1. Algemene gegevens / General Information

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1 Subsidieaanvraagformulier / Grant Application Form 1. Algemene gegevens / General Information Projecttitel / Project title The cost-effectiveness of ST analysis of the fetal electrocardiogram as compared to fetal blood sampling for intrapartum fetal monitoring: a randomised controlled trial Aanvrager / Applicant Drs. A Kwee T: F: E: a.kwee@azu.nl Universitair Medisch Centrum Utrecht Obstetrie, Neonatologie & Gynaecologie Gynaecologie en Obstetrie Postbus GA UTRECHT Projectleden / Project members Prof. dr. G.H. Blijham (Bestuurlijk verantwoordelijke) T: F: E: Universitair Medisch Centrum Utrecht Raad van Bestuur Postbus GA UTRECHT Dr. K.G.M. Moons (Mede aanvrager) T: F: E: Universitair Medisch Centrum Utrecht Julius Centrum voor Huisartsgeneeskunde en Patiëntgebonden onderzoek Huisartsgeneeskunde Postbus AB UTRECHT Dr. B.W.J. Mol (Mede aanvrager) T: F: Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 1

2 Subsidieaanvraagformulier / Grant Application Form E: Maxima Medisch Centrum Gynaecologie/Obstetrie Postbus MB VELDHOVEN Dr. E. Birnie (Mede aanvrager) T: F: E: Academisch Medisch Centrum Sociale Geneeskunde Postbus DD AMSTERDAM ZUIDOOST Nederland Prof. dr. J.G. Nijhuis (Mede aanvrager) T: F: E: Academisch Ziekenhuis Maastricht Gynaecologie Postbus AZ MAASTRICHT Prof. dr. G.H.A. Visser (Mede aanvrager) T: F: E: Universitair Medisch Centrum Utrecht Obstetrie, Neonatologie & Gynaecologie Gynaecologie en Obstetrie Postbus GA UTRECHT Drs. A. Kwee (Projectleider en penvoerder) T: F: E: Universitair Medisch Centrum Utrecht Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 2

3 Subsidieaanvraagformulier / Grant Application Form Obstetrie, Neonatologie & Gynaecologie Gynaecologie en Obstetrie Postbus GA UTRECHT Prof. dr. H.P. van Geijn (Mede aanvrager) T: F: E: Vrije Universiteit medisch centrum Obstetrie en Gynaecologie Postbus MB AMSTERDAM Dr. J.A.M. van der Post (Mede aanvrager) T: F: E: Academisch Medisch Centrum Verloskunde/Gynaecologie Postbus DE AMSTERDAM ZUIDOOST Nederland Dr. E. van Beek (Mede aanvrager) T: F: E: Sint Antonius Ziekenhuis Postbus EM NIEUWEGEIN Nederland Samenwerking / Collaboration Jeroen Bosch Ziekenhuis Obstetrie en Gynaecologie Postbus ME 's-hertogenbosch TweeSteden Ziekenhuis Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 3

4 Subsidieaanvraagformulier / Grant Application Form Verloskunde/ Gynaecologie Dr. Deelenlaan AD TILBURG 2. Projectgegevens / Project information Programma / Programme DoelmatigheidsOnderzoek: deelprogramma Effecten & Kosten / Health Care Efficiency Research Programme: sub-programme Effects & Costs Subsidieronde / Subsidy round round grant applications Datum indienen (via ProjectNet) / Date of application :16 Aandachtsgebieden / Focus Themes: 11 Obstetrics; Themes HTA-methodology: H03 Outcome measures; Projecttype / Project type Onderzoeksproject Samenvatting / Summary BACKGROUND: Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive results and without fetal blood sampling (FBS) it results in an increase in operative deliveries without an improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two RCTs have shown that a combination of CTG and non-invasive ST-analysis (of the fetal ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both RCTs FBS was still performed in both arms, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis. OBJECTIVE: To quantify costs and effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in order to judge whether the ST-analysis can replace FBS. STUDY DESIGN: Multicentre randomised controlled trial in eight hospitals. STUDY POPULATION: Women in labour (above 36 weeks of gestation) with an indication for CTG. Interventions: Women will be randomised for fetal surveillance with CTG + FBS or CTG + ST-analysis. OUTCOME MEASURES: Primary outcome is the incidence of metabolic acidosis (defined as ph below 7.05 and BDecf above 12 mmol/l in the umbilical cord artery). Secondary outcome measures are: Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 4

