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Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review
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Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review Emily A. DeFranco, DO, MS; David F. Lewis, MD, MBA; Anthony O. Odibo, MD, MSCE OBJECTIVE: Our objective was to systematically review the current
medical literature to assess the accuracy of the combination of fetal fibronectin (fFN) plus ultrasound assessment of cervical length (CL) as screening tools for preterm labor and prediction of preterm birth (PTB), and to compare this to the traditional clinical method of digital cervical examination. STUDY DESIGN: We searched PubMed and Cochrane databases without date restriction using the key words “fibronectin” and “cervical length,” limited to human studies published in English. In all, 85 studies were identified and supplemented by 1 additional study found through bibliographic search. RESULTS: Nine studies reported the association between fFN positivity
plus CL measurement with PTB in women presenting with symptomatic uterine contractions. We conducted an analytic review of the sensitivity, specificity, positive predictive value, and negative predictive value of
fFN plus CL for PTB. Further metaanalysis was not performed due to study heterogeneity, especially with respect to the range of gestational ages and variations in cutoff values for the diagnosis of short cervix. Although the clinical diagnostic methodology of preterm labor diagnosis by documenting uterine contractions plus cervical change is currently standard practice, a newer approach combining fFN and CL screening results in a higher sensitivity and positive predictive value for PTB risk while maintaining high negative predictive value. CONCLUSION: We conclude that this combined screening approach
yields useful information regarding short-term risks that can be used to guide acute management, and effectively identifies a population at low risk in whom expensive and potentially dangerous interventions could be avoided. Key words: cervical length, fetal fibronectin, prediction, premature labor, preterm birth, preterm labor
Cite this article as: DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. Am J Obstet Gynecol 2013;208:233.e1-6.
P
reterm birth (PTB) is a major public health burden, affecting ⬎12% of all births in the United States,1 the majority of which are attributable to spontaneous preterm labor. Despite efforts to reduce the prevalence of PTB, its rate continues to rise. Recent studies have demonstrated that administration of progestins to women at risk of PTB provides an effective reduction in the rate of its occurrence.2-5 Although these trials
provide hope for the identification of interventions that may ultimately reduce the overall rate of PTB in the United States, the at-risk populations identified as candidates for intervention comprise only a small proportion of the total number of cases of spontaneous preterm birth. It is estimated that of all cases of PTB, only 8.7%6 and 1.72.3%3,4 of women, respectively, have the risk factors of prior PTB or signif-
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, and the Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH (Dr DeFranco); the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, University of South Alabama, Mobile, AL (Dr Lewis); and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, Washington University in St. Louis, St. Louis, MO (Dr Odibo). Received Sept. 5, 2012; revised Nov. 19, 2012; accepted Dec. 5, 2012. The authors report no conflict of interest. Presented orally at the 79th annual meeting of the Central Association of Obstetricians and Gynecologists, Chicago, IL, Oct. 17-20, 2012 Reprints not available from the authors. 0002-9378/$36.00 • © 2013 Mosby, Inc. All rights reserved. • http://dx.doi.org/10.1016/j.ajog.2012.12.015
icant cervical shortening in the midtrimester and would benefit from prophylactic therapy. Spontaneous preterm labor comprises the majority of cases of PTB. Historically, prediction of spontaneous PTB has not been very successful using the classic criteria for the diagnosis of preterm labor of regular uterine contractions with concomitant cervical change. Using these criteria, ⬎70% of patients diagnosed and treated for preterm labor ultimately deliver at term.7 One of the limitations of any screening approach for preterm labor is that preterm labor is an intermediate diagnosis as there is no gold standard test considering that the ultimate outcome that would define true preterm labor is subsequent PTB. Recently, employment of biomarker results such as fetal fibronectin (fFN) in the diagnostic cascade of preterm labor has yielded sensitivity and specificity for the prediction of PTB of ⬎80%.8,9 Therefore, employ-
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FIGURE
Study inclusion flow diagram
PubMed and Cochrane keywords “fibronectin” and “cervical length” with limits human studies and English language
85 studies Exclude review articles on related topics n = 29
ment of these techniques in the evaluation of threatened preterm labor could ultimately lead to the avoidance of unnecessary interventions to women at low risk and, more importantly, implementation of therapy to those women most likely to deliver preterm. Our aim is to review the current medical literature to summarize the various published methods of fFN plus cervical length (CL) screening utilized to predict PTB risk. Furthermore, we will quantify the screening efficacy of fFN plus CL testing to predict PTB at various pregnancy endpoints.
M ATERIALS AND M ETHODS
Reviewed selected bibliographies to identify additional relevant studies, n=1
Data sources and study selection We searched PubMed and Cochrane databases without date criteria in October 2012 using the key words “fibronectin” and “cervical length” with restriction to English language and human studies. These search criteria yielded 85 studies. In all, 29 review articles were excluded, as were 6 articles on unrelated topics. Of the remaining 50 studies, 39 were excluded because they did not report the association between the combination of fFN and CL in symptomatic women and their association with PTB. A bibliographic review of selected articles was also performed to search for additional studies that may have been missed with the original search terms. One additional study was identified, yielding 12 total studies for review (Figure). Of these 12 studies, 7 reported sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) for PTB.8-14 Two studies provided sufficient data for these values to be calculated by one of the authors of this review (E.A.D.).15,16 The remaining 3 studies did not report sensitivity, spec-
9 studies remaining for final review
FFN, fetal fibronectin; NPV, negative predictive value; PPV, positive predictive value; PTB, preterm birth.
56 studies Exclude unrelated topics, Studies not related to preterm birth n=6 50 studies
Exclude studies not evaluating both fFN and cervical length together for PTB prediction in symptomatic patients, n = 39 Insufficient data to calculate PPV, NPV, sensitivity or specificity, n = 3
8 studies
DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
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TABLE 1
Overview of published studies reporting PTB risk associated with both fFN positivity and shortened cervix in symptomatic women
1
Sample size
Study
Design
Hincz et al,9 2002
Prospective cohort
82
Rozenberg et al,13 1997
Prospective cohort
76
Gomez et al,15 2005
Prospective cohort
215
Schmitz et al,14 2006
Prospective cohort
359
Eroglu et al,8 2007
Prospective cohort
51
Ness et al,16 2007
RCT
Asakura et al,10 2009
Retrospective cohort
Audibert et al,11 2010
Prospective cohort
Singletons or twins Singletons
Criteria for short cervix, mm 21-31
Outcome PTB
Overall rate of PTB
Screenⴙ rate of PTBa
PPV, %
NPV, %
Sensitivity, %
Specificity, %
ⱕ28 d
17.1% (ⱕ28 d) 25.6% (⬍37 wk)
63% (ⱕ28 d)
63b
97b
86b
90b
26.3% (⬍37 wk)
55%
................................................................................................................................................................................................................................................................................................................................................................................
