Abstract
Objective:
To examine the utility of fetal fibronectin (fFN) for predicting spontaneous preterm birth (PTB) in asymptomatic women with a cervical length (CL) <10 mm compared to those with a CL 11–25 mm.
Methods:
Data was collected on all women with non-anomalous singleton and twin gestations who underwent transvaginal CL at a single institution between 2009 and 2012. Women with an incidental short cervix (CL ≤25 mm) between 22–32 weeks who had an fFN result within 7 days thereafter were included. Indicated preterm deliveries at <14 days of fFN, women who underwent cerclage placement, and terminations of pregnancy were excluded. The primary outcome was spontaneous PTB within 7 and 14 days of the fFN. Sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) of fFN for a CL <10 mm was calculated for singletons and twins and compared to those with a CL 11–25 mm.
Results:
Of the 213 women included, 117 (54.9%) were singletons and 96 (45%) were twins. Baseline characteristics were similar between those with a CL <10 mm and with a CL 11–25 mm in both singletons and twins. The NPV of fFN for delivery within 7 days in singletons and twins with a CL <10 mm was 100%, similar to those with a CL 11–25mm (93–100%). The NPV of fFN for delivery within 14 days in singletons and twins with a CL <10 mm remained high (87.5–100%) when compared to those with a CL 11–25mm (93–100%). The PPV of fFN for delivery within 7 and 14 days in both singletons and twins with a CL<10 mm was low (10–25%) and similar to those with a CL 11–25 mm (7.1–24.4%).
Conclusions:
The NPV of fFN in asymptomatic singleton and twin pregnancies with a CL <10 mm is high and comparable to the NPV of fFN in women with a longer CL. Routine fFN collection in this select population should be considered as it may avoid unnecessary and costly admissions, as well as assist with timing of antenatal corticosteroids.
Keywords: fetal fibronectin, cervical length, short cervix, preterm birth
Introduction
Preterm birth (PTB) is a major cause of perinatal morbidity and mortality, affecting 1 out of 10 newborns in the Unites States [1]. Antenatal corticosteroids (ACS) are recommended between 24 and 36 weeks of gestation when there is a risk of delivery within 7 days [2–4]. The administration of ACS within 7 days of PTB significantly reduces complications associated with early delivery [5,6], underscoring that the timing of ACS is critical.
The presence of fetal fibronectin (fFN), a protein found at the interface between the chorion and the decidua, may aid in identifying pregnancies at risk for imminent preterm birth.7 Fetal fibronectin testing in women with threatened preterm labor has a negative predictive value (NPV) for delivery within 7 and 14 days of 97–99%, providing reassurance to obstetricians while avoiding unnecessary and costly interventions [7]. However, the low positive predictive value (PPV) of fFN and lack of association between fFN and prevention of preterm birth has created controversy regarding its use [8,9].
Ultrasound can also be used to identify pregnancies at risk for preterm delivery [10,11]. A short cervix (CL ≤25 mm) on transvaginal ultrasonography has consistently been shown to be a risk factor for spontaneous PTB, with the risk increasing as the CL shortens [11]. This observation has led to CL screening in select populations [12].
The combined use of fFN and CL can be helpful in identifying patients at highest risk of imminent preterm delivery, particularly in those with a short cervix [13,14]. However, the majority of studies investigating the use of fFN with CL have been in symptomatic patients who present with threatened preterm labor [7–9]. Data on the utility of fFN in asymptomatic patients with an incidental finding of a short CL, particularly an extremely short CL (<10 mm) is limited. Therefore, we aimed to determine the positive and negative predictive values of fFN in asymptomatic patients with an extremely short cervix in comparison to those with a CL 11–25mm. We hypothesized that positive and negative predictive values of fFN would be similar in patients with an extremely short cervix compared to those with a CL 11–25 mm.
Materials and Methods
This was a retrospective cohort study of patients who underwent transvaginal CL assessment in a single center between January 2009 and December 2012. Approval from the institutional review board was obtained. All women who had an asymptomatic short cervix (CL ≤25 mm) between 22 and 32 weeks gestation and a fFN collected within 7 days of that CL were eligible for inclusion. During this period of time in our institution, serial CL assessments were performed between 16 and 32 weeks for women with a history of preterm birth, multiple gestations, history of cervical procedures (loop electrosurgical excision procedure (LEEP) and/or cervical conization) and as surveillance in the setting of a short cervix. As a matter of institutional protocol, fFN was not sent in women with cervical dilation >3 cm, vaginal bleeding, or who had any form of vaginal manipulation (defined as sexual intercourse, use of vaginal medication or performance of a transvaginal ultrasound or sterile vaginal exam) <24 hours prior to the visit. If a woman had multiple CLs with an accompanying fFN result, then the fFN associated with the shortest documented CL was used. Women were deemed asymptomatic if they denied labor complaints (i.e. contractions, pelvic pain, pelvic pressure), which were routinely documented. Rarely, depending on the provider, women who denied labor complaints were also placed on the tocometer to evaluate for preterm labor. Those that had documented absence of contractions on the tocometer were deemed asymptomatic and eligible for inclusion.