5 Subsidieaanvraagformulier / Grant Application Form instrumental delivery rate, cost-effectiveness, neonatal outcome (Apgar score, admission to a neonatal ward) and cost-effectiveness of both monitoring strategies across hospitals. POWER/DATA-ANALYSIS: The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5 to 1.5 %, using a two sided test with an alpha of 0.05 and a beta of 0.80, in favour of CTG + ST-analysis, 2400 women have to be randomised (1200 per group). ECONOMIC EVALUATION: The economic evaluation is designed as cost-effectiveness analysis, i.e. the ratio of (I) incremental costs and (II) the reduced rate of metabolic acidosis, associated with the strategies is quantified. TIME SCHEDULE: The total research period is 3 years: a start-up phase of 4 months, an inclusion period of 26 months and 6 months to realise follow-up, analysis and reporting. ACHTERGROND: Het cardiotocogram (CTG) is wereldwijd de methode voor foetale bewaking durante partu. Dit heeft echter niet geleid tot enig voordeel voor de baby, en zonder microbloedonderzoek juist tot een stijging van het aantal interventies. Het MBO is echter invasief, vereist ervaring en geeft slechts een momentopname. Twee gerandomiseerde studies hebben aangetoond dat continue CTG + foetale ECG (ST-analyse) registratie het aantal interventies vanwege foetale nood en het aantal neonaten met metabole acidose significant verminderd. In deze studies werden echter MBO's verricht in beide armen, waardoor het nog steeds onduidelijk is of de resultaten het gevolg waren van de ST-analyse dan wel het verrichten van het MBO in combinatie met ST-analyse. DOEL: Bepalen van de kosten-effectiviteit van de non-invasieve methode van foetale bewaking mbv CTG + foetale ECG tov de standaard-methode met CTG + MBO en te bepalen of de ST-analyse het MBO kan vervangen. STUDIE-OPZET: Multicentrum gerandomiseerde studie in acht ziekenhuizen STUDIEPOPULATIE: Alle vrouwen in partu met een indicatie voor foetale bewaking met behulp van CTG en een zwangerschapsduur boven 36 weken. INTERVENTIE: vrouwen zullen worden gerandomiseerd voor foetale bewaking met behulp van CTG + MBO versus CTG + ST-analyse. UITKOMSTMATEN: primaire uitkomstmaat is de incidentie van metabole acidose (gedefinieerd als ph kleiner dan 7.05 en BDecf meer dan 12 mmol/l in de navelstrengarterie). Secundaire uitkomstmaten zijn: het aantal kunstverlossingen, de kosten-effectiviteit, de neonatale uitkomst (Apgar score, opname couveuseafdeling) en de kosten-effectiviteit van de verschillende ziekenhuizen. POWER-/DATA-ANALYSE: De analyse zal plaatsvinden volgens het intention to treat-principe. Om een reductie van metabole acidose van 3.5 naar 1.5 procent ten gunste van de strategie met ST-analyse aan te tonen moeten 2400 vrouwen (1200 per groep) worden gerandomiseerd. (tweezijdige test met alpha van 0.05 en beta van 0.80) ECONOMISCHE EVALUATIE: De economische evaluatie is opgezet als een kosten-effectiviteitsanalyse, d.w.z. als de verhouding van (I) incrementele kosten en (II) afgenomen incidentie van metabole acidose wordt gekwantificeerd. TIJDSCHEMA: De totale onderzoeksduur bedraagt 3 jaar: 4 maanden opstartfase, een inclusie periode van 26 maanden en een analyse- en rapportage-periode van 6 maanden. 3. Inhoud / Content Probleemstelling / Problem definition The aim of intrapartum fetal monitoring is to identify fetuses at risk for neonatal and long-term injury due to asphyxia. Although cardiotocography (CTG) is applied on a large scale, this technique is still subject to debate (1-3). Long-term follow-up studies have shown no or little benefit of fetal surveillance and Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 5

6 Subsidieaanvraagformulier / Grant Application Form intrapartum monitoring results in a significant increase in operative deliveries (4-6). Fetal blood sampling (FBS) can be used in addition to CTG, but it requires expertise, is invasive, has to be repeated when CTG abnormalities persist and can cause complications (7,8). As a consequence, it is not widely applied.(9) In the Netherlands FBS is available in only 70 % of the hospitals. Because abnormalities in the ST-segment are related to metabolic acidosis of the fetus, detection of changes in the ST-segment of the fetal electrocardiogram (ECG), in combination with CTG, is a non-invasive and promising alternative for FBS.(10,11) Two randomised trials (the Plymouth RCT (2400 cases) and the Swedish RCT (4966 cases)) indeed have shown a decrease in metabolic acidosis and in interventions for fetal distress in favour of the CTG plus ECG-group.(12,13) The rate of infants with encephalopathy in the Swedish RCT was also significantly lower in the CTG + ST group as compared to the group monitored with CTG only.(14) However, in both RCTs FBS was still often performed in both arms. Hence, it was not possible to conclude if the observed improved outcome was indeed due to the monitoring by ST-analysis or because FBS was still used to guide subsequent management. In the previous ZonMW Doelmatigheidsonderzoek round, we proposed an observational diagnostic study aiming to determine the diagnostic value of ST-analysis as compared to FBS. We were advised to study the clinical value of ST-analysis as compared to FBS using a randomised, follow-up design, rather than an observational design. Following the suggestions of the ZONMW committee, we now propose to conduct a randomised trial comparing the (cost-) effectiveness of monitoring using CTG + ST-analysis with usual care monitoring by CTG+FBS. What is the disease / condition, subject of this proposal/subgroup of patients The proposed study evaluates the cost-effectiveness of two strategies for fetal surveillance: a. conventional monitoring (CTG + FBS) or b. CTG + ST analysis. Women in labour with an indication for intrapartum fetal surveillance at a gestational age above 36 weeks of gestation and a singleton fetus in vertex position are included in the study. Describe the usual care in the Netherlands for the (sub-) group of patients involved In the Netherlands women with a medical indication deliver in the hospital. During labour they are monitored by CTG to detect fetal distress. FBS will be performed in addition to the CTG, if the latter provides an indication to do so. However, only 70 % of the Dutch hospitals perform FBS due to its technical aspects and in these hospitals it is not applied in a systematic way. Gynaecologists are responsible for the delivery of pregnant women with a medical indication. In many hospitals registrars or specially trained midwives under supervision of a gynaecologist manage these deliveries. The research setting will be the same as in daily practice; involving gynaecologists, residents as well as midwives working on labour wards. Describe your motivation for the chosen intervention In spite of the above-mentioned evidence on the potential improvement in fetal surveillance using ST-analysis, there is at present still a dilemma for gynaecologists on its clinical value and cost-effectiveness. First, as mentioned above, the effectiveness of CTG + ST-analysis without FBS is unknown. Second, ST-analysis requires financial investment, which are at state considered by many gynaecologists in The Netherlands. Costs are not only related to the procure of the ST-monitor (34000 Euro per monitor), but are also related to the necessity of repeated training of labour ward personnel. In 2000 the University Medical Centre Utrecht (applicants Kwee and Visser) participated in a EU-project regarding the implementation of ST-analysis. The technique has been applied in over 600 women. The results of a study within this project showed that ST-changes were present in all cases with severe metabolic acidosis and that CTG + ST-analysis was more specific in detecting fetal academia than CTG alone.(15) In conclusion, ST-analysis is a promising new technique for detecting fetal distress during labour. However, it is not known whether this technique can be used without FBS. Moreover, ST-analysis is Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 6