2
Singletons
ⱕ26
⬍37 wk
52
84
55
82
................................................................................................................................................................................................................................................................................................................................................................................
3
Singletons
⬍15 ⬍30
⬍35 wk
16% (⬍35 wk)
81% (⬍35 wk) 47% (⬍35 wk)
81 47
89 91
38 53
98 89
35%
35
94
67
81
................................................................................................................................................................................................................................................................................................................................................................................
4
Singletons
16-30
⬍35 wk
13.4% (⬍35 wk)
................................................................................................................................................................................................................................................................................................................................................................................
5
Singletons
⬍20 ⬍25
ⱕ7 dc
⬍20
11.7% (⬍7 d) 19.6% (⬍35 wk)
—d
⬍37 wk ⬍34 wk
24.7% (⬍37 wk) 9.3% (⬍34 wk)
⬍37 wk ⬍34 wk
80 80
97.2 97.0
80 80
97.2 97.0
42.9% (⬍37 wk) 28.6% (⬍34 wk)
43 29
77 92
13 22
94 94
37% (⬍37 wk) 14.8% (⬍34 wk)
44.4% (⬍37 wk) 37% (⬍34 wk)
44 37
65 93
30 62
78 82
⬍37 wk ⬍34 wk ⱕ14 d
23% (⬍37 wk) 14% (⬍34 wk) 6% (ⱕ14 d)
54.2% (⬍37 wk) 39.1% (⬍34 wk) 12.5% (ⱕ14 d)
56 39 13
74 87 92
56 64 50
74 71 64
⬍37 wk ⬍14 d ⬍7 d
17% (⬍37 wk) 2.1% (⬍14 d) 0.7% (⬍7 d)
—d 0 0
— 0 0
— 97.8 99.3
— 0 0
— 96.4 96.4
................................................................................................................................................................................................................................................................................................................................................................................
6
100
Both
................................................................................................................................................................................................................................................................................................................................................................................
7
108
Both
⬍20
................................................................................................................................................................................................................................................................................................................................................................................
8
62
Both
⬍25
................................................................................................................................................................................................................................................................................................................................................................................
9
Rose et al,12 2010
Retrospective cohort
141
Both
16-29 ⱕ15
................................................................................................................................................................................................................................................................................................................................................................................
fFN, fetal fibronectin; NPV, negative predictive value; PPV, positive predictive value; PTB, preterm birth; RCT, randomized controlled trial. a
Combined screening with fFN and cervical length test positive; b Delivery ⱕ28 d; c Primary outcome PTB ⬍35 wk, but only sufficient data to calculate “n’s” from delivery within 7 d as outcome; d Data not reported.
DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
ificity, PPV, NPV, or sufficient data for these values to be calculated, therefore they were also excluded.17-19 Therefore, 9 studies were included in the final review (Table 1). Each of the 9 remaining studies was evaluated by 2 independent investigators (E.A.D. and D.F.L) for study quality. The QUADAS method,20 a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews, was utilized by each investigator to score the studies on several aspects of methodology deemed particularly relevant to this systematic review. We considered a study of high quality if it met 4 of 5 criteria chosen from the QUADAS tool: (1) Was the spectrum of patients representative of the patients who will receive the test in practice? (2) Were selection criteria clearly described? (3) Did the whole sample or a random selection of the sample receive verification using a reference standard of diagnosis? (4) Was the execution of the index and reference tests described in sufficient detail to permit their replication? (5) Were the same clin-
ical data available when test results were interpreted as would be available when the test is used in practice? Using these 5 criteria, all 9 of the studies included in this systematic review were considered high quality. We conducted an analytic review of the sensitivity, specificity, PPV, and NPV of fFN plus CL for PTB in symptomatic women from the 9 included studies. All 9 studies used the same definition of positive fFN (ⱖ50 ng/mL). The studies varied with respect to CL cutoff values used in combination with fFN to be considered test positive, and some reported screening efficacy with ⬎1 lower limit cutoff of CL. The most common definitions of short cervix were ⬍20 mm (3 studies),8,10,16 ⱕ26 mm (1 study),13 and ⬍25 mm (2 studies).8,11 One study reported screening efficacy with a low CL cutoff ⬍15 mm vs a higher cutoff of ⬍30 mm.15 Four others reported screening efficacy in a group of midrange CL: 21-31 mm,9 16-30 mm,11,14 and 16-29 mm.12 Four studies approached screening with fFN and CL in a 2-step contingent
approach where women with very short cervix were considered high risk, or test positive, and further screening with fFN was deferred. In these studies, women with midrange CL then underwent 2-step testing in which the midrange CL was followed by fFN testing, and if fFN was positive then the patient was considered test positive. In the other 5 studies that performed fFN plus CL screening in all women, a result of short CL (less than or within the defined threshold) plus positive fFN was considered test positive. All other results or combinations thereof in which both fFN and CL were obtained were considered test negative. The studies were similar regarding exclusion of patients from fFN and CL screening who presented with contractions and cervical dilation ⬎3 cm,8,11,12,14-16 and 1 excluded patients from screening if the cervical dilation was ⱖ2 cm upon presentation.13 There were 6 different PTB outcome variables with adequately reported screening efficacy to be included in this review. The various outcomes included PTB at
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TABLE 2
Rate of preterm birth in women presenting with symptoms of preterm labor between 18-35 weeks of gestation Variable
PTB rate (95% CI)
No.
No. of studies
Reference
⬍37 wk
30.2% (25.9–34.7)
127/421
5
9-11,13,16
⬍35 wk
16.2% (13.4–19.2)
101/625
3
⬍34 wk
14.6% (10.7–19.2)
39/267
3
ⱕ28 d
17.1% (10.2–26.4)
14/82
1
ⱕ14 d
4.4% (2.2–8.0)
9/203
2
⬍7 d
3.6% (1.6–7.1)
7/192
2
.............................................................................................................................................................................................................................................. 8,14,15 .............................................................................................................................................................................................................................................. 10,11,16 .............................................................................................................................................................................................................................................. 9 .............................................................................................................................................................................................................................................. 11,12 .............................................................................................................................................................................................................................................. 8,12 ..............................................................................................................................................................................................................................................
