Royal Australian and New Zealand College of Obstetricians and Gynaecologists - Royal Australian and New Zealand College of Obstetricians and Gynaecologists

College Statement
C-Obs 26
1st Endorsed: November 2008
Current: November 2011
Review: November 2014

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Women presenting with symptoms of preterm labour pose a common clinical problem, and a challenge for all delivering obstetric care. The majority will go on to deliver at term, but, for the minority who are destined to deliver preterm, there are some beneficial obstetric interventions. These include the use of tocolytic agents to defer delivery to allow transfer to a tertiary centre the administration of corticosteroids to enhance fetal lung maturation, +/- the administration of magnesium sulphate to reduce the risk of cerebral palsy among those destined to deliver preterm.These interventions are costly to health care systems and disruptive to the woman and her family when remote transfer is necessary. It is beneficial to be able to identify those pregnancies at low risk of preterm birth, to minimise intervention.

Fetal fibronectin (fFN) is a glycoprotein promoting adhesion between the fetal chorion and maternal decidua. Fetal fibronectin is typically absent from cervicovaginal secretions between 24 and 36 weeks’ gestation, becoming detectable again as term approaches. Elevated levels of fFN (typically > 50ng/ml) in cervicovaginal secretions between 24 and 36 weeks’ gestation are associated with an increased risk of preterm birth. Following a positive test result the likelihood ratio of symptomatic women delivering within 7days is 4.2. The negative likelihood ratio is 0.29.

The sensitivity of fFN for predicting preterm birth within 7 days among symptomatic women is approximately 76% and the specificity is 82%. Given the background low prevalence of preterm birth even among symptomatic women, this translates to a positive predictive value of 13-30% for preterm birth in the next 7 days, and 40-65% for any preterm delivery.

The greatest clinical utility for fetal fibronectin, however, is in its negative predictive value in symptomatic women. A negative fFN was associated with a 97% Negative Predictive Value for delivery in the next 7 days from a meta-analysis of 32 trials with 5,355 participants where the median rate of birth within the next week following symptoms was 8%. In the same meta-analysis, if fFN was positive, the rate of birth within the next week increased to 28%. The precise positive and negative predictive values depend upon the prevalence of the condition, preterm birth. Nevertheless, knowledge of fFN appears to reduce preterm birth, by unknown mechanisms. Pragmatically, a negative fFN in symptomatic women has been associated with reduced transfers to tertiary centres, reduced admissions for threatened preterm labour, reduced use of tocolytic agents and corticosteroids and reduced mean cost of treatment. Avoiding the financial and personal burden of transfer of women from remote areas is particularly relevant in Australian and New Zealand obstetric care.

A widely used alternative bedside predictive test for preterm labour in symptomatic patients is phosphorylated insulin-like growth factor binding protein-1 (IGFBP1-P) or Actim-Partus (Medix Biochemica http://www.medixbiochemica.com/Actim_tests/Actim_Products/Partus/en_GB/Overview_Partus/).

One advantage of IGFBP1-P is its lower cost. Compared to fetal fibronectin, its interpretation is more reliable when there has been vaginal examination, transvaginal ultrasound or the presence of blood or semen (Dell’Avanzo M 2007). A third advantage is that it provides similar predictive qualities to transvaginal ultrasound and thus may be a reasonable alternative when imaging is not available (Brik 2010) (Rahkonen 2009).

IGFBP1-P does not add additional precision to the prediction of preterm birth if cervical length is already known from ultrasound (Rahkonen 2009). Using IGFBP1-P in a “contingency” screening strategy with ultrasound measured cervical length has not proved as successful as using fetal fibronectin selectively for symptomatic women with cervical length between 20 and 30 mm.

The sensitivity and specificity of IGFBP-1 for the prediction of preterm birth in symptomatic patients is slightly lower than the same test properties for fetal fibronectin. Pooling 9 studies up to publication in 2009 yielded overall sensitivity and specificity of 66.7% and 86.2%, (Wiwanitkit 2010) with at least 2 more promising small studies published recently (Azlin 2010) (Rahkonen 2009). Thus performance is close to, but possibly slightly inferior to fibronectin (Brik 2010). Direct comparison of sensitivity and specificity for IGFBP1-P with fibronectin favoured fibronectin in one study (Audibert 2010).