7 more costly than conventional fetal monitoring. The present proposal offers a unique opportunity to address the question if fetal monitoring with CTG + ST-analysis (without FBS) is more effective than CTG + FBS and provides the possibility of proper cost-effectiveness evaluation before widely introducing ST-analysis in clinical practice. Relevantie / Relevance Subsidieaanvraagformulier / Grant Application Form Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive results and without fetal blood sampling (FBS) it results in a significant increase in operative deliveries without improved outcome. FBS requires additional expertise, is invasive and has to be repeated when CTG abnormalities persist. Accordingly it has not gained popularity among gynaecologists and labouring women. Non-invasive ST analysis of fetal ECG recording seems a promising alternative. Two RCTs have shown that a combination of CTG and ST-analysis reduces the rates of metabolic acidosis and instrumental delivery. However, in both RCTs FBS was still performed in both arms, and it is therefore still unknown if the observed decrease in poor outcome and interventions were indeed due to the ST-analysis or to the use of FBS. Furthermore, the cost-effectiveness of ST-analysis as compared to routine care using FBS is yet unknown How will the results of the proposed study contribute to the resolution of this health care problem? The proposed study will reveal the following answers: 1. The effectiveness of a monitoring strategy using CTG + ST-analysis compared to the conventional monitoring strategy (CTG + FBS). 2. The cost-effectiveness of both strategies. These results will help to resolve an important dilemma in current obstetrical care aiming at maximal prevention of metabolic acidosis with a minimal instrumental delivery rate. Are there any studies underway similar to the present study proposal? As far as we know there are no other studies underway similar to this proposal. Are there any reports by national advisory boards on the subject of your proposal? A guideline of the Dutch Society of Obstetrics and Gynaecology (NVOG) regarding fetal surveillance has recently stated that the use of ST-analysis is still experimental (May 2003). What is the incidence/prevalence of the targeted (sub-) population In The Netherlands, pregnant women per year are monitored during labour using CTG (16). In 2002, approximately (10%) instrumental deliveries were performed in this group due to fetal distress, and approximately 950 (1%) babies with ph in the umbilical cord artery below 7.00 have been born.(17) About 10% of the children with a ph below 7.00 will develop seizures (i.e. 100 children each year), whereas 30 % (30) of these babies will develop long term neurological problems (17,18). There exist many definitions regarding fetal academia. In accordance with the two RCTs on the ST-analysis and knowing that cerebral impairment is very unlikely in case of a more favourable umbilical cord artery ph, we defined metabolic acidosis as a ph below 7.05 with a BDecf above 12 mmol/l in the umbilical cord artery, Although data in The Netherlands about the incidence of metabolic acidosis are not available, the observational study of the UMC Utrecht indicates that the prevalence of metabolic acidosis in a high risk population (women with an indication for CTG monitoring) may be as high as 3.5 %.(15) Estimate the potential effects on health from the intervention(s) that will be evaluated in this proposal compared to the usual care The potential effects of the ST-analysis on health include a significant reduction of babies born with metabolic acidosis and encephalopathy and a reduction of unnecessary instrumental deliveries. The Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 7

8 latter may cause maternal and neonatal morbidity, and even mortality. It can be inferred from the two RCT?s that the rate of metabolic acidosis can be decreased with 66 % and the instrumental delivery rate with 1 %. As said, these results were obtained in a population in which FBS was performed and in a population of both low-risk and high-risk women delivering in a hospital, in contrast to the high-risk population, delivering under responsibility of a gynaecologist in Dutch hospitals. Furthermore, the effects in populations in which FBS is not used (30 % of the Dutch hospitals), are likely to be much larger, since the instrumental delivery rate with CTG alone is much higher than with CTG + FBS (up to 2-3 times higher).(19) In addition, hospital stay is expected to be shorter, both due to a decrease in metabolic acidosis and a decrease in instrumental delivery rate. Estimate the potential effects on costs intervention(s) that will be evaluated in this proposal compared to the usual care The results of the study will be applicable to approximately women per year in The Netherlands. A decrease of the instrumental delivery rate from 10 % to 9 % will result in a reduction of instrumental deliveries resulting in a potential saving of A reduction of the metabolic acidosis rate from 3.5 to 1.5 % would prevent metabolic acidosis in children, resulting in a potential saving of another ,-, not even taking into account any additional costs related to the development of encephalopathy and consequences in later life. Kennisoverdracht, implementatie, bestendiging / Knowledge transfer, implementation, consolidation Due to the apparent positive findings in the two randomised controlled trials on the subject, many obstetricians in The Netherlands are in doubt if they will procure a STAN-monitor for ST-analysis. In view of the large costs of this new technique, there is a crisp need for unbiased information on the cost-effectiveness of the ST-analysis as compared to CTG with FBS. Moreover, the question if or when FBS is still necessary needs to be answered. The proposed study will give definite answers about the cost-effectiveness of the two strategies, and on the amount of failure rates of the two techniques in terms of failed registration as well as failed technique. Due to the fact that the proposed study is multicentered, the results will be transferable to other Dutch centres. No major obstacles are to be foreseen as the outcome of the proposed study will lead to more specific recommendations on fetal monitoring during labour. The Dutch Society of Obstetrics and Gynaecology (NVOG) will be committed to the dissemination of all results of the study. The fact that the study will recruit patients in five large perinatologic centers and in three teaching hospitals in The Netherlands will facilitate implementation of the results. The results of the project will be presented in the Perinatology working group and will be incorporated in the guidelines of the NVOG. Doelstelling / Objective Subsidieaanvraagformulier / Grant Application Form Objective: to quantify the cost-effectiveness of cardiotocography in combination with non-invasive ST-analysis of the fetal electrocardiogram for fetal monitoring during labour as compared to usual care including cardiotocography in combination with fetal blood sampling. Specific Research questions: 1. Is the incidence of developing metabolic acidosis (measured in the umbilical cord artery) decreased with a strategy of fetal monitoring with CTG + ST-analysis, when compared with CTG + FBS? 2. Is the number of instrumental deliveries because of fetal distress decreased in the group monitored with CTG + ST-analysis, when compared with CTG + FBS? 3. Is monitoring by CTG + ST-analysis cost-effective? Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 8