CI, confidence interval; PTB, preterm birth. DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
⬍37 weeks (4 studies),10,11,13,16 ⬍35 weeks (2 studies),14,15 and ⬍34 weeks (3 studies),10,11,16 and delivery in ⱕ28 days (1 study),9 ⱕ14 days (2 studies),11,12 and ⬍7 days (2 studies).8,12 Data from studies with similar outcome variables were combined to calculate pooled sensitivity and specificity, PPV and NPV, and positive and negative likelihood ratios with 95 percent confidence intervals (CIs). Analysis was performed using Stata SE10 (StataCorp, College Station, TX) and OpenEpi, version 2.3.21 Further metaanalysis was not performed due to heterogeneity in study designs, especially with respect to the range of gestational ages screened and variations in cutoff values for the diagnosis of short cervix.
R ESULTS Rate of PTB The rates of PTB in women presenting with symptomatic uterine contractions between 18-35 weeks of gestation are shown in Table 2. Five studies reported the rate of PTB in symptomatic women at ⬍37 weeks.9,10,11,13,16 The overall rate of PTB ⬍37 weeks in these studies was 30.2% (95% CI, 25.9 –34.7%). The rate of PTB within 28 days was 17.1% (95% CI, 10.2–26.4%), within 14 days was 4.4% (95% CI, 2.2– 8.0%),11,12 and within 7 days was 3.6% (95% CI, 1.6 –7.1%).8,12 Plurality and trial design Of the 9 included studies, 4 included both singleton and twin gestations.10-12,16 Of the total number of patients in these 4 233.e4
studies, few were twin gestations (3 of 100,16 13 of 108,10 7 of 62,11 and 1 not specified12). There were no apparent differences in screening test accuracy between the studies that included vs excluded twins. However, given the small number of twins included in these studies, extrapolation of the study’s findings to twin gestations alone should be cautioned.
Inclusion gestational ages The majority of the studies enrolled women with symptoms of preterm labor at gestational ages ranging from 22-35 weeks. One study enrolled women starting at an earlier gestational age, 18-34 weeks.14 The other 8 studies limited enrollment to similar gestational age ranges: 22–35 weeks,15 22–33 weeks,10 24 –35 weeks,8 and 24 –34 weeks for the remaining 5.9,11-13,16 The study that enrolled women at the earliest gestational ages did not appear to vary significantly in screening efficacy or PTB rate when compared to the others. The mean gestational age at enrollment for this study was 29 weeks. This is similar to the mean gestational age at enrollment of the other 8 studies (range, 28 –31.7 weeks). Despite the enrollment criteria allowance to enroll women with preterm labor symptoms as early as 18 weeks of gestation in the study by Schmitz et al,14 it is likely that patients enrolled in their study presented at similar gestational ages as those in the other studies. It is also likely that few, if any, were enrolled ⬍22-24 weeks, although these data are not available by review of the manuscript.
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One-step vs sequential testing approaches Five studies performed fFN and CL assessment of all women meeting study inclusion criteria, whereas the other 411,12,14,16 utilized a 2-step approach where women with very short CL were considered test positive and further screening with fFN was deferred. One study reported the result of both approaches, combined screening for all patients and a contingent approach of either fFN after midrange CL or CL assessment after negative fFN, however this study only presented sufficient data in the manuscript to include its reported sequential approach of CL measurement followed by contingent fFN testing in this review.11 In these studies women with midrange CL then underwent 2-step testing in which the midrange CL was followed by fFN testing. When screening efficacy between the 2 types of screening approaches is compared, the studies using a 2-step approach demonstrate similar specificity (range, 64 – 94%) and NPV (74 –98%) to that of the other 5 studies (81–98% and 84 –97%, respectively). The sensitivity (range, 13– 67%) and PPV (0 –56%) of the 2-step approach was lower, though, than those that performed both tests in all women (sensitivity range, 30 – 86%; PPV range, 37– 81%). Outcome definition Four studies provided data regarding screening efficacy for PTB prediction at ⬍37 weeks,10,11,13,16 2 at ⬍35 weeks,14,15 3 at ⬍34 weeks,10,11,16 1 at ⬍28 days,9 2 at ⱕ14 days,11,12 and 2 at ⬍7 days.8,12 Several of the studies provided screening efficacy data for ⬎1 outcome, or provided sufficient data for the screening efficacy to be calculated by the authors of this study. The studies reporting screening efficacy for the prediction of PTB at later gestational ages (⬍37 weeks) demonstrated lower sensitivity and positive likelihood ratio compared to those aimed to predict PTB at earlier gestational ages (34 and 35 weeks) (Table 3). The highest sensitivities were demonstrated by studies reporting PTB prediction in prescribed time intervals of ⬍7 or
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TABLE 3
Screening efficacy of fetal fibronectin plus cervical length for prediction of preterm birth Timing of birth
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
LRⴙ (95% CI)
LRⴚ (95% CI)
⬍37 wk10,11,13,16
36.8% (28.2–46.3)
83.0% (77.6–87.2)
49.4% (38.6–60.2)
74.4% (68.8–79.3)
2.2 (1.9–2.5)
0.8 (0.7–0.8)
⬍35 wk
48.0% (38.6–57.6)
95.2% (93.1–96.7)
66.2% (54.9–75.9)
90.4% (87.7–92.6)
10.1 (8.9–11.4)
0.5 (0.5–0.6)
⬍34 wk
53.8% (38.6–68.4)
84.3% (79.1–88.5)
36.8% (25.5–49.8)
91.5% (87.0–94.6)
3.4 (3.0–3.9)
0.5 (0.5–0.6)
ⱕ28 d
85.7% (60.1–96.0)
89.7% (80.2–94.9)
63.2% (41.0–80.8)
96.8% (89.1–99.1)
8.3 (6.1–11.3)
0.2 (0.1–0.4)
ⱕ14 d
33.3% (12.1–64.6)
86.0% (80.3–90.3)
10.3% (3.6–26.4)
96.4% (92.3–98.3)
2.4 (0.6–9.5)
0.8 (0.6–1.1)
⬍7 d
71.4% (35.9–91.8)
96.8% (93.1–98.5)
45.4% (21.3–72.0)
98.9% (96.1–99.7)
22.0 (13.6–35.7)
0.3 (0.1–0.8)
................................................................................................................................................................................................................................................................................................................................................................................ 14,15,a ................................................................................................................................................................................................................................................................................................................................................................................ 10,11,16 ................................................................................................................................................................................................................................................................................................................................................................................ 9 ................................................................................................................................................................................................................................................................................................................................................................................ 11,12 ................................................................................................................................................................................................................................................................................................................................................................................ 8,12 ................................................................................................................................................................................................................................................................................................................................................................................