There is also some promise for use of IGFBP1-P for predicting premature birth in asymptomatic patients (Conde-Agudelo 2011, Adeyemi 2010)

 

Recommendations:

Efforts should be made to minimize possible unnecessary interventions associated with threatened preterm labour, given the burden these impose on women and health care providers.

1. The high Negative Predictive Value of fFN in cervicovaginal secretions can be used clinically to minimise potentially dangerous or expensive interventions, such as tertiary transfer, admission to hospital, administration of corticosteroids and tocolytics.

2. Ideally, all units providing obstetric care should have access to bedside fFN testing to assist with clinical decision making in women presenting with ALL of the following:

a) Symptomatic preterm labour, between 24 and 34 weeks’ gestation

b) Intact membranes

c) At less than 3cm cervical dilatation

 

3. Testing technique. The specimen should be collected from the posterior fornix during a speculum examination.

4. Clinicians should be aware of factors that may affect test reliability. These include:

False positive results:

Increased false positive results may occur in situations where there has been cervical manipulation within the previous 24 hours, such as coitus, digital vaginal examination and transvaginal ultrasound examination. Fetal fibronectin is found in blood and semen, and these may cause false positive results,  However, negative results in any of these settings can still be considered reliable,.

False negative results:

The use of intravaginal lubricants and disinfectants may interfere with the antibody reaction, leading to an increase in false negative results.

5. Cervical length may be used to better refine which patients will benefit from fFN testing. Where fFN is restricted to women with a measured cervical length <30mm on transvaginal ultrasonography, 55% of fFN tests can be avoided. Nevertheless, this strategy can only be employed where there is ready access to transvaginal ultrasound equipment and expertise, which limits its value in many settings.

6. fFN has been used as a screening test in asymptomatic women at high risk for preterm birth. Its value in this group is limited by the lack of an effective treatment intervention. The administration of antibiotics to women at high risk of preterm birth with a positive fFN was associated with a non-significant trend toward increased preterm birth and thus possibly worse outcomes. A positive fFN at 24 weeks’ gestation among high risk women, while associated with a likelihood ratio of 15 for delivery <30 weeks’ gestation, was also associated with high levels of maternal anxiety. The exact role of fFN among asymptomatic women remains to be determined.

7. fFN has been shown to have similar test characteristics in women with multiple pregnancies presenting with preterm contractions, with sensitivity, specificity, positive and negative likelihood ratios of 85%, 78%, 3.9, and 0.20 (Conde-Agudelo 2010). 

8. The value of repeating the fFN testing (e.g. to assist discharge planning from a tertiary centre) has not been formally evaluated, but may be considered on an individual basis.

9. Practitioners and institutions that use IGFBP-1 or fFN should be aware that both may produce false positive and false negative results. IGFBP-1 may be less costly and less subject to interpretation problems if the patient has coexisting antepartum haemorrhage or if transvaginal ultrasound is not available. Its interpretation may be simpler than for fFN if the patient has had coitus or a vaginal examination within the last 24 hours. Its sensitivity and specificity for the prediction of preterm birth is slightly inferior to the same properties of fFN.

 

