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Fetal fibronectin testing in patients with short cervix in the midtrimester: can it identify optimal candidates for ultrasound-indicated cerclage?
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OBSTETRICS
Fetal fibronectin testing in patients with short cervix in the midtrimester: can it identify optimal candidates for ultrasound-indicated cerclage? Sean M. Keeler, MD; Ashley S. Roman, MD, MPH; Jaclyn M. Coletta, MD; Daniel G. Kiefer, MD; Martin Feuerman, MS; Orion A. Rust, MD OBJECTIVE: The objective of the study was to determine the relation-
RESULTS: Spontaneous preterm birth prior to 35 weeks’ gestation oc-
ship between fetal fibronectin (fFN) testing prior to ultrasound-indicated cerclage and obstetric outcome.
curred in 15 (44.1%) fFN-positive-cerclage patients and 16 (55.2%) fFN-positive no-cerclage patients (P ⫽ .45). Similarly, it occurred in 16 (17.8%) fFN-negative cerclage patients and 11 (17%) fFN-no-cerclage patients (P ⫽ .99).
STUDY DESIGN: Singleton pregnancies between 18 and 24 weeks’
gestation with an ultrasound-diagnosed short cervix (⬍ 25 mm) and funneling (⬎ 25%) of the chorioamniotic membranes into the endocervical canal were analyzed. The fFN testing was performed and patients were randomized to cerclage or no-cerclage. Groups were stratified by fFN result. Cerclage patients were compared with no-cerclage patients. The primary outcome was delivery prior to 35 weeks’ gestation.
CONCLUSION: fFN did not identify optimal candidates for cerclage.
However, fFN testing before an ultrasound-indicated cerclage aids in counseling patients, anticipating the outcome of pregnancies complicated by cervical shortening. Key words: cerclage, fetal fibronectin, preterm birth, short cervix
Cite this article as: Keeler SM, Roman AS, Coletta JM, et al. Fetal fibronectin testing in patients with short cervix in the midtrimester: can it identify optimal candidates for ultrasound-indicated cerclage? Am J Obstet Gynecol 2009;200:158.e1-158.e6.
C
ervical cerclage remains a common treatment for an ultrasound-diagnosed short cervix despite data from randomized trials challenging its efficacy.1,2 Clinical efforts to identify patients at highest risk for preterm birth have been From the Department of Obstetrics and Gynecology, New York University Medical Center, New York, NY (Drs Keeler, Roman, and Coletta); the Department of Obstetrics, Gynecology, and Reproductive Medicine, Stony Brook University School of Medicine, Stony Brook, NY (Dr Kiefer); the Department of Academic Affairs, Winthrop University Hospital, Mineola, NY (Mr Feuerman); and the Department of Obstetrics and Gynecology, Lehigh Valley Hospital, Allentown, PA (Dr Rust). Received June 16, 2008; accepted Aug. 20, 2008. Reprints not available from the authors. 0002-9378/free © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.08.050
For Editors’ Commentary, see Table of Contents
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valuable; however, the lack of proven treatment modalities has challenged physicians caring for these patients. The combination of fetal fibronectin (fFN) and transvaginal sonography is an effective tool for early identification of patients at risk for preterm birth.3-7 However, the clinical value of both modalities lies in their negative predictive value. fFN is an extracellular matrix protein that functions as an adhesive glue at the choriodecidua junction.8 It is normally present in low concentrations in the vagina after 18 weeks’ gestation, and its presence has been a useful marker of a pathologic disruption of the maternalfetal interface.9 Cervical shortening has been described as a continuum in which multiple pathophysiologic processes convert a competent cervix into a distensible conduit that is incapable of retaining the conceptus.10 This pathophysiology makes a short cervix the anatomical manifestation of a final common pathway of the preterm parturition syndrome.11,12
American Journal of Obstetrics & Gynecology FEBRUARY 2009
Studies have validated the accuracy of fetal fibronectin testing in women after cerclage placement for predicting preterm birth.13 However, no studies to date have evaluated the value of fetal fibronectin testing prior to cerclage placement for short cervix (Medline search using key words “cerclage,” “fetal fibronectin,” “short cervix,” and “preterm birth”). We hypothesized that fFN-positive patients represent a subgroup with choriodecidual disruption and inflammation and therefore would not benefit from cerclage. The fFN-negative group excludes those patients with choriodecidual disruption in whom cerclage may be beneficial. In addition, we hypothesized that women who were fFN positive would have a higher risk of spontaneous preterm birth than fFN negative, regardless of intervention. The objective of this study was to determine the relationship between fFN testing prior to ultrasoundindicated cerclage and obstetric outcome.
M ATERIALS AND M ETHODS After institutional review board approval was obtained, the Lehigh Valley
Obstetrics
www.AJOG.org Hospital cerclage database was analyzed from April 1998 to July 2006. This database consists of patients randomized to various interventions for prevention of spontaneous preterm birth in women with a short cervix in the midtrimester (ie, cerclage, 17␣-hydroxyprogesterone caproate [17P], or no intervention). Our study cohort was composed of the following patients: 113 patients participated in previously published studies of cerclage vs no cerclage;12,14 64 patients participated in a randomized controlled trial of cerclage vs 17P;15 and the remaining 128 patients were enrolled in an ongoing study protocol of cerclage vs nocerclage. The outcomes data of these patients have not been previously reported in the literature. All asymptomatic, singleton pregnancies between 18 and 24 weeks’ gestation found to have sonographic evidence of premature dilatation of the internal os, a functional cervical length less than 25 mm, and prolapse of the chorioamniotic membranes into the endocervical canal were analyzed. These patients were stratified by their fFN status (positive/negative), and cerclage vs no-cerclage patients were compared. Patients receiving 17P were excluded from this analysis. The details of the Lehigh Valley Hospital standardized treatment protocol for patients with premature cervical shortening in the midtrimester have been previously reported.12 In brief, cervical length measurements were obtained using transvaginal sonography. The standardized technique included obtaining a sagittal image of the cervix with an empty bladder while the patient was in the dorsal lithotomy position. Four cervical measurements were obtained. These included the following measurements: (1) width of dilatation of the internal os, (2) depth of membrane prolapse into the endocervical canal (funnel), (3) distal cervical length, and (4) total cervical length. The distal cervical length was defined as the measured distance from the tip of the funnel to the external os along the closed endocervical canal. The total cervical length was defined as the measurement from the dilated internal os to the external os. These 4 measurements were repeated
after provocative maneuvers of transfundal and suprapubic pressure. The standardized treatment protocol for all patients included inpatient bed rest, education regarding signs and symptoms of preterm labor, an amniocentesis to exclude intraamniotic infection, a complete blood count, fFN sampling, urogenital cultures, and empiric treatment with indomethacin (100 mg oral loading dose and then 50 mg every 6 hours) and clindamycin (900 mg intravenous every 8 hours) for 48-72 hours. Fetal fibronectin testing was performed using speculum-directed sampling of the cervicovaginal secretions in the posterior vaginal fornix using a Dacron polyester swab. Tests were reported as positive or negative, with 50 ng/dL or greater signifying a positive test. The fFN sample was obtained at the time of randomization and at least 24 hours after the last vaginal exam. Consulting maternal-fetal medicine physicians were not blinded to fFN results. Fetal fibronectin results were not available until after randomization was complete. The fFN results did not alter the patients’ postcerclage surveillance protocol. Patients received transvaginal sonographic evaluation of their cervix every 1-2 weeks per study protocol. After this initial treatment period, all patients underwent transvaginal ultrasound to exclude rapidly progressing cervical shortening and prolapse of membranes beyond the external cervical os. Patients with evidence of chorioamnionitis diagnosed by amniotic fluid analysis or physical examination were excluded from randomization. Patients were or were not randomly assigned to cerclage. The cerclage group received a single-stitch McDonald cervical cerclage with 1-0 Prolene (Ethicon, Inc, Summerville, NJ) placed by a maternal-fetal medicine physician under regional anesthesia. The no-cerclage group was expectantly managed on modified bed rest. Cerclage was discontinued at 36 weeks’ gestation. Cerclage was removed earlier for the following clinical scenarios: rupture of membranes, preterm labor placing tension of the cerclage and refractory to tocolytic therapy, preterm labor with contraindications to tocolytic
