Objective
The purpose of this study was to determine the effect of sexual intercourse on the accuracy of quantitative fetal fibronectin (qfFN) in the prediction of spontaneous preterm birth (sPTB) in asymptomatic high-risk women.
Study Design
This was a prospective masked predefined subanalysis of a larger study of cervicovaginal fluid qfFN concentration in high-risk women asymptomatic of preterm labor. Women who had sexual intercourse within 48 hours of qfFN testing (n = 61; 18 +0 -34 +6 weeks’ gestation) were compared with controls from the same database without a history of pretest sexual intercourse, matched according to gestational age at testing and delivery, risk factor for sPTB, and ultrasonographic cervical length measurement.
Results
The median concentration of qfFN in women who had sexual intercourse within 48 hours of testing was 53 ng/mL (quartiles 6, 189), compared with 5 ng/mL (quartiles 2, 12) in the control group. The average qfFN concentration was 6.36 (95% confidence interval [CI], 3.43–11.8) times higher in the sexual intercourse group compared with controls ( P < .0001). The false-positive rate was 56% (27 of 50) compared with 6% (3 of 52) in the control group (risk difference, 48%; 95% CI, 33–63; P < .001). The false-negative rate was 45% (5 of 11) vs 89% (8 of 9) in the control group (risk difference, –43%; 95% CI, –79 to –8; P = .043).
Conclusion
Sexual intercourse within 48 hours of testing is associated with increased levels of fetal fibronectin in vaginal secretions and an increased rate of false-positive results in the prediction of sPTB in asymptomatic women.
Spontaneous preterm birth (sPTB) is the most common cause of neonatal morbidity and mortality globally. The unpredictable nature of sPTB and paucity of accurate bedside tests to stratify risk makes diagnosis and prediction a challenge. The ability to accurately detect women at greatest risk of preterm delivery would allow clinicians to target interventions such as admission to hospital, corticosteroids, and in utero transfer, as appropriate.
Fetal fibronectin (fFN) is a glycoprotein found at the maternal fetal interface of the amniotic membranes, between the chorion and the decidua. The presence of fFN in the cervicovaginal fluid indicates a degree of choriodecidual disruption, which may represent a separation of the fetal membranes from the decidua preceding premature labor. Testing for the presence of fFN in the cervicovaginal fluid (CVF) of women symptomatic of preterm birth to establish the risk of delivery has been recognized as a useful adjunct to clinical assessment, predominantly on the basis of a high negative predictive value for sPTB in both asymptomatic and symptomatic women.
Although the fFN test traditionally used in clinical practice provides a negative or positive result based on a threshold of 50 ng/mL, a novel bedside quantitative fFN (qfFN) analyzer (Hologic, Marlborough, MA) allows the rapid quantification of fFN concentrations (qfFN). This has been shown to enhance the positive predictive value of the traditional test by generating alternative thresholds to more accurately define risk of sPTB. Manufacturers of the qualitative and quantitative bedside fFN kits advise to avoid testing women who have had sexual intercourse in the preceding 24 hours because it may increase the false-positive rate of the test.
In a test that relies on clearly defined thresholds, with an already modest positive predictive value, a higher false-positive rate is clearly undesirable. Previous studies have investigated effects only on the qualitative, negative/positive test on nonpregnant women in small numbers (n = 14). It is not known whether the test may have value at a different threshold because intercourse may reveal a high risk following cervical disturbance or whether false-positive rates increase through assay crossover.
The aim of this study was to compare the qfFN results (Hologic) in a group of asymptomatic women deemed to be at high risk of preterm birth who had had sexual intercourse up to 48 hours before the test was performed, with a matched group of high-risk women who had not had intercourse prior to taking the test. The CVF qfFN concentrations in each group were compared, together with the predictive statistics for sPTB.
Materials and Methods
This was a prospective, masked subanalysis of a larger observational study (Evaluation of Quantitative fetal fIbronectin in Prediction of Preterm birth) of CVF qfFN concentrations (nanograms per milliliter) in women between 18 +0 and 34 +6 weeks’ gestation deemed to be at high risk of preterm delivery. The study was conducted from October 2010 through February 2012 at St Thomas’ Hospital (London, United Kingdom). Ethical approval was obtained from the South East London Research Ethics Committee. Written informed consent was obtained from all participants.
Gestational ages were confirmed with standard early ultrasound scans. Women were invited to attend the Preterm Surveillance Clinic if they had 1 or more of the following: previous sPTB, previous preterm premature rupture of membranes (PPROM), previous late miscarriage (16-23 +6 weeks), previous cervical surgery (large loop excision of the transformation zone, cone biopsy), uterine abnormality, or a cervical length less than 25 mm in the current pregnancy. Results from women with vaginal bleeding, PPROM, multiple pregnancy, cervical dilation of 3 cm or greater, or a history of regular douching were excluded from the analysis.