9 Subsidieaanvraagformulier / Grant Application Form Plan van aanpak / Strategy Clinical Study Preliminary studies by applicants on the subject of this proposal: At the University Medical Centre Utrecht we recently performed a relatively small, single-centre observational diagnostic accuracy study among high-risk women in labour (15). This study was part of a European Community multi-centre project: a program of dissemination of knowledge -regarding the STAN-methodology- based on the Centre of Excellence structure. In this preliminary study all women underwent CTG analysis, fetal ST analysis, and FBS when indicated. Umbilical cord blood analysis functioned as reference test to determine the true presence or absence of metabolic acidosis. In two years, 637 women were included. We found that the sensitivity and specificity of ST analysis were 72 % and 90 %, respectively, whereas the positive and negative predictive values were 98 % and 18 %. For CTG, the sensitivity and specificity were 100 % and 18 % and the positive and negative predictive values were 100 % and 4 % respectively. In 22 % of the women FBS was performed. There were five cases of severe metabolic acidosis (ph in the umbilical artery below 7.00) that were all preceded by ST-segment changes, whereas in 3 cases FBS was still negative and -unnecessarily- delayed delivery (i.e. false negatives). Addition of fetal ST-analysis to CTG in a high-risk population resulted in a considerable reduction of the percentage of false negative (i.e. missing the presence of metabolic acidosis) and false positive (i.e. falsely diagnosing the presence of metabolic acidosis leading to unnecessary instrumental deliveries) test results. Study Design: The proposed trial is a pragmatic randomised, multicentre study. The study will be performed in five level III perinatal centres, which have recently joined research efforts to increase population size of studies, supplemented with three large regional hospitals. The cost-effectiveness of fetal monitoring during labour with CTG + ST-analysis is quantified and compared with the standard monitoring method including CTG + FBS. Eligible patients will be informed by the attending doctor or midwife. (see Appendix A) In case of informed consent, essential patient data will be entered in a web-based database program. This program subsequently randomly allocate the patient to one of the strategies. Randomisation will be stratified for centre and parity (no previous vaginal delivery versus one or more previous vaginal deliveries). This on-line system will also be used for the DIGITAT study (ZonMW grant ) and thus already known by most of the participating centres. Women will be randomly allocated to either monitoring by CTG + FBS or CTG + ST-analysis. Women who are offered randomisation, but who decide not to participate in the study will be monitored and managed confirm routine care including CTG + FBS. The study will be an open label study, as it is impossible to blind the patients and health care workers involved for the strategy to which the woman is allocated. Both strategies will be performed according to strict protocols (see below). In every centre an independent gynaecologist will be responsible for the study in that centre. A dedicated research nurse/midwife will monitor the study protocol in each centre by attending patients meetings and providing feedback on potential protocol violation. This person will collect data and will be available for more detailed information both for patients and labour ward personnel. Resources for training and technical support will be made available by the participating centres, and not from the funding applied for. Rationale of the design: ST-analysis is a promising new technique for detecting fetal distress during labour. It is a non-invasive, and thus promising alternative for FBS. Two randomised trials (the Plymouth RCT (2.400 cases) and the Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 9

