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The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients
OBSTETRICS OBSTETRICS
The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients Amanda Skoll, MD,1 Patrick St. Louis, PhD,2 Neda Amiri,1 Marie-France Delisle, MD,1 Sayrin Lalji, MD1 1
Department of Obstetrics and Gynaecology, Children’s and Women’s Health Centre of BC, Vancouver BC
2
Department of Biochemistry, Sainte-Justine Hospital, Montreal QC
Abstract Objective: This study was conducted to evaluate the usefulness of testing for fetal fibronectin (fFN) to rule out the diagnosis of preterm labour in symptomatic patients in a Canadian setting. Methods: This was a prospective, blinded clinical evaluation of fFN testing in women presenting with threatened preterm labour at between 24 and 34 weeks’ gestation at two Canadian tertiary care centres. Results: Of the 149 women tested, 32 had a positive fFN test. In the total patient population, 10.1% delivered within seven days of testing, and 18.2% delivered prior to 34 weeks. A negative fFN result was associated with a 97.4% likelihood of delivering more than seven days after testing and with a 91.4% chance of delivering after 34 weeks. Conclusion: The fFN test appears to provide useful information in the risk assessment of Canadian women presenting with symptoms compatible with preterm labour. A negative test has a high predictive value for delivering more than seven days after presentation.
Résumé Objectif : La présente étude a été menée en vue d’évaluer l’utilité du test visant la fibronectine fœtale (FNf) pour écarter le diagnostic de travail préterme chez les patientes symptomatiques, en milieu canadien. Méthodes : Il s’agissait d’une évaluation clinique prospective et à l’aveugle du test FNf chez les femmes présentant une menace de e e travail préterme entre la 24 et la 34 semaine de gestation, au sein de deux centres de soins tertiaires canadiens. Résultats : Des 149 femmes soumises au test FNf, 32 ont obtenu des résultats positifs. Au sein de la population totale de patientes, 10,1 % des femmes ont accouché dans les sept jours suivant l’administration du test et 18,2 % des femmes ont accouché avant e la 34 semaine de gestation. L’obtention de résultats négatifs au test FNf a été associée à une probabilité d’accoucher plus de sept jours à la suite de l’administration du test de l’ordre de 97,4 %, Key Words: Preterm labour, fetal fibronectin, prematurity, screening Competing Interests: None declared. Received on July 27, 2005 Accepted on October 7, 2005
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ainsi qu’à une probabilité d’accoucher après la 34 semaine de gestation de l’ordre de 91,4 %. Conclusion : Le test FNf semble offrir des renseignements utiles pour l’évaluation du risque chez les Canadiennes qui présentent des symptômes compatibles avec le travail préterme. L’obtention d’un test négatif compte une valeur prédictive élevée en ce qui concerne l’accouchement plus de sept jours à la suite de l’administration du test. J Obstet Gynaecol Can 2006;28(3):206–213
INTRODUCTION
he problem of preterm birth continues to be one of the most important challenges in obstetrics. Preterm delivery accounts for the vast majority of perinatal morbidity and mortality, as well as leading to long-term sequelae for many survivors.1-3 Unfortunately, attempts to counter this problem with the development of new tocolytic therapies have generally been unsuccessful.4-7
T
Our desire to intervene in patients who appear to be at risk of preterm delivery has resulted in the use of therapies such as corticosteroids, tocolytics, antibiotics, and other drugs in many patients who were found subsequently not to be in labour.8 The maternal and fetal risks of these therapies,9-14 added to the financial and social costs of maternal transfers and hospitalization,7,15,16 demand a more rational approach to the patient who presents with symptoms consistent with preterm labour. Fetal fibronectin (fFN) has been very widely studied over the last 14 years as a potential marker for the selection of patients who require intervention for true preterm labour.17 Fibronectin is an extracellular protein associated with basement membranes. fFN contains a unique glycoprotein region. It can be detected in the cervicovaginal secretions of women in early pregnancy,18 but in a normal pregnancy it becomes no longer detectable after 24 weeks’ gestation
The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients
because the fetal membranes are isolated from the upper vagina and lower cervix by the thick secretions within the cervical canal. However, as labour approaches, it reappears in cervicovaginal secretions because of separation of the membranes from the decidua in the lower uterine segment. It has been proposed that the presence of fFN in the cervicovaginal fluid after 24 weeks is a marker for preterm labour, although the positive predictive value for preterm delivery is not high.19-24 More importantly, in symptomatic patients a negative result is associated with a significantly decreased risk of delivery within 7 to 10 days.25 Of women with a negative test result, more than 95% have been reported not to deliver within one week of testing.25-27 Before implementing this test in our centres, we felt compelled to examine its performance in our patient populations for a number of different reasons. First, it has clearly been shown by numerous investigators that one of the most important underlying etiologies for idiopathic preterm labour is inflammation.28-30 The vaginal flora appear to play a crucial role in the risk for preterm labour, with ascending infection causing activation of inflammatory mediators in the decidua.29,31,32 Thus the prevalence of various vaginal organisms in the patient population targeted may have an important influence on the pathogenesis and the incidence of preterm labour. The majority of the large studies that have investigated the efficacy of fFN testing in the prediction—or more importantly, in the ruling out—of preterm labour were performed in large public hospitals in the United States.10,17,19,24,26,27,33 These centres may have patient populations with rates of infection that are different from those in Canadian centres. For example, the United States Centers for Disease Control cite a median chlamydial infection rate of 7.4% (range 2.4–19.7%) in women 15 to 29 years of age attending prenatal clinics,34 but in British Columbia, women of the same age had a rate of chlamydial infection of 1.4% during the same time period.35 A similar difference is seen in the prevalence of gonorrhea in these groups, with a median rate of 1% (range 0–3.7%) in the American population34 versus 0.06% in BC.36 These potential differences in vaginal flora could have a significant effect on a test like fFN. Moreover, the usefulness of fFN testing in reducing the overtreatment of preterm labour depends on its negative predictive value. This characteristic is dependent on the incidence of the disease in the population. Therefore, unless the outcome for the study (in this case, the incidence of preterm delivery) is relatively frequent, there is no great benefit in having a high negative predictive value. In a population where very few patients actually go on to deliver prematurely, the a priori risk is already so low that another test
is unlikely to change their predicted risk. This is a problem for a number of the fFN studies published to date.37,38 For this reason, we wished to determine whether the test performed as well in a population with a much higher rate of preterm delivery. In the Canadian context, many patients present for care far away from facilities that can provide adequate care for preterm infants. It is imperative to be extremely confident in the ability of a test to rule out true preterm labour before we can recommend its integration into clinical practice. The objective of the study was to determine the sensitivity, specificity, and positive and negative predictive values for delivery within seven days, and for delivery prior to 34 weeks’ gestation, of testing for fetal fibronectin in the cervicovaginal secretions of patients presenting with symptoms of preterm labour in two Canadian tertiary care centres. Our primary focus was to determine the usefulness of fFN testing in ruling out preterm labour in symptomatic patients. METHODS Study Patients
