http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2014; 27(15): 1576–1579 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2013.870550
ORIGINAL ARTICLE
Endocervical and high vaginal quantitative fetal fibronectin in predicting preterm birth J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
Katy Kuhrt, Christina Unwin, Natasha Hezelgrave, Paul Seed, and Andrew Shennan Woman’s Health Academic Centre, Kings College London, London, UK
Abstract
Keywords
Objective: Accurate prediction of spontaneous preterm birth (sPTB) is essential to target interventions. Fetal fibronectin (fFN) is a leading predictor. A quantitative fFN (qfFN) test has improved prediction, based on high vaginal swabs (HVS). It is not known how endocervical (ECS) fFN levels compare, or which has the best predictive value. Our principal aim was to determine the difference in fFN concentration between HVS and ECS and compare their ability to predict sPTB. Methods: Asymptomatic high risk women (18þ0–30þ0 weeks gestation) had secretions sampled from the endocervix (ECS) and vaginal fornix (HVS), analyzed by the quantitative fFN analyzer (Hologic). Mean concentrations were compared; ROC curves were calculated using area under the curve (AUC) for prediction of delivery 530 and 37 weeks. Results: Mean HVS value was lower than ECS (80 ng/ml (SD142) versus 217 (SD 212) (p50.05). Predictive ability was similar: AUC of 0.92 and 0.94, respectively, for prediction of sPTB537 and 0.84 and 0.82 for 530 weeks. Conclusions: Endocervical qfFN is higher than HVS and clinicians should avoid ECS if using traditional thresholds. ECS and HVS are both useful predictors, but require different threshold values. Further work is needed to determine whether ECS is a better and safe test to justify the difficulty in sampling.
Predictive test, premature labour, sampling site
Introduction Every year 15 million babies are born preterm, 537 weeks’ gestation [1] and 1.1 million die from complications. Survivors face greater risk of serious health problems [2], which in the US costs $26 billion annually [3], and despite advances in prenatal care, the rate of spontaneous preterm birth (sPTB) has not declined [2]. Effective prediction tools will allow identification of women who are most likely to give birth prematurely; on the basis of this information clinicians will be able to individualize management and intervene in these women and potentially prevent sPTB. The most clinically reliable tests to identify pregnant women at high risk of sPTB are transvaginal ultrasound assessment of cervical length (CL) and the detection of fetal fibronectin (fFN) in cervicovaginal fluid [4,5]. fFN is a glycoprotein found at the chorion–decidual interface. The appearance in the cervicovaginal secretions of fFN between 22þ0 and 35þ0 weeks’ gestation is thought to represent disruption of this interface, which likely explains
Address for correspondence: Prof. Andrew Shennan, Woman’s Health Academic Centre, Kings College London, London, UK. Tel: 07976 822634 (Mobile). E-mail: [email protected]
History Received 17 July 2013 Accepted 26 November 2013 Published online 13 January 2014
why the presence of fFN in these secretions has been shown to be the best predictor of sPTB [6]. The current qualitative fFN test provides a positive or negative result based on a threshold of 50 ng/mL [7]. There is now a strong evidence to suggest quantitative measurement of fFN (qfFN), where an absolute concentration is obtained, improves the test still further in both symptomatic and asymptomatic women [8,9]. fFN samples are collected by high vaginal swab (HVS) from the vaginal fornix; the level of vaginal fFN is related to the risk of sPTB [10]. It is not known how HVS and ECS fFN levels compare, or whether one has superior predictive value over the other. As traditional qualitative fFn tests are based on a single threshold, and ECS values are theoretically higher (although more difficult to take), it could be that ECS levels have higher false positive results or alternatively, may have improved accuracy at a different threshold as a better reflection of endocervical integrity. The advent of bedside quantitative measurements means variable thresholds can be applied to swabs collected from different sites, to predict risk and dictate management. The principal purpose of this study (powered for) was to determine whether there is a difference in fFN concentration between HVS and ECS and to compare their ability to predict outcome.