10 Subsidieaanvraagformulier / Grant Application Form Swedish RCT (4.966 cases)) have shown a decrease in metabolic acidosis and in interventions for fetal distress in favour of the CTG plus ECG-group. (12,13)The rate of infants with encephalopathy in the Swedish RCT was also significantly lower in the CTG + ST group as compared to the group monitored with CTG only.(14) However, in both RCTs FBS was still often performed in both arms. Hence, it was not possible to conclude if the observed improved outcome was indeed due to the monitoring by ST-analysis or because FBS was still used to guide subsequent management. We now propose to conduct a randomised trial comparing the (cost-)effectiveness of monitoring using CTG + ST-analysis with usual care monitoring by CTG+FBS. In the CTG + ST-analysis group it is only allowed to perform FBS in case of poor signal quality of the fetal ECG-signal. The present proposal offers a unique opportunity to address the question if fetal monitoring with CTG + ST-analysis (without FBS) is more effective than CTG + FBS, and provides the possibility of proper cost-effectiveness evaluation before ST-analysis is widely introduced in clinical practice. Study Population: Women will be eligible if they are in labour with a singleton fetus in vertex position, a gestational age above 36 weeks and a medical indication for electronic fetal monitoring. A medical indication is defined by either a high-risk pregnancy, induction or augmentation of labour, epidural anaesthesia, meconium stained amniotic fluid or non-reassuring fetal heart rate. Exclusion criteria are fetus in breech presentation, twin pregnancies and absent informed consent. The proposed study concerns a multicentre study in five perinatal centres and three large regional teaching hospitals, in The Netherlands: Maxima Medical Centre Veldhoven, Academic Hospital Maastricht, Free University Medical Centre Amsterdam, University Medical Centre Utrecht, Academic Medical Centre Amsterdam. St.Antonius Hospital Nieuwegein, TweeSteden Hospital Tilburg and Jeroen Bosch Medical Centre Den Bosch. Measurements/interventions: Women will be randomly assigned to routine care including fetal monitoring by cardiotocography with fetal blood sampling (CTG + FBS group) or to the index group including cardiotocography with ST-analysis (CTG + ST group). (See Appendix B). Clinical management in the CTG + FBS group (routine care) will be guided by guidelines produced by the FIGO.(20) FBS is recommended in case of a suboptimal or abnormal CTG pattern. In cases with scalp blood ph lower than 7.20 or preterminal cardiotocograms delivery is recommended. In the CTG + ST group, clinical management will be supported by computerised ST waveform assessment and will be guided by the STANâ guidelines, indicating when intervention is recommended.(30, see Appendix C) In case of poor signal quality of the fetal ECG-signal it is allowed to perform a FBS in the first stage of labour. From each woman, we will systematically (by protocol) document demographics and medical history, as well as CTG analysis, fetal ST-analyis and FBS results. Finally, the umbilical cord artery results, the performance of an instrumental delivery and neonatal outcome until discharge from the hospital will be documented. (see Appendix D) Long term neonatal outcome is no endpoint of the study because the expectation of children with impaired neurological outcome will be only 1 in a group of 2400 women. Assuming a rate of 1 % neonates born wit severe metabolic acidosis (ph below 7.00), one would expect that of these 24 neonates 10 % (=2.4) will develop seizures and of these children 30 % (= about 1) will develop neurological problems in later life. (17,18) Therefore we focus on short-term neonatal outcome. CTG and FBS: In women randomised to the control group, a scalp electrode will be applied to the fetal head and connected to the conventional CTG-monitor conform routine practice of CTG monitoring. If the ph of the first measurement is below 7,20 delivery is recommended unless the cause of fetal distress can be alleviated. If the ph is between 7,20 and 7,25 FBS will be repeated after 30 minutes. If the ph is above 7,25 FBS is repeated according to CTG pattern according to the attending doctor or Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 10

11 Subsidieaanvraagformulier / Grant Application Form midwife. The number of failed FBS will be recorded. CTG and ST-analysis: In women randomised to the index group, a scalp electrode will be applied to the fetal head and connected to the STANâ-monitor conform routine practice of CTG monitoring. This electrode will allow both standard fetal heart rate monitoring (CTG) as well as ST-analysis. The CTG will be classified as normal, intermediate, abnormal or preterminal according to the FIGO-guidelines for fetal heart rate monitoring.(20). The ST log automatically alerts the attending doctor or midwife if a significant ST-event occurs.(21) Delivery is recommended when there are significant ST-changes (see appendix) unless the cause of fetal distress can be alleviated. It is only allowed to perform FBS in the CTG + ST-analysis arm in case of poor signal quality of the fetal ECG in combination with an intermediate or abnormal fetal heart rate pattern in the first stage. From our preliminary study, we know that in 10 % of cases the fetal ECG had a poor signal quality.(15) This percentage can be lowered by more appropriate placing and replacing of the electrodes. Furthermore, this is only of clinical value when the CTG is intermediate or abnormal. In our study 30 % of the CTG?s in the first stage were not normal. We estimate that in maximally 3 % of cases there will exist a situation of poor signal quality and an intermediate or abnormal CTG, indicating FBS. Otherwise, FBS will not be performed in this group. Outcome parameters: Primary Outcome: Presence or absence of metabolic acidosis defined as a ph below 7.05 and a BDecf above 12 mmol/l in the umbilical cord artery.(22) Secondary outcome: 1. Instrumental delivery rate for the following indications: fetal distress, failure to progress or a combination. 2. Cost-effectiveness of both strategies: see below 3. Neonatal outcome defined by low Apgar scores, defined as < 4 after 1 minute and/or < 7 after 5 minutes 4. Need for admission to the neonatal medium or intensive care unit 5. Cost-effectiveness of both monitoring strategies across hospitals, particularly, comparing academic and non-academic hospitals. Power analysis The aim of the present trial is to determine the difference in cost-effectiveness of CTG + ST-analysis versus the standard treatment including CTG + FBS for intrapartum fetal monitoring. The analysis will follow the intention to treat principle. For the primary outcome, difference in incidence in metabolic acidosis across both groups, the relative risk estimate (95% CI) will be estimated. The same analysis will be done for the dichotomous secondary outcomes. For cost-effectiveness analysis see below. The sample size calculation is based on the primary endpoint: metabolic acidosis in the umbilical cord artery. Although in the two randomised trials the incidence of metabolic acidosis decreased from 1.5 % to 0.5 % in favour of the CTG + ST-analysis group (12,13), we assume that the incidence of metabolic acidosis in our high-risk population (women delivering in the hospital with a medical indication) is higher and estimated on 3.5 %, as found in our preliminary study (15). A similar relative reduction of metabolic acidosis in our study would imply a reduction from 3.5 to 1.15 %, in favour of the CTG + ST-analysis arm. To be more conservative, assuming a reduction of 3.5 % to 1.5 %, 2106 women should be randomised (1053 per arm), using an alpha of 0.05 (2-sided) and a power of Accounting for 10% Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 11

