Danielle Abbott

Quantitative Fetal Fibronectin to Predict Preterm Birth in Asymptomatic Women at High Risk

OBJECTIVE: To evaluate the diagnostic accuracy of cervicovaginal fluid quantitative fetal fibronectin, measured by a bedside analyzer, to predict spontaneous preterm birth before 34 weeks of gestation. METHODS: We conducted a prospective masked observational cohort study of cervicovaginal fluid quantitative fetal fibronectin concentration in asymptomatic women at high risk of spontaneous preterm birth (n=1,448; 22–27 6/7 weeks of gestation) measured using a rapid bedside analyzer. The routine qualitative result (positive–negative) was made available to clinicians at the time of testing, but the quantitative result remained blinded until after delivery. RESULTS: Spontaneous preterm birth (less than 34 weeks of gestation) increased from 2.7%, 11.0%, 14.9%, 33.9%, and 47.6% with increasing concentration of fetal fibronectin (less than 10, 10–49, 50–199, 200–499, and 500 ng/mL or greater, respectively). A threshold of 200 ng/mL had a positive predictive value of 37.7 (95% confidence interval [CI] 26.9–49.4) with specificity 96% (95% CI 95.3–97.3). Women with a fetal fibronectin concentration of less than 10 ng/mL had a very low risk of spontaneous preterm birth at less than 34 weeks of gestation (2.7%), no higher than the background spontaneous preterm birth rate of the general hospital population (3.3%). The quantitative fetal fibronectin test predicted birth at less than 34 weeks of gestation with an area under the curve (AUC) of 0.78 (95% CI 0.73–0.84) compared with the qualitative test AUC 0.68 (95% CI 0.63–0.73). Quantitative fetal fibronectin discriminated risk of spontaneous preterm birth at less than 34 weeks of gestation among women with a short cervix (less than 25 mm); 9.5% delivered prematurely less than 10 ng/mL compared with 55.1% greater than 200 ng/mL (P<.001). DISCUSSION: Alternative risk thresholds (less than 10 ng/mL and greater than 200 ng/mL) improve accuracy when using quantitative fetal fibronectin measurements to define risk of spontaneous preterm birth. This is particularly relevant for asymptomatic women with a short cervix. LEVEL OF EVIDENCE: II

Cervical cerclage: A review of current evidence

Cervical cerclage is commonly used in the management of women considered to be at high risk of second‐trimester loss and spontaneous preterm birth. Insertion is dictated by factors such as multiple pregnancy, uterine anomalies, a history of cervical trauma through destructive procedures or forced dilatation, and cervical shortening seen on transvaginal ultrasound examination. However, its use and efficacy in these different groups is highly controversial as there is contradiction in the results of individual studies and meta‐analyses. This review examines the contemporary evidence on cervical cerclage and its current role in obstetrics.

Obstetric anal sphincter injury

#### Summary points Anal sphincter injury during childbirth is a leading cause of anal incontinence. In a study of more than 20 000 consecutive vaginal deliveries, clinically diagnosed obstetric anal sphincter injury occurred in 2.9% of primiparous women and 0.8% of multiparous ones.1 Of women who have sustained such an injury, 60-80% are asymptomatic at 12 months, of whom most report incontinence of flatus only, rather than faeces.2 w1 w2 Establishing a correct diagnosis at time of injury will facilitate adequate repair and may prevent future incontinence.3 In one epidemiological study, only a third of people with faecal incontinence had ever discussed the problem with a doctor because of embarrassment or fear of stigma.4 This review outlines the determinants, diagnosis, and management of obstetric anal sphincter injury. Women affected by obstetric anal sphincter injury require acute management at the time of delivery, together with follow-up or referral when newly presenting with symptoms months or years after childbirth. This review is relevant to all who provide care during childbirth and to doctors and healthcare professionals to whom women may subsequently present. #### Sources and selection criteria We searched Medline and PubMed from 1980 to 2009, focusing on evidence based publications on obstetric anal sphincter injury and randomised trials for management of such injury. We supplemented these sources with selected systematic reviews and good …

Quantitative Fetal Fibronectin at 18 Weeks of Gestation to Predict Preterm Birth in Asymptomatic High-Risk Women.