Research
therapy, and clinical diagnosis of chorioamnionitis or abruptio placentae. Antepartum care was by standard obstetric practice. Additionally, rescue/revision arms were developed for the cerclage and nocerclage treatment groups. Patients in the cerclage group who demonstrated continued dilatation of the internal os with prolapse of the membranes beyond the level of the cerclage during the postcerclage surveillance protocol were offered a revision procedure. Patients in the no-cerclage group were offered a rescue procedure if they developed progressive prolapse of chorioamniotic membranes beyond the level of the external cervical os. No revision procedures were attempted greater than 24 weeks of gestation. The primary outcome of this study was spontaneous preterm birth prior to 35 weeks of gestation. Secondary outcomes included chorioamnionitis, abruptio placentae, preterm premature rupture of membranes, mean gestational age at delivery, days from enrollment to delivery, and prevalence of premature birth. Neonatal morbidity was stratified and analyzed by outcome: no morbidity was defined as no neonatal intensive care admission and routine newborn care; mild morbidity was defined as neonatal intensive care admission without severe morbidity; severe morbidity was defined as life-threatening morbidity, such as respiratory distress syndrome requiring mechanical ventilation greater than 24 hours, intraventricular hemorrhage, neonatal sepsis, or necrotizing enterocolitis. Perinatal death included any stillbirth or neonatal death during the study period. The baseline characteristics of the 2 groups (fFN positive vs fFN negative) were compared. These included maternal age, race, parity, insurance type, and gestational age at study entry. Risk factors for spontaneous preterm birth included prior second-trimester loss between 16 and 24 weeks of gestation; prior preterm birth between 24 and 36 weeks of gestation; earliest preterm birth; prior cervical surgery; width, depth, and proportion of prolapse of fetal membranes into the endocervical canal; total cervical
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Research
Obstetrics
www.AJOG.org come is not rare in this study (greater than 25% of the study population delivered prior to 35 weeks of gestation), we chose to utilize a recently developed method to adjust relative risks.16 This method is being used more commonly in the medical literature and has been implemented in statistical packages.17,18 Results were considered statistically significant at P ⬍ .05. All calculations were performed using SAS 9.3 for Windows (SAS Institute, Cary, NC).
FIGURE 1
Study distribution
R ESULTS
SPTB, spontaneous preterm birth. Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
length; and distal cervical length. Infectious risk factors included Chlamydia trachomatis, Neisseria gonorrhea, and Gardnerella vaginalis. Interval data were analyzed using a 1-way analysis of variance (ANOVA). If the data were not normally distributed, we utilized the nonparametric analogue of the ANOVA (ie, the Kruskal-Wallis test). Tukey’s pairwise multiple comparison test was used to determine the
sources of significance when the overall ANOVA was significant. Categorical data were analyzed using Fisher’s exact test. Kaplan-Meier curves were generated to compare gestational age at birth by fFN and cerclage status; comparison of curves was done by log-rank test. To control for differences in baseline characteristics—notably, distal cervical length at study entry—we performed a multivariate analysis. Because our out-
Of the 217 patients in our cohort, 63 patients were fFN positive and 154 were fFN negative (Figure 1). In the fFN-positive group, there were 34 cerclage patients and 29 no-cerclage patients. The fFN-negative group had 90 cerclage patients and 64 no-cerclage patients. The demographic characteristics of women who were fFN positive and fFN negative are presented in Table 1 with no difference between groups. When risk factors for spontaneous preterm birth were compared (Table 2), there was no difference in the number of prior second-trimester losses, previous spontaneous preterm births, or earliest gestation of previous preterm births observed between each group. Fetal fibronectin-positive cerclage patients were more likely to have a shorter cervix and deeper funnel.
TABLE 1
Baseline demographics fFN positive
fFN negative
Characteristic
Cerclage (n ⴝ 34)
No cerclage (n ⴝ 64)
Cerclage (n ⴝ 90)
No cerclage (n ⴝ 29)
P value
Age (y)
28.8 ⫾ 5.4
27.8 ⫾ 6.5
28.0 ⫾ 6.7
29.1 ⫾ 6.9
.71a
................................................................................................................................................................................................................................................................................................................................................................................ b
Race (%)
.33
.......................................................................................................................................................................................................................................................................................................................................................................
White
24/34 (70.6)
22/29 (75.9)
56/90 (62.2)
44/64 (68.8)
Hispanic
5/34 (14.7)
4/29 (13.8)
24/90 (26.7)
8/64 (12.5)
African American
3/34 (8.8)
3/29 (10.3)
9/90 (10.0)
9/64 (14.1)
Other
2/34 (5.9)
0/29 (0.0)
1/90 (0.01)
3/64 (4.7)
Private insurance (%)
20/34 (58.8)
19/29 (65.5)
57/90 (63.3)
41/64 (64.0)
.95
Multiparity (%)
19/34 (55.9)
19/29 (65.5)
53/90 (58.9)
40/64 (62.5)
.85
Gestational age at entry (wk)
20.9 ⫾ 1.8
21.4 ⫾ 2.0
20.8 ⫾ 1.9
21.4 ⫾ 1.8
.13
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a
b
Kruskal-Wallis test; Fisher’s exact test.
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Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
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TABLE 2
Risk factors for spontaneous preterm birth fFN positive Variable
Cerclage
fFN negative No cerclage
Cerclage
No cerclage
P value
Historical risk factors
....................................................................................................................................................................................................................................................................................................................................................................... a
Prior second-trimester loss 16-23 wk (%)
11/34 (32.4)
5/29 (17.2)
23/90 (25.6)
14/64 (21.9)
.52
Prior preterm birth 24-36 wk (%)
10/34 (29.4)
13/29 (44.8)
19/90 (21.1)
14/64 (21.9)
.06
Earliest preterm birth (wk ⫾ SD)
25.5 ⫾ 7.1
27.3 ⫾ 5.7
24.3 ⫾ 5.9
25.0 ⫾ 6.4
.43
Prior cervical surgery (%)
11/34 (32.4)
14/90 (15.6)
15/64 (23.4)
.19
....................................................................................................................................................................................................................................................................................................................................................................... a ....................................................................................................................................................................................................................................................................................................................................................................... b ....................................................................................................................................................................................................................................................................................................................................................................... a
5/29 (17.2)
................................................................................................................................................................................................................................................................................................................................................................................