DOI: 10.3109/14767058.2013.870550
Endocervical and high vaginal quantitative fFN in predicting PTB
1577
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
Methods The study population was asymptomatic women recruited from the Preterm Surveillance Clinic at St Thomas’ Hospital. Women were between 18þ0 and 30þ0 weeks’ gestation and were at a high risk of PTB, defined as one or more of previous PTB, previous preterm rupture of membranes (PPROM), previous late miscarriage (16–23 þ 6), previous cervical surgery or cervical length 525 mm in the current pregnancy. Women with a previous vaginal examination or sexual intercourse within the last 24 h, a blood stained swab, or rupture of membranes before the test were excluded from the study due to potential interference with fFN measurement. After application of exclusion criteria, the population analyzed consisted of 20 women, each with a contemporaneous HVS and ECS qfFN measurement. These women were sampled under regional block prior to an ultrasound indicated cerclage in order to accurately identify the endocervix. Polyester swabs were used to collect cervicovaginal secretions from the endocervix (10 s) and then the posterior fornix of the vagina (10 s) during a sterile speculum examination. One aliquot (200 ml) of each sample was analyzed by the quantitative Rapid fFN analyzer (HologicÔ, Bedford, MA) and results were recorded in a spreadsheet along with participants’ demographic characteristics, risk factors and obstetric and gynecological history. Written informed consent was obtained from all participants and the study approved by South East London Research Ethics Committee. Statistical analysis was performed with Stata software (version 11.2; StataCorp LP, College Station, TX). Based on our previous data (n ¼ 617 women) the standard deviation for log fFN is 1.79. Assuming conservatively that the correlation between the measure is 0.9, 14 subjects are sufficient to test at the 5% significance level for a doubling in the average fFN level. To improve accuracy we collected 20 cases. A paired t-test was used to find the mean and the confidence interval for the size of the difference between the HVS and ECS measurements. The validity of the paired t method depends on the assumption that the differences are from a Normal distribution and a q norm plot was created to check this assumption [11]. A ladder plot was used to display each woman’s HVS and ECS value and indicate her gestation at delivery so that this could be related to her qfFN result (Figure 1). To determine how the tests derived from the two different sample sites performed at different qfFN thresholds predictive statistics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and false positive rate (FPR) were calculated at three different thresholds, 20 ng/ml, 200 ng/ml and 4500 ng/ml. Given the small numbers involved, we used Receiver Operating Characteristic (ROC), which evaluates all data at all thresholds. The area under the ROC curve (AUROC) was calculated as a summary measure of how well HVS and ECS predicted outcome.
Results A total of 20% of women delivered preterm (537 weeks). Demographics and baseline risk characteristics for the included women are described in Table 1.
Figure 1. Ladder plot of all the data, indicating gestation at delivery. 500 ng/ml is the upper limit of detection, and therefore values cannot be recorded higher than this. Table 1. Demographic characteristics (n ¼ 20). Demographic Ethnicity White Black Asian Other BMI 520 20–25 26–30 430 Smoking Never Current Stopped prior to/during pregnancy Risk factors Previous preterm delivery Previous late miscarriage (16þ0–23þ6) Previous cervical surgery
n
Percentage
10 5 2 3
50% 25% 10% 15%
3 8 5 4
15% 40% 25% 20%
17 0 3
85% 0% 15%
5 9 8
25% 45% 40%
A q norm plot showed that the data was normally distributed. The mean HVS value was significantly lower than the ECS values (80 ng/ml (SD142) versus 217 (SD 212) for ECS (p50.05). Both swabs result in a range of fFN concentrations, ECS values tending to be higher except for the woman where both results are recorded as 4500 ng/ml, where ECS could be higher (but out with the range of measurement).