The study was carried out at Sainte-Justine Hospital (Université de Montréal) in Montreal, and BC Women’s Hospital (University of British Columbia) in Vancouver. Women presenting at between 24 and 34 completed weeks of gestation for evaluation of symptoms compatible with preterm labour were eligible for inclusion in the study. They were approached for possible participation in the study if there was (1) no rupture of membranes; (2) no moderate or severe vaginal bleeding; and (3) no indication for preterm delivery, including non-reassuring fetal assessment, chorioamnionitis, severe maternal hypertension, or fetal death. Candidates who agreed to participate were asked to sign a consent form after the study was explained to them. At the time of speculum examination for evaluation of the cervix and collection of swabs for culture as clinically indicated, a swab was collected from the posterior vaginal fornix by the house staff physician or attending physician for the quantification of fFN. If the physician excluded the diagnosis of preterm labour on clinical assessment and vaginal examination and discharged the patient home, the swab for fFN quantification was discarded and the patient was not included in the final analysis. The ethics committees of the University of British Columbia, BC Children’s and Women’s Hospital, Université de Montréal and Sainte-Justine Hospital approved the study. MARCH JOGC MARS 2006 l
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Table 1. Clinical characteristics of the 160 study patients
Site of admission
n
%
Vancouver
104
65.0
Montreal
56
35.0
42
26.3
Primigravidae Cerclage in current pregnancy
0
0
Previous preterm birth
26
16.3
Single
147
91.9
Twin
12
7.5
Triplet
1
0.6
Contractions
92
70.8
Bleeding
10
7.7
Abdominal / back pain
23
17.7
Cramps / tightening
29
22.3
Discharge / fluid‡
8
8.2
Pressure
5
3.8
PIH
1
0.8
Number of fetuses
Reason for admission*†
*The presenting symptoms are not mutually exclusive. †Available for only 130 patients. ‡Rupture of membranes was ruled out prior to enrolment. PIH: pregnancy-induced hypertension.
Laboratory Essays and Data Collection
For the purposes of the study, included specimens were stored in the laboratory at –4º C and run in weekly batches. Analysis was performed using the TLiIQ System (Adeza Biomedical Corporation, CA). A level of 50 ng/mL or greater is considered positive. Information was collected at the time of the specimen collection regarding the clinical presentation. This included gestational age, reason for admission, presence and frequency of uterine contractions, cervical examination (dilatation, effacement, consistency, position), and presence of blood in the vagina. In addition, information was recorded regarding any digital examinations, sexual intercourse, or endovaginal ultrasound tests within the 24 hours preceding swab collection. Treating physicians were blinded to the results of the fFN test. Decisions regarding admission, use of tocolytics, antenatal steroid therapy, and antibiotics were made on clinical grounds by each physician, and details were recorded for each patient. For patients who were transferred to the tertiary centre from outside institutions, use of these therapies preceding transfer was also recorded. At the time of delivery, data recorded included gestational age at delivery, interval from fFN testing to delivery, birth 208
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weight, and need for neonatal intensive care unit (NICU) admission for the newborn. Statistical Analysis
Categorical values were calculated using descriptive analysis. Two models were constructed to analyze the association between tocolytics, antibiotics, and steroids and delivery within seven days of the fFN test. The first, model A, used the forward likelihood ratio as a criterion to consider variables that were significant. The second, model B, considered all variables. They were analyzed by the significance of the coefficients of each independent variable. In order to demonstrate a significant association (set at P < 0.05) between fFN levels and preterm delivery, with a negative predictive value of 95% and a positive predictive value of 50%, we sought to study at least 186 patients.24 RESULTS
In total, 184 women were recruited into the study over a two-year period. Fetal fibronectin results were not available for 24 (for reasons such as label detached, not enough sample, sample leaked), leaving a total of 160 women for whom test results were available. One hundred four women were recruited in Vancouver and 56 in Montreal. Eleven patients were lost to follow-up, leaving 149 patients for final data analysis.
The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients
Table 2. Clinical characteristics of the positively and negatively tested patients
Days admitted without delivery
Statistics
fFN Positive
fFN Negative
mean
3.6563 (SE = 1.39021)
3.8103 (SE = 0.6765)
0.8209
2.4720
95% Confidence interval for mean
Days between test and delivery
GA at admission
upper boundary
6.4916
5.1487
variance
61.846
52.955
standard deviation
7.86421
7.27702
mean
29.0000
62.4655
(SE = 5.24789)
(SE = 2.58645)
lower boundary
18.2969
57.3423
upper boundary
39.7031
67.5888
variance
881.290
776.007
standard deviation
29.68653
27.85691
Median
32.5
38.0
95% Confidence interval for mean
GA at delivery
lower boundary
Minimum
25.0
26.0
Maximum
41.0
42.0
Range
16.0
16.0
Interquartile range
7.0
2.0
Median
29.07
28.71
Minimum
23
20
Maximum
34
35
Range
11
15
Interquartile range
3
4
fFN: fetal fibronectin; GA: gestational age; SE: standard error
The clinical characteristics of the population are outlined in Table 1. The mean maternal age was 29 years (range 17–43 years). The reason for admission was available for 130 patients. The patients’ presenting complaints were most frequently uterine contractions (92 cases or 71%); the full list of presenting symptoms is shown in Table 1. The mean gestational age at testing was 28.8 weeks, and the mean test-to-delivery interval was 54.9 days. The mean gestational age at delivery for the total group was 36.6 weeks. A total of 32 patients had a positive fFN result, leaving 117 with a negative test. The clinical characteristics of these patients are shown in Table 2. Twelve patients with a positive test delivered within seven days of testing, and the remaining 20 delivered at some time after seven days. Among the patients with a negative result, three delivered within seven days and the remaining 114 patients delivered more than seven days after the test. Thus, test sensitivity was 80.0% (95% confidence intervals [CI] 51.4, 94.7), specificity 85.1% (95% CI 77.6, 90.4), and prevalence was 10.1%. The positive predictive value of the fFN test for delivery within seven days of
testing was 37.5% (95% CI 21.7, 56.3). The negative predictive value for the same outcome was 97.4% (95% CI 92.1, 99.3). These results are summarized in Table 3. For delivery before 34 weeks’ gestation, the test demonstrated sensitivity of 63.0% (95% CI 42.4, 79.9), specificity of 87.6% (95% CI 80.1, 92.7), with a prevalence of 18.2%. Positive predictive value and negative predictive values of 63.0% (95% CI 35, 70.5) and 91.4% (95% CI 84.3, 95.6) were calculated for the fFN result for this outcome (Table 4). Seventeen patients who tested positive for fFN delivered prior to 34 weeks, and the remaining 15 delivered at or after 34 weeks. Among the negatively tested population, 27 patients delivered before 34 weeks and 121 patients at or after 34 weeks. The variables of tocolytics, antibiotics, and steroids were tested for association with delivery within seven days of testing using both statistical models (A and B). In model A, only fFN appeared to explain the outcome. In model B, although all variables were entered in the model, none but fFN had significant correlation coefficients (the 95% CI were very wide and crossed unity in all cases). This finding MARCH JOGC MARS 2006 l
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Table 3. Results of fetal fibronectin testing by incidence of delivery within seven days of testing Statistic
Value
95% CI
Sensitivity
0.80
0.514
0.947
Specificity
0.851
0.776
0.904
Positive predictive
0.375
0.217
0.563
Negative predictive
0.974
0.921
0.993
Positive LR
5.36
3.327
8.635
Negative LR
0.235
0.085
0.648
CI: confidence interval; LR: likelihood ratio.