Cervical ultrasound characteristics
....................................................................................................................................................................................................................................................................................................................................................................... c
Total cervical length (mm ⫾ SD)
37.0 ⫾ 9.0
35.0 ⫾ 9.0
29.9 ⫾ 11.0
31.9 ⫾ 8.0
.002
Distal cervical length (mm ⫾ SD)
12.0 ⫾ 8.0
15.0 ⫾ 7.0
17.8 ⫾ 7.0
18.9 ⫾ 6.0
.0002
Depth of funnel (mm ⫾ SD)
25.0 ⫾ 13.0
19.0 ⫾ 10.0
15.5 ⫾ 10.0
13.0 ⫾ 9.0
.0001
....................................................................................................................................................................................................................................................................................................................................................................... d ....................................................................................................................................................................................................................................................................................................................................................................... e ....................................................................................................................................................................................................................................................................................................................................................................... e
Proportion funneling (depth/total cervical length)
0.653 ⫾ 0.27
0.542 ⫾ 0.22
0.437 ⫾ 0.2
0.403 ⫾ 0.2
⬍ .0001
....................................................................................................................................................................................................................................................................................................................................................................... b
Width of funnel (mm ⫾ SD)
17.0 ⫾ 9.0
18.0 ⫾ 11.0
14.4 ⫾ 7.0
14.1 ⫾ 5.0
.32
Cervical length after cerclage (mm)
31.3 ⫾ 12.6
N/A
29.7 ⫾ 9.1
N/A
.45
....................................................................................................................................................................................................................................................................................................................................................................... f ................................................................................................................................................................................................................................................................................................................................................................................
Urogenital cultures
....................................................................................................................................................................................................................................................................................................................................................................... a
Bacterial vaginosis (%)
6/34 (17.6)
9/29 (31.0)
12/90 (13.3)
10/64 (15.6)
.17
C trachomatis (%)
0/34 (0.0)
1/29 (3.4)
1/90 (1.1)
0/64 (0.0)
0.40
0/34 (0.0)
0/29 (0.0)
1/90 (1.1)
1/64 (1.6)
....................................................................................................................................................................................................................................................................................................................................................................... a ....................................................................................................................................................................................................................................................................................................................................................................... a
N gonorrhea (%)
0.82
................................................................................................................................................................................................................................................................................................................................................................................ a
b
c
d
Fisher’s exact test; Kruskal-Wallis test; ANOVA, significant difference between fFN positive/cerclage vs fFN negative/cerclage and fFN negative/no-cerclage (Tukey test); Kruskal-Wallis, significant difference between fFN positive/cerclage vs fFN negative/cerclage and fFN negative/no-cerclage (Tukey test); e Kruskal-Wallis, significant difference between fFN positive/cerclage vs fFN negative/cerclage, and fFN positive/no-cerclage vs fFN negative/no-cerclage (Tukey test); f Unpaired t-test.
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Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
There was no difference in urogenital culture status of each patient. Of the patients who tested fFN positive, preterm birth prior to 35 weeks’ gestation occurred in 15 cerclage patients (44.1%) and 16 no-cerclage patients (55.2%; P ⫽ .45). Of patients who tested fFN negative, preterm birth prior to 35 weeks’ gestation occurred in 16 fFN cerclage patients (17.8%) and 11 fFN nocerclage patients (17%; P ⫽ .99). Pregnancy outcomes are summarized in Table 3. There was no difference in spontaneous preterm birth prior to 35 weeks of gestation in the fFN-negative group when cerclage was compared with no cerclage (P ⫽ .99). A similar finding was seen in the fFN-positive group as well (P ⫽ .45). Among patients who did not receive a cerclage, significantly more fFN-positive patients subsequently experienced evidence of abruption when compared with fFN-negative patients (20.7% vs 3.1%; P ⫽ .01).
Fetal fibronectin-positive patients were more likely to experience preterm premature rupture of the membranes; however, cerclage did not alter this outcome (17.7% vs 31.0%; P ⫽ .25). The constructed survival curve analyzing gestational age at birth shows fFN-positive patients delivered much earlier compared with fFN-negative patients (Figure 2). There is no significant difference (P ⫽ .37) between the 2 lower curves (cerclage vs no cerclage for fFN-positive patients). Also, there is no significant difference (P ⫽ .20) between the 2 upper curves (cerclage vs no cerclage for fFN-negative patients). Fetal fibronectin–positive patients delivered earlier across all gestational ages, regardless of whether a cerclage was placed. To control for differences in baseline characteristics, fFN status and distal cervical length were entered into the statistical model. Depth of funneling and proportion funneling were highly
correlated with each other and with distal cervical length. We chose to include distal cervical length, because this is likely the most reliably measured and easily interpretable in the clinical setting. Treatment (ie, cerclage vs no cerclage) was not an independent predictor of outcome and therefore did not enter the model. After adjusting for distal cervical length, fFN status remained an independent predictor of delivery prior to 35 weeks of gestation (adjusted relative risk, 2.20; 95% confidence interval, 1.39-3.47). The neonatal outcomes of both groups are summarized in Table 3. There were no differences between neonatal outcomes based on intervention (cerclage vs no cerclage) once stratified by fFN status. If the neonatal morbidity and mortality are ranked (0, no morbidity; 1, mild; 2, severe; and 3, death), the mean morbidity/mortality for fFN-positive patients was higher (0.824 for cerclage and 0.793
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TABLE 3
Obstetric outcome fFN positive Outcome
Cerclage
fFN negative No cerclage
P value
Chorioamnionitis
7/34 (20.6)
No cerclage 4/29 (13.8)
Cerclage 14/90 (15.6)
4/64 (6.3)
.19a
Abruptio placentae
2/34 (5.9)
6/29 (20.7)
7/90 (7.8)
2/64 (3.1)
.03
Preterm premature rupture of membranes
6/34 (17.6)
9/29 (31.0)
8/90 (8.9)
2/64 (3.1)
.0007
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ c ................................................................................................................................................................................................................................................................................................................................................................................ d
Gestational age at delivery
32.6 ⫾ 6.1
32.7 ⫾ 5.0
35.9 ⫾ 4.8
36.6 ⫾ 4.7
Days from enrollment to birth
82.8 ⫾ 42.4
79.1 ⫾ 39.9
105.7 ⫾ 34.8
104.9 ⫾ 32.5
⬍ .001
................................................................................................................................................................................................................................................................................................................................................................................ d
.0005
................................................................................................................................................................................................................................................................................................................................................................................
Preterm birth
....................................................................................................................................................................................................................................................................................................................................................................... e
⬍ 37 wk gestation
22/34 (64.7)
21/29 (72.4)
34/90 (37.8)
21/64 (32.8)
.0002
⬍ 35 wk gestation
15/34 (44.1)
16/29 (55.2)
16/90 (17.8)
11/64 (17.2)
⬍ .0001
⬍ 32 wk gestation
12/34 (35.3)
9/29 (31.0)
12/90 (13.3)
8/64 (12.5)
.007
⬍ 28 wk gestation
11/34 (32.3)
6/29 (20.7)
9/90 (10.0)
6/64 (9.4)
.007
....................................................................................................................................................................................................................................................................................................................................................................... e ....................................................................................................................................................................................................................................................................................................................................................................... e ....................................................................................................................................................................................................................................................................................................................................................................... e ................................................................................................................................................................................................................................................................................................................................................................................
Neonatal morbidity (%)
.......................................................................................................................................................................................................................................................................................................................................................................
None
21/34 (61.8)
14/29 (48.3)
73/90 (81.2)
52/64 (81.2)
Mild
4/34 (11.8)
9/29 (31.0)
5/90 (5.5)
6/64 (9.4)
Severe
3/34 (8.8)
4/29 (13.8)
7/90 (7.8)
3/64 (4.7)
Death
7/34 (20.6)
2/29 (6.9)
5/90 (5.6)
3/64 (4.7)
Mean morbidity
0.82
0.79
0.38
0.33
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... f
.024
................................................................................................................................................................................................................................................................................................................................................................................ a
Fisher’s exact test; b Fisher’s exact test, significant difference between fFN positive/no-cerclage vs fFN negative/no-cerclage; c Fisher’s exact test, significant difference between fFN positive/cerclage or no-cerclage vs fFN negative/cerclage or no-cerclage; d Kruskal-Wallis test, significant difference between fFN positive/cerclage or no-cerclage vs fFN negative/cerclage or no-cerclage (Tukey test); e Fisher’s exact test, significant difference between fFN positive/cerclage or no-cerclage vs fFN negative/cerclage or no-cerclage; f Kruskal-Wallis test, significant difference between fFN positive/no-cerclage vs either fFN negative group (Tukey test).