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
1578
K. Kuhrt et al.
J Matern Fetal Neonatal Med, 2014; 27(15): 1576–1579
Table 2 describes the predictive statistics from the ECS and HVS sites across three different thresholds, 20 ng/ml, 200 ng/ml and4500 ng/ml. Overall the prediction has value at either of the sites and clinically useful predictions are apparent at both, but at different thresholds. As expected, the 50 ng/ml threshold HVS performed well with high sensitivity and specificity (75 and 81%, respectively). Comparable (numerically better) accuracy is seen for ECS but at a higher threshold of 500 ng/ml (75 and 94%, respectively). ROC curve analysis showed that, over a range of thresholds and at different gestations at delivery, HVS and ECS have similar predictive ability. At 530 weeks’ and 537 weeks’ gestation at delivery, HVS and ECS have similar AUROC. Figure 2 demonstrates the AUROC for each test site. These are comparable (0.92 and 0.94 for HVS and ECS, respectively) for predicting sPTB 530 weeks’ and 537 weeks’ gestation (0.84 and 0.82).
Discussion We have demonstrated that qfFN is significantly higher when taken from the endocervix, compared to the high vagina. Sampling the endocervix resulted in a high false positive rate and a low specificity at the conventional 50 ng/ml threshold. Given that the inability to correctly identify
women who will not deliver prematurely can result in unnecessary, expensive and potentially harmful interventions, including admission of antenatal corticosteroids, tocolysis and in utero transfer to tertiary centres [12–14] it is important that clinicians are careful to avoid the endocervix on collection of a qfFN sample if the conventional 50 ng/ml threshold is used. Despite containing consistently higher concentrations of qfFN than HVS samples, ECS samples have a predictive ability equivalent to HVS samples when higher threshold values are applied. At all three thresholds analyzed (50, 200 and 500 ng/ml), ECS has a higher sensitivity compared with HVS samples, whilst the specificity of the HVS test was higher at all thresholds aside from 500 ng/ml where specificities were comparable. In fact at the 500 ng/ml threshold, HVS failed to identify two of the women who delivered prematurely, both of whom were detected by the ECS. It is reasonable to suggest that ECS swabs might constitute a more accurate measure of fFN because the endocervix is closer to the chorion–decidua interface where fFN normally exists. Furthermore, given that ECS results tend to be higher, a low value in a high risk woman could be particularly reassuring, perhaps more so than the same result after a HVS. The areas under the ROC curves confirm that, in this data set, both sample sites have considerable clinical value. Further research could establish if ECS at different thresholds is a better test, along with assessment of feasibility.
Table 2. Predictive statistics from the ECS and HVS sites across three different thresholds, 20 ng/ml, 200 ng/ml and 4500 ng/ml. 50 threshold
Ratio of ‘‘positive’’:‘‘negative’’ tests* PPV NPV Sensitivity Specificity False þ rate
200 threshold
4500 threshold
HVS
ECS
HVS
ECS
HVS
ECS
14:6 50% 93% 75% 81% 19%
6:14 29% 100% 100% 37.50% 62.50%
8:12 67% 88% 50% 94% 6%
3:17 37.50% 92% 75% 69% 31%
4:16 100% 84% 25% 100% 0%
1:19 75% 94% 75% 94% 6%
*As defined by each threshold.
Figure 2. ROC curves to show overall ability of high vaginal and endocervical fetal fibronectin swabs (HVS, ECS) to predict PTB across all thresholds.
DOI: 10.3109/14767058.2013.870550
Endocervical and high vaginal quantitative fFN in predicting PTB
Acknowledgements We thank Jenny Carter and Judy Filmer who assisted with patient recruitment and sample processing.
6.
Declaration of interest
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Supported by Tommy’s Baby Charity number 1060508 and minority financial and equipment assistance from Hologic USA (Marlborough, MA). A.H.S. received financial assistance from Hologic USA for providing educational talks on preterm birth.
7. 8.
9.