Table 4. Results of fetal fibronectin testing by incidence of delivery before 34 weeks’ gestation Statistic
Value
95% CI
Sensitivity
0.63
0.424
Specificity
0.876
0.801
0.927
Positive predictive
0.531
0.35
0.705
Negative predictive
0.914
0.843
0.956
Positive LR
5.079
2.916
8.847
Negative LR
0.423
0.258
0.693
0.799
CI: confidence interval; LR: likelihood ratio.
supports the hypothesis that the outcome was not a function of tocolysis or other factor, but rather was predicted by fFN testing alone. Model B had better predictive capabilities and a higher explanation of the overall outcome (Nagelkerke R Square = 0.430) than did model A (0.346). However, model B includes many independent variables (i.e., is considered “saturated”) and only the fFN result made a statistically significant contribution. DISCUSSION
In this study, we attempted to determine the usefulness of fFN in a population of Canadian patients symptomatic for preterm labour. The positive predictive value of the test was 37.5% for delivery within seven days of testing and 63% for delivery before 34 weeks of gestation, values that are higher than those in many of the previously published reports. More importantly for our research question, we found that fFN, when measured in symptomatic patients at between 24 and 34 completed weeks of gestation, provides a high negative predictive value for continuing pregnancy beyond seven days after testing and for prolonging gestation beyond 34 weeks. This is clinically important for a number of reasons. 210
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Steroids have been clearly shown to reduce perinatal morbidity and mortality when administered to women who go on to deliver prior to 34 weeks’ gestation.39 However, the question remains regarding the duration of the efficacy of antenatal steroid therapy. It is clear that the ideal situation would be that all babies born prior to 34 weeks receive only one full course of antenatal steroids within one to two weeks of their delivery. The corollary is that, in the ideal situation, a baby delivered after 34 weeks should not be exposed to steroids unnecessarily. Thus, the fact that a negative fFN result confers a 97.4% chance of not delivering within the next seven days permits the withholding of antenatal corticosteroids in the acute period. Three patients in the study with negative fFN results went on to deliver within seven days of testing. These patients merit a more detailed review. The first patient was seen at 33 weeks’ gestation. Her cervical dilatation was 4 cm to 5 cm at the first evaluation and fFN testing was negative, but she delivered spontaneously on the day after testing. Other authors have reported a greater incidence of false negative testing in patients with more advanced cervical change than in patients with minimal cervical dilatation.37 This is of little clinical importance, since the diagnosis of preterm labour is already clear in such cases, and does not require fFN testing to make management decisions.
The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients
The second patient who delivered within a week of testing was admitted at 26 weeks’ gestation with severe hypertension and proteinuria. Five days after admission she developed uterine contractions that lasted for more than four hours, and she was assessed for the possibility of preterm labour and entered the study at that time. Her cervix had not changed significantly, but she was subsequently delivered by Caesarean section because of non-reassuring fetal status. There is no evidence that she would have gone on to deliver spontaneously within seven days. The third patient presented to the hospital with uterine tightenings at 28 weeks. On evaluation, she was found to have a long, closed cervix that did not demonstrate significant change despite her contractions. However, she was noted to have significant hypertension, and she underwent Caesarean section four days later for this reason. Thus, of the three patients who delivered within seven days of a negative test, one would have been admitted in any case because of her advanced cervical dilatation, and the other two were delivered because of maternal or fetal indications and not because of spontaneous preterm labour. The endpoint of delivery after 34 weeks was chosen because this is the gestational age at which the risks of prematurity are no longer high enough to justify the potential consequences of attempting to arrest labour. The negative predictive value of this study demonstrates that a symptomatic patient with a negative fFN test has a greater than 91% chance of never requiring tocolysis or antenatal steroid therapy during this pregnancy. Although the body of literature related to fFN testing is large, it is very heterogeneous. Some published studies include only symptomatic patients, and others include asymptomatic patients considered to be “at risk.” Other studies have evaluated the use of fFN testing with or without other predictors (including risk scoring systems, bacterial vaginosis, or cervical ultrasound measurements) in low-risk populations. In 1999, Crane et al. published a report of the use of fFN testing in a Canadian population.38 However, this study, unlike ours, assessed a group of asymptomatic patients. The fFN test used at that time was the ELISA analysis rather than the current rapid test. Overall, there was a 6.4% spontaneous preterm birth rate (defined as delivery prior to 37 weeks) with the vaginal fFN test demonstrating a negative predictive value (NPV) of 96.5%. It is difficult to evaluate the usefulness of such a NPV when the incidence of preterm birth in the population was so low, as would be expected in a study of asymptomatic patients. Thus this study is unable to reassure us that the test performs well in a symptomatic Canadian population.
