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Deshpande SN, van Asselt ADI, Tomini F, et al. Rapid fetal fibronectin testing to predict preterm birth in women with symptoms of premature labour: a systematic review and cost analysis. Southampton (UK): NIHR Journals Library; 2013 Sep. (Health Technology Assessment, No. 17.40.)

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Rapid fetal fibronectin testing to predict preterm birth in women with symptoms of premature labour: a systematic review and cost analysis.

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Appendix 10Protocol

DIAGNOSTIC ASSESSMENT REPORT COMMISSIONED BY THE NIHR HTA PROGRAMME

Title of project

The cost effectiveness of fetal fibronectin (fFN) testing in suspected premature labour.

Name of External Assessment Group (EAG) and project lead

Kleijnen Systematic Reviews Ltd. Assessment Group.

Project lead:

Marie Westwood

Kleijnen Systematic Reviews Ltd

Unit 6, Escrick Business Park

Riccall Road, Escrick

York YO19 6FD

Tel: 01904 727983

Email: marie@systematic-reviews.com

1. Plain English Summary:

The World Health Organization (WHO) defines a premature birth as an infant born before 37 completed weeks of gestation.1 The incidence of spontaneous preterm birth is 7–12% of pregnancies before 37 weeks’ gestation and about 4% of pregnancies before the completion of 34 weeks’ gestation.2–5 One in 13 live births in England and Wales are preterm.6 The incidence of preterm births before 37 weeks’ gestation is reported to be greater in multiple pregnancies (61.9%) as compared to singleton pregnancies (11.1%).4 In the majority of developed countries, preterm birth is one of the major causes of neonatal mortality and severe morbidities1. Preterm births account for about 60 to 80% of the neonatal mortality and about 75% of severe morbidities.7,8 These severe morbidities can cause significant psychological, sociological and financial burdens on the parents or the carers.9

The recent developments in perinatal health care have not significantly reduced the incidence of spontaneous preterm labour.4 The Cochrane review by Crowley10 reported the effectiveness of antenatal steroids in significantly reducing the rate of neonatal mortality and morbidities in symptomatic women. However, to maximise the effectiveness of antenatal steroid therapy, it is important to diagnose preterm labor in early stages after the appearance of signs and symptoms.

The use of fetal fibronectin (fFN) testing is proposed to diagnose preterm labor in the women displaying symptoms. fFN can be detected in cervicovaginal secretions in early pregnancy and before birth. fFN is released into the cervix or vagina because of the mechanical damage caused to the fetal membrane before the onset of birth. However, in the normal course of pregnancy it is unusual to detect fFN between 22 to 37 weeks’ gestational ages.11 Hence, the detection of elevated levels of fFN in cervicovaginal secretion between 22 to 37 weeks’ gestation can be considered an indicator of preterm labour in symptomatic women.12

The purpose of this project is to assess the cost-effectiveness of adding fFN to conventional management, compared with conventional management alone, in women who are symptomatic for preterm birth. The conventional methods of managing pre-term labour in symptomatic women include hospitalisation for longer periods, antenatal steroid therapy and occasional in-utero transfer.13 However, only about 20% of admissions for suspected preterm labor will actually progress and deliver the baby prematurely. The remaining 80% of admissions have normal delivery after 37 weeks’ gestation; this means that there are many unnecessary and costly inpatient admissions and treatments for suspected preterm labor.14 It is hoped that the addition of fFN testing to the diagnostic work-up of women with suspected pre-term labour will help to identify those 20% of women who require active management, and thus avoid unnecessary interventions, hospitalizations and associated costs.

4. Decision problem

4.1 Aims & objectives:

Aim:

The aim of this project is to assess the impact of early diagnosis of pre-term labour, using fetal fibronectin testing, on NHS resources and to propose possible changes in maternal management.