References 1. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012;379:2162–72. 2. Howson CP, Kinney MV, Lawn JE. Born too soon: the global action report on preterm birth. Geneva: World Health Organisation; 2012. Available from: http://www.who.int [last accessed 29 Feb 2013]. 3. Behrman RE, Butler AS. Committee on understanding premature birth and assuring healthy outcomes; preterm birth: causes, consequences, and prevention. US: Institute of Medicine; 2007/ Available from: http://www.ncbi.nlm.nih.gov/books/NBK11374 [last accessed 14 April 2013]. 4. Honest H, Forbes CA, Duree KH, et al. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess 2009;13:1–627. 5. Bolt LA, Chandiramani M, de Greeff A, et al. The value of combined cervical length measurement and fetal fibronectin
10.
11. 12. 13.
14.
1579
testing to predict spontaneous preterm birth in asymptomatic high risk women. J Matern Fetal Neonatal Med 2011;24: 928–32. Goldenberg RL, Mercer BM, Meis PJ, et al. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 1996;87:643–8. Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5–20. Abbott DS, Radford SK, Seed PT, et al. Evaluation of quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. Am J Obstet Gynecol 2013;208:122 e1–6. Available from: http://www.sciencedirect.com/science/article/pii/ S0002937812020376 [last accessed 5 Feb 2013]. Kurtzman J, Chandaramani M, Briley A, et al. Quantitative fetal fibronectin in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery. Am J Obstet Gynecol 2009;200:263.e1–6. Available from: http://www.sciencedirect. com/science/article/pii/S0002937809001008 [last accessed 12 Feb 2013]. Blanch G, Ola´h KS, Walkinshaw S. The presence of fetal fibronectin in the cervicovaginal secretions of women at term – its role in the assessment of women before labor induction and in the investigation of the physiologic mechanisms of labor. Am J Obstet Gynecol 1996;174:262–6. Bland M. An introduction to medical statistics. 3rd ed. Oxford: Oxford University Press; 2000. Peaceman AM, Andrews WW, Thorp JM, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 1997;177:8–13. Goldenberg RL, Iams JD, Mercer BM, et al. The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health 1998;88:233–8. Guinn DA, Goepfert AR, Owen J, et al. Management options in women with preterm uterine contractions: a randomized clinical trial. Am J Obstet Gynecol 1997;177:814–18.
ORIGINAL ARTICLE
Endocervical and high vaginal quantitative fetal fibronectin in predicting preterm birth J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
Katy Kuhrt, Christina Unwin, Natasha Hezelgrave, Paul Seed, and Andrew Shennan Woman’s Health Academic Centre, Kings College London, London, UK
Abstract
Keywords
Objective: Accurate prediction of spontaneous preterm birth (sPTB) is essential to target interventions. Fetal fibronectin (fFN) is a leading predictor. A quantitative fFN (qfFN) test has improved prediction, based on high vaginal swabs (HVS). It is not known how endocervical (ECS) fFN levels compare, or which has the best predictive value. Our principal aim was to determine the difference in fFN concentration between HVS and ECS and compare their ability to predict sPTB. Methods: Asymptomatic high risk women (18þ0–30þ0 weeks gestation) had secretions sampled from the endocervix (ECS) and vaginal fornix (HVS), analyzed by the quantitative fFN analyzer (Hologic). Mean concentrations were compared; ROC curves were calculated using area under the curve (AUC) for prediction of delivery 530 and 37 weeks. Results: Mean HVS value was lower than ECS (80 ng/ml (SD142) versus 217 (SD 212) (p50.05). Predictive ability was similar: AUC of 0.92 and 0.94, respectively, for prediction of sPTB537 and 0.84 and 0.82 for 530 weeks. Conclusions: Endocervical qfFN is higher than HVS and clinicians should avoid ECS if using traditional thresholds. ECS and HVS are both useful predictors, but require different threshold values. Further work is needed to determine whether ECS is a better and safe test to justify the difficulty in sampling.