OBJECTIVE: To compare quantitative fetal fibronectin measurement from 18 to 21 weeks of gestation to measurement at 22–27 weeks of gestation for the prediction of spontaneous preterm birth. METHODS: In a prospective cohort study, we studied the accuracy of cervicovaginal fluid quantitative fetal fibronectin concentrations measured between 18 0/7 weeks of gestation and 21 6/7 weeks of gestation in high-risk asymptomatic women to predict spontaneous preterm birth before 34 weeks of gestation. Predefined fibronectin thresholds were 10 or greater, 50 or greater, and 200 ng/mL or greater. Diagnostic accuracy of the early test (n=898) was compared with the standard test performed between 22 0/7 and 27 6/7 weeks of gestation (n=691) in the same cohort. Subgroup analysis was performed according to cervical length measurement. RESULTS: Of 898 women, 8.7% delivered spontaneously before 34 weeks of gestation. Only 3.8% of the women with concentrations less than 10 ng/mL (65% of test results) delivered before 34 weeks of gestation. A concentration threshold of 10 ng/mL measured at 18 and 22 weeks of gestation had comparably high sensitivity (early 0.71, 95% confidence interval 0.60–0.81; standard 0.76, 0.63–0.87) and negative predictive value (early 0.96, 0.94–0.98; standard 0.97, 0.95–0.99) for delivery before 34 weeks of gestation. Specificity was also comparable (early 0.69, 0.65–0.72; standard 0.70, 0.66–0.74). A threshold of 200 ng/mL had high specificity (early 0.96, 0.94–0.98; standard 0.96, 0.94–0.97) with lower sensitivity (early 0.26, 0.17–0.37; standard 0.35, 0.22–0.49). Consideration of cervical length strengthened prediction. CONCLUSION: Quantitative cervicovaginal fetal fibronectin measured from 18 to 21 weeks of gestation has similar predictive value as measurement at 22–27 weeks of gestation for prediction of spontaneous preterm birth. Low fibronectin concentrations are associated with spontaneous preterm birthrates approaching population background levels.

PPO.01 EQUIPP: Evaluation of Fetal Fibronectin with a novel bedside Quantitative Instrument for the Prediction of Preterm birth

Introduction Fetal fibronectin (fFN) is a leading predictor of spontaneous preterm birth (sPTB) in high-risk asymptomatic women. As a positive/negative test (threshold of 50 ng/mL) the negative predictive value is high but positive predictive value (PPV) modest. The EQUIPP study aimed to determine if quantitative analysis of fFN (qfFn) improved prediction. Methods A prospective masked observational study (n = 1387) of high-risk asymptomatic women who underwent qfFN testing between 22+0– 27+6 weeks’ gestation at 5 UK centres. Primary endpoint: sPTB <34 weeks’. Results sPTB rate <34 weeks’ was 7.1%. Only 2.8% (26/941) of women with qfFN concentration < 10 ng/mL delivered <34 weeks’. The PPV for sPTB <34 weeks’ increased from 16.6%, 24.1%, 36.8%. 45.0% with increasing thresholds (10, 50, 200, and 500 ng/mL) respectively. Compared with qfFN <10 ng/mL, the relative risk of sPTB was 3.8 (95% CI, 2.3–6.6), 5.7 (3.2–10.0), 12.3 (7.3–20.8) and 16.3 (8.8–30.1) (p < 0.0001). The area under the Receiver Operating Characteristic curve for sPTB <34 weeks’ was 0.79 (0.74–0.84). Women with a short cervix on ultrasound (<25 mm) had a ten-fold increase in sPTB with qfFN concentration ≥200 ng/mL (18/45, 40%) vs. qfFN <10 ng/mL (3/68, 4.4%). Conclusion qfFN provides alternative thresholds to define risk of sPTB compared with qualitative assessment. For high-risk women with qfFN <10 ng/mL (68% of cohort) risk of sPTB equalled background risk (3.3%) providing reassurance and potential discharge from intensive surveillance. qfFN ≥200 ng/mL offers improved positive prediction over conventional testing and is a valuable tool for risk assessment in women with a short cervix.

PM.61 The Use of Quantitative Fetal Fibronectin to Predict Obstetric Outcome: A Comparison of a New and Established Quantitative Bedside Analyser in Asymptomatic High-Risk Women

