Journal of Obstetrics and Gynaecology

ISSN: 0144-3615 (Print) 1364-6893 (Online) Journal homepage: http://www.tandfonline.com/loi/ijog20

The use of fetal fibronectin in suspected pre-term labour A. Anwar, S. W. Lindow, L. Greaves, S. Hall & R. Jha To cite this article: A. Anwar, S. W. Lindow, L. Greaves, S. Hall & R. Jha (2014) The use of fetal fibronectin in suspected pre-term labour, Journal of Obstetrics and Gynaecology, 34:1, 45-47 To link to this article: http://dx.doi.org/10.3109/01443615.2013.823923

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Date: 06 November 2015, At: 00:40

Journal of Obstetrics and Gynaecology, January 2014; 34: 45–47 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2013.823923

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The use of fetal fibronectin in suspected pre-term labour A. Anwar, S. W. Lindow, L. Greaves, S. Hall & R. Jha

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Hull and East Yorkshire Hospitals NHS Trust, Hull, UK

Pre-term delivery is the leading cause of neonatal mortality and morbidity. The aim of this study is to determine the diagnostic accuracy of the fetal fibronectin (FF) test in predicting pre-term birth, the test interpretation and subsequent action taken in normal clinical practice in a busy tertiary centre setting. A total of 133 symptomatic women were included in the study and underwent the FF test. The use of tocolysis and corticosteroids were significantly greater in test-positive patients (p ⬍ 0.001). A negative test for detecting pre-term delivery within 10 days of the test was 100% sensitive with 100% negative predictive value (NPV). Our study has confirmed that a negative FF is an excellent short-term test to exclude pre-term delivery. The use of FF testing in routine clinical practice results in test characteristics similar to those found in research studies. This implies that the conclusions reached by researchers can be reliably translated into clinical practice. Keywords: Fetal fibronectin test, morbidity, neonatal mortality, pre-term, uterine tightening

almost undetectable in vaginal secretions from 24 to 36 weeks’ gestation (Lockwood et al. 1991). Chemical or mechanical induced disruption of the maternal–fetal interface before the onset of active labour, releases FF into vaginal secretion (Sibille et al. 1986), making it a good biochemical marker for pre-term delivery. Many research studies claim that the cervicovaginal FF test can accurately predict spontaneous pre-term birth in clinical settings. The utility of any test used in the research setting may not be duplicated in the clinical setting for a number of different reasons, such as staff training, correct indications to perform the test and the correct interpretation of a result. In addition the finding of a positive result must be acted upon appropriately. The aim of the present study is to determine the diagnostic accuracy of the FF test in predicting pre-term birth, the test interpretation and subsequent action taken in normal clinical practice in a busy tertiary centre setting.

Materials and methods Introduction Pre-term delivery is the leading cause of neonatal mortality and morbidity in England and Wales, with 7.3% of live births born prematurely under 37 weeks’ gestation. Spontaneous pre-term birth between 32 and 36 weeks’ gestation occurs in 4.8% of live singleton deliveries (NHS 2011). In total, 2% of extremely pre-term born babies will develop a permanent disability, such as cerebral palsy associated with severe or moderate motor disability (Marlow et al. 2005). Targeted use of antenatal steroids significantly improves neonatal and longterm outcomes for the pre-term infant and reduced morbidity and mortality related to prematurity (Crowley 2000). Timely institution of antenatal steroids in clinical practice is very much dependant on accurate prediction of spontaneous preterm birth. Pre-term birth prediction using history and basic clinical examination alone is poor, and using clinical criteria, only two-thirds of women delivering before 34 weeks receive steroids (Mahony et al. 2010). In recent years, there have been efforts made to devise laboratory tests. which can help clinicians to identify the likelihood of a pre-term birth in symptomatic women, in order to optimise antenatal care to women who are likely to deliver pre-term. Fetal fibronectin (FF) is a glycoprotein found in amniotic fluid and placental tissue (Matsuura and Hakomori 1985). In the vast majority of normal uncomplicated pregnancies, FF should be

This was a retrospective study. The subjects were women who presented with symptoms of pre-term labour and underwent an FF test between September 2008 and October 2009, in Hull and East Yorkshire Women and Children’s Hospital – a tertiary hospital with a delivery rate of nearly 6,000/year. All staff who performed the FF test were trained in the use of the equipment and the indications to perform FF testing. According to regional guidelines, the FF test was performed on women who presented with symptoms of pre-term labour in the form of uterine tightening, at ⬍ 34 weeks’ gestation. All the patients who were included in this study had no evidence of fetal or maternal compromise. Women with threatened pre-term labour with evidence of SROM, vaginal bleeding or a history of sexual intercourse within 24 h of presentation, were not suitable for FF testing and were excluded from the study. The FF specimen was collected during a speculum examination, before a digital vaginal examination was performed, and analysed immediately in the labour ward. Lubricating gel was avoided for the examination, as it interferes with the test results. The test result was analysed by the HOLOGIC TLiIQ® System. Once the FF test was completed, all the patients were examined digitally to assess the cervical dilatation. Patients with cervical effacement (cervical length ⬍ 1 cm long) and dilatation ⬎ 2 cm were excluded from the study. Test data was collected prospectively for clinical governance purposes; however, details of delivery and hospital stay were

Correspondence: A. Anwar, Hull and East Yorkshire Hospitals, NHS Trust, Hull, UK. E-mail: [email protected]

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A. Anwar et al.