Asymptomatic high-risk women who answered yes to a routine questionnaire enquiring about sexual intercourse within 48 hours of fFN testing were included. Information on whether the intercourse was protected or unprotected was sought, and only the latter were included in the study.
Participants were matched with women from the same database without a history of recent sexual intercourse according to the following: risk factor for preterm birth (previous sPTB, previous PPROM, previous late miscarriage [16-23 +6 weeks], previous cervical surgery (large loop excision of the transformation zone, cone biopsy), uterine abnormality or a cervical length less than 25 mm in the current pregnancy), and both gestational age at testing and delivery.
The qfFN samples were collected by speculum examination, as per the manufacturer’s instructions (Hologic). Dacron swabs were placed in the posterior fornix and rotated for 10 seconds. The saturated swabs were placed in a buffer containing a specific monoclonal antibody (FDC-6) against the oncofetal domain of fFN. Two hundred microliter aliquots were then analyzed simultaneously with the commercially available qualitative Rapid fFN TLI IQ analyzer (Hologic) and quantitative Rapid fFN 10Q analyser (Hologic).
Cervical length measurements were performed following the sample collection as part of standard surveillance within the clinic. The qualitative result was made available to the clinician (positive, qfFN of ≥50 ng/mL), whereas the qfFN concentration result remained masked. The 10Q analyzer (Hologic) has a range between 0 and 500 ng/mL, with 500 ng/mL being the upper limit reported. The reliability of the Rapid 10Q analyzer has previously been reported.
Women undergoing iatrogenic delivery before 37 weeks’ gestation were excluded from the analysis. Following standard practice, a true-positive result was defined as spontaneous onset of labour (or PPROM) prior to 37 week’s gestation with qfFN greater than 50 ng/mL, and the sensitivity as the proportion of positive tests among the cases. A false-positive result was likewise defined as a CVF qfFN of 50 ng/mL or greater at testing and delivery at longer than 36 +6 weeks’ gestation and the false-positive rate as the rate of positive tests among the controls. The false-positive rates in women with a term delivery were compared between the 2 groups.
Statistical analysis was performed using Stata software (version 11.2; StataCorp LP, College Station, TX). Standard distributional checks were carried out. Quantitative fFN values were found to be highly asymmetric, with very large standard deviations compared with the means in both groups of women. Values were therefore logged and checks repeated. Geometric means were generated after transformation of log-normal distributions, with zeroes replaced by 0.5 mg/mL.
The qfFN values were compared between groups using Student t tests on the logged values and (nonparametric) area under the receiver-operating characteristic (ROC) curves. Results are reported as ratios of geometric means. When comparing percentages, the exact significance test was used, with the Wallenstein method with continuity correction for confidence intervals to get close agreement with the test result.
Quantitative fFN values were compared between groups using Student t tests on the logged values and (nonparametric) area under the ROC curves. Medians were compared using the Wilcoxon rank sum test.
Linear regression was used to look for differences in the qfFN levels according to time since sexual intercourse. To allow for the matching, random effects generalized least squares regression was used, with robust standard errors. Results were presented as ratios of the geometric mean between groups.
Results
A total of 64 participants with singleton pregnancies between 18 +0 and 34 +6 weeks’ gestation who had intercourse in the preceding 48 hours before the test were identified. Three women were excluded from the analysis because of iatrogenic preterm deliveries (induction of labor at 32 +1 weeks because of antepartum haemorrhage, prelabor emergency cesarean section at 30 +6 weeks because of significant antepartum hemorrhage, prelabor emergency cesarean at 30 +2 weeks because of suspected fetal compromise), leaving a total of 61 women fulfilling criteria for analysis. Demographic, background, and obstetric characteristics for study participants are described in the Table .
| Characteristic | SI <48 h | Control |
|---|---|---|
| Age, mean (SD) | 29 (6) | 31 (5) |
| Body mass index, kg/m 2 , mean (SD) | 25 (5) | 26 (6) |
| Race, n, % | ||
| White | 33 (54) | 35 (57) |
| Black | 16 (26) | 20 (33) |
| Other | 12 (20) | 6 (10) |
| Preterm birth, n, % | 27 (44) | 25 (40) |
| Previous PROM, n, % | 11 (18) | 10 (16) |
| Previous second-trimester miscarriage, n, % | 11 (18) | 10 (16) |
| Previous cervical surgery, n, % | 16 (26) | 16 (26) |
| Smoking history % | ||
| Current | 8 (13) | 3 (5) |
| Ex-smoker | 11 (18) | 5 (8) |
| Never | 42 (69) | 53 (87) |
| History of domestic violence, n, % | 3 (5) | 2 (3) |
| Mean gestational age at testing, SD | 23 +4 (3 +3 ) | 23 +4 (3 +2 ) |
| Mean gestational age at delivery, SD | 38 +3 (2 +4 ) | 38 +3 (2 +4 ) |
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