12 Subsidieaanvraagformulier / Grant Application Form loss to follow-up, the study would require inclusion of 2400 women in order to obtain 2106 analysable cases. We will plan to perform after each 300 included subjects a group-sequential-analysis to determine whether enough evidence is gathered and the trial could be stopped before all patients are randomised.(23,24) Feasibility of recruitment Based on the experience of our previous study, per year 200 parturients per monitor can be recorded. Six hundred thirty seven women were included in 26 months, with one monitor during 12 months and two monitors during the remaining 14 months.(15) This means that per STAN-monitor 400 women per year can be randomised (200 in the CTG + FBS arm and 200 in the CTG + ST-analysis arm). To be conservative we assume that per monitor 250 women will be randomised. To recruit the required 2400 women 11 STAN-monitors will be needed. The participating centres have in total 14 monitors (UMCU 3 monitors, VUMC 5 monitors, AZM 1 monitor, MMC 1 monitor, AMC 1 monitor, St Antonius Hospital 1 monitor, TweeSteden hospital 1 monitor and Jeroen Bosch Medicentrum 1 monitor) who will be able to recruit 480 women per monitor in two years. The required number of 2400 women can be recruited. We refer to the letters of intention to participate in this study. See appendix E for detailed patient inflow. Data-analysis and presentation/synthesis The analysis will be done by intention to treat. The experimental and standard policy will be compared. Relative risks and 95 % confidence intervals will be calculated for the relevant outcome measures. The analysis will be stratified for centre and parity (no previous vaginal deliveries versus 1 or more previous vaginal deliveries). Moreover, for each of the two strategies (CTG+ST-analysis or CTG+FBS), accuracy can be determined with the umbilical cord ph and blood gasses as reference testing. Fetal monitoring is performed to detect fetal hypoxia, which is an indication for instrumental delivery. The primary aim is not to miss cases of fetal hypoxia (false negatives) as they may lead to neonatal complications, but on the other hand also avoid unnecessary instrumental deliveries (false positives) as they may lead to maternal as well as neonatal morbidity. Economic evaluation General considerations: The aim of the economic evaluation is to compare the optimality of two intrapartum diagnostic strategies in terms of costs and health effects: a. CTG+ST-analysis (experimental strategy), versus b. CTG+FBS (reference strategy), in singleton pregnant women with a gestational age of at least 36 weeks for whom intrapartum fetal monitoring is indicated. Generally, the CTG+ST is preferred to conventional CTG+FBS if the incremental health effects of CTG+ST compared to CTG+FBS outweigh the incremental costs of the experimental strategy compared to CTG+FBS. Specifically, data on diagnostic accuray of the strategies CTG+ST-analysis and CTG+FBS (ph in umbilical artery as gold standard), as well as data on neonatal outcome and costs of the true positive (TP), true negative (TN), false positive (FP) and false negative (FN) subgroups allow a comparison of costs and health effects of the experimental diagnostic strategy (CTG+ST) versus CTG+FBS. Given the superiority design of the clinical study, the economic evaluation is primarily designed as a costs-effectiveness analysis (CEA): the optimal strategy is the one with the most favourable trade-off between avoided adverse neonatal outcome (fetal distress/metabolic acidosis) and cost differences. Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 12

13 Subsidieaanvraagformulier / Grant Application Form For each of the diagnostic strategies, costs and outcomes are analysed according to intention- to-treat and described with appropriate statistical measures/tests. The sensitivity of costs and health outcomes for various model parameters is tested by sensitivity analysis and sampling techniques and visualised in ICER-graphs and acceptability curves. Scenarios for relevant subgroups are added. If differences in diagnostic accuracy imply differences in poor neonatal outcome and/or caesarean section rates, a long-term analysis is performed using a decision analytic approach. Discounting is applied only if the time horizon of analysis exceeds 12 months. Cost analysis: The process of care is distinguished into two cost stages (delivery/childbirth stage, postnatal stage) and three cost categories (direct medical costs [all costs in the health care sector], direct non-medical costs [costs outside the health care sector that are affected by health status or health care], and indirect costs [productivity costs, costs of sick leave]). For each stage and each cost category, costs are measured as the volumes of resources used multiplied with appropriate valuations (e.g. cost-per-unit estimates, reimbursement fees, national reference prices). Cost volumes in the childbirth stage consists of direct medical costs (all interventions and types of maternal and fetal monitoring during childbirth, e.g. CTG, FBS, FBS in ST group, ST-analysis, lab tests, care/costs associated with intrapartum complications; type of delivery) and includes the costs of training (education and interpretation associated with ST-analysis and learning). Direct non-medical and indirect costs in that stage may relate to the women's partners and families. Cost volumes in the postnatal stage consist of maternal care (hospitalisation) and neonatal care (admission to NICU/neonatalogy ward, outpatient vists) and possibly primary care after discharge. If neonatal health at birth or at discharge is suboptimal, additional direct medical, direct non-medical and/or indirect costs may occur. Hence for these infants, resource use of infants and/or parents is measured during 6 months after childbirth. Volumes of health care resource use are recorded prospectively alongside the clinical study in all participating centres as part of the CRF. Resource use outside hospitals is recorded by means of questionnaires or interviews. Valuations of direct medical resources are estimated as cost per unit estimates comprising 'true' economic costs, i.e. including shares of fixed costs and hospital overheads. Cost per unit is estimated for at least one teaching and one non-teaching hospital. An analysis based on reimbursement fees/dbcs is added. Direct medical volumes outside the hospital and direct non-medical volumes are valued using national reference prices.(25) Indirect costs are quantified according to the friction cost method. Study specific costs are excluded from analysis. Patient outcome analysis: Patient outcome in this study comprises the health effects that accrue to pregnant women/mothers, neonates/infants, as well as women's/parent's preferences for the diagnostic strategies. Expectedly, CTG+ST compared to CTG+FBS is thought to reduce the false positive and false negative rates and thereby to reduce the rate of metabolic acidosis and the rate of instrumental deliveries, the latter reducing the unfavourable maternal and neonatal health consequences (maternal and neonatal morbdity). Neonatal outcome is quantified as presence/absence of metabolic acidosis (see primary outcome section for exact definition). If neonatal health at birth or at discharge is compromised, postnatal follow-up of infants at 6 and 12 months will take place. Short-term maternal morbidity is measured as the rate of mild and severe complications during childbirth and in the postnatal stage; and the type of delivery (instrumental delivery/cs) during the childbirth stage. Mid-term maternal health effects are measured with conventional health status questionnaires (symptom cheklists, quality of life measures [e.g. MOS-SF36]), including record of complications and complaints, at months after childbirth. If neonatal health at discharge is compromised, parents' burden is measured at the same intervals. Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 13