Predictive test, premature labour, sampling site
Introduction Every year 15 million babies are born preterm, 537 weeks’ gestation [1] and 1.1 million die from complications. Survivors face greater risk of serious health problems [2], which in the US costs $26 billion annually [3], and despite advances in prenatal care, the rate of spontaneous preterm birth (sPTB) has not declined [2]. Effective prediction tools will allow identification of women who are most likely to give birth prematurely; on the basis of this information clinicians will be able to individualize management and intervene in these women and potentially prevent sPTB. The most clinically reliable tests to identify pregnant women at high risk of sPTB are transvaginal ultrasound assessment of cervical length (CL) and the detection of fetal fibronectin (fFN) in cervicovaginal fluid [4,5]. fFN is a glycoprotein found at the chorion–decidual interface. The appearance in the cervicovaginal secretions of fFN between 22þ0 and 35þ0 weeks’ gestation is thought to represent disruption of this interface, which likely explains
Address for correspondence: Prof. Andrew Shennan, Woman’s Health Academic Centre, Kings College London, London, UK. Tel: 07976 822634 (Mobile). E-mail: [email protected]
History Received 17 July 2013 Accepted 26 November 2013 Published online 13 January 2014
why the presence of fFN in these secretions has been shown to be the best predictor of sPTB [6]. The current qualitative fFN test provides a positive or negative result based on a threshold of 50 ng/mL [7]. There is now a strong evidence to suggest quantitative measurement of fFN (qfFN), where an absolute concentration is obtained, improves the test still further in both symptomatic and asymptomatic women [8,9]. fFN samples are collected by high vaginal swab (HVS) from the vaginal fornix; the level of vaginal fFN is related to the risk of sPTB [10]. It is not known how HVS and ECS fFN levels compare, or whether one has superior predictive value over the other. As traditional qualitative fFn tests are based on a single threshold, and ECS values are theoretically higher (although more difficult to take), it could be that ECS levels have higher false positive results or alternatively, may have improved accuracy at a different threshold as a better reflection of endocervical integrity. The advent of bedside quantitative measurements means variable thresholds can be applied to swabs collected from different sites, to predict risk and dictate management. The principal purpose of this study (powered for) was to determine whether there is a difference in fFN concentration between HVS and ECS and to compare their ability to predict outcome.
DOI: 10.3109/14767058.2013.870550
Endocervical and high vaginal quantitative fFN in predicting PTB
1577
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
Methods The study population was asymptomatic women recruited from the Preterm Surveillance Clinic at St Thomas’ Hospital. Women were between 18þ0 and 30þ0 weeks’ gestation and were at a high risk of PTB, defined as one or more of previous PTB, previous preterm rupture of membranes (PPROM), previous late miscarriage (16–23 þ 6), previous cervical surgery or cervical length 525 mm in the current pregnancy. Women with a previous vaginal examination or sexual intercourse within the last 24 h, a blood stained swab, or rupture of membranes before the test were excluded from the study due to potential interference with fFN measurement. After application of exclusion criteria, the population analyzed consisted of 20 women, each with a contemporaneous HVS and ECS qfFN measurement. These women were sampled under regional block prior to an ultrasound indicated cerclage in order to accurately identify the endocervix. Polyester swabs were used to collect cervicovaginal secretions from the endocervix (10 s) and then the posterior fornix of the vagina (10 s) during a sterile speculum examination. One aliquot (200 ml) of each sample was analyzed by the quantitative Rapid fFN analyzer (HologicÔ, Bedford, MA) and results were recorded in a spreadsheet along with participants’ demographic characteristics, risk factors and obstetric and gynecological history. Written informed consent was obtained from all participants and the study approved by South East London Research Ethics Committee. Statistical analysis was performed with Stata software (version 11.2; StataCorp LP, College Station, TX). Based on our previous data (n ¼ 617 women) the standard deviation for log fFN is 1.79. Assuming conservatively that the correlation between the measure is 0.9, 14 subjects are sufficient to test at the 5% significance level for a doubling in the average fFN level. To improve accuracy we collected 20 cases. A paired t-test was used to find the mean and the confidence interval for the size of the difference between the HVS and ECS measurements. The validity of the paired t method depends on the assumption that the differences are from a Normal distribution and a q norm plot was created to check this assumption [11]. A ladder plot was used to display each woman’s HVS and ECS value and indicate her gestation at delivery so that this could be related to her qfFN result (Figure 1). To determine how the tests derived from the two different sample sites performed at different qfFN thresholds predictive statistics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and false positive rate (FPR) were calculated at three different thresholds, 20 ng/ml, 200 ng/ml and 4500 ng/ml. Given the small numbers involved, we used Receiver Operating Characteristic (ROC), which evaluates all data at all thresholds. The area under the ROC curve (AUROC) was calculated as a summary measure of how well HVS and ECS predicted outcome.