CI, confidence interval; LR⫹, likelihood ratio of positive test; LR–, likelihood ratio of negative test; NPV, negative predictive value; PPV, positive predictive value. a
Data from both cervical length cutoff values of ⬍30 mm and ⬍15 mm included in calculations.
DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
⬍28 days when compared to those utilizing gestational age cutoffs of 34, 35, and 37 weeks. The pooled specificities were high for all included studies, regardless of outcome definition (specificity range, 83–97%).
C OMMENT PTB remains one of the most vexing complications of pregnancy. Despite significant efforts aimed toward its prevention, the rate of PTB continues to rise. Many tocolytic medications used to relax the uterus and treat preterm labor have been studied but have not demonstrated adequate efficacy to effectively prevent PTB or improve neonatal outcomes. Correct identification of women presenting with symptoms of preterm labor who will ultimately go on to deliver preterm has also been an obstetrical challenge. The classic criteria used to diagnose preterm labor, regular uterine contractions with cervical change documented by digital examination, has demonstrated limited PPV with ⬎70% of women diagnosed with preterm labor in some reports ultimately delivering at term.7 Similarly, in this review we found that 30.2% (95% CI, 25.9 –34.7) of women diagnosed by classic clinical criteria delivered preterm at ⬍37 weeks of gestation. The question of whether tocolytics could prove efficacious if a more reliable method of preterm labor diagnosis was available remains unanswered. Through this systematic review of published studies reporting the efficacy of the combination of fFN and ultra-
sound assessment of CL we conclude that this approach has a modest PPV for PTB at ⬍37 weeks of 49.4%, but higher than that of clinical diagnostic criteria alone. The sensitivity and positive likelihood for this combined screening approach is higher for predicting PTB risk within short periods of time (⬍7 days) and at earlier gestational ages (⬍28 weeks), when neonatal risks related to prematurity are highest. We found that the sensitivity of predicting PTB in short intervals of time, ⬍7 days from onset of diagnosis, is ⬎70%. Likewise, the NPV for delivery within this short time period is also very high, ⬎98%. Therefore, this combined screening approach not only yields useful information regarding short-term risks that can be used to guide acute management, but also effectively identifies a population at low risk in whom expensive and potentially dangerous interventions could be avoided. As evident in one trial comparing outcomes when the results of the screening test were made available,16 an approach combining knowledge of CL measurement and fFN results compared to management based on clinical criteria alone results in a significant reduction in PTB. This brings into question whether the efficacy of tocolytics for PTB prevention should be reevaluated using this approach to screen first for trial participants. The possibility that the obstetrical community has underestimated the effectiveness of tocolytic medications is now brought into question.
Although screening with fFN alone in women who present with symptoms of preterm labor may have a slightly higher sensitivity for early PTB ⬍34 weeks (50%)11 compared to a contingent approach (29%)16 or fully combined approach of fFN and CL (37%),10 the sensitivity of any of these approaches is modest. Maximizing specificity and NPV may provide the benefit of avoiding interventions such as unnecessary hospital admission, tocolysis, and steroid administration. Indeed, the specificity and NPV for early preterm delivery is highest with the fully combined approach of fFN and CL (93% and 82%, respectively)10 and the contingent approach (92% and 94%)16 compared to fFN screening alone (85% and 85%)11 or CL screening alone (58% and 87%).11 One study demonstrated that a combined screening approach using fFN and CL assessment in women who present with symptoms of preterm labor is cost-effective,12 likely related to shorter outpatient observation periods prior to discharge in those at low risk16 and lower frequency of inpatient admission for treatment of preterm labor.12 However, these studies do not address the issue related to cost and time involved in education and implementation of this new screening approach in centers that choose to change their clinical practice approach and begin to utilize CL screening more frequently on their labor and delivery units. In addition, screening accuracy of ultrasound measurement of CL in clinical practice may not be as robust as test accuracy re-
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CAOG Papers ported in clinical trials considering that the individuals performing the test in clinical trials may have more structured training and experience. The next step to incorporate this useful screening tool would be to use this combined screening approach of fFN and CL in future clinical trials involving patients with threatened preterm labor. These data summarized in this review suggest that utilization of this approach in clinical practice is not only cost-effective,12 but also helps to identify patients who could safely avoid hospital admission and treatment for preterm labor and might result in a reduced frequency of PTB.16 f REFERENCES 1. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2005. Natl Vital Stat Rep 2007;56:1-103. 2. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419-24. 3. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-9. 4. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011;38:18-31. 5. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-
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www.AJOG.org hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-85. 6. Odibo AO, Stamilio DM, Macones GA, Polsky D. 17Alpha-hydroxyprogesterone caproate for the prevention of preterm delivery: a costeffectiveness analysis. Obstet Gynecol 2006; 108:492-9. 7. Guinn DA, Goepfert AR, Owen J, Brumfield C, Hauth JC. Management options in women with preterm uterine contractions: a randomized clinical trial. Am J Obstet Gynecol 1997;177:814-8. 8. Eroglu D, Yanik F, Oktem M, Zeyneloglu HB, Kuscu E. Prediction of preterm delivery among women with threatened preterm labor. Gynecol Obstet Invest 2007;64:109-16. 9. Hincz P, Wilczynski J, Kozarzewski M, Szaflik K. Two-step test: the combined use of fetal fibronectin and sonographic examination of the uterine cervix for prediction of preterm delivery in symptomatic patients. Acta Obstet Gynecol Scand 2002;81:58-63. 10. Asakura H, Fukami T, Kurashina R, Tateyama N, Doi D, Takeshita T. Significance of cervical gland area in predicting preterm birth for patients with threatened preterm delivery: comparison with cervical length and fetal fibronectin. Gynecol Obstet Invest 2009;68:1-8. 11. Audibert F, Fortin S, Delvin E, et al. Contingent use of fetal fibronectin testing and cervical length measurement in women with preterm labor. J Obstet Gynaecol Can 2010;32:307-12. 12. Rose CH, McWeeney DT, Brost BC, Davies NP, Watson WJ. Cost-effective standardization of preterm labor evaluation. Am J Obstet Gynecol 2010;203:250.e1-5. 13. 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;176:196-9. 14. 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
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with preterm labor. Am J Obstet Gynecol 2006;194:138-43. 15. 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;192:350-9. 16. Ness A, Visintine J, Ricci E, Berghella V. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. Am J Obstet Gynecol 2007;197:426. e1-7. 17. Ben-Haroush A, Poran E, Yogev Y, Glezerman M. Vaginal fetal fibronectin evaluation before and immediately after ultrasonographic vaginal cervical length measurements in symptomatic women at risk of preterm birth: a pilot study. J Matern Fetal Neonatal Med 2010;23: 854-6. 18. 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;27:368-72. 19. Yoneyama K, Kimura A, Kogo M, Kiuchi Y, Morimoto T, Okai T. Clinical predictive factors for preterm birth in women with threatened preterm labor or preterm premature ruptured membranes? Aust N Z J Obstet Gynaecol 2009;49:16-21. 20. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol 2003;3:25. 21. Dean AG, Sullivan KM, Soe MM. OpenEpi: Open Source Epidemiologic Statistics for Public Health, version 2.3.1. Updated June 23, 2011. Available at: www.OpenEpi.com. Accessed Oct. 1, 2012.