Women were excluded if they had a cerclage, fetal anomalies, pregnancy termination or a medically indicated delivery within 14 days of fFN collection. Maternal characteristics such as age, weight, race, and parity were collected. A detailed medical, surgical, and obstetrical history including the use of any form of progesterone was abstracted from each medical record. If a woman had more than one pregnancy during the time period, information on the subsequent pregnancy was collected as a separate pregnancy episode.
Singletons and twins were stratified into two separate groups based on CL measurements: ≤10 mm and 11–25 mm. The threshold of 10 mm for CL was chosen as this group of women appears to be at high risk for interventions in the setting of such a short cervix. The primary outcome was delivery within 7 and 14 days of the fFN result. Secondary outcomes included delivery <34 and <37 weeks. The sensitivity, specificity, PPV, and NPV of fFN was compared between singletons with a CL ≤10 mm and those with a CL 11–25 mm. The same comparison was performed in twins.
Test characteristics were analyzed in singletons and twins separately. Student’s t-test and Fisher’s exact test were used for continuous and categorical variables, respectively.
Results
During the study period, a total of 3696 women had a transvaginal CL performed. After applying our exclusion criteria, 213 patients (117 (54.9%) singletons and 96 (45.1%) twin gestations) comprised the cohort and were further analyzed (Figure 1). A CL ≤10 mm was found in 40 singletons (40/117, 34.0%) and 34 twins (34/96, 35.4%). Baseline demographics, including risk factors for preterm birth, were similar between women with a CL ≤10 mm and those with a CL 11–25 mm in both singleton and twin pregnancies (Tables 1 and 2). Among singleton pregnancies, 38.5% (45/117) had a prior pregnancy complicated by spontaneous PTB, while 5.2% (5/96) of twins had a history of spontaneous PTB (Tables 1 and 2).
I.
Flow diagram illustrating the exclusion process in the study cohort.
CL, cervical length; fFN, fetal fibronectin; GA, gestational age.
Table 1.
Baseline characteristics and risk factors for preterm delivery in singletons.
| Characteristic | Cervical length ≤10 mm (n = 40) |
Cervical length 11-25 mm (n = 77) |
P value |
|---|---|---|---|
| Mean (± SD) maternal age – year | 30.6 ± 6.42 | 32.8 ± 6.22 | 0.07 |
| Race or ethnic group – no. (%) | |||
| African American | 3 (7.5) | 11 (14.2) | 0.28 |
| Hispanic | 6 (15) | 11 (14.2) | 0.92 |
| White | 5 (12.5) | 14 (18.1) | 0.43 |
| Other | 19 (47.5) | 25 (32.4) | 0.11 |
| Unknown | 7 (17.5) | 16 (20.8) | 0.67 |
| Nulliparous – no. (%) | 16 (4.0) | 23 (29.9) | 0.27 |
| History of spontaneous PTB – no. (%) | 13 (32.5) | 32 (41.6) | 0.34 |
| In vitro fertilization – no. (%) | 1 (2.5) | 3 (3.9) | 0.69 |
| History of cervical surgery – no. (%) | 7 (17.5) | 7 (9.0) | 0.18 |
| History of D&C and/or D&E – no. (%) | 15 (37.5) | 29 (37.7) | 0.99 |
| Maternal infection – no. (%) | 1 (2.5) | 7 (9.1) | 0.18 |
| Tobacco and/or drug use – no. (%) | 0 | 1 (1.3) | 1.0 |
| Received 17α-hydroxyprogesterone caproate – no. (%) | 13 (32.5) | 22 (28.6) | 0.68 |
| Received vaginal progesterone suppository – no. (%) | 24 (60.0) | 30 (39.0) | 0.03 |
PTB, preterm birth; D&C, dilation and curettage; D&E, dilation and evacuation.
Table 2.