Objectives:

  1. To assess the effectiveness and accuracy of the fFN test (commercial rapid test kit) in diagnosing spontaneous pre-term labour in symptomatic women.
  2. To assess, from an NHS perspective, the cost-effectiveness of the use of Fibronectin (rapid fFN testing) to diagnose spontaneous pre-term labor in symptomatic women in comparison to no testing (current care).

4.2 Intervention:

Fetal fibronectin is an extracellular matrix glycoprotein produced by amniocytes and by cytotrophoblast.1 It is thought to be present mainly in the choriodecidual interface, which is a union between maternal and fetal tissues.15 Normally, fFN is present in the cervicovaginal secretions of pregnant women until 22 weeks’ gestation. However, the level of fFN in cervicovaginal secretions drops after 22 weeks’ gestation (< 50 ng/mL). If the pregnancy is not normal, the level of fFN found in a cervicovaginal swab may be high (≥ 50 ng/mL) at or after 22 weeks’ gestation; elevated levels of fFN may indicate early onset of labour.1

The fFN test can be used to assess the risk of preterm birth, within 7 to 14 days of testing, in symptomatic women. The fetal fibronectin test is available in two formats: a quantitative solid-phase enzyme-linked immunosorbent assay (ELISA) or a qualitative membrane immunosorbent assay (Rapid fFN for the TLi™ System, which recently changed to FullTerm™).16–18 Rapid fFN testing is a more practical approach for diagnosing preterm labour as it gives the results instantly (30 min) unlike the ELISA assay which delivers the results 4 to 48 hours after sample collection.17 However, there is limited clinical evidence on the use of rapid fFN to detect preterm labour as majority of evidence is based on ELISA.

Rapid fFN testing is a lateral flow, solid-phase immunosorbent assay designed to perform a qualitative detection (positive/negative) of fFN in cervicovaginal specimens collected in the Adeza Biomedical Collection Kit.17 The cervicovaginal specimen (vaginal swab) is mixed with a liquid buffer in a collection tube and a portion of this sample is pipetted to the lateral flow, rapid fFN cassette in the TLi™ IQ Analyser.17 The assay takes about approximately 30 min to process the sample and deliver the results. The TLi™ automatically prints and displays positive or negative results along with patient details (an fFN level of ≥ 50 ng/mL is positive result and an fFN level of < 50 ng/mL is negative result).17

The intervention considered in this review is rapid fFN testing in addition to usual care.

Population:

The data from England and Wales suggest that the estimated number of spontaneous preterm births before 37 weeks’ gestation was 76,000 in 2004.6 The majority of neonatal deaths occur in the infants born before 34 weeks’ gestation; surviving babies tend to suffer from serious morbidities such as bronchopulmonary dysplasia, respiratory distress syndrome (RDS), necrotizing enterocolitis, intraventricular haemorrhage (IVH), retrolental fibroplasia, sepsis, long term cognitive difficulties etc.1,15 Also, some of the premature infants who are classified as normal with respect to their development, or who have mild abnormalities, can have multiple health problems later in life.19 Preterm births not only affect the infant and family but also increases NHS resource use (longer hospital stays, or use of neonatal intensive care services).20

The actual pathogenesis of preterm labour is unknown but there are several risk factors which are believed to be predictive of preterm birth (e.g. ethnicity, smoking, young/old maternal age, multiple pregnancy, stress, infection, low socioeconomic status and history of previous preterm birth).21,22 Multiple pregnancies are more likely to be at risk of preterm labour than singleton pregnancies. In developed countries the incidence of multiple pregnancies has increased in last 20–30 years mainly because of advanced reproductive techniques such as drugs used to induce ovulation and in vitro fertilisation.20 Most studies on fFN testing exclude women with multiple pregnancies because of the associated complications. However, in this review both singleton and multiple pregnancies will be considered.