In a study of symptomatic patients in Nova Scotia (Armson et al., 2004 personal communication), a total of 193 patients were available for analysis. Although the NPV for fetal Fibronectin in this study was 99.4% for delivery within 14 days and 90% for delivery prior to 37 weeks, the actual preterm birth rate was less than 4%. Thus, the test did not actually add a great deal to the clinical assessment. Most of the original data on the use of fFN testing in symptomatic patients originated in studies in the large publicly funded centres in the United States. The prenatal populations of these centres have a high rate of genital infection, as reflected in the data from the Centers for Disease Control. There is very strong evidence that infection and inflammation play a strong role in the pathogenesis of so-called “idiopathic” preterm labour.40 The vaginal flora of those US patient populations may be significantly different from those of Canadian patient populations, and these differences may modify the effectiveness of a test based on vaginal secretions in the prediction of preterm birth. Fortunately, we can now be reassured that the fFN test does perform equally well to rule out true preterm labour in Canadian populations. The other strength of our study comes from the high rate of preterm birth in our population. This is due to a number of factors. First, we recruited only symptomatic patients. Review of the patient demographics indicated that our patient population had a fairly high a priori risk of preterm labour, since 27% of our population had previously experienced preterm delivery and 8.6% were carrying multiple gestations. Finally, the methodology of the study favoured the selection of patients truly at risk because we discarded the specimens of those patients who were assessed clinically as not being in preterm labour. If the physician already felt comfortable discharging the patient based on clinical assessment and examination, we reasoned that there was no benefit to be gained from adding a relatively expensive biochemical test. As a result of these factors, the rate of preterm delivery prior to 34 weeks in our study was 18%. In addition, more than 10% of our patients delivered within seven days of testing. Now that we have documented the performance of this test in our patient population, we feel comfortable applying the results of studies in other populations that show similar results. The use of fFN testing should indeed reduce the transfers of pregnant women to tertiary care centres41-43 and should decrease the use of tocolytics, antenatal steroids, and other interventions for women who are not actually at risk of preterm delivery. The challenge remains for us to educate physicians and other caregivers in the appropriate use and interpretation of this test.44 MARCH JOGC MARS 2006 l
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CONCLUSION
The rapid test for the quantification of fFN in the cervicovaginal secretions of Canadian women presenting with symptoms of preterm labour between 24 and 34 weeks’ gestation is useful in predicting which patients will continue their pregnancy for at least seven days and beyond 34 weeks’ gestation. As such, it is a useful adjunct in the assessment of patients with suspected preterm labour. ACKNOWLEDGEMENTS
The authors would like to thank Victor Espinosa for his extensive statistical help. REFERENCES 1. Morrison JC. Preterm birth: a puzzle worth solving. Obstet Gynecol 1990;76:5S–12S. 2. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985;312:82–90. 3. Hack M, Fanaroff AA. Outcomes of extremely immature infants: a perinatal dilemma. N Engl J Med 1993;329:1649–50. 4. Klam SL, Leduc L. Management options for preterm labour in Canada. J Obstet Gynaecol Can 2004;26:339-45. 5. ACOG Practice Bulletin no. 43: management of preterm labor vol 101. Obstet Gynecol 2003;5:1039–47. 6. McWhorter J, Carlan SJ, O’Leary TD, Richichi K, O’Brien WF. Rofecoxib versus magnesium sulfate to arrest preterm labor: a randomized trial. Obstet Gynecol. 2004;103:923–30. 7. Smith GN. What are the realistic expectations of tocolytics? BJOG 2003;110:103–6 8. Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl J Med 1992;327:308–12. 9. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 2000;342:534–40. 10. Goldenberg RL, Thom E, Moawad AH, Johnson F, Roberts J, Caritis SN. The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection: NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 1996;87:656–60. 11. Thorp JM Jr, Hartmann KE, Berkman ND, Carey TS, Lohr KN, Gavin NI, et al. Antibiotic therapy for the treatment of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2002;186:587–92. 12. Berkman ND, Thorp JM Jr, Lohr KN, Carey TS, Hartmann KE, Gavin NI, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol 2003;188:1648–59. 13. Sanchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of maintenance therapy after acute tocolysis: a meta-analysis. Am J Obstet Gynecol 1999;181:484–90. 14. Meirowitz NB, Ananth CV, Smulian JC, Vintzileos AM. Value of maintenance therapy with oral tocolytics: a systematic review. J Matern Fetal Med 1999;8:177–83. 15. Moutquin J-M. Preterm births in Canada. Where do we go from here? JSOGC 1999;21:12–5. 16. St John EB, Nelson KG, Cliver SP, Bishnoi RR, Goldenberg RL. Cost of neonatal care according to gestational age at birth and survival status. Am J Obstet Gynecol 2000;182:170–5.
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17. Lockwood CJ, Senyei AE, Dische MR, Casal D, Shah KD, Thung SN, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 1991;325:669–74. 18. Feinberg RF, Kliman HJ, Lockwood CJ. Is oncofetal fibronectin a trophoblast glue for human implantation? Am J Path 1991;138:537–43. 19. Lockwood CJ, Wein R, Lapinski R, Casal D, Berkowitz G, Alvarez M, et al. The presence of cervical and vaginal fetal fibronectin predicts preterm delivery in an inner-city obstetric population. Am J Obstet Gynecol 1993;169:798–804. 20. Faron G, Boulvain M, Irion O, Bernard PM, Fraser WD. Prediction of preterm delivery by fetal fibronectin: A meta-analysis. Obstet Gynecol 1998;92:153–8. 21. Goldenberg RL, Mercer BM, Iams JD, Moawad AH, Meis PJ, Das A, et al. The preterm prediction study: patterns of cervicovaginal fetal fibronectin as predictors of spontaneous preterm delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1997;177:8–12. 22. Hellemans P, Gerris J, Verdonk P. Fetal fibronectin detection for prediction of preterm birth in low risk women. Br J Obstet Gynaecol 1995;102:207–12. 23. Joeffe GM, Jacques D, Bermis-Heys R, Burton R, Skram B, Shelburne P. Impact of the fetal fibronectin assay on admission for preterm labor. Am J Obstet Gynecol 1999;180:581–6. 24. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 1997;177:13–8. 25. Revah A, Hanna ME, Sue-A-Quan AK. Fetal fibronectin as a predictor of preterm birth: an overview. Am J Perin 1998;15:621. 26. Roman AS, Koklanaris N, Paidas MJ, Mulholland J, Levitz M, Rebarber A. “Blind” vaginal fetal fibronectin as a predictor of spontaneous preterm delivery. Obstet Gynecol 2005;105:285–9. 27. Roman AS, Rebarber A, Lipkind H, Mulholland J, Minior V, Roshan D. Vaginal fetal fibronectin as a predictor of spontaneous preterm delivery after multifetal pregnancy reduction. Am J Obstet Gynecol 2004;190:142–6. 28. Romero R, Espinoza J, Chaiworapongsa T, Kalache K. Infection and prematurity and the role of preventive strategies. Semin Neonatol 2002;7:259–74. 29. Goncalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002;8:3–13. 30. Simhan HN, Caritis SN, Krohn MA, Hillier SL. The vaginal inflammatory milieu and the risk of early premature preterm rupture of membranes. Am J Obstet Gynecol 2005;192:213–8. 31. Locksmith G, Duff P. Infection, antibiotics, and preterm delivery. Semin Perinatol 2001;25:295-309. 32. Sherman DJ, Tovbin J, Lazarovich T, Avrech O, Reif R, Hoffmann S, et al. Chorioamnionitis caused by gram-negative bacteria as an etiologic factor in preterm birth. Eur J Clin Microbiol Infect Dis 1997;16:417–23. 33. Ascarelli MH, Morrison JC. Use of fetal fibronectin in clinical practice. Obstet Gynecol Surv 1997;52:S1–12. 34. Dept of Health and Human Services (US) [DHHS]. STD Surveillance, 2003 [report on the Internet]. Atlanta (GA): Centers for Disease Control and Prevention [CDC]; 2003 [cited 2005 Jun 13]. Available at: http://www.cdc.gov/std/stats/toc2003.htm 35. BC Center for Disease Control (CAN) [BCCDC]. STD/AIDS Control, 2003 [report on the Internet]. Vancouver (BC): Chlamydia Statistics; 2003 [cited 2005 Jun 13]. Available at: http://www.bccdc.org/downloads/pdf/ std/reports/chlamydia%202003.pdf
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37. Andersen HF. Use of fetal fibronectin in women at risk for preterm delivery. Clin Obstet Gynecol 2000;43:746–58.