References

1. Adeza Biomedical Fetal Fibronectin Immunoassay and rapid TLiIQ system. Information for health care providers. 2003 December 2003 [cited 2008 16 Feb]; Available from: http://fullterm.net/pdfs/FullTerm_Product_Insert.pdf
2. Sanchez-Ramos L, Delke I, Zamora J, Kaunitz AM. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol. 2009 Sep;114(3):631-40.
3. Parry, E., et al., Improved management in threatened preterm labour with rapid fetal fibronectin testing. Aust N Z J Obstet Gynaecol, 2006. 46(3): p. 240-1
4. Groom KM, Liu E, Allenby K. The impact of fetal fibronectin testing for women with symptoms of preterm labour in routine clinical practice within a New Zealand population. Aust NZ J Obstet Gynaecol 2006; 46: 440-5.
5. Schmitz T, Maillard F, Bessard-Bacquaert S et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labour. Am J Obstet Gynecol 2006; 194: 138-43.
6. Singer W, Pilpel S, Bsat F et al. Accuracy of fetal fibronectin to predict preterm birth in twin gestations with symptoms of labor. Obstet Gynecol 2007; 109: 1083-7.
7. Smith V, Devane D, Begley CM et al. A systematic review and quality assessment of systematic reviews of fetal fibronectin and transvaginal length for predicting preterm birth. Eur J Obstet Gynecol and Reprod Biol 2007; 133: 134-42.
8. Giles W. Fetal fibronectin use in the management of threatened preterm labour. O and G. Spring 2006.
9. Giles W, Bistis A, Knox M et al. The effect of fetal fibronectin testing on admissions to a tertiary maternal-fetal medicine unit and cost savings. Am J Obstet Gynecol 2000; 182: 439-42.
10. Rozenberg, P., et al., Evaluating the risk of preterm delivery: a comparison of fetal fibronectin and transvaginal ultrasonographic measurement of cervical length. Am J Obstet Gynecol, 1997. 176(1 Pt 1): p. 196-9
11. Iams, J.D., Prediction and early detection of preterm labor. Obstet Gynecol, 2003. 101(2): p. 402-12
12. Shennan, A., et al., A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006. 113(1): p. 65-74.
13. Andrews, W.W., et al., Randomized clinical trial of metronidazole plus erythromycin to prevent spontaneous preterm delivery in fetal fibronectin-positive women. Obstet Gynecol, 2003. 101(5 Pt 1): p. 847-55
14. Shennan A, Jones G, Hawken J et al. Fetal fibronectin test predicts delivery before 30 weeks gestation in high risk women, but increases anxiety. BJOG 2005; 112: 293-8.
15. Conde-Agudelo A, Romero R. Cervicovaginal fetal fibronectin for the prediction of spontaneous preterm birth in multiple pregnancies: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2010 Dec;23(12):1365-76
16. Berghella V, Hayes E, Visintine J, Baxter JK. Fetal fibronectin testing for reducing the risk of preterm birth Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006843.
17. Dell’Avanzo M, Nicolini U. Cervical phIGFBP-1 in the evaluation of the risk of preterm delivery. Acta Obstet Gynecol Scand 2007; 86: 151–155
18. Brik M, Hernández AI, Pedraz CC, Perales A. Phosphorylated insulin-like growth factor binding protein-1 and cervical measurement in women with threatening preterm birth. Acta Obstet Gynecol Scand. 2010;89(2):268-74.
19. Rahkonen L, Unkila-Kallio L, Nuutila M, Sainio S, Saisto T, Rutanen EM, Paavonen J. Cervical length measurement and cervical phosphorylated insulin-like growth factor binding protein-1 testing in prediction of preterm birth in patients reporting uterine contractions. Acta Obstet Gynecol Scand. 2009;88(8):901-8
20. Wiwanitkit V. Diagnostic property of cervical phosphorylated insulin-like growth factor binding protein-1 in the prediction of preterm labor in symptomatic patients. Arch Gynecol Obstet. 2010 Jan;281(1):175-6. Epub 2009 Apr 22.
21. Azlin MI, Bang HK, An LJ, Mohamad SN, Mansor NA, Yee BS, Zulkifli NH, Tamil AM. Role of phIGFBP-1 and ultrasound cervical length in predicting pre-term labour. J Obstet Gynaecol. 2010;30(5):456-9.
22. Audibert F, Fortin S, Delvin E, Djemli A, Brunet S, Dubé J, Fraser WD. Contingent use of fetal fibronectin testing and cervical length measurement in women with preterm labour. J Obstet Gynaecol Can. 2010 Apr;32(4):307-12.
23. Conde-Agudelo A, Papageorghiou AT, Kennedy SH, Villar J. Novel biomarkers for the prediction of the spontaneous preterm birth phenotype: a systematic review and meta-analysis. BJOG. 2011 Aug;118(9):1042-54.
24. Adeyemi O, Osoba L. The role of phosphorylated insulin-like growth factor binding protein-1 in predicting pre-term labour in twin pregnancies. J Obstet Gynaecol. 2010;30(6):571-3

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Disclaimer

This College Statement is intended to provide general advice to Practitioners. The statement should never be relied on as a substitute for proper assessment with respect to the particular circumstances of each case and the needs of each patient.

The statement has been prepared having regard to general circumstances. It is the responsibility of each Practitioner to have regard to the particular circumstances of each case, and the application of this statement in each case. In particular, clinical management must always be responsive to the needs of the individual patient and the particular circumstances of each case.

This College statement has been prepared having regard to the information available at the time of its preparation, and each Practitioner must have regard to relevant information, research or material which may have been published or become available subsequently.

Whilst the College endeavours to ensure that College statements are accurate and current at the time of their preparation, it takes no responsibility for matters arising from changed circumstances or information or material that may have become available after the date of the statements.