Background Preterm birth (PTB) remains a significant cause of neonatal morbidity and mortality. The most accurate predictors of PTB are ultrasound determined cervical length (CL) and fetal fibronectin (fFN)1. Quantitative fFN can be used to further outline risk in symptomatic women2. New devices are appearing on the market. Objectives To compare the capacity of two different quantitative fetal fibronectin (fFN) systems to predict cervical shortening in asymptomatic women at high-risk of PTB. Methods Women underwent CL measurement and fFN testing between 20+0 and 24+6 week of gestation in the Preterm Surveillance Clinic at St. Thomas’ Hospital (August to November 2012). Fetal fibronectin samples were run using a bedside immunoassay system (10Q system, Hologic, Marlborough) and bedside chemiluminescence system (DryLab, Audit Diagnostics, Ireland). Results 130 fFN tests were taken from 89 women. Comparison of all test results showed considerable difference between methods (R2 0.22). A short cervix (<25 mm) was found in 14 women. The 10Q system was able to significantly detect cervical shortening (Area under the curve 0.69, 95% CI 0.57–0.82, p = 0.002), however DryLab system could not (AUC 0.52, 95% CI 0.35–0.71, p = 0.12). Hologic 10Q had a better positive predictive value than DryLab (29% vs. 22% respectively), but similar negative predictive values (88% vs 87% respectively). Secondary outcomes such as gestational age at delivery will be presented. Conclusion Quantitative fFN is associated with cervical shortening and therefore risk of imminent preterm birth in asymptomatic women. Not all commercial devices are accurate. References Bolt LA, Chandiramani M, De Greef A, Seed PT, Kurtzman J & Shennan AH. The Value of combined cervical length measurement and fetal fibronectin testing to predict spontaneous preterm birth in asymptomatic high-risk women. J Matern Fetal Neonatal Med 2011;24(7):928–932. Abbott DS, Radford SK, Seed OT, et al. Evaluation of quantitative fetal fibronectin test for spontaneous preterm birth in symptomatic women. AJOG 2012.

PM.24 Quantitative Fetal Fibronectin as a Predictor of Preterm Birth in Asymptomatic Women with Trans-Abdominal Cerclage

Background Preterm birth (PTB) remains a significant cause of neonatal morbidity and mortality. The most accurate predictors of PTB are ultrasound determined cervical length (CL) and fetal fibronectin (fFN). Cervical cerclage in situ gives more false positive fFN results1 but its value in abdominal cerclage is unknown. The aim of this study is to assess the accuracy of quantitative fFN for prediction of PTB (<34 weeks’) in asymptomatic high-risk women with abdominal cerclage. Method Secondary analysis of quantitative fFN results from EQUIPP study, taken between 20+0 and 24+6 week’ in asymptomatic women referred to specialist antenatal clinics (2010–2012), with a trans-abdominal, elective or ultrasound-indicated (emergency) cervical cerclage. Results Quantitative fFN may be most accurate for predicting PTB at <34 weeks’ in women with abdominal cerclage (AUC 1.0 (95% CI 0.0–1.0), 0.82 (95% CI 0.70 – 0.94) and 0.60 (95% CI 0.45–0.75) respectively). For delivery at <34 weeks’ the sensitivity and specificity of fFN testing was lower in women with elective and emergency cervical cerclage compared to women with abdominal cerclage (Table 1). The positive predictive value of the test is similar between groups. Abstract PM.24 Table 1 Type of Cerclage Sensitivity Specificity NPV PPV Abdominal (n = 20) 100% 95% 100% 50% Elective Cervical (n = 67) 69% 81% 92% 47% Emergency Cervical (n = 55) 74% 44% 70% 49% Conclusion Asymptomatic high-risk women with cervical cerclage in situ may have more false positive fFN test than women with an abdominal cerclage. Quantitative fFN is an accurate predictor of PTB in women with abdominal cerclage. Reference Duhig K, Chandiramani M, Seed PT, Briley AT, Kenyon AP & Shennan AH. Fetal fibronectin as a predictor of spontaneous preterm labour in asymptomatic women with cervical cerclage. BJOG 2009.116: 799–803

PF.02 The Role of Quantitative Fetal Fibronectin and Cervical Length in Predicting Spontaneous Preterm Birth in Multiple Pregnancies

Background Multiple pregnancies are associated with a higher risk of spontaneous preterm birth (sPTB). Whilst fetal fibronectin (fFN) and cervical length (CL) measurement can predict sPTB in singleton pregnancies (Kurtzman et al, 2009), their value for twin pregnancies is unknown. Methods Prospective blinded secondary analysis of longitudinal samples of cervicovaginal fluid fFN concentration (nanograms per mililiter) using a bedside 10 qfFN analyzer (HOLOGIC, USA), and transvaginal ultrasound CL of 93 consecutive women with multiple pregnancies attending a Preterm Surveillance Clinic at St. Thomas Hospital from 18 weeks gestation (Oct 2010–Jan 2012). qfFN was assigned 4 ranges; <10, 10–50, 50–200, >200 (ng/ml) to detect spontaneous delivery before 30, 34 and 37 weeks. qfFN was blinded to clinicians using an embedded code in the analyzer. Results The rate of sPTB (<37 weeks) rose increased with increasing qfFN from 17.5% (<10 ng/ml) to 61.5% (>200 ng/ml) and the negative prediction value for sPTB <30 weeks at <10 ng/ml was 98%. 4/13 (30%) of women with qfFN > 200 ng/ml delivered <30 weeks gestation. Using combined CL/qfFN testing, the positive prediction value of a qfFN value >200 ng/ml and CL < 25 mm was 87.5% for SPTB <37 weeks. Conclusion This is the first report of 10 qfFN in twins, demonstrating that it adds predictive value to the qualitative results (negative cut-off at 50 ng/ml). High levels, even in early pregnancy, are associated with preterm delivery. Using cervical length and qfFN, management can be targeted to this group; e.g. antenatal maternal steroids. Further research should evaluate interventions to prolong pregnancy in this highest risk group, while lower risk women can be reassured.