42. Giles W, Bisits A, Knox M, Madsen G, Smith R. 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.
38. Crane JM, Armson BA, Dodds L, Feinberg RF, Kennedy W, Kirkland S. Risk scoring, fetal fibronectin, and bacterial vaginosis to predict preterm delivery. Obstet Gynecol 1999;93:517–22. 39. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement Feb 28–March 2, 194: 12(2):1–24. 40. Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet RL. A review of premature birth and subclinical infection. Am J Obstet Gynecol 1992:166:1515–28.
43. Lowe MP, Zimmerman B, Hansen W. Prospective randomized controlled trial of fetal fibronectin on preterm labor management in a tertiary care center. Am J Obstet Gynecol 2004;190:358–62. 44. Grobman WA, Welshman EE, Calhoun EA. Does fetal fibronectin use in the diagnosis of preterm labor affect physician behavior and health care costs? A randomized trial. Am J Obstet Gynecol 2004;191;235–40.
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The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients Amanda Skoll, MD,1 Patrick St. Louis, PhD,2 Neda Amiri,1 Marie-France Delisle, MD,1 Sayrin Lalji, MD1 1
Department of Obstetrics and Gynaecology, Children’s and Women’s Health Centre of BC, Vancouver BC
2
Department of Biochemistry, Sainte-Justine Hospital, Montreal QC
Abstract Objective: This study was conducted to evaluate the usefulness of testing for fetal fibronectin (fFN) to rule out the diagnosis of preterm labour in symptomatic patients in a Canadian setting. Methods: This was a prospective, blinded clinical evaluation of fFN testing in women presenting with threatened preterm labour at between 24 and 34 weeks’ gestation at two Canadian tertiary care centres. Results: Of the 149 women tested, 32 had a positive fFN test. In the total patient population, 10.1% delivered within seven days of testing, and 18.2% delivered prior to 34 weeks. A negative fFN result was associated with a 97.4% likelihood of delivering more than seven days after testing and with a 91.4% chance of delivering after 34 weeks. Conclusion: The fFN test appears to provide useful information in the risk assessment of Canadian women presenting with symptoms compatible with preterm labour. A negative test has a high predictive value for delivering more than seven days after presentation.
Résumé Objectif : La présente étude a été menée en vue d’évaluer l’utilité du test visant la fibronectine fœtale (FNf) pour écarter le diagnostic de travail préterme chez les patientes symptomatiques, en milieu canadien. Méthodes : Il s’agissait d’une évaluation clinique prospective et à l’aveugle du test FNf chez les femmes présentant une menace de e e travail préterme entre la 24 et la 34 semaine de gestation, au sein de deux centres de soins tertiaires canadiens. Résultats : Des 149 femmes soumises au test FNf, 32 ont obtenu des résultats positifs. Au sein de la population totale de patientes, 10,1 % des femmes ont accouché dans les sept jours suivant l’administration du test et 18,2 % des femmes ont accouché avant e la 34 semaine de gestation. L’obtention de résultats négatifs au test FNf a été associée à une probabilité d’accoucher plus de sept jours à la suite de l’administration du test de l’ordre de 97,4 %, Key Words: Preterm labour, fetal fibronectin, prematurity, screening Competing Interests: None declared. Received on July 27, 2005 Accepted on October 7, 2005
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e
ainsi qu’à une probabilité d’accoucher après la 34 semaine de gestation de l’ordre de 91,4 %. Conclusion : Le test FNf semble offrir des renseignements utiles pour l’évaluation du risque chez les Canadiennes qui présentent des symptômes compatibles avec le travail préterme. L’obtention d’un test négatif compte une valeur prédictive élevée en ce qui concerne l’accouchement plus de sept jours à la suite de l’administration du test. J Obstet Gynaecol Can 2006;28(3):206–213
INTRODUCTION
he problem of preterm birth continues to be one of the most important challenges in obstetrics. Preterm delivery accounts for the vast majority of perinatal morbidity and mortality, as well as leading to long-term sequelae for many survivors.1-3 Unfortunately, attempts to counter this problem with the development of new tocolytic therapies have generally been unsuccessful.4-7
T
Our desire to intervene in patients who appear to be at risk of preterm delivery has resulted in the use of therapies such as corticosteroids, tocolytics, antibiotics, and other drugs in many patients who were found subsequently not to be in labour.8 The maternal and fetal risks of these therapies,9-14 added to the financial and social costs of maternal transfers and hospitalization,7,15,16 demand a more rational approach to the patient who presents with symptoms consistent with preterm labour. Fetal fibronectin (fFN) has been very widely studied over the last 14 years as a potential marker for the selection of patients who require intervention for true preterm labour.17 Fibronectin is an extracellular protein associated with basement membranes. fFN contains a unique glycoprotein region. It can be detected in the cervicovaginal secretions of women in early pregnancy,18 but in a normal pregnancy it becomes no longer detectable after 24 weeks’ gestation
The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients
because the fetal membranes are isolated from the upper vagina and lower cervix by the thick secretions within the cervical canal. However, as labour approaches, it reappears in cervicovaginal secretions because of separation of the membranes from the decidua in the lower uterine segment. It has been proposed that the presence of fFN in the cervicovaginal fluid after 24 weeks is a marker for preterm labour, although the positive predictive value for preterm delivery is not high.19-24 More importantly, in symptomatic patients a negative result is associated with a significantly decreased risk of delivery within 7 to 10 days.25 Of women with a negative test result, more than 95% have been reported not to deliver within one week of testing.25-27 Before implementing this test in our centres, we felt compelled to examine its performance in our patient populations for a number of different reasons. First, it has clearly been shown by numerous investigators that one of the most important underlying etiologies for idiopathic preterm labour is inflammation.28-30 The vaginal flora appear to play a crucial role in the risk for preterm labour, with ascending infection causing activation of inflammatory mediators in the decidua.29,31,32 Thus the prevalence of various vaginal organisms in the patient population targeted may have an important influence on the pathogenesis and the incidence of preterm labour. The majority of the large studies that have investigated the efficacy of fFN testing in the prediction—or more importantly, in the ruling out—of preterm labour were performed in large public hospitals