Table I. Management and delivery details of test-positive and -negative patients.

Test results (n ⫽ 133) Positive FFN Negative FFN Hospital admission (n ⫽ 116) Test-positive patients admitted (n ⫽ 24) Test-negative patients admitted (n ⫽ 92)

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Use of atosiban (n ⫽ 128) Total no of patients received Atosiban Test-positive patients (n ⫽ 26) Test-negative patients (n ⫽ 102) Use of steroids (n ⫽ 129) Total no. of patients received steroids Test-positive patients (n ⫽ 26) Test-negative patients (n ⫽ 103) Test delivery interval (n ⫽ 126) Test-negative patients (n ⫽ 101) Mean test delivery interval Range Test-positive patients (n ⫽ 25) Mean test delivery interval Range

n

(%)

28 105

21 79

22 34

92 37

p value

⬍ 0.01 19 13 6

14 50 5.7 ⬍ 0.001

41 19 22

32 73 21 ⬍ 0.001

57.8 days 14–122 days 37.8 days 1–120 days

retrieved from case notes after the delivery. Data was analysed using Microsoft Excel. The χ2-test was used for categorical data, with p ⬍ 0.05 considered significant. Permission to perform the study was provided by the trust audit committee.

Results During the study period, 133 symptomatic patients underwent the FF test. The mean age was 25.8 years (range 16–41) and the median gestational age at the time of the test was 31 weeks (range 25–34). Out of 133 patients who were tested, 28 (21%) had a positive test result while 105 patients (79%) were test negative. Information about the hospital admission was available for 116 patients. Among test positive patients, 92% of patients were admitted in hospital for administration of steroids and atosiban while 37% of test negative patients were discharged home at the time of initial presentation. In-utero transfer to another unit due to unavailability of NICU bed in our hospital at the time of presentation was needed for 5 patients. All in-utero transfer cases had a positive FF result. Table I demonstrates that significantly more test-positive patients received tocolysis, compared with test-negative patients (50% vs 5.7%). Similarly, the use of corticosteroids

was significantly more in test-positive patients compared with test-negative patients (73% vs 21%). The mean test-delivery interval was longer in test-negative patients and no test-negative patients delivered within 14 days of the test. A negative test for detecting the pre-term delivery within 10 days of the test was 100% sensitive with 100% negative predictive value (NPV). For the prediction of delivery under 34 weeks, it has specificity of 81.8%, with an NPV of over 90%. Although the test was more sensitive for short-term prediction, its specificity and NPV remains higher than the 80% for prediction of delivery at ⬍ 37 weeks’ gestation (Table II). The positive predictive value was 16% and 44% for delivery in 10 days, before 37 weeks, respectively.

Discussion The data from this study showed that the FF is an excellent shortterm predictor of pre-term delivery. The test was more accurate in ruling out than diagnosing pre-term labour in symptomatic women. With the negative test result, 100% of patients were pregnant at the end of 14 days and 95.5% were still pregnant at 34 weeks’ gestation. These findings are in agreement with previous research studies. A meta-analyses of 40 previous studies in symptomatic women demonstrated the likelihood ratio of pre-term delivery was 0.25 (0.20–0.31), with negative results on the test (Honest et al. 2002). This is consistent with a study by Peaceman et al. (1997), who found, among the women with a negative result, 99.5% were pregnant 7 days later and 99.2% were still pregnant 14 days later (Peaceman et al. 1997). High negative predictive value for delivery within 7 days of the test and before 34 weeks’ gestation was also confirmed by other studies (Iams et al. 1995; Parker et al. 1995). A more recent meta-analysis has found likelihood ratios for a positive and negative FF test were 4.20 (95% CI 3.53–4.99) and 0.29 (95% CI 0.22–0.38), respectively in symptomatic patients (Sanchez-Ramos et al. 2009). This result has led to changes in practice and decision-making in the management of threatened pre-term labour in our unit. For test-negative symptomatic patients, hospital admission and administration of steroids and atosiban is not offered. This change of practice may have huge cost-saving implications (Joffe et al. 1999). With the positive test result, the likelihood of delivery within 10 days was low, with a positive predictive value of 16%. The meta-analysis found a likelihood ratio of 5.42 (4.36–6.74) for delivery within 10 days of a positive test (Honest et al. 2002). Thus, in agreement with the meta-analysis of research data, the FF test proved to be a more reliable test to rule out preterm labour than predict pre-term labour. The accuracy of predicting true pre-term labour with FF can alter the therapeutic effectiveness of corticosteroids and avoid unnecessary administration of corticosteroids. It also facilitates clinicians to