Baseline characteristics and risk factors for preterm delivery in twins.
| Characteristic | Cervical length ≤10 mm (n = 34) |
Cervical length 11-25 mm (n = 62) |
P value |
|---|---|---|---|
| Mean (± SD) maternal age – year | 31.7 ± 6.7 | 33.0 ± 5.1 | 0.32 |
| Race or ethnic group – no. (%) | |||
| African American | 1 (2.9) | 3 (4.8) | 0.66 |
| Hispanic | 7 (20.6) | 9 (14.5) | 0.45 |
| White | 13 (38.2) | 21 (33.9) | 0.67 |
| Other | 6 (17.6) | 22 (35.5) | 0.07 |
| Unknown | 7 (20.6) | 7 (11.3) | 0.22 |
| Nulliparous – no. (%) | 25 (73.5) | 46 (74.2) | 0.94 |
| History of spontaneous PTB – no. (%) | 2 (5.9) | 3 (4.8) | 0.83 |
| In vitro fertilization – no. (%) | 15 (44.1) | 34 (54.8) | 0.31 |
| History of cervical surgery – no. (%) | 0 | 1 (1.6) | 1.0 |
| History of D&C and/or D&E – no. (%) | 5 (14.7) | 10 (16.1) | 0.85 |
| Maternal infection – no. (%) | 2 (5.9) | 0 | 1.0 |
| Tobacco and/or drug use – no. (%) | 0 | 0 | |
| Received 17α-hydroxyprogesterone caproate – no. (%) | 1 (2.9) | 2 (3.2) | 1.0 |
| Received vaginal progesterone suppository – no. (%) | 13 (28.3) | 13 (21.0) | 0.09 |
PTB, preterm birth; D&C, dilation and curettage; D&E, dilation and evacuation.
The overall prevalence of PTB <37 weeks was 39.3% in singletons 69.8% in twins. The diagnosis of a short cervix was made at a mean gestational age of 27.2 weeks (standard deviation 2.36) for singletons and 28.0 weeks (standard deviation 2.35) for twins. There was no difference in the gestational age at diagnosis of short cervix and gestational age at delivery between the two groups in singletons (Table 3). A short cervix was diagnosed at a significantly earlier gestational age in twins with a CL ≤10 mm compared to those with a CL 11–25 mm (P = 0.004) (Table 4). Furthermore, twins with a CL ≤10 mm delivered at a significantly earlier gestational age than those with a CL 11–25 mm (P = 0.048) (Table 4). The mean interval from diagnosis of a short CL to delivery was not different between the two CL groups in singletons and in twins (Tables 3 and 4). More than half (51.2%) of the study group took some form of progesterone (either intramuscular 17α-hydroxyprogesterone caproate or vaginal progesterone suppositories) during their pregnancies. The prevalence of singletons receiving vaginal progesterone was significantly increased (P = 0.03) in women with a CL ≤10 mm compared to those with a CL 11–25 mm (Table 1). The cervical length measurement in twins with a short cervix did not alter the prevalence of treatment with either form of progesterone (Table 2).
Table 3.
Pregnancy outcomes and characteristics in singletons.
| Outcome | Cervical length ≤10 mm (n = 40) |
Cervical length 11-25 mm (n = 77) |
P value |
|---|---|---|---|
| Mean (± SD) GA at diagnosis of short CL – weeks | 26.7 ± 2.4 | 27.4 ± 2.4 | 0.13 |
| Mean (± SD) GA at delivery – weeks | 35.6 ± 4.6 | 36.7 ± 3.3 | 0.13 |
| Delivery < 34 weeks – no. (%) | 10 (25) | 12 (15.6) | 0.22 |
| Delivery < 37 weeks – no. (%) | 17 (42.5) | 29 (37.7) | 0.61 |
| Mean (± SD) interval between short CL and delivery – weeks | 8.88 ± 4.57 | 9.31 ± 3.27 | 0.60 |
GA, gestational age; CL, cervical length.
Table 4.
Pregnancy outcomes and characteristics in twins.
| Outcome | Cervical length ≤10 mm (n = 34) |
Cervical length 11-25 mm (n = 62) |
P value |
|---|---|---|---|
| Mean (± SD) GA at diagnosis of short CL – weeks | 27.1 ± 2.1 | 28.5 ± 2.4 | 0.004 |
| Mean (± SD) GA at delivery – weeks | 33.4 ± 3.7 | 34.9 ± 3.3 | 0.048 |
| Delivery < 34 weeks – no. (%) | 15 (44.1) | 20 (32.2) | 0.248 |
| Delivery < 37 weeks – no. (%) | 27 (79.4) | 40 (64.5) | 0.128 |
| Mean (± SD) interval between short CL and delivery – weeks | 6.3 ± 3.6 | 6.4 ± 3.3 | 0.923 |
GA, gestational age; CL, cervical length.