in the United States.10,17,19,24,26,27,33 These centres may have patient populations with rates of infection that are different from those in Canadian centres. For example, the United States Centers for Disease Control cite a median chlamydial infection rate of 7.4% (range 2.4–19.7%) in women 15 to 29 years of age attending prenatal clinics,34 but in British Columbia, women of the same age had a rate of chlamydial infection of 1.4% during the same time period.35 A similar difference is seen in the prevalence of gonorrhea in these groups, with a median rate of 1% (range 0–3.7%) in the American population34 versus 0.06% in BC.36 These potential differences in vaginal flora could have a significant effect on a test like fFN. Moreover, the usefulness of fFN testing in reducing the overtreatment of preterm labour depends on its negative predictive value. This characteristic is dependent on the incidence of the disease in the population. Therefore, unless the outcome for the study (in this case, the incidence of preterm delivery) is relatively frequent, there is no great benefit in having a high negative predictive value. In a population where very few patients actually go on to deliver prematurely, the a priori risk is already so low that another test
is unlikely to change their predicted risk. This is a problem for a number of the fFN studies published to date.37,38 For this reason, we wished to determine whether the test performed as well in a population with a much higher rate of preterm delivery. In the Canadian context, many patients present for care far away from facilities that can provide adequate care for preterm infants. It is imperative to be extremely confident in the ability of a test to rule out true preterm labour before we can recommend its integration into clinical practice. The objective of the study was to determine the sensitivity, specificity, and positive and negative predictive values for delivery within seven days, and for delivery prior to 34 weeks’ gestation, of testing for fetal fibronectin in the cervicovaginal secretions of patients presenting with symptoms of preterm labour in two Canadian tertiary care centres. Our primary focus was to determine the usefulness of fFN testing in ruling out preterm labour in symptomatic patients. METHODS Study Patients
The study was carried out at Sainte-Justine Hospital (Université de Montréal) in Montreal, and BC Women’s Hospital (University of British Columbia) in Vancouver. Women presenting at between 24 and 34 completed weeks of gestation for evaluation of symptoms compatible with preterm labour were eligible for inclusion in the study. They were approached for possible participation in the study if there was (1) no rupture of membranes; (2) no moderate or severe vaginal bleeding; and (3) no indication for preterm delivery, including non-reassuring fetal assessment, chorioamnionitis, severe maternal hypertension, or fetal death. Candidates who agreed to participate were asked to sign a consent form after the study was explained to them. At the time of speculum examination for evaluation of the cervix and collection of swabs for culture as clinically indicated, a swab was collected from the posterior vaginal fornix by the house staff physician or attending physician for the quantification of fFN. If the physician excluded the diagnosis of preterm labour on clinical assessment and vaginal examination and discharged the patient home, the swab for fFN quantification was discarded and the patient was not included in the final analysis. The ethics committees of the University of British Columbia, BC Children’s and Women’s Hospital, Université de Montréal and Sainte-Justine Hospital approved the study. MARCH JOGC MARS 2006 l
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Table 1. Clinical characteristics of the 160 study patients
Site of admission
n
%
Vancouver
104
65.0
Montreal
56
35.0
42
26.3
Primigravidae Cerclage in current pregnancy
0
0
Previous preterm birth
26
16.3
Single
147
91.9
Twin
12
7.5
Triplet
1
0.6
Contractions
92
70.8
Bleeding
10
7.7
Abdominal / back pain
23
17.7
Cramps / tightening
29
22.3
Discharge / fluid‡
8
8.2
Pressure
5
3.8
PIH
1
0.8
Number of fetuses
Reason for admission*†
*The presenting symptoms are not mutually exclusive. †Available for only 130 patients. ‡Rupture of membranes was ruled out prior to enrolment. PIH: pregnancy-induced hypertension.
Laboratory Essays and Data Collection
For the purposes of the study, included specimens were stored in the laboratory at –4º C and run in weekly batches. Analysis was performed using the TLiIQ System (Adeza Biomedical Corporation, CA). A level of 50 ng/mL or greater is considered positive. Information was collected at the time of the specimen collection regarding the clinical presentation. This included gestational age, reason for admission, presence and frequency of uterine contractions, cervical examination (dilatation, effacement, consistency, position), and presence of blood in the vagina. In addition, information was recorded regarding any digital examinations, sexual intercourse, or endovaginal ultrasound tests within the 24 hours preceding swab collection. Treating physicians were blinded to the results of the fFN test. Decisions regarding admission, use of tocolytics, antenatal steroid therapy, and antibiotics were made on clinical grounds by each physician, and details were recorded for each patient. For patients who were transferred to the tertiary centre from outside institutions, use of these therapies preceding transfer was also recorded. At the time of delivery, data recorded included gestational age at delivery, interval from fFN testing to delivery, birth 208
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weight, and need for neonatal intensive care unit (NICU) admission for the newborn. Statistical Analysis
Categorical values were calculated using descriptive analysis. Two models were constructed to analyze the association between tocolytics, antibiotics, and steroids and delivery within seven days of the fFN test. The first, model A, used the forward likelihood ratio as a criterion to consider variables that were significant. The second, model B, considered all variables. They were analyzed by the significance of the coefficients of each independent variable. In order to demonstrate a significant association (set at P < 0.05) between fFN levels and preterm delivery, with a negative predictive value of 95% and a positive predictive value of 50%, we sought to study at least 186 patients.24 RESULTS
In total, 184 women were recruited into the study over a two-year period. Fetal fibronectin results were not available for 24 (for reasons such as label detached, not enough sample, sample leaked), leaving a total of 160 women for whom test results were available. One hundred four women were recruited in Vancouver and 56 in Montreal. Eleven patients were lost to follow-up, leaving 149 patients for final data analysis.