Table II. Test predictive values for delivery. Delivery within 10 days of test Test-positive (n ⫽ 26) TP ⫽ 4 Test-negative (n ⫽ 101) FN ⫽ 0 Delivery before 34 weeks of gestation Test-positive (n ⫽ 26) TP ⫽ 4 Test-negative (n ⫽ 99) FN ⫽ 4 Delivery before 37 weeks of gestation Test-positive (n ⫽ 26) TP ⫽ 11 Test-negative (n ⫽ 99) FN ⫽ 16

FP ⫽ 21 TN ⫽ 101

Positive predictive value 16% Negative predictive value 100%

Sensitivity 100% Specificity 82.7%

FP ⫽ 21 TN ⫽ 95

Positive predictive value 16% Negative predictive value 95.5%

Sensitivity 50% Specificity 81.8%

FP ⫽ 14 TN ⫽ 83

Positive predictive value 44% Negative predictive value 83.8%

Sensitivity 40.7% Specificity 85.5%

TP, True positive; FP, False positive; FN, False negative; TN, True negative.

The use of fetal fibronectin in suspected pre-term labour: predictive value in clinical practice 47

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use corticosteroids in a more judicious manner. The therapeutic effectiveness of the use of antenatal steroids depends on the risk of spontaneous pre-term birth after presentation. The number of women that needed to be treated to prevent respiratory distress syndrome will be low if we limit the use in women with a high risk of pre-term birth. In this study, 41 patients received steroids. If steroids were to be used for all symptomatic women without FF testing, then 133 patients would have been treated with steroids. However, with the recent change in practice, only patients with positive results will receive the steroids, thus reducing the unnecessary use of antenatal steroids. Similarly, unnecessary inutero transfers to other units can be reduced by the finding of a negative test result. From the data, the use of FF testing in routine clinical practice results in test characteristics similar to those found in research studies. This implies that the conclusions reached by researchers can be reliably translated into clinical practice. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References Crowley P. 2000. Prophylactic corticosteroids for preterm birth. Cochrane Database of Systematic Reviews (2):CD000065. Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. 2002. Accuracy of cervicovaginal fetal fibronectin test in predicting spontaneous preterm birth: systematic review. British Medical Journal 325:301–304. Iams JD, Casal D, McGregor JA, Goodwin TM, Kreaden US, Lowensohn R et al. 1995. Fetal fibronectin improves the accuracy of diagnosis of preterm labour. American Journal of Obstetrics and Gynecology 173:141–145.

Joffe GM, Jacques D, Bemis-Heys R, Burton R, Skram B, Shelburne P. 1999. Impact of the fetal fibronectin assay on admissions for preterm labour. American Journal of Obstetrics and Gynecology 180:581–586. Lockwood CJ, Senyei AE, Dische MR, Casal D, Shah KD, Thung SN et al. 1991. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. New England Journal of Medicine 325:669–674. Mahony R, McKeating A, Murphy T, McAuliffe F, O’Herlihy C, Foley M. 2010. Appropriate antenatal corticosteroids use women at risk of preterm birth before 34 weeks of gestation. British Journal of Obstetrics and Gynaecology 117:963–967. Marlow N, Wolke D, Bracewell M, Samara M. 2005. EPICure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth. New England Journal of Medicine 352:9–19. Matsuura H, Hakomori S. 1985. The oncofetal domain of fibronectin defined by monoclonal antibody FDC-6: its presence in fibronectins from fetal and tumour tissues and its absence in those from normal adult tissues and plasma. Proceedings of the National Academy of Sciences of the USA 82:6517–6521. NHS. 2011. Hospital episode statistics: NHS maternity statistics 2010–2011. Health and London: Social Care Information Centre. Available at: www. hesonline.nhs.uk/Ease/servlet/ContentServer?siteID ⫽ 1937. Parker J, Bell R, Brennecke S. 1995. Fetal fibronectin in the cervicovaginal fluid of women with threatened preterm labour as a predictor of delivery before 34 weeks’ gestation. Australian and New Zealand Journal of Obstetrics and Gynaecology 35:257. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD et al. 1997. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. American Journal of Obstetrics and Gynecology 177:13–18. Sanchez-Ramos L, Delke I, Zamora J, Kaunitz AM. 2009. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a metaanalysis. Obstetrics and Gynecology 114:631. Sibille Y, Lwebuga-Mukasa JS, Polomski L, Merrill WW, Ingbar DH, Gee JB. 1986. An in vitro model for polymorphonuclear-leukocyte-induced injury to an extracellular matrix. Relative contribution of oxidants and elastase to fibronectin release from amnionic membranes. American Review of Respiratory Disease 134:134–140.

The use of fetal fibronectin in suspected pre-term labour.

Pre-term delivery is the leading cause of neonatal mortality and morbidity. The aim of this study is to determine the diagnostic accuracy of the fetal...
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