This assessment will consider the population of women with singleton or multiple pregnancies displaying symptoms of labour before completing the 37 weeks gestational period (preterm labour). The clinical signs and symptoms that indicate onset of preterm labour are uterine contractions, low abdominal pain, dull backache, pelvic pressure, change in volume or consistency of vaginal discharge, and menstrual-like or intestinal cramping.23–25 Also, an important sign of preterm labour is cervical effacement (80%) and dilation (< 3 cm).

Comparator (usual care):

Currently, the diagnosis of preterm labour is based mainly on signs and symptoms, clinical history and physical examination of the patient. Physical examination of the cervix indicating dilation of ≥ 3 cm and at least 80% effacement is indicative of preterm labour within 24 hours to 7 days.17 If a woman is diagnosed with preterm labour by a physical examination then she can be treated to postpone her delivery by administering tocolytic agents. However, in some cases it is not possible to postpone the delivery and preparations have to be made for a preterm delivery. Clinicians need to take a number of key decisions before preparing for a preterm delivery, e.g. use of maternal intramuscular corticosteroid injection to facilitate the development of lungs and to avoid respiratory distress syndrome.9 Antenatal corticosteroids are most effective in the infants who have been delivered after 2–7 days after the administration of the drugs.10 Also, it is important to check for the availability of neonatal intensive care unit space before in utero transfers. The arrangements for in utero transfers may take some time due to geographical constrains or long waiting periods.26 Thus, considering the time required for the corticosteroid drugs to show maximum effectiveness (2–7 days) as well as the time required for making in utero transfer arrangements it is very important for the clinicians to have advance timely knowledge of preterm birth in symptomatic women.

Where physical examination does not confirm the diagnosis of preterm labour, symptomatic women have to be hospitalised under observation for longer periods to assess if the symptoms are subsiding or increasing.21,24,25 During this period of hospitalisation, complete bed rest is suggested and clinicians may administer tocolytic drugs or antibiotics as required. The main concern for clinical diagnosis based on symptoms is that it is very unreliable, and leads to over diagnosis of preterm labour.27 The overdiagnosis of preterm labour incurs unnecessary hospitalisation, unnecessary interventions and wastage of resources; there is, therefore, a need for improved diagnostic testing.

Current evidence:

A number of systematic reviews have previously evaluated the effectiveness of the fFN testing. Honest et al.9 conducted a HTA review on screening to prevent spontaneous preterm birth in symptomatic and asymptomatic women. They evaluated several screening interventions which can be used to predict and prevent spontaneous preterm birth, including the fFN test. However, the conclusions of this review did not focus on the cost effectiveness of fFN testing. A recent systematic review, exclusively evaluating the accuracy of fFN testing to predict the preterm birth in women with multiple pregnancies, concluded that fFN testing can be most accurate in predicting the spontaneous preterm birth within 7 days of testing (pooled sensitivity, specificity, and positive and negative likelihood ratios of 85%, 78%, 3.9, and 0.20, respectively) in women with twin pregnancies.24 Similarly, an earlier review by Honest et al.15 evaluated the accuracy of fFN testing in predicting spontaneous preterm labour and concluded that fFN testing is most accurate in predicting spontaneous preterm birth with 7–10 days of testing among the symptomatic women. However, this review evaluated only the quantitative solid-phase ELISA test. A systematic review by Ramos,28 evaluated the effectiveness of fFN testing and, in contrast to the studies detailed above, concluded that fFN has limited accuracy in predicting preterm birth within 7 days of sampling in symptomatic pregnant women.

Two previous systematic reviews have assessed rapid fFN testing for predicting preterm labour in symptomatic women. The first study was carried out in Australia by the Medical Service Advisory Committee29 which determined the test to be safe but it did not determine the effectiveness for symptomatic labour. The second study was carried out by the Institute of Health Economics in Canada. The study concludes by supporting the previous findings that the rapid fFN test can be used to diagnose preterm labour in symptomatic women based on its higher negative predictive values.17

Given the current evidence base and clinical imperative for rapid information, evaluate rigorous, up-to-date evaluation of the cost effectiveness of rapid fFN testing to predict the preterm labour in the symptomatic women is needed. Some countries (Australia and Canada) have already assessed rapid fFN testing with respect to their healthcare settings. However, to date, no similar assessment has been carried out for the UK setting; the current assessment will evaluate the cost effectiveness of fetal fibronectin testing in suspected premature labour in the UK.