14 Subsidieaanvraagformulier / Grant Application Form A study of women's/parent's preferences for each of the diagnostic strategies using trade-off techniques is added, as well as a study on the relative weight of maternal health and neonatal outcome in preferences and trade-offs. These will be studied as part of the HTA-Methodology study 'When outcome is a balance' (ZonMW grant DO ). Systematic review Search terms:labour, fetal ECG, ST-analysis, CTG, FBS, Outcome -population: women in labour -intervention: ST-analysis, fetal ECG -Comparison/control:cardiotocography eventually with FBS -Outcome: Neonatal outcome: metabolic acidosis, cephalopathy. Maternal outcome: instrumental delivery rate -methodological filters: human study, randomised controlled trial or observational study using STAN-monitor (type 8801 or S21) Databases used and number of manuscripts retrieved: Medline and Cochrane library.(26) Seven manuscripts retrieved in which the current method of ST-analysis with the STAN-monitor was used. (2 RCT, 1 follow-up study and 4 observational studies).(12-15,27-29) Selection procedure, validity assessment: In fact this systematic review was already performed by JP Neilson in the Cochrane Library.(24) This meta-analysis dates from February 2003 and includes two RCT?s based on ST-analysis and 1 RCT based on the PR-interval. The latter one is excluded in our review. The development of ST-analysis has a long history, with the first clinical observation in Thereafter followed years of technical developments leading up to a model for automatic ST waveform assessment. First, the STAN 8801-monitor was used in the Plymouth RCT published in 1994 (12). The second model, STAN S21-monitor was used in the observational studies and the Swedish RCT and is the model available at this moment.(13-15,27-29) We only included the studies with the STAN 8801-monitor and STAN S21-monitor, because these used automatic assessment of the ST-segment, what is used in the proposed study. Results (primary outcome parameter/secondary outcome parameter/economic evaluation): There are two randomised trials (Plymouth RCT and Swedish RCT) comparing CTG only with CTG + ST analysis, in total including 7400 women (12,13). FBS was performed at discretion of the doctor in both trials. The use of ST-waveform analysis was associated with fewer babies with severe metabolic acidosis (cord ph less than 7.05 and base deficit greater than 12 mmol/l) (relative risk (RR) 0.44, 95 % confidence interval (CI) , data from 6672 babies). This was achieved along with fewer fetal scalp samples during labour (RR 0.86, 95 % CI ) and fewer operative deliveries (RR 0.89, 95 % CI ). A follow-up study of the Swedish RCT showed a significant reduction of babies with encephalopathy from 0.33 (8/2447) in the cardiotocography-only group to 0.04 % (1/2519) in the cardiotocography + ST group.(14) The Nordic observational study describes 574 cases.(27) The cases were managed on the basis of CTG information and FBS, although ST-information was available. All fifteen cases of intrapartum hypoxia (metabolic acidosis or neuromuscular neonatal symptoms) were identified by ST-analysis. This means a sensitivity of 100 %. The specificity was 95 %. A total of 47 FBS were taken from 36 fetuses. Four of these had a ph below 7.20, and all these cases displayed ST-changes before the sampling. Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 14

