vs. Placebo
122
7.8 (0.5–136.0)
1.4 (0.4–5.09)
1.3 (0.6–3.1)
1.9 (0.8–2.3)
Abbreviations: CI, confidence interval; CL, cervical length; FFN, fetal fibronectin; NC, not calculated, odds ratio not defined because of cell(s) with 0 observations; OR, odds ratio; PTB, preterm birth; 17OHPc, 17-hydroxyprogesterone caproate. a p < 0.05. b p < 0.001, otherwise not significant (p > 0.05). c Logistic regression, adjusted for four predictors shown, includes only patients who had both FFN and cervical length screening.
speculum versus blind-swab FFN techniques, based on lower “cutoff” values of cervical length (e.g., only 10 women had cervical length 20 mm), or based on individual centers. Another limitation is that some women were not screened, introducing the possibility of ascertainment bias. Even though we found no significant differences between those who were screened and those not screened (►Table 1), there may have been unknown differences between them that influenced the results. Another potential limitation is the lack of blinding of the cervical length measurements. It is possible that caregivers intervened in some way in response to the finding of a short cervix and that the intervention reduced the risk of preterm birth, thereby reducing or negating the predictive value of cervical length. However, we are unaware of any intervention that has been shown to reduce risk of preterm birth in twin pregnancy after a finding of short cervix. Vaginal micronized progesterone was not allowed in our protocol. Another limitation is the exclusion of monochorionic twins, which prevents us from making any conclusions about this group. A final limitation is inherent in the multicenter nature of the study. That is, there may have been between-center differences in the methods used for FFN collection, cervical length measurement, or other unknown factors. The principal reason why we included screening for FFN and cervical length in our trial was to explore whether the efficacy of 17OHPc might be better or worse in various subgroups based on screening results. The efficacy analysis, presented in ►Table 2, is tangential to the central thrust of the present report but is of interest nonetheless. Just as the overall trial found no effect of 17OHPc on the rate of preterm birth at any gestational age,18 we found no significant effect of 17OHPc on the rate of preterm birth in subgroups defined by cervical
length or FFN results. However, as implied by the relatively wide CIs in ►Table 2, our statistical power is limited in reaching a negative conclusion. Another trial of 17OHPc versus placebo for twins similarly found no effect of 17OHPc on the rate of preterm birth in the subgroup with a short cervix.23 Previous studies comparing cervical length and FFN as predictors of preterm birth have yielded contradictory results. In screening singleton pregnancies without symptoms of preterm labor, some studies have found that FFN is a stronger predictor of preterm birth12–15 and others have found that cervical length is a stronger predictor.24,25 Similar contradictions exist among studies of singleton pregnancies in which there are signs of preterm labor16,26–31 and among studies of asymptomatic twin pregnancies.32–37 In asymptomatic triplet pregnancies, cervical length and FFN were found to have similar test performance in predicting preterm birth.38 The reasons underlying these apparent contradictions are complex and likely include differences in patient selection (symptomatic vs. asymptomatic, singleton vs. multiple pregnancy, race/ethnicity, socioeconomic factors), gestational age at sampling, single-versus-serial measurements, end points (mean gestational age at delivery, various gestational age cutoffs, latency to delivery), study designs (evaluation of combined vs. sequential vs. contingent testing), and study quality. These and other issues have been extensively reviewed elsewhere.3,39 Our results do not imply that cervical length has no value in predicting preterm birth in twin pregnancy. In the univariable analysis, cervical length 25 mm was significantly associated with birth < 32 weeks, with an odds ratio of 4.0 (95% CI, 1.2–13.0). Further, cervical length 25 mm had a positive likelihood ratio between 2.55 and 3.31 for prediction American Journal of Perinatology
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Type of analysis, group
FFN versus Cervical Length as Predictors of Preterm Birth in Twin Pregnancy of preterm birth in every gestational age category studied (►Table 3). These values are similar to those reported in a recent meta-analysis of cervical length screening in asymptomatic twins pregnancies (cervical length 25 mm after 24 weeks of gestation had positive likelihood ratio 2.7, 2.3, and 1.8 for prediction of birth < 32, < 34, and < 37 weeks, respectively).40 Cervical length at 20 to 24 weeks may have better test performance (positive likelihood ratio 10.1, 9.0, and 4.4, respectively) than screening after 24 weeks.40 These results and our own suggest that cervical length may be useful if the FFN result is unknown, for example, because a valid FFN result cannot be obtained owing to recent intercourse, bleeding, pelvic examination, or transvaginal sonogram. Our results do suggest, however, that cervical length at 24 to 26 weeks of gestation adds little or nothing to the prediction of preterm birth in twin pregnancy if the FFN result is known. Twin pregnancies are at high risk of preterm birth, even the large majority with negative FFN and cervical length > 25 mm. In our series, these delivered at a mean gestational age of 35.8 weeks. This is comparable to a nationwide mean of 35.3 2.1 weeks among twins during the study period.41 Our results confirm some other studies in finding that positive FFN is stronger than cervical length as a predictor of early preterm birth in asymptomatic twin pregnancies,33,36 but this contradicts other studies.32,35 It will likely be impossible to reconcile the differences. For the time being, this is an academic question because, given the lack of a proven effective treatment after finding a short cervix or positive FFN in twin pregnancy, it is not currently recommended to screen asymptomatic twin pregnancies with these tests.4,5 This may change if future trials demonstrate that progestational agents or other interventions can reduce the risk of preterm birth in twin pregnancies complicated by short cervix or positive FFN. In that case, it may be important to know that 17OHPc treatment does not appear to substantially alter the predictive value of FFN.