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Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review Emily A. DeFranco, DO, MS; David F. Lewis, MD, MBA; Anthony O. Odibo, MD, MSCE OBJECTIVE: Our objective was to systematically review the current
medical literature to assess the accuracy of the combination of fetal fibronectin (fFN) plus ultrasound assessment of cervical length (CL) as screening tools for preterm labor and prediction of preterm birth (PTB), and to compare this to the traditional clinical method of digital cervical examination. STUDY DESIGN: We searched PubMed and Cochrane databases without date restriction using the key words “fibronectin” and “cervical length,” limited to human studies published in English. In all, 85 studies were identified and supplemented by 1 additional study found through bibliographic search. RESULTS: Nine studies reported the association between fFN positivity
plus CL measurement with PTB in women presenting with symptomatic uterine contractions. We conducted an analytic review of the sensitivity, specificity, positive predictive value, and negative predictive value of
fFN plus CL for PTB. Further metaanalysis was not performed due to study heterogeneity, especially with respect to the range of gestational ages and variations in cutoff values for the diagnosis of short cervix. Although the clinical diagnostic methodology of preterm labor diagnosis by documenting uterine contractions plus cervical change is currently standard practice, a newer approach combining fFN and CL screening results in a higher sensitivity and positive predictive value for PTB risk while maintaining high negative predictive value. CONCLUSION: We conclude that this combined screening approach
yields useful information regarding short-term risks that can be used to guide acute management, and effectively identifies a population at low risk in whom expensive and potentially dangerous interventions could be avoided. Key words: cervical length, fetal fibronectin, prediction, premature labor, preterm birth, preterm labor
Cite this article as: DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. Am J Obstet Gynecol 2013;208:233.e1-6.
P
reterm birth (PTB) is a major public health burden, affecting ⬎12% of all births in the United States,1 the majority of which are attributable to spontaneous preterm labor. Despite efforts to reduce the prevalence of PTB, its rate continues to rise. Recent studies have demonstrated that administration of progestins to women at risk of PTB provides an effective reduction in the rate of its occurrence.2-5 Although these trials
provide hope for the identification of interventions that may ultimately reduce the overall rate of PTB in the United States, the at-risk populations identified as candidates for intervention comprise only a small proportion of the total number of cases of spontaneous preterm birth. It is estimated that of all cases of PTB, only 8.7%6 and 1.72.3%3,4 of women, respectively, have the risk factors of prior PTB or signif-
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, and the Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH (Dr DeFranco); the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, University of South Alabama, Mobile, AL (Dr Lewis); and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, College of Medicine, Washington University in St. Louis, St. Louis, MO (Dr Odibo). Received Sept. 5, 2012; revised Nov. 19, 2012; accepted Dec. 5, 2012. The authors report no conflict of interest. Presented orally at the 79th annual meeting of the Central Association of Obstetricians and Gynecologists, Chicago, IL, Oct. 17-20, 2012 Reprints not available from the authors. 0002-9378/$36.00 • © 2013 Mosby, Inc. All rights reserved. • http://dx.doi.org/10.1016/j.ajog.2012.12.015
icant cervical shortening in the midtrimester and would benefit from prophylactic therapy. Spontaneous preterm labor comprises the majority of cases of PTB. Historically, prediction of spontaneous PTB has not been very successful using the classic criteria for the diagnosis of preterm labor of regular uterine contractions with concomitant cervical change. Using these criteria, ⬎70% of patients diagnosed and treated for preterm labor ultimately deliver at term.7 One of the limitations of any screening approach for preterm labor is that preterm labor is an intermediate diagnosis as there is no gold standard test considering that the ultimate outcome that would define true preterm labor is subsequent PTB. Recently, employment of biomarker results such as fetal fibronectin (fFN) in the diagnostic cascade of preterm labor has yielded sensitivity and specificity for the prediction of PTB of ⬎80%.8,9 Therefore, employ-
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FIGURE
Study inclusion flow diagram
PubMed and Cochrane keywords “fibronectin” and “cervical length” with limits human studies and English language
85 studies Exclude review articles on related topics n = 29
ment of these techniques in the evaluation of threatened preterm labor could ultimately lead to the avoidance of unnecessary interventions to women at low risk and, more importantly, implementation of therapy to those women most likely to deliver preterm. Our aim is to review the current medical literature to summarize the various published methods of fFN plus cervical length (CL) screening utilized to predict PTB risk. Furthermore, we will quantify the screening efficacy of fFN plus CL testing to predict PTB at various pregnancy endpoints.
M ATERIALS AND M ETHODS
Reviewed selected bibliographies to identify additional relevant studies, n=1
Data sources and study selection We searched PubMed and Cochrane databases without date criteria in October 2012 using the key words “fibronectin” and “cervical length” with restriction to English language and human studies. These search criteria yielded 85 studies. In all, 29 review articles were excluded, as were 6 articles on unrelated topics. Of the remaining 50 studies, 39 were excluded because they did not report the association between the combination of fFN and CL in symptomatic women and their association with PTB. A bibliographic review of selected articles was also performed to search for additional studies that may have been missed with the original search terms. One additional study was identified, yielding 12 total studies for review (Figure). Of these 12 studies, 7 reported sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) for PTB.8-14 Two studies provided sufficient data for these values to be calculated by one of the authors of this review (E.A.D.).15,16 The remaining 3 studies did not report sensitivity, spec-
9 studies remaining for final review
FFN, fetal fibronectin; NPV, negative predictive value; PPV, positive predictive value; PTB, preterm birth.