The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients
Table 2. Clinical characteristics of the positively and negatively tested patients
Days admitted without delivery
Statistics
fFN Positive
fFN Negative
mean
3.6563 (SE = 1.39021)
3.8103 (SE = 0.6765)
0.8209
2.4720
95% Confidence interval for mean
Days between test and delivery
GA at admission
upper boundary
6.4916
5.1487
variance
61.846
52.955
standard deviation
7.86421
7.27702
mean
29.0000
62.4655
(SE = 5.24789)
(SE = 2.58645)
lower boundary
18.2969
57.3423
upper boundary
39.7031
67.5888
variance
881.290
776.007
standard deviation
29.68653
27.85691
Median
32.5
38.0
95% Confidence interval for mean
GA at delivery
lower boundary
Minimum
25.0
26.0
Maximum
41.0
42.0
Range
16.0
16.0
Interquartile range
7.0
2.0
Median
29.07
28.71
Minimum
23
20
Maximum
34
35
Range
11
15
Interquartile range
3
4
fFN: fetal fibronectin; GA: gestational age; SE: standard error
The clinical characteristics of the population are outlined in Table 1. The mean maternal age was 29 years (range 17–43 years). The reason for admission was available for 130 patients. The patients’ presenting complaints were most frequently uterine contractions (92 cases or 71%); the full list of presenting symptoms is shown in Table 1. The mean gestational age at testing was 28.8 weeks, and the mean test-to-delivery interval was 54.9 days. The mean gestational age at delivery for the total group was 36.6 weeks. A total of 32 patients had a positive fFN result, leaving 117 with a negative test. The clinical characteristics of these patients are shown in Table 2. Twelve patients with a positive test delivered within seven days of testing, and the remaining 20 delivered at some time after seven days. Among the patients with a negative result, three delivered within seven days and the remaining 114 patients delivered more than seven days after the test. Thus, test sensitivity was 80.0% (95% confidence intervals [CI] 51.4, 94.7), specificity 85.1% (95% CI 77.6, 90.4), and prevalence was 10.1%. The positive predictive value of the fFN test for delivery within seven days of
testing was 37.5% (95% CI 21.7, 56.3). The negative predictive value for the same outcome was 97.4% (95% CI 92.1, 99.3). These results are summarized in Table 3. For delivery before 34 weeks’ gestation, the test demonstrated sensitivity of 63.0% (95% CI 42.4, 79.9), specificity of 87.6% (95% CI 80.1, 92.7), with a prevalence of 18.2%. Positive predictive value and negative predictive values of 63.0% (95% CI 35, 70.5) and 91.4% (95% CI 84.3, 95.6) were calculated for the fFN result for this outcome (Table 4). Seventeen patients who tested positive for fFN delivered prior to 34 weeks, and the remaining 15 delivered at or after 34 weeks. Among the negatively tested population, 27 patients delivered before 34 weeks and 121 patients at or after 34 weeks. The variables of tocolytics, antibiotics, and steroids were tested for association with delivery within seven days of testing using both statistical models (A and B). In model A, only fFN appeared to explain the outcome. In model B, although all variables were entered in the model, none but fFN had significant correlation coefficients (the 95% CI were very wide and crossed unity in all cases). This finding MARCH JOGC MARS 2006 l
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Table 3. Results of fetal fibronectin testing by incidence of delivery within seven days of testing Statistic
Value
95% CI
Sensitivity
0.80
0.514
0.947
Specificity
0.851
0.776
0.904
Positive predictive
0.375
0.217
0.563
Negative predictive
0.974
0.921
0.993
Positive LR
5.36
3.327
8.635
Negative LR
0.235
0.085
0.648
CI: confidence interval; LR: likelihood ratio.
Table 4. Results of fetal fibronectin testing by incidence of delivery before 34 weeks’ gestation Statistic
Value
95% CI
Sensitivity
0.63
0.424
Specificity
0.876
0.801
0.927
Positive predictive
0.531
0.35
0.705
Negative predictive
0.914
0.843
0.956
Positive LR
5.079
2.916
8.847
Negative LR
0.423
0.258
0.693
0.799
CI: confidence interval; LR: likelihood ratio.
supports the hypothesis that the outcome was not a function of tocolysis or other factor, but rather was predicted by fFN testing alone. Model B had better predictive capabilities and a higher explanation of the overall outcome (Nagelkerke R Square = 0.430) than did model A (0.346). However, model B includes many independent variables (i.e., is considered “saturated”) and only the fFN result made a statistically significant contribution. DISCUSSION
In this study, we attempted to determine the usefulness of fFN in a population of Canadian patients symptomatic for preterm labour. The positive predictive value of the test was 37.5% for delivery within seven days of testing and 63% for delivery before 34 weeks of gestation, values that are higher than those in many of the previously published reports. More importantly for our research question, we found that fFN, when measured in symptomatic patients at between 24 and 34 completed weeks of gestation, provides a high negative predictive value for continuing pregnancy beyond seven days after testing and for prolonging gestation beyond 34 weeks. This is clinically important for a number of reasons. 210
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Steroids have been clearly shown to reduce perinatal morbidity and mortality when administered to women who go on to deliver prior to 34 weeks’ gestation.39 However, the question remains regarding the duration of the efficacy of antenatal steroid therapy. It is clear that the ideal situation would be that all babies born prior to 34 weeks receive only one full course of antenatal steroids within one to two weeks of their delivery. The corollary is that, in the ideal situation, a baby delivered after 34 weeks should not be exposed to steroids unnecessarily. Thus, the fact that a negative fFN result confers a 97.4% chance of not delivering within the next seven days permits the withholding of antenatal corticosteroids in the acute period. Three patients in the study with negative fFN results went on to deliver within seven days of testing. These patients merit a more detailed review. The first patient was seen at 33 weeks’ gestation. Her cervical dilatation was 4 cm to 5 cm at the first evaluation and fFN testing was negative, but she delivered spontaneously on the day after testing. Other authors have reported a greater incidence of false negative testing in patients with more advanced cervical change than in patients with minimal cervical dilatation.37 This is of little clinical importance, since the diagnosis of preterm labour is already clear in such cases, and does not require fFN testing to make management decisions.