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Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
for no-cerclage) when compared with fFN-negative patients (0.378 for cerclage and 0.328 for no-cerclage). A total of 13 patients underwent a rescue/revision procedure during the study period: 4 fFN positive/cerclage, 1 fFN positive/no-cerclage, 5 fFN negative/cerclage, and 3 fFN negative/no-cerclage. Four of the 5 fFN-positive patients delivered at 23-24 weeks of gestation; all 4 infants died in the neonatal period. Chorioamnionitis or abruptio placentae occurred in 3 of these cases. Two of the 8 fFN-negative patients delivered at 24 weeks of gestation, 4 delivered between 29 and 36 weeks of gestation, and 1 delivered at term. Chorioamnionitis and abruptio placentae occurred in 3 of 8 of these cases.
C OMMENT Multiple biochemical pathways lead to spontaneous premature birth.19 Historically, clinicians have attempted to pre158.e5
vent prematurity by treating all at-risk patients with a common intervention (ie, progesterone or cerclage), with the hope that it would be successful. However, this carte blanche approach has proved ineffective, and pathway-specific treatment modalities may prove to be most effective in reducing spontaneous premature birth. Thus, there is a great need to identify effective individualized interventions for patients at highest risk for spontaneous preterm birth. We hypothesized that fetal fibronectin testing would identify a subgroup of women more likely to benefit from ultrasound-indicated cerclage. Our results, however, did not support this hypothesis and demonstrated no difference in the risk of preterm birth prior to 35 weeks of gestation. Fetal fibronectin testing did identify patients with asymptomatic cervical shortening on transvaginal ultrasound at highest risk of spontaneous preterm birth. When we compared fFN-
American Journal of Obstetrics & Gynecology FEBRUARY 2009
FIGURE 2
Pregnancy survival curve stratified by fFN status and cerclage use
Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
Obstetrics
www.AJOG.org negative and fFN-positive patients overall, with and without cerclage, fFNpositive patients delivered at significantly earlier gestational ages than fFN-negative patients. The strength of our study is that it is the first report of pregnancy outcome utilizing fFN prior to cerclage placement (Medline search using key words “cerclage,” “fetal fibronectin,” “short cervix,” and “preterm birth”). The KaplanMeier survival curve showed a pronounced divergence between fFNpositive and fFN-negative patients beginning at 24 weeks’ gestation, a time of highest neonatal morbidity and mortality. Testing for fFN before an ultrasound-indicated cerclage will be very helpful in counseling patients and, more importantly, anticipating the outcome of pregnancies complicated by cervical shortening. A limitation of this study is that it is a secondary analysis of data from randomized controlled trials and is thus subject to potential confounding. Also, subsequent treating physicians were not blinded to the fFN results after patient randomization, thus allowing for potential treatment bias (ie, more or less aggressive treatment based on the fFN status), which could affect outcome. We do not believe that the initial fFN led to a systematic bias for several reasons. First, consistent with product labeling, fFN testing prior to 24 weeks of gestation is not routinely performed at Lehigh Valley Hospital. Practitioners were aware that this result was obtained under a research protocol and there are few data on how to interpret fFN results in asymptomatic patients prior to 24 weeks. In addition, only 8 patients (4 fFN positive and 4 fFN negative) delivered within 2 weeks following fFN sampling, the time frame most often quoted in the literature during which fFN has its highest negative predictive value. Third, there were specific indications for cerclage removal in our study protocol. Patients who represented with signs or
symptoms of preterm labor were evaluated by standard obstetric practice. Additional cervical length measurements and fFN sampling were performed at the discretion of the primary obstetricians. Notably, a unique aspect of our study was that all patients had a negative amniocentesis to rule out an intraamniotic infection at study entry. There are several possible reasons that fFN was unable to identify a subpopulation of women with a short cervix who would benefit from cerclage therapy. First, surgical therapy for a short cervix may not convey pregnancy prolongation and reduce spontaneous premature birth regardless of the underlying pathophysiology. Additionally, fFN may not be the appropriate assay to evaluate candidates for an ultrasound-indicated cerclage. Perhaps additional assays involving cytokines or other biomarkers will f prove to be more beneficial.20 REFERENCES 1. Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women with short cervix found on transvaginal ultrasound examination: a randomized trial. Am J Obstet Gynecol 2004;191:1311-7. 2. To MS, Alfirevic Z, Heath VCF, et al. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004;363:1849-53. 3. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery: National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. N Engl J Med 1996;334:567-72. 4. Owen J, Yost N, Berghella V, et al. Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth. JAMA 2001;286:1340-8. 5. Goldenberg RL, Iams JD, Das D, et al. The preterm prediction study: sequential cervical length and fetal fibronectin testing for the prediction of spontaneous preterm birth. Am J Obstet Gynecol 2000;182:636-43. 6. Goldenberg RL, Mercer BM, Meis PJ, et al. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. Obstet Gynecol 1996;87:643-8. 7. Lockwood CJ, Senyei AE, Dische MR, et al. Fetal fibronectin in cervical and vaginal secre-
Research
tions as a predictor of preterm delivery. N Engl J Med 1991;325:669-74. 8. Feinberg RF, Kleiman HJ, Lockwood CJ. Is oncofetal fibronectin a trophoblast glue for human implantation? Am J Pathol 1991;138: 537-43. 9. Goldenberg RL, Klebanoff M, Carey JC, et al. Vaginal fetal fibronectin measurements from 8 to 22 weeks’ gestation and subsequent spontaneous preterm birth. Am J Obstet Gynecol 2000;183:469-75. 10. Iams JD, Johnson FF, Sonek J, Sachs L, Gebauer C, Samuels P. Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance. Am J Obstet Gynecol 1995;172:1097-106. 11. Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG 2007;113:17-42. 12. Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J. Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help. Am J Obstet Gynecol 2001;185:1098-105. 13. Roman AS, Rebarber A, Sfakianaki AK, et al. Vaginal fetal fibronectin as a predictor of spontaneous preterm delivery in the patient with cervical cerclage. Am J Obstet Gynecol 2003; 189:1368-73. 14. Rust OA, Atlas RO, Jones KJ, Benham BN, Balducci J. A randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os. Am J Obstet Gynecol 2000;183:830-5. 15. Rust O, Larkin R, Roberts W, et al. A randomized controlled trial of cerclage versus 17hydroxyprogesterone (17P) for the treatment of short cervix. Am J Obstet Gynecol 2007; 195:S112. 16. Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702-6. 17. Lindquist K. SAS FAQ: How to estimate relative risk in SAS using PROC GENMOD for common outcomes in cohort studies. Available at: http://www.ats.ucla.edu/stat/sas/faq/ relative_risk.htm. Accessed February 5, 2008. 18. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol 2005;162:199-200. 19. Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999; 27:5-20. 20. Saki M, Shiozaki A, Tabata M, et al. Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus. Am J Obstet Gynecol 2006; 194:14-9.