PL.05 Use of Quantitative Fetal Fibronection For Prediction of Spontaneous Preterm Birth in High Risk Asymptomatic Women

Introduction Prediction of spontaneous preterm birth (sPTB) remains a challenge in obstetrics. Fetal fibronectin (fFN) is a strong negative predictor of sPTB (Berghella et al, 2008). Quantitative measurements of fFN may provide additional discriminatory information, improve positive prediction and be more clinically useful in predicting risk and outcome. The aim of this study was to determine if risk of sPTB correlated with concentration of fFN. Study design A prospective blinded study of cervico-vaginal fFN concentration (ng/mL) in asymptomatic women considered at high risk of spontaneous preterm birth (n = 744; 22–27+6 weeks’) using a 10Q analyser (Hologic®). Clinicians were blinded to the result until post-delivery but the qualitative TLIIQ (Hologic®) fFN result was made available. Results The rate of sPTB (<34 weeks’) was lowest (2%) for women with concentrations 0–9 ng/ml, and highest for those with concentrations ≥200 ng/mL (31%). Compared to <10 ng/mL fFN, the relative risk of delivery was: (10–49 ng/ml) 4.3 (95% CI 0.03 to 0.13), (50–199 ng/mL) 4.3 (95% CI 0.005 to 0.15), (≥200 ng/mL) 13 (95% CI 0.16 to 0.42). The positive predictive value for sPTB (<34 weeks’) increased from 15, 19, 31% with increasing thresholds (10, 50, 200 ng/mL respectively), yet negative prediction remained >95%. Conclusion Risk of sPTB is increased for concentrations above 10 ng/mL. Quantitative fFN provides additional thresholds (10 and 200 ng/mL) over the qualitative method (50 ng/mL) to discriminate risk of sPTB in high risk asymptomatic women.

PF.08 Quantitative Fibronectin Can Be Used For Earlier Prediction of Preterm Birth from 18 Weeks, But the Positive Threshold Needs Redefining

Introduction Fetal fibronectin (fFN) is an excellent predictor of spontaneous preterm birth (sPTB) and is used qualitatively (<50 ng/ml negative threshold) from 22 weeks gestation. Its value at earlier gestations using a quantitative test (qfFN) is unknown. Methods A prospective secondary analysis of 431 asymptomatic women at high risk of sPTB, who underwent qfFN testing at 18–21 + 6 weeks. 327 women underwent later testing at 22–26 + 6 weeks (acting as their own controls). The end-points were sPTB/preterm premature rupture of membranes and delivery before 30, 34 and 37 weeks gestation and within 8 weeks of testing. Results Early qfFN predicted delivery within 8 weeks of testing, <30, <34 and <37 weeks with receiver operating characteristics (ROC) areas of 0.66 (0.54–0.80, p < 0.05), 0.68 (0.56–0.79, p < 0.01), 0.68 (0.58–0.78 p < 0.001) and 0.64 (0.57–0.72, p < 0.001). 22-week test prediction was ROC areas of 0.77 (0.63–0.91 p < 0.001), 0.78 (0.61–0.95, p < 0.001) and 0.79 (0.70–0.89, p < 0.001) respectively. A qFFN result of <10 ng/ml at earlier gestations had only 1%, 2% and 4.3% of women delivered within 8 weeks, <30 and <34 weeks gestation, rising to 6.7%, 8.1% and 14.1% with values between 10–49.9 ng/ml (all differences statistically significant, p = 0.03, 0.02, 0.004 by Fishers-Exact). The 22-week test had 1.0%, 1.0% and 2% respectively, rising to 6.7%, 3.3% and 14% with values between 10–49.9 ng/ml (p = 0.02, 0.23, 0.004). Conclusion qfFN is valid for screening for sPTB at 18 weeks, but has inferior predictive value to 22 weeks. Early identification may enable earlier targeted management. A threshold of <10 ng/ml is more appropriate than current practise to define low risk at 18 weeks.