Tables 5 and 6 report the predictive properties of fFN in singletons and twins with a CL ≤10 mm compared to those with a CL 11–25 mm. In singletons, the sensitivity and NPV of fFN for delivery within 7 and 14 days were both 100%, regardless of CL (Table 5). The PPV of fFN for delivery within 7 and 14 days was higher in with a CL ≤10mm (18.6%, 25%) compared to those with a CL 11–25mm (5.8%, 11.8%) (Table 5). The NPV of fFN for PTB <34 and <37 weeks was 89.5% and 70.8% with a CL ≤10mm and was 88.6% and 68.4% in singletons with a CL 11–25mm (Table 5). In singletons, The PPV of fFN for PTB <34 and <37 weeks was higher with a CL ≤10mm compared to those with CL 11–25mm (Table 5).
Table 5.
Test characteristics of fetal fibronectin for predicting spontaneous preterm birth in singletons.
| Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | |
|---|---|---|---|---|
| CL ≤ 10 mm (n = 40) | ||||
| Delivery < 7 days | 100 | 64.9 | 18.6 | 100 |
| Delivery < 14 days | 100 | 66.7 | 25 | 100 |
| Delivery < 34 weeks | 80 | 73.9 | 57.1 | 89.5 |
| Delivery < 37 weeks | 58.8 | 73.9 | 62.5 | 70.8 |
| CL 11–25 mm (n = 77) | ||||
| Delivery < 7 days | 100 | 78 | 5.8 | 100 |
| Delivery < 14 days | 100 | 73.2 | 11.8 | 100 |
| Delivery < 34 weeks | 58.3 | 84.7 | 50 | 88.6 |
| Delivery < 37 weeks | 35.7 | 84.7 | 58.8 | 68.4 |
CL, cervical length; PPV, positive predictive value; NPV, negative predictive value
Table 6.
Test characteristics of fetal fibronectin for predicting spontaneous preterm birth in twins.
| Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | |
|---|---|---|---|---|
| CL ≤ 10mm (n = 34) | ||||
| Delivery < 7 days | 100 | 72.7 | 10 | 100 |
| Delivery < 14 days | 25 | 70 | 10 | 87.5 |
| Delivery < 34 weeks | 33.3 | 72.7 | 83.3 | 37.5 |
| Delivery < 37 weeks | 33.3 | 70 | 90 | 25 |
| CL 11–25mm (n = 62) | ||||
| Delivery < 7 days | 25 | 75.5 | 7.1 | 93 |
| Delivery < 14 days | 5 | 78.4 | 21.4 | 93 |
| Delivery < 34 weeks | 38.9 | 84.2 | 70 | 59.2 |
| Delivery < 37 weeks | 28.9 | 82.4 | 78.6 | 34.1 |
CL, cervical length; PPV, positive predictive value; NPV, negative predictive value
Among twin gestations, the NPV of fFN for PTB within 7 and 14 days was also high and similar in women with a CL ≤10mm (100%, 87.5%) compared to those with a CL 11–25mm (93%) (Table 6). The NPV of fFN for PTB <34 and <37 weeks was 37.5% and 25% with a CL ≤10mm and was 59.2% and 34.1% with a CL 11–25mm (Table 6). In twins, the PPV of fFN for PTB <34 and <37 weeks was higher with a CL ≤10mm compared to those with CL 11–25mm (Table 6).
Discussion
This study indicates that the NPV of fFN in predicting PTB within 7 and 14 days is high in asymptomatic singletons and twins with an extremely short cervix (CL ≤10 mm) and comparable to the predictive values of fFN in women with CL between 11–25 mm. Although the PPV of fFN increased in singletons with a CL ≤10 mm versus CL 11–25 mm for delivery within 7 (18.6% vs 5.8%) and 14 (25% vs 11.8%) days, the PPV was still low.
While it is known that an incidental short cervix during pregnancy is an independent risk factor for preterm birth, it is unclear when the delivery will take place. The poor PPV of a short cervix alone has prompted the development of biomarkers, in addition to fFN, to aid in timing of antenatal corticosteroid administration or hospital admission [8,15–17]. The majority of studies investigating the predictive value of fFN for spontaneous PTB include pregnancies with symptoms of preterm labor [18–21]. Fetal fibronectin was intended to be used in symptomatic singleton pregnancies with a CL between 20 and 30 mm [22–24]. While optimal timing of ACS is key in providing the maximal neonatal benefit, clinicians have continued to administer them with suboptimal timing [15,25].