5. Methods of assessing clinical effectiveness

5.1 Inclusion and Exclusion criteria:

Population:

Studies including pregnant women with singleton or twin gestations who have signs and symptoms of pre-term labour (e.g. uterine contractions, dull backache, pelvic pressure, change in volume or consistency of vaginal discharge, and menstrual-like or intestinal cramping) before 37 weeks’ gestation.

Setting:

Secondary care.

Intervention:

Studies assessing swab testing for fetal fibronectin using a commercial rapid test kit done before 37 weeks’ gestation + usual care, for the diagnosis of pre-term labour. Studies using rapid fetal fibronectin test in participants after 37 weeks’ gestation or studies assessing fetal fibronectin for detecting any other risks than preterm birth will be excluded from this review.

Comparator (clinical effectiveness studies only):

Usual care, without fibronectin, testing for managing pre-term birth.

Reference Standard (accuracy studies only):

Spontaneous preterm births before 37 weeks’ gestation.

Outcomes:

  • Incidence of spontaneous pre-term birth before 37 weeks’ gestation, before 34 weeks’ gestation, or within 24 hours, 48 hours, or 7–10 days of testing (time required for corticosteroids to exert beneficial effects and the potential for in utero transfer and tocolytic administration). – primary outcome measure.
  • Changes in maternal management
    1. Admission to hospital
    2. Use of corticosteroids
    3. Changes in frequency of monitoring
    4. Changes from usual care.
  • Outcomes in the new born, morbidity, mortality.
  • Outcomes of maternal health.
  • Diagnostic accuracy of the test.
  • Cost-effectiveness.

Study Design:

Step 1: Randomised and non-randomised trials where participants are assigned to the intervention group or comparator group, and which report patient-relevant outcomes (changes to maternal management, maternal health outcomes, new born morbidity and mortality) and/or incidence of pre-term birth (before 37 weeks).

Step 2: If insufficient evidence for the clinical effectiveness testing is identified, diagnostic cohort studies will be included in order to assess test accuracy.

Included test accuracy studies will be required to report sufficient data to construct 2 × 2 contingency tables, i.e. numbers of true positive, false negative, false positive, and true negative test results.

The following study/publication types will be excluded:

  • Studies with < 10 participants.
  • Pre-clinical and animal.
  • Reviews, editorials, and opinion pieces.
  • Case reports and diagnostic case-control studies.

5.2 Search strategy

Search strategies will be based on target condition and intervention, as recommended in the Centre for Reviews and Dissemination (CRD) guidance for undertaking reviews in health care and the Cochrane Handbook for Diagnostic Test Accuracy Reviews.30–32

Additional supplementary searches, for data to populate economic models, will be carried out as necessary. Searches for studies for cost and quality of life will also be included, see Section 6 for further detail.

The following databases will be searched for relevant studies from 2000 to the present:

  • MEDLINE (OvidSP)
  • MEDLINE In-Process Citations and Daily Update (OvidSP)
  • EMBASE (OvidSP)
  • Cochrane Database of Systematic Reviews (CDSR) (Internet)
  • Cochrane Central Register of Controlled Trials (CENTRAL) (Internet)
  • Database of Abstracts of Reviews of Effects (DARE) (CRD website)
  • Health Technology Assessment Database (HTA) (CRD website)
  • NHS Economic Evaluation Database (NHSEED) (CRD website)
  • Science Citation Index (SCI) (Web of Science)
  • Maternity and Infant Care
  • Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO)

Completed and on-going trials will be identified by searches of the following resources (2000–2010):

Key conference proceedings will be screened for the last five years. These may include Society for Maternal-Fetal Medicine, Blair Bell Research Society, European Association of Perinatal Medicine.