56 studies Exclude unrelated topics, Studies not related to preterm birth n=6 50 studies
Exclude studies not evaluating both fFN and cervical length together for PTB prediction in symptomatic patients, n = 39 Insufficient data to calculate PPV, NPV, sensitivity or specificity, n = 3
8 studies
DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
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TABLE 1
Overview of published studies reporting PTB risk associated with both fFN positivity and shortened cervix in symptomatic women
1
Sample size
Study
Design
Hincz et al,9 2002
Prospective cohort
82
Rozenberg et al,13 1997
Prospective cohort
76
Gomez et al,15 2005
Prospective cohort
215
Schmitz et al,14 2006
Prospective cohort
359
Eroglu et al,8 2007
Prospective cohort
51
Ness et al,16 2007
RCT
Asakura et al,10 2009
Retrospective cohort
Audibert et al,11 2010
Prospective cohort
Singletons or twins Singletons
Criteria for short cervix, mm 21-31
Outcome PTB
Overall rate of PTB
Screenⴙ rate of PTBa
PPV, %
NPV, %
Sensitivity, %
Specificity, %
ⱕ28 d
17.1% (ⱕ28 d) 25.6% (⬍37 wk)
63% (ⱕ28 d)
63b
97b
86b
90b
26.3% (⬍37 wk)
55%
................................................................................................................................................................................................................................................................................................................................................................................
2
Singletons
ⱕ26
⬍37 wk
52
84
55
82
................................................................................................................................................................................................................................................................................................................................................................................
3
Singletons
⬍15 ⬍30
⬍35 wk
16% (⬍35 wk)
81% (⬍35 wk) 47% (⬍35 wk)
81 47
89 91
38 53
98 89
35%
35
94
67
81
................................................................................................................................................................................................................................................................................................................................................................................
4
Singletons
16-30
⬍35 wk
13.4% (⬍35 wk)
................................................................................................................................................................................................................................................................................................................................................................................
5
Singletons
⬍20 ⬍25
ⱕ7 dc
⬍20
11.7% (⬍7 d) 19.6% (⬍35 wk)
—d
⬍37 wk ⬍34 wk
24.7% (⬍37 wk) 9.3% (⬍34 wk)
⬍37 wk ⬍34 wk
80 80
97.2 97.0
80 80
97.2 97.0
42.9% (⬍37 wk) 28.6% (⬍34 wk)
43 29
77 92
13 22
94 94
37% (⬍37 wk) 14.8% (⬍34 wk)
44.4% (⬍37 wk) 37% (⬍34 wk)
44 37
65 93
30 62
78 82
⬍37 wk ⬍34 wk ⱕ14 d
23% (⬍37 wk) 14% (⬍34 wk) 6% (ⱕ14 d)
54.2% (⬍37 wk) 39.1% (⬍34 wk) 12.5% (ⱕ14 d)
56 39 13
74 87 92
56 64 50
74 71 64
⬍37 wk ⬍14 d ⬍7 d
17% (⬍37 wk) 2.1% (⬍14 d) 0.7% (⬍7 d)
—d 0 0
— 0 0
— 97.8 99.3
— 0 0
— 96.4 96.4
................................................................................................................................................................................................................................................................................................................................................................................
6
100
Both
................................................................................................................................................................................................................................................................................................................................................................................
7
108
Both
⬍20
................................................................................................................................................................................................................................................................................................................................................................................
8
62
Both
⬍25
................................................................................................................................................................................................................................................................................................................................................................................
9
Rose et al,12 2010
Retrospective cohort
141
Both
16-29 ⱕ15
................................................................................................................................................................................................................................................................................................................................................................................
fFN, fetal fibronectin; NPV, negative predictive value; PPV, positive predictive value; PTB, preterm birth; RCT, randomized controlled trial. a
Combined screening with fFN and cervical length test positive; b Delivery ⱕ28 d; c Primary outcome PTB ⬍35 wk, but only sufficient data to calculate “n’s” from delivery within 7 d as outcome; d Data not reported.
DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
ificity, PPV, NPV, or sufficient data for these values to be calculated, therefore they were also excluded.17-19 Therefore, 9 studies were included in the final review (Table 1). Each of the 9 remaining studies was evaluated by 2 independent investigators (E.A.D. and D.F.L) for study quality. The QUADAS method,20 a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews, was utilized by each investigator to score the studies on several aspects of methodology deemed particularly relevant to this systematic review. We considered a study of high quality if it met 4 of 5 criteria chosen from the QUADAS tool: (1) Was the spectrum of patients representative of the patients who will receive the test in practice? (2) Were selection criteria clearly described? (3) Did the whole sample or a random selection of the sample receive verification using a reference standard of diagnosis? (4) Was the execution of the index and reference tests described in sufficient detail to permit their replication? (5) Were the same clin-
ical data available when test results were interpreted as would be available when the test is used in practice? Using these 5 criteria, all 9 of the studies included in this systematic review were considered high quality. We conducted an analytic review of the sensitivity, specificity, PPV, and NPV of fFN plus CL for PTB in symptomatic women from the 9 included studies. All 9 studies used the same definition of positive fFN (ⱖ50 ng/mL). The studies varied with respect to CL cutoff values used in combination with fFN to be considered test positive, and some reported screening efficacy with ⬎1 lower limit cutoff of CL. The most common definitions of short cervix were ⬍20 mm (3 studies),8,10,16 ⱕ26 mm (1 study),13 and ⬍25 mm (2 studies).8,11 One study reported screening efficacy with a low CL cutoff ⬍15 mm vs a higher cutoff of ⬍30 mm.15 Four others reported screening efficacy in a group of midrange CL: 21-31 mm,9 16-30 mm,11,14 and 16-29 mm.12 Four studies approached screening with fFN and CL in a 2-step contingent
approach where women with very short cervix were considered high risk, or test positive, and further screening with fFN was deferred. In these studies, women with midrange CL then underwent 2-step testing in which the midrange CL was followed by fFN testing, and if fFN was positive then the patient was considered test positive. In the other 5 studies that performed fFN plus CL screening in all women, a result of short CL (less than or within the defined threshold) plus positive fFN was considered test positive. All other results or combinations thereof in which both fFN and CL were obtained were considered test negative. The studies were similar regarding exclusion of patients from fFN and CL screening who presented with contractions and cervical dilation ⬎3 cm,8,11,12,14-16 and 1 excluded patients from screening if the cervical dilation was ⱖ2 cm upon presentation.13 There were 6 different PTB outcome variables with adequately reported screening efficacy to be included in this review. The various outcomes included PTB at
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TABLE 2
Rate of preterm birth in women presenting with symptoms of preterm labor between 18-35 weeks of gestation Variable
PTB rate (95% CI)
No.