Combs et al.
itan Hospital, San Jose, CA); Hugh Miller, MD, Diane Mercer, RN (Obstetrix Medical Group, Tucson Medical Center, Tucson, AZ); Cecilia Lyons, MD, Kenneth Chan, MD, James Kurtzman, MD, Christine Preslicka, RN, Marie McCann, LVN (Obstetrix Medical Group, Long Beach Memorial Medical Center, Long Beach, CA; Saddleback Memorial Medical Center, Laguna Hills, CA); David Luthy, MD, David Gorenberg, MD, Tina Lopez, RN, Dawn Artis, RN (Swedish Medical Center, Seattle, WA); Richard Porreco, MD, Greg Lindsay, MD, Kent Heyborne, MD, R. William Stettler, MD, Leslie Harden, PNNP, Maryanne Bruno, PNP, Gwen Dubois, RM, Marilyn Hall, CNM, Dian Lucero, PNNP (Obstetrix Medical Group, Presbyterian Saint Luke’s Hospital, Rose Medical Center, Denver, CO; Swedish Medical Center, Englewood, CO; Skyridge Medical Center, Lone Tree, CO); David Adair, MD, Lorrie Mason, NNP (Regional Obstetrical Consultants, Erlanger Medical Center, Chattanooga, TN); Manuel Porto, MD, Pamela Rumney, RNC (University of California Irvine Women’s Healthcare Group, Irvine, CA); Bannie Tabor, MD, Alaine McAfee, PNP, Mary Root, RN (Obstetrix Medical Group, Harris Methodist Fort Worth Hospital, Fort Worth, TX); George Lu, MD, Mary Jean Brown, RN (Obstetrix Medical Group, Saint Luke’s Hospital, Kansas City, MO); Neil Mandsager, MD, Amie Dawes, RN, Denise Cope, PNNP (Obstetrix Des Moines Perinatal Group, Mercy Medical Center, Des Moines, IA); Jon Rosnes, MD, Kristina Jones, RN (Obstetrix Medical Group, Baylor University Medical Center, Dallas, TX); Carolyn Kline, MD, Martin Walker, MD, Sally Ann deVitry Smith, RN (Obstetrix Medical Group, Evergreen Hospital, Kirkland, WA); and Donald Roberts, MD (University Perinatology, University Medical Center of Southern Nevada, Las Vegas, NV).
References 1 Martin JA, Hamilton BE, Ventura SJ, Osterman MJK, Wilson EC,
Acknowledgments The trial was funded by a research grant from the Center for Research, Education, and Quality, Mednax, Inc., Sunrise, FL. Fetal fibronectin test kits for this trial were donated by the manufacturer, Adeza Biomedical, Inc., Sunnyvale, CA. Dr. Combs, Dr. Garite, and Dr. Das have served on advisory boards for Hologic, Inc., Bedford, MA, which acquired Adeza in 2007, during the trial. Members of the Obstetrix Collaborative Research Network, in addition to the authors, were as follows: Alan Spitzer, MD, Sunrise, FL; James Thorp, MD, Pensacola, FL; Michael Gravett, MD, Seattle, WA; and Paul Meis, MD, Winston-Salem, NC (Data Safety and Monitoring Board, Center for Research, Education and Quality, Pediatrix Medical Group); Diana Abril, MS, CRM (Senior Clinical Coordinator, Gilbert, AZ); Richard Lee, MD, John Elliott, MD, Melissa Ingersoll, RN, Ana Bodea Braescu, MSN, MPH, RN (Obstetrix Medical Group, Phoenix Perinatal Associates, Banner Good Samaritan Hospital, Phoenix, AZ; Banner Desert Samaritan Hospital, Mesa, AZ); Kimberly Mallory, RN (Obstetrix Medical Group, Good SamarAmerican Journal of Perinatology
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