Identified references will be downloaded in Endnote X4 software for further assessment and handling.

The bibliographies of retrieved articles and relevant systematic reviews will be checked for additional studies.

Search strategies will be developed specifically for each database and the keywords will be adapted according to the configuration of each database.

No restrictions on language or publication status will be applied. Limits will be applied to remove animal studies. Searches will take into account generic and other product names for the intervention. Examples of the search strategies to be used are presented in Appendix 1.

5.3 Data extraction strategy

Two reviewers will independently screen titles and abstracts of all reports identified by searches and discrepancies will be discussed. Full copies of all studies deemed potentially relevant, after discussion, will be obtained and two reviewers will independently assess these for inclusion; any disagreements will be resolved by consensus or discussion with a third reviewer.

Data relating to study details, participants, intervention and comparator tests, gold standard (test accuracy studies only), and outcome measures will be extracted by one reviewer, using a piloted, standard data extraction form. A second reviewer will check data extraction and any disagreements will be resolved by consensus or discussion with a third reviewer.

5.4. Quality assessment strategy

The methodological quality of included studies will be assessed using standard tools.32 The QUADAS tool,33 is recommended for assessing the methodological quality of test accuracy studies,30,32 but a revised version of QUADAS (QUADAS-2) is soon to be published (submitted for publication May 2011). QUADAS-2 will more closely resemble the approach and structure of the Cochrane risk of bias tool. The QUADAS-2 tool will be used in this assessment, with the permission of the QUADAS steering group, of which one of the reviewers is a member.

The results of the quality assessment will be used for descriptive purposes to provide an evaluation of the overall quality of the included studies and to provide a transparent method of recommendation for design of any future studies. In addition, if enough data are available from the included studies, quality components will be included as covariates in SROC models, to investigate their possible association with test performance. Based on the findings of the quality assessment, recommendations will be made for the conduct of future studies.

5.5. Methods of analysis/synthesis

The results of initial scoping searches suggest that trial data are likely to be sparse or non-existent. This section therefore focuses on the synthesis of data from test accuracy studies.

For test accuracy data, absolute numbers of true positive, false negative, false positive and true negative test results, as well as sensitivity and specificity values, with 95% confidence intervals will be presented for each study and patient group reported. Where appropriate, and where sufficient accuracy data are available, summary receiver operating characteristic (SROC) curves will be calculated to summarise test accuracy data. SROC modelling will use the bivariate approach.30,34,35 Potential sources of heterogeneity will be investigated by extending SROC models to include study level covariates, (e.g. participant age, ethnicity, smoking status, concomitant infection, previous history of pre-term birth, risk of bias criteria); the bivariate approach to modelling allows investigation of the effects of covariates on sensitivity and specificity separately.

Where meta-analysis is considered unsuitable for some or all of the data identified (e.g. due to the heterogeneity and/or small numbers of studies), we will employ a narrative synthesis. Typically, this will involve the use of text and tables to summarise data. These will allow the reader to consider any outcomes in the light of differences in study designs and potential sources of bias for each of the studies being reviewed. Studies will be organised by clinical application (singleton, multiple pregnancies), relevant patient sub-groups, and the outcomes assessed. Where data are insufficient to support meta-analyses, the following graphical representations will be presented: plots in ROC space (without summary curves) and/or paired forest plots of sensitivity and specificity for test accuracy data; forest plots for any trial data.

A detailed commentary on the major methodological problems or biases that affected the studies will also be included, together with a description of how this may have affected the individual study results. Recommendations for further research will be made based on any gaps in the evidence or methodological flaws.