No. of studies
Reference
⬍37 wk
30.2% (25.9–34.7)
127/421
5
9-11,13,16
⬍35 wk
16.2% (13.4–19.2)
101/625
3
⬍34 wk
14.6% (10.7–19.2)
39/267
3
ⱕ28 d
17.1% (10.2–26.4)
14/82
1
ⱕ14 d
4.4% (2.2–8.0)
9/203
2
⬍7 d
3.6% (1.6–7.1)
7/192
2
.............................................................................................................................................................................................................................................. 8,14,15 .............................................................................................................................................................................................................................................. 10,11,16 .............................................................................................................................................................................................................................................. 9 .............................................................................................................................................................................................................................................. 11,12 .............................................................................................................................................................................................................................................. 8,12 ..............................................................................................................................................................................................................................................
CI, confidence interval; PTB, preterm birth. DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
⬍37 weeks (4 studies),10,11,13,16 ⬍35 weeks (2 studies),14,15 and ⬍34 weeks (3 studies),10,11,16 and delivery in ⱕ28 days (1 study),9 ⱕ14 days (2 studies),11,12 and ⬍7 days (2 studies).8,12 Data from studies with similar outcome variables were combined to calculate pooled sensitivity and specificity, PPV and NPV, and positive and negative likelihood ratios with 95 percent confidence intervals (CIs). Analysis was performed using Stata SE10 (StataCorp, College Station, TX) and OpenEpi, version 2.3.21 Further metaanalysis was not performed due to heterogeneity in study designs, especially with respect to the range of gestational ages screened and variations in cutoff values for the diagnosis of short cervix.
R ESULTS Rate of PTB The rates of PTB in women presenting with symptomatic uterine contractions between 18-35 weeks of gestation are shown in Table 2. Five studies reported the rate of PTB in symptomatic women at ⬍37 weeks.9,10,11,13,16 The overall rate of PTB ⬍37 weeks in these studies was 30.2% (95% CI, 25.9 –34.7%). The rate of PTB within 28 days was 17.1% (95% CI, 10.2–26.4%), within 14 days was 4.4% (95% CI, 2.2– 8.0%),11,12 and within 7 days was 3.6% (95% CI, 1.6 –7.1%).8,12 Plurality and trial design Of the 9 included studies, 4 included both singleton and twin gestations.10-12,16 Of the total number of patients in these 4 233.e4
studies, few were twin gestations (3 of 100,16 13 of 108,10 7 of 62,11 and 1 not specified12). There were no apparent differences in screening test accuracy between the studies that included vs excluded twins. However, given the small number of twins included in these studies, extrapolation of the study’s findings to twin gestations alone should be cautioned.
Inclusion gestational ages The majority of the studies enrolled women with symptoms of preterm labor at gestational ages ranging from 22-35 weeks. One study enrolled women starting at an earlier gestational age, 18-34 weeks.14 The other 8 studies limited enrollment to similar gestational age ranges: 22–35 weeks,15 22–33 weeks,10 24 –35 weeks,8 and 24 –34 weeks for the remaining 5.9,11-13,16 The study that enrolled women at the earliest gestational ages did not appear to vary significantly in screening efficacy or PTB rate when compared to the others. The mean gestational age at enrollment for this study was 29 weeks. This is similar to the mean gestational age at enrollment of the other 8 studies (range, 28 –31.7 weeks). Despite the enrollment criteria allowance to enroll women with preterm labor symptoms as early as 18 weeks of gestation in the study by Schmitz et al,14 it is likely that patients enrolled in their study presented at similar gestational ages as those in the other studies. It is also likely that few, if any, were enrolled ⬍22-24 weeks, although these data are not available by review of the manuscript.
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One-step vs sequential testing approaches Five studies performed fFN and CL assessment of all women meeting study inclusion criteria, whereas the other 411,12,14,16 utilized a 2-step approach where women with very short CL were considered test positive and further screening with fFN was deferred. One study reported the result of both approaches, combined screening for all patients and a contingent approach of either fFN after midrange CL or CL assessment after negative fFN, however this study only presented sufficient data in the manuscript to include its reported sequential approach of CL measurement followed by contingent fFN testing in this review.11 In these studies women with midrange CL then underwent 2-step testing in which the midrange CL was followed by fFN testing. When screening efficacy between the 2 types of screening approaches is compared, the studies using a 2-step approach demonstrate similar specificity (range, 64 – 94%) and NPV (74 –98%) to that of the other 5 studies (81–98% and 84 –97%, respectively). The sensitivity (range, 13– 67%) and PPV (0 –56%) of the 2-step approach was lower, though, than those that performed both tests in all women (sensitivity range, 30 – 86%; PPV range, 37– 81%). Outcome definition Four studies provided data regarding screening efficacy for PTB prediction at ⬍37 weeks,10,11,13,16 2 at ⬍35 weeks,14,15 3 at ⬍34 weeks,10,11,16 1 at ⬍28 days,9 2 at ⱕ14 days,11,12 and 2 at ⬍7 days.8,12 Several of the studies provided screening efficacy data for ⬎1 outcome, or provided sufficient data for the screening efficacy to be calculated by the authors of this study. The studies reporting screening efficacy for the prediction of PTB at later gestational ages (⬍37 weeks) demonstrated lower sensitivity and positive likelihood ratio compared to those aimed to predict PTB at earlier gestational ages (34 and 35 weeks) (Table 3). The highest sensitivities were demonstrated by studies reporting PTB prediction in prescribed time intervals of ⬍7 or
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TABLE 3
Screening efficacy of fetal fibronectin plus cervical length for prediction of preterm birth Timing of birth
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
LRⴙ (95% CI)
LRⴚ (95% CI)
⬍37 wk10,11,13,16
36.8% (28.2–46.3)
83.0% (77.6–87.2)
49.4% (38.6–60.2)
74.4% (68.8–79.3)
2.2 (1.9–2.5)
0.8 (0.7–0.8)
⬍35 wk
48.0% (38.6–57.6)
95.2% (93.1–96.7)
66.2% (54.9–75.9)
90.4% (87.7–92.6)
10.1 (8.9–11.4)
0.5 (0.5–0.6)
⬍34 wk
53.8% (38.6–68.4)
84.3% (79.1–88.5)
36.8% (25.5–49.8)
91.5% (87.0–94.6)
3.4 (3.0–3.9)
0.5 (0.5–0.6)
ⱕ28 d
85.7% (60.1–96.0)
89.7% (80.2–94.9)
63.2% (41.0–80.8)
96.8% (89.1–99.1)
8.3 (6.1–11.3)
0.2 (0.1–0.4)
ⱕ14 d
33.3% (12.1–64.6)
86.0% (80.3–90.3)
10.3% (3.6–26.4)
96.4% (92.3–98.3)
2.4 (0.6–9.5)
0.8 (0.6–1.1)
⬍7 d
71.4% (35.9–91.8)
96.8% (93.1–98.5)
45.4% (21.3–72.0)
98.9% (96.1–99.7)
22.0 (13.6–35.7)
0.3 (0.1–0.8)
................................................................................................................................................................................................................................................................................................................................................................................ 14,15,a ................................................................................................................................................................................................................................................................................................................................................................................ 10,11,16 ................................................................................................................................................................................................................................................................................................................................................................................ 9 ................................................................................................................................................................................................................................................................................................................................................................................ 11,12 ................................................................................................................................................................................................................................................................................................................................................................................ 8,12 ................................................................................................................................................................................................................................................................................................................................................................................