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OBSTETRICS
Fetal fibronectin testing in patients with short cervix in the midtrimester: can it identify optimal candidates for ultrasound-indicated cerclage? Sean M. Keeler, MD; Ashley S. Roman, MD, MPH; Jaclyn M. Coletta, MD; Daniel G. Kiefer, MD; Martin Feuerman, MS; Orion A. Rust, MD OBJECTIVE: The objective of the study was to determine the relation-
RESULTS: Spontaneous preterm birth prior to 35 weeks’ gestation oc-
ship between fetal fibronectin (fFN) testing prior to ultrasound-indicated cerclage and obstetric outcome.
curred in 15 (44.1%) fFN-positive-cerclage patients and 16 (55.2%) fFN-positive no-cerclage patients (P ⫽ .45). Similarly, it occurred in 16 (17.8%) fFN-negative cerclage patients and 11 (17%) fFN-no-cerclage patients (P ⫽ .99).
STUDY DESIGN: Singleton pregnancies between 18 and 24 weeks’
gestation with an ultrasound-diagnosed short cervix (⬍ 25 mm) and funneling (⬎ 25%) of the chorioamniotic membranes into the endocervical canal were analyzed. The fFN testing was performed and patients were randomized to cerclage or no-cerclage. Groups were stratified by fFN result. Cerclage patients were compared with no-cerclage patients. The primary outcome was delivery prior to 35 weeks’ gestation.
CONCLUSION: fFN did not identify optimal candidates for cerclage.
However, fFN testing before an ultrasound-indicated cerclage aids in counseling patients, anticipating the outcome of pregnancies complicated by cervical shortening. Key words: cerclage, fetal fibronectin, preterm birth, short cervix
Cite this article as: Keeler SM, Roman AS, Coletta JM, et al. Fetal fibronectin testing in patients with short cervix in the midtrimester: can it identify optimal candidates for ultrasound-indicated cerclage? Am J Obstet Gynecol 2009;200:158.e1-158.e6.
C
ervical cerclage remains a common treatment for an ultrasound-diagnosed short cervix despite data from randomized trials challenging its efficacy.1,2 Clinical efforts to identify patients at highest risk for preterm birth have been From the Department of Obstetrics and Gynecology, New York University Medical Center, New York, NY (Drs Keeler, Roman, and Coletta); the Department of Obstetrics, Gynecology, and Reproductive Medicine, Stony Brook University School of Medicine, Stony Brook, NY (Dr Kiefer); the Department of Academic Affairs, Winthrop University Hospital, Mineola, NY (Mr Feuerman); and the Department of Obstetrics and Gynecology, Lehigh Valley Hospital, Allentown, PA (Dr Rust). Received June 16, 2008; accepted Aug. 20, 2008. Reprints not available from the authors. 0002-9378/free © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.08.050
For Editors’ Commentary, see Table of Contents
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valuable; however, the lack of proven treatment modalities has challenged physicians caring for these patients. The combination of fetal fibronectin (fFN) and transvaginal sonography is an effective tool for early identification of patients at risk for preterm birth.3-7 However, the clinical value of both modalities lies in their negative predictive value. fFN is an extracellular matrix protein that functions as an adhesive glue at the choriodecidua junction.8 It is normally present in low concentrations in the vagina after 18 weeks’ gestation, and its presence has been a useful marker of a pathologic disruption of the maternalfetal interface.9 Cervical shortening has been described as a continuum in which multiple pathophysiologic processes convert a competent cervix into a distensible conduit that is incapable of retaining the conceptus.10 This pathophysiology makes a short cervix the anatomical manifestation of a final common pathway of the preterm parturition syndrome.11,12
American Journal of Obstetrics & Gynecology FEBRUARY 2009
Studies have validated the accuracy of fetal fibronectin testing in women after cerclage placement for predicting preterm birth.13 However, no studies to date have evaluated the value of fetal fibronectin testing prior to cerclage placement for short cervix (Medline search using key words “cerclage,” “fetal fibronectin,” “short cervix,” and “preterm birth”). We hypothesized that fFN-positive patients represent a subgroup with choriodecidual disruption and inflammation and therefore would not benefit from cerclage. The fFN-negative group excludes those patients with choriodecidual disruption in whom cerclage may be beneficial. In addition, we hypothesized that women who were fFN positive would have a higher risk of spontaneous preterm birth than fFN negative, regardless of intervention. The objective of this study was to determine the relationship between fFN testing prior to ultrasoundindicated cerclage and obstetric outcome.
M ATERIALS AND M ETHODS After institutional review board approval was obtained, the Lehigh Valley
Obstetrics
www.AJOG.org Hospital cerclage database was analyzed from April 1998 to July 2006. This database consists of patients randomized to various interventions for prevention of spontaneous preterm birth in women with a short cervix in the midtrimester (ie, cerclage, 17␣-hydroxyprogesterone caproate [17P], or no intervention). Our study cohort was composed of the following patients: 113 patients participated in previously published studies of cerclage vs no cerclage;12,14 64 patients participated in a randomized controlled trial of cerclage vs 17P;15 and the remaining 128 patients were enrolled in an ongoing study protocol of cerclage vs nocerclage. The outcomes data of these patients have not been previously reported in the literature. All asymptomatic, singleton pregnancies between 18 and 24 weeks’ gestation found to have sonographic evidence of premature dilatation of the internal os, a functional cervical length less than 25 mm, and prolapse of the chorioamniotic membranes into the endocervical canal were analyzed. These patients were stratified by their fFN status (positive/negative), and cerclage vs no-cerclage patients were compared. Patients receiving 17P were excluded from this analysis. The details of the Lehigh Valley Hospital standardized treatment protocol for patients with premature cervical shortening in the midtrimester have been previously reported.12 In brief, cervical length measurements were obtained using transvaginal sonography. The standardized technique included obtaining a sagittal image of the cervix with an empty bladder while the patient was in the dorsal lithotomy position. Four cervical measurements were obtained. These included the following measurements: (1) width of dilatation of the internal os, (2) depth of membrane prolapse into the endocervical canal (funnel), (3) distal cervical length, and (4) total cervical length. The distal cervical length was defined as the measured distance from the tip of the funnel to the external os along the closed endocervical canal. The total cervical length was defined as the measurement from the dilated internal os to the external os. These 4 measurements were repeated
after provocative maneuvers of transfundal and suprapubic pressure. The standardized treatment protocol for all patients included inpatient bed rest, education regarding signs and symptoms of preterm labor, an amniocentesis to exclude intraamniotic infection, a complete blood count, fFN sampling, urogenital cultures, and empiric treatment with indomethacin (100 mg oral loading dose and then 50 mg every 6 hours) and clindamycin (900 mg intravenous every 8 hours) for 48-72 hours. Fetal fibronectin testing was performed using speculum-directed sampling of the cervicovaginal secretions in the posterior vaginal fornix using a Dacron polyester swab. Tests were reported as positive or negative, with 50 ng/dL or greater signifying a positive test. The fFN sample was obtained at the time of randomization and at least 24 hours after the last vaginal exam. Consulting maternal-fetal medicine physicians were not blinded to fFN results. Fetal fibronectin results were not available until after randomization was complete. The fFN results did not alter the patients’ postcerclage surveillance protocol. Patients received transvaginal sonographic evaluation of their cervix every 1-2 weeks per study protocol. After this initial treatment period, all patients underwent transvaginal ultrasound to exclude rapidly progressing cervical shortening and prolapse of membranes beyond the external cervical os. Patients with evidence of chorioamnionitis diagnosed by amniotic fluid analysis or physical examination were excluded from randomization. Patients were or were not randomly assigned to cerclage. The cerclage group received a single-stitch McDonald cervical cerclage with 1-0 Prolene (Ethicon, Inc, Summerville, NJ) placed by a maternal-fetal medicine physician under regional anesthesia. The no-cerclage group was expectantly managed on modified bed rest. Cerclage was discontinued at 36 weeks’ gestation. Cerclage was removed earlier for the following clinical scenarios: rupture of membranes, preterm labor placing tension of the cerclage and refractory to tocolytic therapy, preterm labor with contraindications to tocolytic
Research
therapy, and clinical diagnosis of chorioamnionitis or abruptio placentae. Antepartum care was by standard obstetric practice. Additionally, rescue/revision arms were developed for the cerclage and nocerclage treatment groups. Patients in the cerclage group who demonstrated continued dilatation of the internal os with prolapse of the membranes beyond the level of the cerclage during the postcerclage surveillance protocol were offered a revision procedure. Patients in the no-cerclage group were offered a rescue procedure if they developed progressive prolapse of chorioamniotic membranes beyond the level of the external cervical os. No revision procedures were attempted greater than 24 weeks of gestation. The primary outcome of this study was spontaneous preterm birth prior to 35 weeks of gestation. Secondary outcomes included chorioamnionitis, abruptio placentae, preterm premature rupture of membranes, mean gestational age at delivery, days from enrollment to delivery, and prevalence of premature birth. Neonatal morbidity was stratified and analyzed by outcome: no morbidity was defined as no neonatal intensive care admission and routine newborn care; mild morbidity was defined as neonatal intensive care admission without severe morbidity; severe morbidity was defined as life-threatening morbidity, such as respiratory distress syndrome requiring mechanical ventilation greater than 24 hours, intraventricular hemorrhage, neonatal sepsis, or necrotizing enterocolitis. Perinatal death included any stillbirth or neonatal death during the study period. The baseline characteristics of the 2 groups (fFN positive vs fFN negative) were compared. These included maternal age, race, parity, insurance type, and gestational age at study entry. Risk factors for spontaneous preterm birth included prior second-trimester loss between 16 and 24 weeks of gestation; prior preterm birth between 24 and 36 weeks of gestation; earliest preterm birth; prior cervical surgery; width, depth, and proportion of prolapse of fetal membranes into the endocervical canal; total cervical