The Evaluation of the Fetal Fibronectin Test for Prediction of Preterm Delivery in Symptomatic Patients
The second patient who delivered within a week of testing was admitted at 26 weeks’ gestation with severe hypertension and proteinuria. Five days after admission she developed uterine contractions that lasted for more than four hours, and she was assessed for the possibility of preterm labour and entered the study at that time. Her cervix had not changed significantly, but she was subsequently delivered by Caesarean section because of non-reassuring fetal status. There is no evidence that she would have gone on to deliver spontaneously within seven days. The third patient presented to the hospital with uterine tightenings at 28 weeks. On evaluation, she was found to have a long, closed cervix that did not demonstrate significant change despite her contractions. However, she was noted to have significant hypertension, and she underwent Caesarean section four days later for this reason. Thus, of the three patients who delivered within seven days of a negative test, one would have been admitted in any case because of her advanced cervical dilatation, and the other two were delivered because of maternal or fetal indications and not because of spontaneous preterm labour. The endpoint of delivery after 34 weeks was chosen because this is the gestational age at which the risks of prematurity are no longer high enough to justify the potential consequences of attempting to arrest labour. The negative predictive value of this study demonstrates that a symptomatic patient with a negative fFN test has a greater than 91% chance of never requiring tocolysis or antenatal steroid therapy during this pregnancy. Although the body of literature related to fFN testing is large, it is very heterogeneous. Some published studies include only symptomatic patients, and others include asymptomatic patients considered to be “at risk.” Other studies have evaluated the use of fFN testing with or without other predictors (including risk scoring systems, bacterial vaginosis, or cervical ultrasound measurements) in low-risk populations. In 1999, Crane et al. published a report of the use of fFN testing in a Canadian population.38 However, this study, unlike ours, assessed a group of asymptomatic patients. The fFN test used at that time was the ELISA analysis rather than the current rapid test. Overall, there was a 6.4% spontaneous preterm birth rate (defined as delivery prior to 37 weeks) with the vaginal fFN test demonstrating a negative predictive value (NPV) of 96.5%. It is difficult to evaluate the usefulness of such a NPV when the incidence of preterm birth in the population was so low, as would be expected in a study of asymptomatic patients. Thus this study is unable to reassure us that the test performs well in a symptomatic Canadian population.
In a study of symptomatic patients in Nova Scotia (Armson et al., 2004 personal communication), a total of 193 patients were available for analysis. Although the NPV for fetal Fibronectin in this study was 99.4% for delivery within 14 days and 90% for delivery prior to 37 weeks, the actual preterm birth rate was less than 4%. Thus, the test did not actually add a great deal to the clinical assessment. Most of the original data on the use of fFN testing in symptomatic patients originated in studies in the large publicly funded centres in the United States. The prenatal populations of these centres have a high rate of genital infection, as reflected in the data from the Centers for Disease Control. There is very strong evidence that infection and inflammation play a strong role in the pathogenesis of so-called “idiopathic” preterm labour.40 The vaginal flora of those US patient populations may be significantly different from those of Canadian patient populations, and these differences may modify the effectiveness of a test based on vaginal secretions in the prediction of preterm birth. Fortunately, we can now be reassured that the fFN test does perform equally well to rule out true preterm labour in Canadian populations. The other strength of our study comes from the high rate of preterm birth in our population. This is due to a number of factors. First, we recruited only symptomatic patients. Review of the patient demographics indicated that our patient population had a fairly high a priori risk of preterm labour, since 27% of our population had previously experienced preterm delivery and 8.6% were carrying multiple gestations. Finally, the methodology of the study favoured the selection of patients truly at risk because we discarded the specimens of those patients who were assessed clinically as not being in preterm labour. If the physician already felt comfortable discharging the patient based on clinical assessment and examination, we reasoned that there was no benefit to be gained from adding a relatively expensive biochemical test. As a result of these factors, the rate of preterm delivery prior to 34 weeks in our study was 18%. In addition, more than 10% of our patients delivered within seven days of testing. Now that we have documented the performance of this test in our patient population, we feel comfortable applying the results of studies in other populations that show similar results. The use of fFN testing should indeed reduce the transfers of pregnant women to tertiary care centres41-43 and should decrease the use of tocolytics, antenatal steroids, and other interventions for women who are not actually at risk of preterm delivery. The challenge remains for us to educate physicians and other caregivers in the appropriate use and interpretation of this test.44 MARCH JOGC MARS 2006 l
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CONCLUSION
The rapid test for the quantification of fFN in the cervicovaginal secretions of Canadian women presenting with symptoms of preterm labour between 24 and 34 weeks’ gestation is useful in predicting which patients will continue their pregnancy for at least seven days and beyond 34 weeks’ gestation. As such, it is a useful adjunct in the assessment of patients with suspected preterm labour. ACKNOWLEDGEMENTS
The authors would like to thank Victor Espinosa for his extensive statistical help. REFERENCES 1. Morrison JC. Preterm birth: a puzzle worth solving. Obstet Gynecol 1990;76:5S–12S. 2. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985;312:82–90. 3. Hack M, Fanaroff AA. Outcomes of extremely immature infants: a perinatal dilemma. N Engl J Med 1993;329:1649–50. 4. Klam SL, Leduc L. Management options for preterm labour in Canada. J Obstet Gynaecol Can 2004;26:339-45. 5. ACOG Practice Bulletin no. 43: management of preterm labor vol 101. Obstet Gynecol 2003;5:1039–47. 6. McWhorter J, Carlan SJ, O’Leary TD, Richichi K, O’Brien WF. Rofecoxib versus magnesium sulfate to arrest preterm labor: a randomized trial. Obstet Gynecol. 2004;103:923–30. 7. Smith GN. What are the realistic expectations of tocolytics? BJOG 2003;110:103–6 8. Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine. N Engl J Med 1992;327:308–12. 9. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 2000;342:534–40. 10. Goldenberg RL, Thom E, Moawad AH, Johnson F, Roberts J, Caritis SN. The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection: NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 1996;87:656–60. 11. Thorp JM Jr, Hartmann KE, Berkman ND, Carey TS, Lohr KN, Gavin NI, et al. Antibiotic therapy for the treatment of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2002;186:587–92. 12. Berkman ND, Thorp JM Jr, Lohr KN, Carey TS, Hartmann KE, Gavin NI, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol 2003;188:1648–59. 13. Sanchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of maintenance therapy after acute tocolysis: a meta-analysis. Am J Obstet Gynecol 1999;181:484–90. 14. Meirowitz NB, Ananth CV, Smulian JC, Vintzileos AM. Value of maintenance therapy with oral tocolytics: a systematic review. J Matern Fetal Med 1999;8:177–83. 15. Moutquin J-M. Preterm births in Canada. Where do we go from here? JSOGC 1999;21:12–5. 16. St John EB, Nelson KG, Cliver SP, Bishnoi RR, Goldenberg RL. Cost of neonatal care according to gestational age at birth and survival status. Am J Obstet Gynecol 2000;182:170–5.
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