6. Methods of assessing cost-effectiveness

The economic component of the project, assessing the value of the use of Fibronectin (rapid fFN testing) to diagnose spontaneous pre-term labor in symptomatic women will consist of two parts. First a review of the economic literature will be performed. Secondly, a de novo cost-effectiveness model will be built and run. We consider the design and use of a de novo model (or adaptation of any other suitable model that might be identified in the literature) essential since the cost-effectiveness model that was described in the HTA-report by Honest et al. was based on estimating the incremental cost per preterm birth avoided or cost per perinatal death avoided. This analysis did not distinguish between preterm birth at < 34 weeks’ gestation and between 34 to 37 weeks’ gestation, which has impact on costs. In the de novo model we intend to differentiate between < 34 and 34–37 weeks of gestation Also, the analysis by Honest et al did not take into account the long-term effects on costs, life expectancy and quality of life of the child resulting from the use of fFN testing. Dependent on time and budgetary constraints, we may also adopt a longer time horizon, use outcome measures such as life expectancy and QALYs, and explore the possible impact of the use of Fibronectin on the life expectancy of the mother.

6.1 Identifying and reviewing published cost-effectiveness studies

The objective of the review of economic evaluations of the diagnosis of preterm labor is to summarize methods and findings of existing peer reviewed studies.

Exploration of the literature regarding published economic evaluations will be performed in the databases listed in the systematic review part of this protocol. In addition, specific health economic databases will be searched (e.g. NHSEED (NHS Economic Evaluation Database), PEDE (Paediatric Economic Database Evaluation), and HEED (Health Economic Evaluation Database); an example search strategy is included in Appendix 1. Searches will focus on original papers that report on cost, cost-accuracy, cost-effectiveness or cost-utility analyses studying diagnostics of preterm labor. For our assessment only full economic evaluations, i.e. those that explicitly compare different decision options will be selected. Clinical trials as well as modelling studies and cohort studies will be considered relevant within the frame of our project. The intention of this component of the project is not to perform a systematic review, but to use the studies identified to support the development of an economic model that will aim to answer the research questions of this project.

The results and the methodological quality of the studies selected will be summarised. Assessment of methodological quality will follow the criteria for economic evaluations in health care as described in the NICE methodological guidance.32 Data extraction will focus on technologies compared, indicated population, main results in terms of costs and consequences of the alternatives compared, and the incremental cost-effectiveness, but also on methods of modelling used (if applicable), analytical methods and robustness of the study findings.

6.2 Evaluation of costs, quality of life and cost-effectiveness

The model will evaluate the cost-effectiveness of rapid fFN testing in symptomatic women in addition to a diagnosis based on clinical signs and symptoms (uterine contractions, low abdominal pain, dull backache, pelvic pressure, change in volume or consistency of vaginal discharge, and menstrual-like or intestinal cramping). The focus of the evaluation of fFN testing in this population will be in assessing the accuracy of testing. Identifying a woman to be at high risk for preterm labor, either based on clinical signs and symptoms only or based on fFN-testing, will lead to preventive actions. In the model the following actions will be included: hospitalisation under observation for longer periods (including complete bed rest, and possibly administration of tocolytic drugs or antibiotics) to assess if the symptoms are subsiding or increasing. If preterm birth is unavoidable preparation is required, e.g. by administration of maternal intramuscular corticosteroid injection. In the current situation a false positive identification of high risk of preterm labor will lead to inefficient care (avoidable hospitalization and treatment). A false negative judgement based on testing might lead to preventable preterm delivery and preventable maternal and paediatric morbidity and mortality.