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www.AJOG.org come is not rare in this study (greater than 25% of the study population delivered prior to 35 weeks of gestation), we chose to utilize a recently developed method to adjust relative risks.16 This method is being used more commonly in the medical literature and has been implemented in statistical packages.17,18 Results were considered statistically significant at P ⬍ .05. All calculations were performed using SAS 9.3 for Windows (SAS Institute, Cary, NC).
FIGURE 1
Study distribution
R ESULTS
SPTB, spontaneous preterm birth. Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
length; and distal cervical length. Infectious risk factors included Chlamydia trachomatis, Neisseria gonorrhea, and Gardnerella vaginalis. Interval data were analyzed using a 1-way analysis of variance (ANOVA). If the data were not normally distributed, we utilized the nonparametric analogue of the ANOVA (ie, the Kruskal-Wallis test). Tukey’s pairwise multiple comparison test was used to determine the
sources of significance when the overall ANOVA was significant. Categorical data were analyzed using Fisher’s exact test. Kaplan-Meier curves were generated to compare gestational age at birth by fFN and cerclage status; comparison of curves was done by log-rank test. To control for differences in baseline characteristics—notably, distal cervical length at study entry—we performed a multivariate analysis. Because our out-
Of the 217 patients in our cohort, 63 patients were fFN positive and 154 were fFN negative (Figure 1). In the fFN-positive group, there were 34 cerclage patients and 29 no-cerclage patients. The fFN-negative group had 90 cerclage patients and 64 no-cerclage patients. The demographic characteristics of women who were fFN positive and fFN negative are presented in Table 1 with no difference between groups. When risk factors for spontaneous preterm birth were compared (Table 2), there was no difference in the number of prior second-trimester losses, previous spontaneous preterm births, or earliest gestation of previous preterm births observed between each group. Fetal fibronectin-positive cerclage patients were more likely to have a shorter cervix and deeper funnel.
TABLE 1
Baseline demographics fFN positive
fFN negative
Characteristic
Cerclage (n ⴝ 34)
No cerclage (n ⴝ 64)
Cerclage (n ⴝ 90)
No cerclage (n ⴝ 29)
P value
Age (y)
28.8 ⫾ 5.4
27.8 ⫾ 6.5
28.0 ⫾ 6.7
29.1 ⫾ 6.9
.71a
................................................................................................................................................................................................................................................................................................................................................................................ b
Race (%)
.33
.......................................................................................................................................................................................................................................................................................................................................................................
White
24/34 (70.6)
22/29 (75.9)
56/90 (62.2)
44/64 (68.8)
Hispanic
5/34 (14.7)
4/29 (13.8)
24/90 (26.7)
8/64 (12.5)
African American
3/34 (8.8)
3/29 (10.3)
9/90 (10.0)
9/64 (14.1)
Other
2/34 (5.9)
0/29 (0.0)
1/90 (0.01)
3/64 (4.7)
Private insurance (%)
20/34 (58.8)
19/29 (65.5)
57/90 (63.3)
41/64 (64.0)
.95
Multiparity (%)
19/34 (55.9)
19/29 (65.5)
53/90 (58.9)
40/64 (62.5)
.85
Gestational age at entry (wk)
20.9 ⫾ 1.8
21.4 ⫾ 2.0
20.8 ⫾ 1.9
21.4 ⫾ 1.8
.13
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a
b
Kruskal-Wallis test; Fisher’s exact test.
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Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
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TABLE 2
Risk factors for spontaneous preterm birth fFN positive Variable
Cerclage
fFN negative No cerclage
Cerclage
No cerclage
P value
Historical risk factors
....................................................................................................................................................................................................................................................................................................................................................................... a
Prior second-trimester loss 16-23 wk (%)
11/34 (32.4)
5/29 (17.2)
23/90 (25.6)
14/64 (21.9)
.52
Prior preterm birth 24-36 wk (%)
10/34 (29.4)
13/29 (44.8)
19/90 (21.1)
14/64 (21.9)
.06
Earliest preterm birth (wk ⫾ SD)
25.5 ⫾ 7.1
27.3 ⫾ 5.7
24.3 ⫾ 5.9
25.0 ⫾ 6.4
.43
Prior cervical surgery (%)
11/34 (32.4)
14/90 (15.6)
15/64 (23.4)
.19
....................................................................................................................................................................................................................................................................................................................................................................... a ....................................................................................................................................................................................................................................................................................................................................................................... b ....................................................................................................................................................................................................................................................................................................................................................................... a
5/29 (17.2)
................................................................................................................................................................................................................................................................................................................................................................................
Cervical ultrasound characteristics
....................................................................................................................................................................................................................................................................................................................................................................... c
Total cervical length (mm ⫾ SD)
37.0 ⫾ 9.0
35.0 ⫾ 9.0
29.9 ⫾ 11.0
31.9 ⫾ 8.0
.002
Distal cervical length (mm ⫾ SD)
12.0 ⫾ 8.0
15.0 ⫾ 7.0
17.8 ⫾ 7.0
18.9 ⫾ 6.0
.0002
Depth of funnel (mm ⫾ SD)
25.0 ⫾ 13.0
19.0 ⫾ 10.0
15.5 ⫾ 10.0
13.0 ⫾ 9.0
.0001
....................................................................................................................................................................................................................................................................................................................................................................... d ....................................................................................................................................................................................................................................................................................................................................................................... e ....................................................................................................................................................................................................................................................................................................................................................................... e
Proportion funneling (depth/total cervical length)
0.653 ⫾ 0.27
0.542 ⫾ 0.22
0.437 ⫾ 0.2
0.403 ⫾ 0.2
⬍ .0001
....................................................................................................................................................................................................................................................................................................................................................................... b
Width of funnel (mm ⫾ SD)
17.0 ⫾ 9.0
18.0 ⫾ 11.0
14.4 ⫾ 7.0
14.1 ⫾ 5.0
.32
Cervical length after cerclage (mm)
31.3 ⫾ 12.6
N/A
29.7 ⫾ 9.1
N/A
.45
....................................................................................................................................................................................................................................................................................................................................................................... f ................................................................................................................................................................................................................................................................................................................................................................................