CI, confidence interval; LR⫹, likelihood ratio of positive test; LR–, likelihood ratio of negative test; NPV, negative predictive value; PPV, positive predictive value. a
Data from both cervical length cutoff values of ⬍30 mm and ⬍15 mm included in calculations.
DeFranco. Combination of fFN and cervical length for preterm labor screening. Am J Obstet Gynecol 2013.
⬍28 days when compared to those utilizing gestational age cutoffs of 34, 35, and 37 weeks. The pooled specificities were high for all included studies, regardless of outcome definition (specificity range, 83–97%).
C OMMENT PTB remains one of the most vexing complications of pregnancy. Despite significant efforts aimed toward its prevention, the rate of PTB continues to rise. Many tocolytic medications used to relax the uterus and treat preterm labor have been studied but have not demonstrated adequate efficacy to effectively prevent PTB or improve neonatal outcomes. Correct identification of women presenting with symptoms of preterm labor who will ultimately go on to deliver preterm has also been an obstetrical challenge. The classic criteria used to diagnose preterm labor, regular uterine contractions with cervical change documented by digital examination, has demonstrated limited PPV with ⬎70% of women diagnosed with preterm labor in some reports ultimately delivering at term.7 Similarly, in this review we found that 30.2% (95% CI, 25.9 –34.7) of women diagnosed by classic clinical criteria delivered preterm at ⬍37 weeks of gestation. The question of whether tocolytics could prove efficacious if a more reliable method of preterm labor diagnosis was available remains unanswered. Through this systematic review of published studies reporting the efficacy of the combination of fFN and ultra-
sound assessment of CL we conclude that this approach has a modest PPV for PTB at ⬍37 weeks of 49.4%, but higher than that of clinical diagnostic criteria alone. The sensitivity and positive likelihood for this combined screening approach is higher for predicting PTB risk within short periods of time (⬍7 days) and at earlier gestational ages (⬍28 weeks), when neonatal risks related to prematurity are highest. We found that the sensitivity of predicting PTB in short intervals of time, ⬍7 days from onset of diagnosis, is ⬎70%. Likewise, the NPV for delivery within this short time period is also very high, ⬎98%. Therefore, this combined screening approach not only yields useful information regarding short-term risks that can be used to guide acute management, but also effectively identifies a population at low risk in whom expensive and potentially dangerous interventions could be avoided. As evident in one trial comparing outcomes when the results of the screening test were made available,16 an approach combining knowledge of CL measurement and fFN results compared to management based on clinical criteria alone results in a significant reduction in PTB. This brings into question whether the efficacy of tocolytics for PTB prevention should be reevaluated using this approach to screen first for trial participants. The possibility that the obstetrical community has underestimated the effectiveness of tocolytic medications is now brought into question.
Although screening with fFN alone in women who present with symptoms of preterm labor may have a slightly higher sensitivity for early PTB ⬍34 weeks (50%)11 compared to a contingent approach (29%)16 or fully combined approach of fFN and CL (37%),10 the sensitivity of any of these approaches is modest. Maximizing specificity and NPV may provide the benefit of avoiding interventions such as unnecessary hospital admission, tocolysis, and steroid administration. Indeed, the specificity and NPV for early preterm delivery is highest with the fully combined approach of fFN and CL (93% and 82%, respectively)10 and the contingent approach (92% and 94%)16 compared to fFN screening alone (85% and 85%)11 or CL screening alone (58% and 87%).11 One study demonstrated that a combined screening approach using fFN and CL assessment in women who present with symptoms of preterm labor is cost-effective,12 likely related to shorter outpatient observation periods prior to discharge in those at low risk16 and lower frequency of inpatient admission for treatment of preterm labor.12 However, these studies do not address the issue related to cost and time involved in education and implementation of this new screening approach in centers that choose to change their clinical practice approach and begin to utilize CL screening more frequently on their labor and delivery units. In addition, screening accuracy of ultrasound measurement of CL in clinical practice may not be as robust as test accuracy re-
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CAOG Papers ported in clinical trials considering that the individuals performing the test in clinical trials may have more structured training and experience. The next step to incorporate this useful screening tool would be to use this combined screening approach of fFN and CL in future clinical trials involving patients with threatened preterm labor. These data summarized in this review suggest that utilization of this approach in clinical practice is not only cost-effective,12 but also helps to identify patients who could safely avoid hospital admission and treatment for preterm labor and might result in a reduced frequency of PTB.16 f REFERENCES 1. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2005. Natl Vital Stat Rep 2007;56:1-103. 2. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419-24. 3. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-9. 4. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011;38:18-31. 5. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-
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