Results A total of 20% of women delivered preterm (537 weeks). Demographics and baseline risk characteristics for the included women are described in Table 1.
Figure 1. Ladder plot of all the data, indicating gestation at delivery. 500 ng/ml is the upper limit of detection, and therefore values cannot be recorded higher than this. Table 1. Demographic characteristics (n ¼ 20). Demographic Ethnicity White Black Asian Other BMI 520 20–25 26–30 430 Smoking Never Current Stopped prior to/during pregnancy Risk factors Previous preterm delivery Previous late miscarriage (16þ0–23þ6) Previous cervical surgery
n
Percentage
10 5 2 3
50% 25% 10% 15%
3 8 5 4
15% 40% 25% 20%
17 0 3
85% 0% 15%
5 9 8
25% 45% 40%
A q norm plot showed that the data was normally distributed. The mean HVS value was significantly lower than the ECS values (80 ng/ml (SD142) versus 217 (SD 212) for ECS (p50.05). Both swabs result in a range of fFN concentrations, ECS values tending to be higher except for the woman where both results are recorded as 4500 ng/ml, where ECS could be higher (but out with the range of measurement).
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
1578
K. Kuhrt et al.
J Matern Fetal Neonatal Med, 2014; 27(15): 1576–1579
Table 2 describes the predictive statistics from the ECS and HVS sites across three different thresholds, 20 ng/ml, 200 ng/ml and4500 ng/ml. Overall the prediction has value at either of the sites and clinically useful predictions are apparent at both, but at different thresholds. As expected, the 50 ng/ml threshold HVS performed well with high sensitivity and specificity (75 and 81%, respectively). Comparable (numerically better) accuracy is seen for ECS but at a higher threshold of 500 ng/ml (75 and 94%, respectively). ROC curve analysis showed that, over a range of thresholds and at different gestations at delivery, HVS and ECS have similar predictive ability. At 530 weeks’ and 537 weeks’ gestation at delivery, HVS and ECS have similar AUROC. Figure 2 demonstrates the AUROC for each test site. These are comparable (0.92 and 0.94 for HVS and ECS, respectively) for predicting sPTB 530 weeks’ and 537 weeks’ gestation (0.84 and 0.82).
Discussion We have demonstrated that qfFN is significantly higher when taken from the endocervix, compared to the high vagina. Sampling the endocervix resulted in a high false positive rate and a low specificity at the conventional 50 ng/ml threshold. Given that the inability to correctly identify
women who will not deliver prematurely can result in unnecessary, expensive and potentially harmful interventions, including admission of antenatal corticosteroids, tocolysis and in utero transfer to tertiary centres [12–14] it is important that clinicians are careful to avoid the endocervix on collection of a qfFN sample if the conventional 50 ng/ml threshold is used. Despite containing consistently higher concentrations of qfFN than HVS samples, ECS samples have a predictive ability equivalent to HVS samples when higher threshold values are applied. At all three thresholds analyzed (50, 200 and 500 ng/ml), ECS has a higher sensitivity compared with HVS samples, whilst the specificity of the HVS test was higher at all thresholds aside from 500 ng/ml where specificities were comparable. In fact at the 500 ng/ml threshold, HVS failed to identify two of the women who delivered prematurely, both of whom were detected by the ECS. It is reasonable to suggest that ECS swabs might constitute a more accurate measure of fFN because the endocervix is closer to the chorion–decidua interface where fFN normally exists. Furthermore, given that ECS results tend to be higher, a low value in a high risk woman could be particularly reassuring, perhaps more so than the same result after a HVS. The areas under the ROC curves confirm that, in this data set, both sample sites have considerable clinical value. Further research could establish if ECS at different thresholds is a better test, along with assessment of feasibility.