Urogenital cultures
....................................................................................................................................................................................................................................................................................................................................................................... a
Bacterial vaginosis (%)
6/34 (17.6)
9/29 (31.0)
12/90 (13.3)
10/64 (15.6)
.17
C trachomatis (%)
0/34 (0.0)
1/29 (3.4)
1/90 (1.1)
0/64 (0.0)
0.40
0/34 (0.0)
0/29 (0.0)
1/90 (1.1)
1/64 (1.6)
....................................................................................................................................................................................................................................................................................................................................................................... a ....................................................................................................................................................................................................................................................................................................................................................................... a
N gonorrhea (%)
0.82
................................................................................................................................................................................................................................................................................................................................................................................ a
b
c
d
Fisher’s exact test; Kruskal-Wallis test; ANOVA, significant difference between fFN positive/cerclage vs fFN negative/cerclage and fFN negative/no-cerclage (Tukey test); Kruskal-Wallis, significant difference between fFN positive/cerclage vs fFN negative/cerclage and fFN negative/no-cerclage (Tukey test); e Kruskal-Wallis, significant difference between fFN positive/cerclage vs fFN negative/cerclage, and fFN positive/no-cerclage vs fFN negative/no-cerclage (Tukey test); f Unpaired t-test.
................................................................................................................................................................................................................................................................................................................................................................................
Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
There was no difference in urogenital culture status of each patient. Of the patients who tested fFN positive, preterm birth prior to 35 weeks’ gestation occurred in 15 cerclage patients (44.1%) and 16 no-cerclage patients (55.2%; P ⫽ .45). Of patients who tested fFN negative, preterm birth prior to 35 weeks’ gestation occurred in 16 fFN cerclage patients (17.8%) and 11 fFN nocerclage patients (17%; P ⫽ .99). Pregnancy outcomes are summarized in Table 3. There was no difference in spontaneous preterm birth prior to 35 weeks of gestation in the fFN-negative group when cerclage was compared with no cerclage (P ⫽ .99). A similar finding was seen in the fFN-positive group as well (P ⫽ .45). Among patients who did not receive a cerclage, significantly more fFN-positive patients subsequently experienced evidence of abruption when compared with fFN-negative patients (20.7% vs 3.1%; P ⫽ .01).
Fetal fibronectin-positive patients were more likely to experience preterm premature rupture of the membranes; however, cerclage did not alter this outcome (17.7% vs 31.0%; P ⫽ .25). The constructed survival curve analyzing gestational age at birth shows fFN-positive patients delivered much earlier compared with fFN-negative patients (Figure 2). There is no significant difference (P ⫽ .37) between the 2 lower curves (cerclage vs no cerclage for fFN-positive patients). Also, there is no significant difference (P ⫽ .20) between the 2 upper curves (cerclage vs no cerclage for fFN-negative patients). Fetal fibronectin–positive patients delivered earlier across all gestational ages, regardless of whether a cerclage was placed. To control for differences in baseline characteristics, fFN status and distal cervical length were entered into the statistical model. Depth of funneling and proportion funneling were highly
correlated with each other and with distal cervical length. We chose to include distal cervical length, because this is likely the most reliably measured and easily interpretable in the clinical setting. Treatment (ie, cerclage vs no cerclage) was not an independent predictor of outcome and therefore did not enter the model. After adjusting for distal cervical length, fFN status remained an independent predictor of delivery prior to 35 weeks of gestation (adjusted relative risk, 2.20; 95% confidence interval, 1.39-3.47). The neonatal outcomes of both groups are summarized in Table 3. There were no differences between neonatal outcomes based on intervention (cerclage vs no cerclage) once stratified by fFN status. If the neonatal morbidity and mortality are ranked (0, no morbidity; 1, mild; 2, severe; and 3, death), the mean morbidity/mortality for fFN-positive patients was higher (0.824 for cerclage and 0.793
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TABLE 3
Obstetric outcome fFN positive Outcome
Cerclage
fFN negative No cerclage
P value
Chorioamnionitis
7/34 (20.6)
No cerclage 4/29 (13.8)
Cerclage 14/90 (15.6)
4/64 (6.3)
.19a
Abruptio placentae
2/34 (5.9)
6/29 (20.7)
7/90 (7.8)
2/64 (3.1)
.03
Preterm premature rupture of membranes
6/34 (17.6)
9/29 (31.0)
8/90 (8.9)
2/64 (3.1)
.0007
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ c ................................................................................................................................................................................................................................................................................................................................................................................ d
Gestational age at delivery
32.6 ⫾ 6.1
32.7 ⫾ 5.0
35.9 ⫾ 4.8
36.6 ⫾ 4.7
Days from enrollment to birth
82.8 ⫾ 42.4
79.1 ⫾ 39.9
105.7 ⫾ 34.8
104.9 ⫾ 32.5
⬍ .001
................................................................................................................................................................................................................................................................................................................................................................................ d
.0005
................................................................................................................................................................................................................................................................................................................................................................................
Preterm birth
....................................................................................................................................................................................................................................................................................................................................................................... e
⬍ 37 wk gestation
22/34 (64.7)
21/29 (72.4)
34/90 (37.8)
21/64 (32.8)
.0002
⬍ 35 wk gestation
15/34 (44.1)
16/29 (55.2)
16/90 (17.8)
11/64 (17.2)
⬍ .0001
⬍ 32 wk gestation
12/34 (35.3)
9/29 (31.0)
12/90 (13.3)
8/64 (12.5)
.007
⬍ 28 wk gestation
11/34 (32.3)
6/29 (20.7)
9/90 (10.0)
6/64 (9.4)
.007
....................................................................................................................................................................................................................................................................................................................................................................... e ....................................................................................................................................................................................................................................................................................................................................................................... e ....................................................................................................................................................................................................................................................................................................................................................................... e ................................................................................................................................................................................................................................................................................................................................................................................
Neonatal morbidity (%)
.......................................................................................................................................................................................................................................................................................................................................................................
None
21/34 (61.8)
14/29 (48.3)
73/90 (81.2)
52/64 (81.2)
Mild
4/34 (11.8)
9/29 (31.0)
5/90 (5.5)
6/64 (9.4)
Severe
3/34 (8.8)
4/29 (13.8)
7/90 (7.8)
3/64 (4.7)
Death
7/34 (20.6)
2/29 (6.9)
5/90 (5.6)
3/64 (4.7)
Mean morbidity
0.82
0.79
0.38
0.33
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... f
.024
................................................................................................................................................................................................................................................................................................................................................................................ a
Fisher’s exact test; b Fisher’s exact test, significant difference between fFN positive/no-cerclage vs fFN negative/no-cerclage; c Fisher’s exact test, significant difference between fFN positive/cerclage or no-cerclage vs fFN negative/cerclage or no-cerclage; d Kruskal-Wallis test, significant difference between fFN positive/cerclage or no-cerclage vs fFN negative/cerclage or no-cerclage (Tukey test); e Fisher’s exact test, significant difference between fFN positive/cerclage or no-cerclage vs fFN negative/cerclage or no-cerclage; f Kruskal-Wallis test, significant difference between fFN positive/no-cerclage vs either fFN negative group (Tukey test).