There is limited data regarding the use of fFN in asymptomatic patients diagnosed with a short cervix. Our findings are comparable with previously published studies. Magro-Malosso and colleagues [26] evaluated the accuracy of fFN in asymptomatic singletons with a CL < 20 mm. The NPV for delivery within 7 and 14 days in those women was 98% and 94% respectively, while the PPV remained low at 20%. Furthermore, Matthews et al. investigated the utility of fFN in asymptomatic twins with a CL <25 mm. Both the NPV (66.7%) and PPV (80%) for delivery <35 weeks were relatively high among patients in their cohort [27]. However, they did not report predictabilities of PTB within 7 and 14 days of CL, a critical period when determining timing of ACS. In addition, neither of these studies took into consideration the degree of cervical shortening. Fox and colleagues [28] evaluated the degree of CL shortening alone, or in combination with fFN, to assess the risk of spontaneous PTB in asymptomatic twin pregnancies. They concluded that the risk of sPTB before 35 weeks increased with a decreasing cervical length and positive fFN result.
The impact of CL and fFN screening on ACS exposure in asymptomatic twin pregnancies has been studied. Lifshitz et al. found that routine use of CL and fFN in asymptomatic twins was associated with improved rates of optimal ACS exposure (defined as either ACS within 1–7 days of delivery or 1–14 days of delivery) without increasing overall exposure to ACS [29]. Among patients who delivered within 7 and 14 days of ACS exposure, the most common indication for ACS administration was preterm labor or preterm prelabor rupture of membranes and not an asymptomatic short CL or positive fFN [29]. This further reiterates the clinical dilemma of management of twin pregnancies who present with an asymptomatic short CL alone. Nevertheless, these findings support the use of ACS in twin pregnancies presenting with asymptomatic short CL and a positive fFN.
The use of progesterone for a short cervix in this study was provider dependent, as its utilization was not universal at the time when these women were receiving care. Nevertheless, about half of this cohort received either intramuscular progesterone for a history of preterm delivery or vaginal progesterone due to a short cervix. Initiation of vaginal progesterone in singletons with a mid-trimester CL ≤25 mm has been shown to reduce the risk of PTB [30]. Similarly, use of vaginal progesterone in twins with a mid-trimester CL ≤25 mm reduces the risk of PTB, as well as neonatal mortality and morbidity [31]. While this intervention may impact the time interval from diagnosis of short cervix to delivery, the impact of vaginal progesterone on the predictability of fFN requires further study.
Strengths of the study
This study has several strengths. We included twin pregnancies, which tend to be an understudied group. In order to make the results clinically useful, we reported the predictive values of fFN in time increments of 7 and 14 days. This study adds to the limited existing literature regarding clinical management of a very high-risk group (CL ≤10mm), one that may receive ACS regardless of symptoms.
Limitations of the study
There are also several limitations. Due to the retrospective nature of the study, there is the risk of underreporting of patient symptoms, as symptomatic patients may have been inaccurately deemed as asymptomatic. In addition, the diagnosis of an extremely short cervix is not a common occurrence11, contributing to the overall small number of patients in the cohort.
The management of an incidentally detected short CL remains controversial and unclear. This is a clinical dilemma that obstetricians face when encountering a singleton or twin pregnancy with an asymptomatic short cervix, particularly when the cervix is extremely short. Our data suggest that fFN can be a useful tool in asymptomatic women diagnosed with an extremely short cervix even in the setting of twins. If the fFN is negative, the likelihood for delivery within 7 days nears 0% and antenatal corticosteroids and inpatient observation can be deferred to a later point. While the risk of delivery within 7 and 14 days was low for both singletons and twins with a negative fFN and CL ≤10 mm compared to those with a CL 11–25mm, twins with a CL ≤10 mm delivered at an earlier gestational age. This highlights the importance of counseling twin pregnancies that despite a low anticipated delivery risk with a negative fFN and extremely short cervix, they are at high risk for a premature delivery nonetheless. The low PPV of fFN in women with a CL <10mm and the lack of association between a positive fFN and prevention of spontaneous PTB in recent studies, has resulted in questioning the use of fFN [32]. However, given the high likelihood of PTB in such patients, administering antenatal corticosteroids when fFN is positive is reasonable. Although large prospective studies are needed to confirm our findings, the results of this study can aid practitioners in determining when steroids are indicated and help in counseling patients with a new diagnosis of short cervix.
Footnotes
Disclosure Statement
Disclosure of Interest
The authors report no conflict of interest.
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