The perspective will be that of the NHS and the timeframe used will initially consider time to delivery (short term analysis) and may also consider a lifetime time horizon (long time analysis). Short-term costs will include the costs of fFN-testing, perinatal hospitalization cost of mother and child, and costs of delivery. For this purpose a distinction will be made between the situation of delivery after 37 weeks’ gestation, between 34 and 37 weeks’ gestation and earlier than 34 weeks’ gestation. Short-term consequences will be expressed as probability of preterm delivery (< 37 weeks’ gestation) and very early preterm delivery (< 34 weeks’ gestation) and consequently the cost-effectiveness will be expressed as the cost per case of preterm delivery avoided (both < 34 and < 37 weeks’ gestation). Besides this, perinatal death will be assessed in this short term analysis and expressed as the cost per perinatal death avoided. If undertaken, long-term cost-effectiveness will assess the costs per life year and the cost per QALY. In this analysis life expectancy and QALY will be based on the general population expectancy, according to the three subgroups specified based on duration of gestation (< 34 weeks; 34–37 weeks, and > 37 weeks). Lifetime health care costs (non-perinatal costs) may be considered if sufficient data are available for analysis. Data for the cost analyses will be drawn from routine NHS sources (e.g. NHS reference costs, Personal Social Services Research Unit (PSSRU), British National Formulary (BNF)), and discussions with individual hospitals where necessary.

Besides the impact of preterm diagnosis on the child a possible impact on the mortality of the mother will be assessed in a separate calculation.

Any assumption used in the models and any parameter value will be based primarily on literature and supplemented by clinical expert opinion as appropriate. Extensive one-way sensitivity analyses will be performed, besides a comprehensive probabilistic sensitivity analysis. If assessed, longer-term costs and consequences will be discounted using the UK discount rates of 3.5% of both costs and effects. Decision uncertainty regarding the alternatives will be reflected using cost-effectiveness planes and cost-effectiveness acceptability curves. Value of information analysis will be performed for those model parameters for which empirical distributions can be defined.

The following major assumptions will be basis for the cost-effectiveness calculations:

  • A possible impact on preterm delivery will impact on the perinatal mortality, life expectancy, and quality of life of the child. The possible short-term impact of preterm birth on the morbidity of the mother and the long-term impact on the parents are considered to be beyond the scope of this economic model.
  • The analysis will be based on a closed cohort population. Variability within the population is not part of the analyses. If the review on efficacy of fibronectin reveals heterogeneity within the population, this will be dealt with using subgroup analyses in the model.
  • Life expectancy and quality of life of a newborn that is born > 37 weeks’ gestation is considered to be equal to the general population.
  • In the analysis no distinctions will be made between singletons and twins.
  • Preterm birth before 34 weeks’ gestation will have impact on perinatal mortality and morbidity of the child. Besides this, preterm birth will have impact on life expectancy and quality of life of the child.
  • Elective preterm deliveries are considered beyond the scope of this model.

A preliminary version of the decision analytic model is shown in the figure 1 below. Validation and possibly adaptation of the structure of this model will depend on the findings from the literature review and consultation with clinical experts. In addition, the existence/availability of any other electronic models that reflect the cost-effectiveness of diagnostic and treatment pathways for these patients, and are representative of current care within the NHS, will be determined.

FIGURE 1. Decision analytic model.

FIGURE 1

Decision analytic model.

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Centre for Reviews and Dissemination. Systematic Reviews: CRD's guidance for undertaking reviews in health care [Internet]. York: University of York, 2009. [cited 23.03.11] Available from: http://www​.york.ac.uk​/inst/crd/SysRev/!SSL!/WebHelp/SysRev3​.htm.
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Appendix: 1