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Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
for no-cerclage) when compared with fFN-negative patients (0.378 for cerclage and 0.328 for no-cerclage). A total of 13 patients underwent a rescue/revision procedure during the study period: 4 fFN positive/cerclage, 1 fFN positive/no-cerclage, 5 fFN negative/cerclage, and 3 fFN negative/no-cerclage. Four of the 5 fFN-positive patients delivered at 23-24 weeks of gestation; all 4 infants died in the neonatal period. Chorioamnionitis or abruptio placentae occurred in 3 of these cases. Two of the 8 fFN-negative patients delivered at 24 weeks of gestation, 4 delivered between 29 and 36 weeks of gestation, and 1 delivered at term. Chorioamnionitis and abruptio placentae occurred in 3 of 8 of these cases.
C OMMENT Multiple biochemical pathways lead to spontaneous premature birth.19 Historically, clinicians have attempted to pre158.e5
vent prematurity by treating all at-risk patients with a common intervention (ie, progesterone or cerclage), with the hope that it would be successful. However, this carte blanche approach has proved ineffective, and pathway-specific treatment modalities may prove to be most effective in reducing spontaneous premature birth. Thus, there is a great need to identify effective individualized interventions for patients at highest risk for spontaneous preterm birth. We hypothesized that fetal fibronectin testing would identify a subgroup of women more likely to benefit from ultrasound-indicated cerclage. Our results, however, did not support this hypothesis and demonstrated no difference in the risk of preterm birth prior to 35 weeks of gestation. Fetal fibronectin testing did identify patients with asymptomatic cervical shortening on transvaginal ultrasound at highest risk of spontaneous preterm birth. When we compared fFN-
American Journal of Obstetrics & Gynecology FEBRUARY 2009
FIGURE 2
Pregnancy survival curve stratified by fFN status and cerclage use
Keeler. Fetal fibronectin prior to cerclage. Am J Obstet Gynecol 2009.
Obstetrics
www.AJOG.org negative and fFN-positive patients overall, with and without cerclage, fFNpositive patients delivered at significantly earlier gestational ages than fFN-negative patients. The strength of our study is that it is the first report of pregnancy outcome utilizing fFN prior to cerclage placement (Medline search using key words “cerclage,” “fetal fibronectin,” “short cervix,” and “preterm birth”). The KaplanMeier survival curve showed a pronounced divergence between fFNpositive and fFN-negative patients beginning at 24 weeks’ gestation, a time of highest neonatal morbidity and mortality. Testing for fFN before an ultrasound-indicated cerclage will be very helpful in counseling patients and, more importantly, anticipating the outcome of pregnancies complicated by cervical shortening. A limitation of this study is that it is a secondary analysis of data from randomized controlled trials and is thus subject to potential confounding. Also, subsequent treating physicians were not blinded to the fFN results after patient randomization, thus allowing for potential treatment bias (ie, more or less aggressive treatment based on the fFN status), which could affect outcome. We do not believe that the initial fFN led to a systematic bias for several reasons. First, consistent with product labeling, fFN testing prior to 24 weeks of gestation is not routinely performed at Lehigh Valley Hospital. Practitioners were aware that this result was obtained under a research protocol and there are few data on how to interpret fFN results in asymptomatic patients prior to 24 weeks. In addition, only 8 patients (4 fFN positive and 4 fFN negative) delivered within 2 weeks following fFN sampling, the time frame most often quoted in the literature during which fFN has its highest negative predictive value. Third, there were specific indications for cerclage removal in our study protocol. Patients who represented with signs or
symptoms of preterm labor were evaluated by standard obstetric practice. Additional cervical length measurements and fFN sampling were performed at the discretion of the primary obstetricians. Notably, a unique aspect of our study was that all patients had a negative amniocentesis to rule out an intraamniotic infection at study entry. There are several possible reasons that fFN was unable to identify a subpopulation of women with a short cervix who would benefit from cerclage therapy. First, surgical therapy for a short cervix may not convey pregnancy prolongation and reduce spontaneous premature birth regardless of the underlying pathophysiology. Additionally, fFN may not be the appropriate assay to evaluate candidates for an ultrasound-indicated cerclage. Perhaps additional assays involving cytokines or other biomarkers will f prove to be more beneficial.20 REFERENCES 1. Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women with short cervix found on transvaginal ultrasound examination: a randomized trial. Am J Obstet Gynecol 2004;191:1311-7. 2. To MS, Alfirevic Z, Heath VCF, et al. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004;363:1849-53. 3. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery: National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. N Engl J Med 1996;334:567-72. 4. Owen J, Yost N, Berghella V, et al. Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth. JAMA 2001;286:1340-8. 5. Goldenberg RL, Iams JD, Das D, et al. The preterm prediction study: sequential cervical length and fetal fibronectin testing for the prediction of spontaneous preterm birth. Am J Obstet Gynecol 2000;182:636-43. 6. Goldenberg RL, Mercer BM, Meis PJ, et al. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. Obstet Gynecol 1996;87:643-8. 7. Lockwood CJ, Senyei AE, Dische MR, et al. Fetal fibronectin in cervical and vaginal secre-
Research
tions as a predictor of preterm delivery. N Engl J Med 1991;325:669-74. 8. Feinberg RF, Kleiman HJ, Lockwood CJ. Is oncofetal fibronectin a trophoblast glue for human implantation? Am J Pathol 1991;138: 537-43. 9. Goldenberg RL, Klebanoff M, Carey JC, et al. Vaginal fetal fibronectin measurements from 8 to 22 weeks’ gestation and subsequent spontaneous preterm birth. Am J Obstet Gynecol 2000;183:469-75. 10. Iams JD, Johnson FF, Sonek J, Sachs L, Gebauer C, Samuels P. Cervical competence as a continuum: a study of ultrasonographic cervical length and obstetric performance. Am J Obstet Gynecol 1995;172:1097-106. 11. Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG 2007;113:17-42. 12. Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J. Revisiting the short cervix detected by transvaginal ultrasound in the second trimester: why cerclage therapy may not help. Am J Obstet Gynecol 2001;185:1098-105. 13. Roman AS, Rebarber A, Sfakianaki AK, et al. Vaginal fetal fibronectin as a predictor of spontaneous preterm delivery in the patient with cervical cerclage. Am J Obstet Gynecol 2003; 189:1368-73. 14. Rust OA, Atlas RO, Jones KJ, Benham BN, Balducci J. A randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os. Am J Obstet Gynecol 2000;183:830-5. 15. Rust O, Larkin R, Roberts W, et al. A randomized controlled trial of cerclage versus 17hydroxyprogesterone (17P) for the treatment of short cervix. Am J Obstet Gynecol 2007; 195:S112. 16. Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702-6. 17. Lindquist K. SAS FAQ: How to estimate relative risk in SAS using PROC GENMOD for common outcomes in cohort studies. Available at: http://www.ats.ucla.edu/stat/sas/faq/ relative_risk.htm. Accessed February 5, 2008. 18. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol 2005;162:199-200. 19. Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999; 27:5-20. 20. Saki M, Shiozaki A, Tabata M, et al. Evaluation of effectiveness of prophylactic cerclage of a short cervix according to interleukin-8 in cervical mucus. Am J Obstet Gynecol 2006; 194:14-9.
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