BACKGROUND: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth.
OBJECTIVES: To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness.
DESIGN: The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin.
DATA SOURCES/SETTING: The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres.
PARTICIPANTS: Pregnant women at 22+0-34+6 weeks' gestation with signs and symptoms of preterm labour.
HEALTH TECHNOLOGY BEING ASSESSED: Quantitative fetal fibronectin.
MAIN OUTCOME MEASURES: Spontaneous preterm birth within 7 days.
RESULTS: The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R 2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days.
LIMITATIONS: The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation.
CONCLUSIONS: A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour.
FUTURE WORK: The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model.
STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423.
FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.
Bibliographical noteFunding Information:
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.
The research reported in this issue of the journal was funded by the HTA programme as project number 14/32/01. The contractual start date was in December 2015. The draft report began editorial review in May 2019 and was accepted for publication in December 2019. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
Declared competing interests of authors: Sarah J Stock reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, non-financial support from Hologic, Inc. (Marlborough, MA, USA), non-financial support from Parsagen Diagnostics, Inc. (Boston, MA, USA) and non-financial support from Medix Biochemica Ab (Espoo, Finland) during the conduct of the study. In addition, Sarah J Stock declares membership of the HTA Programme Funding Committee (General) (2016 to present). Kathleen Boyd reports grants from the NIHR HTA programme and NIHR Public Health Research (PHR) programme outside the submitted work during the conduct of the study. Lorna Aucott declares membership of the PHR Research Funding Board (2017 to present). Rachel K Morris reports grants from the NIHR HTA and NIHR Research for Patient Benefit programmes outside the submitted work during the conduct of the study. Jon Dorling reports grants from the NIHR HTA programme and Nutrinia Ltd (Ramat Gan, Israel) outside the submitted work; the grant from Nutrinia Ltd (2017–18) was for part of his salary to work as an expert advisor on a trial. Jon Dorling was a member of the NIHR HTA General Board (2017–18) and the NIHR HTA Maternity, Newborn and Child Health Panel (2013–18). Manju Chandiramani reports that she undertakes unpaid advisory work for Hologic, Inc., unrelated to the submitted work, and has been supported by Hologic, Inc., to attend a conference in the preceding 12 months. Anna David reports personal fees from Hologic, Inc., outside the submitted work, and salary support from the NIHR UCLH/UCL Biomedical Research Centre. Asma Khalil reports grants and prediction tests from Parsagen Diagnostics, Inc., paid to the institution, during the conduct of the study and declares being a member of the HTA Programme Funding Committee (2018 to present). Andrew Shennan reports grants and prediction tests from Hologic, Inc., for basic science on preterm markers, paid to the institution, and was a member of the HTA Funding Committee (Commissioning) during the conduct of the study (2018 to present). Tina Lavender declares membership of the HTA Obesity Themed Call Board (2013). Ben Mol reports a Practitioner Fellowship from the National Health and Medical Research Council, personal fees from ObsEva SA (Geneva, Switzerland), personal fees and other funding from Merck Sharp & Dohme (Kenilworth, NJ, USA), personal fees from Guerbet (Villepinte, France), travel support to present at meetings from Guerbet, and grants from Merck Sharp & Dohme, outside the submitted work. Richard D Riley reports grants from the NIHR HTA programme outside the submitted work during the conduct of the study. Jane Norman reports grants from the NIHR HTA and the NIHR Global Health programmes and the Medical Research Council, and personal fees from Dilafor AB (Solna, Sweden), outside the submitted work, and was a member of the HTA Maternal, Neonatal and Child Health Panel during the conduct of the study (2013–18); she was a member of the NIHR HTA and Efficacy and Mechanism Evaluation (EME) Editorial Board (2012–14). John Norrie reports grants from the University of Aberdeen and the University of Edinburgh during the conduct of the study, and membership of the following NIHR boards: CPR Decision-Making Committee, HTA Programme Funding Committee (Commissioning), HTA Commissioning Sub-Board (Expression of Interest), HTA Funding Boards Policy Group, HTA Programme Funding Committee (General), HTA Post-board funding teleconference, Clinical Trials Unit Standing Advisory Committee, HTA and EME Editorial Board and Pre-exposure Prophylaxis Impact Review Panel during the conduct of the study.
© Queen’s Printer and Controller of HMSO 2021.
- Cohort Studies
- Infant, Newborn
- Obstetric Labor, Premature/diagnosis
- Premature Birth/diagnosis
- Prospective Studies
ASJC Scopus subject areas
- Health Policy