Clinical effectiveness search for SRs and RCTs

Medline (OvidSP): 2000-2011/6/wk1

Searched: 10.06.11

  1. fibronectins/ (18793)
  2. (86088-83-7 or fibronectin$).af. (30593)
  3. (fFN or tli system$).ti,ab,ot. (126)
  4. (tli adj iq).ti,ab,ot. (1)
  5. or/1-4 (30620)
  6. exp Obstetric Labor, Premature/ (14510)
  7. ((Pre term or preterm or premature or early or immature) adj5 (labo?r or birth$ or childbirth$ or deliver$ or partu$ or ruptur$)).ti,ab,ot,hw. (39734)
  8. (PROM or PROM or PTB).ti,ab,ot. (3046)
  9. ((Short$ or reduced or multiple) adj4 gestation$).ti,ab,ot. (3052)
  10. or/6-9 (44101)
  11. 5 and 10 (404)
  12. randomized controlled trial.pt. (308386)
  13. controlled clinical trial.pt. (82578)
  14. randomized.ab. (214849)
  15. placebo.ab. (125246)
  16. drug therapy.fs. (1456618)
  17. randomly.ab. (155580)
  18. trial.ab. (221813)
  19. groups.ab. (1034167)
  20. meta-analysis.mp,pt. or review.pt. or search:.tw. (1741286)
  21. or/12-20 (4106833)
  22. exp animals/ not humans.sh. (3598690)
  23. 21 not 22 (3569496)
  24. 23 and 11 (173)
  25. limit 24 to yr="2000 -Current" (116)

SR filter:

Montori VM, Wilczynski NL, Morgan D, Haynes RB. Optimal search strategies for retrieving systematic reviews from MEDLINE: analytical survey (top strategy minimising the difference between sensitivity and specificity). BMJ 2005;330(7482):68.

RCT filter:

Lefebvre C, Manheimer E, Glanville J. Chapter 6: searching for studies. Box 6.4.c: Cochrane Highly sensitive search strategy for identifying randomized controlled trials in Medline: Sensitivity-maximizing version (2008 version); OVID format. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org

Economic evaluations search

Medline (OvidSP): 1948-2011/6/wk1

Searched: 13.06.11

  1. fibronectins/ (18793)
  2. (86088-83-7 or fibronectin$).af. (30593)
  3. (fFN or tli system$).ti,ab,ot. (126)
  4. (tli adj iq).ti,ab,ot. (1)
  5. or/1-4 (30620)
  6. exp Obstetric Labor Complications/ (43593)
  7. (labo?r or birth$ or childbirth$ or deliver$ or partu$ or ruptur$).ti,ab,ot,hw. (711882)
  8. (PROM or PROM or PTB).ti,ab,ot. (3046)
  9. ((Short$ or reduced or multiple) adj4 gestation$).ti,ab,ot. (3052)
  10. or/6-9 (720210)
  11. 5 and 10 (1116)
  12. economics/ (26052)
  13. exp "costs and cost analysis"/ (156819)
  14. economics, dental/ (1829)
  15. exp "economics, hospital"/ (17190)
  16. economics, medical/ (8404)
  17. economics, nursing/ (3847)
  18. economics, pharmaceutical/ (2236)
  19. (economic$ or cost or costs or costly or costing or price or prices or pricing or pharmacoeconomic$).ti,ab. (335890)
  20. (expenditure$ not energy).ti,ab. (14210)
  21. (value adj1 money).ti,ab. (20)
  22. budget$.ti,ab. (14415)
  23. or/12-22 (448370)
  24. ((energy or oxygen) adj cost).ti,ab. (2292)
  25. (metabolic adj cost).ti,ab. (594)
  26. ((energy or oxygen) adj expenditure).ti,ab. (13122)
  27. or/24-26 (15392)
  28. 23 not 27 (444870)
  29. letter.pt. (716157)
  30. editorial.pt. (276466)
  31. historical article.pt. (275084)
  32. or/29-31 (1254908)
  33. 28 not 32 (420635)
  34. Animals/ (4763447)
  35. Humans/ (11766611)
  36. 34 not (34 and 35) (3517445)
  37. 33 not 36 (396750)
  38. 37 and 11 (37)

Costs filter:

Centre for Reviews and Dissemination. NHS EED Economics Filter: Medline (Ovid) monthly search [Internet]. York: Centre for Reviews and Dissemination; 2010 [cited 28.9.10]. Available from: http://www.crd.york.ac.uk/crdweb/html/helpdoc.htm#MEDLINE_NHSEED

Image 10-130-01-fig1
Copyright © Queen's Printer and Controller of HMSO 2013. This work was produced by Deshpande et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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Bookshelf ID: NBK261019
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