Table 2. Predictive statistics from the ECS and HVS sites across three different thresholds, 20 ng/ml, 200 ng/ml and 4500 ng/ml. 50 threshold
Ratio of ‘‘positive’’:‘‘negative’’ tests* PPV NPV Sensitivity Specificity False þ rate
200 threshold
4500 threshold
HVS
ECS
HVS
ECS
HVS
ECS
14:6 50% 93% 75% 81% 19%
6:14 29% 100% 100% 37.50% 62.50%
8:12 67% 88% 50% 94% 6%
3:17 37.50% 92% 75% 69% 31%
4:16 100% 84% 25% 100% 0%
1:19 75% 94% 75% 94% 6%
*As defined by each threshold.
Figure 2. ROC curves to show overall ability of high vaginal and endocervical fetal fibronectin swabs (HVS, ECS) to predict PTB across all thresholds.
DOI: 10.3109/14767058.2013.870550
Endocervical and high vaginal quantitative fFN in predicting PTB
Acknowledgements We thank Jenny Carter and Judy Filmer who assisted with patient recruitment and sample processing.
6.
Declaration of interest
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/03/15 For personal use only.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Supported by Tommy’s Baby Charity number 1060508 and minority financial and equipment assistance from Hologic USA (Marlborough, MA). A.H.S. received financial assistance from Hologic USA for providing educational talks on preterm birth.
7. 8.
9.
References 1. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012;379:2162–72. 2. Howson CP, Kinney MV, Lawn JE. Born too soon: the global action report on preterm birth. Geneva: World Health Organisation; 2012. Available from: http://www.who.int [last accessed 29 Feb 2013]. 3. Behrman RE, Butler AS. Committee on understanding premature birth and assuring healthy outcomes; preterm birth: causes, consequences, and prevention. US: Institute of Medicine; 2007/ Available from: http://www.ncbi.nlm.nih.gov/books/NBK11374 [last accessed 14 April 2013]. 4. Honest H, Forbes CA, Duree KH, et al. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technol Assess 2009;13:1–627. 5. Bolt LA, Chandiramani M, de Greeff A, et al. The value of combined cervical length measurement and fetal fibronectin
10.
11. 12. 13.
14.
1579
testing to predict spontaneous preterm birth in asymptomatic high risk women. J Matern Fetal Neonatal Med 2011;24: 928–32. Goldenberg RL, Mercer BM, Meis PJ, et al. The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 1996;87:643–8. Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5–20. Abbott DS, Radford SK, Seed PT, et al. Evaluation of quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. Am J Obstet Gynecol 2013;208:122 e1–6. Available from: http://www.sciencedirect.com/science/article/pii/ S0002937812020376 [last accessed 5 Feb 2013]. Kurtzman J, Chandaramani M, Briley A, et al. Quantitative fetal fibronectin in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery. Am J Obstet Gynecol 2009;200:263.e1–6. Available from: http://www.sciencedirect. com/science/article/pii/S0002937809001008 [last accessed 12 Feb 2013]. Blanch G, Ola´h KS, Walkinshaw S. The presence of fetal fibronectin in the cervicovaginal secretions of women at term – its role in the assessment of women before labor induction and in the investigation of the physiologic mechanisms of labor. Am J Obstet Gynecol 1996;174:262–6. Bland M. An introduction to medical statistics. 3rd ed. Oxford: Oxford University Press; 2000. Peaceman AM, Andrews WW, Thorp JM, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 1997;177:8–13. Goldenberg RL, Iams JD, Mercer BM, et al. The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health 1998;88:233–8. Guinn DA, Goepfert AR, Owen J, et al. Management options in women with preterm uterine contractions: a randomized clinical trial. Am J Obstet Gynecol 1997;177:814–18.