15 Subsidieaanvraagformulier / Grant Application Form Our own observational study (described in more detail above, section preliminary studies by applicants of this proposal) includes 637 women.(15) Conclusion of the study was that ST changes were present in all five cases with severe metabolic acidosis (umbilical artery ph below 7.00) and in 46 % of cases with mild metabolic acidosis (ph between 7.00 and 7.05). Furthermore, CTG + ST-analysis was more specific in detecting fetal academia than CTG alone. The study of Dervaitis describes 143 women, managed on the basis of CTG information and blinded for the ST-information.(28) Afterwards, CTG was combined with the ST-information and when applying the STAN clinical guidelines they found a sensitivity of 43 %, specificity of 74 %, negative predictive value of 96 % and a positive predictive value of 8 % for metabolic acidosis. However, metabolic acidosis was defined as an umbilical cord artery ph below 7.15 and base deficit above 12 mmol/l and no neonates with a metabolic acidosis as defined in the other studies and our proposal (ph below 7.05 with base deficit more than 12 mmol/l) were born. Luttkus evaluated 911 cases (part of the EU multi centre study) where a scalp ph was obtained, including 53 cases with cord artery academia (ph below 7.06).(29) Forty-three fetuses were identified by CTG + ST as being in need for intervention 31 (25-46) minutes before delivery. In five, no indications were given and in another five there were inadequate data. They conclude that cardiotocography plus ST-analysis provides accurate information about intrapartum hypoxia similar to that obtained by scalp ph. There are no data about economic evaluation. Summary and Conclusion: The findings of the two RCTs support the use of fetal ST-analysis when a decision has been made to undertake continuous fetal heart rate monitoring during labour.(12,13) Both rates of metabolic acidosis and instrumental deliveries can be lowered using CTG + ST-analysis instead of CTG alone. This is underlined by three of the four observational studies.(15,27,29) The only study showing a poor positive predictive and low sensitivity used another definition of metabolic acidosis and did not include neonates with metabolic acidosis as defined for this proposal.(27) However, there are no data about using ST-analysis without fetal blood sampling and the cost-effectiveness of ST-analysis. Time schedule: Month 1-4: run-in period for the study set-up Month 5-30: inclusion of women Month 31-36: data analysis and reporting Expertise, voorgaande activiteiten en producten / Expertise, prior activities and products Drs. A.Kwee is involved in research in obstetrics, with a focus on fetal monitoring during labour and instrumental delivery rates and complications. She has participated in a multicentre project, supported by a EU grant, based on the Centre of Excellence structure, to implement the STAN-methodology in the UMC Utrecht (September 2000). A paper on the use of the STAN has recently been published. In 2005 she will finish her thesis on the above-mentioned subjects. Prof.Dr G.H.A. Visser has a longstanding experience with fetal monitoring and is one of the editors of the Dutch book on fetal monitoring. Recently he and his group have tested another new new monitoring technique during labour (pulsoxymetry), which appeared not ready for implementation into daily clinical practice. He was also involved in the above mentioned EU-study regarding implementation of the Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 15

16 Subsidieaanvraagformulier / Grant Application Form ST-analysis. Dr K.G.M. Moons has a vast experience in clinical epidemiology. His research comprised both theoretical and applied (empirical) research, in close collaboration with national and international universities and hospitals. Recently, he has obtained several ZONMW/VAZ/Ontwikkelingsgeneeskunde research grants, including a personal VIDI-grant to study advanced methods for diagnostic evaluations. Furthermore, he, for example, conducted studies on the cost?effectiveness of routine diagnostic management in children with neck stiffness and with fever without apparent focus (OG ), on methods for design and analysis of diagnostic research (NWO ), and on defining an optimal strategy for diagnosis of heart failure (NWO ). Dr B.W.J. Mol (clinical epidemiologist and gynaecologist) has been involved in many projects in the field of Obstetrics and Gynaecology, and is (co-) author of >100 international publications. His thesis, which focussed on the evaluation of diagnostic and prognostic tests in subfertility, was awarded with the Jan Swammerdam prize. Over the last three years, he has supervised three doctorates on the evaluation of abnormal vaginal bleeding, diagnosis and treatment of fetal lung maturity, and treatment of dysfunctional uterine bleeding, respectively. In 2002, he has initiated the Dutch OFO-project, a study that aims to evaluate the effectiveness and cost-effectiveness of the basic fertility work-up. In this study, which is supported by ZON-MW, about 40 fertility clinics in The Netherlands are collaborating, and the aimed 6000 subfertile couples have been included 6 months prior to the aimed recruitment period. A study proposal entitled: Use of probabilistic decision rules in Obstetrics and Gynaecology was granted in the VIDI program of ZonMW. The total amount of grants obtained exceeds Prof. dr H.P. van Geijn did his training in Obstetrics and Gynaecology at the University of Nijmegen, the Netherlands. Next he moved in 1978 to Columbus Ohio, USA, for a fellowship in Maternal-Fetal Medicine at the Ohio State University (head: Prof dr FP Zuspan). In 1980 he entered the staff of Obstetrics and Gynaecology at the Vrije Universiteit Medical Center (VUmc), Amsterdam, the Netherlands. He fulfilled since then various positions in this department. Currently he is Head of the Department of Obstetrics and Gynaecology and Director of the Residency Training Programme. He is a member of the Dutch Society of Obstetrics and Gynaecology, FIGO study group Assessment of New Technologies in Obstetrics and Gynaecology, and the Board of the International Society 'The Fetus as a Patient'. Earlier he has been Projectleader of European Concerted actions on Fetal Surveillance for 10 years. His research interests include perinatal medicine, fetal surveillance, preterm delivery and maternal vascular diseases and stress. He has published over 160 papers in international peer-review journals, edited two books and published a substantial number of book chapters. As an invited speaker in international meetings he regularly addresses various aspects of the topics Fetal Monitoring, Preterm Delivery and Maternal Diseases. Publicaties / Publications 1. Kwee A, Van der Hoorn-van den Beld CW, Veerman J, Dekkers AHS, Visser GHA.STAN S21-monitor for fetal surveillance during labour: an observational study in 637 patients. J Mat Fet Neonat Med 2004;15: Dekkers AHS, Kwee A, Van Wijk HPJ, Van der Hoorn-van den Beld CW, Veerman J, Visser GHA. Occurrence of non-significant ST-changes in CTG + ECG recordings with the STANâ S21-monitor during labour. Submitted. 3. Luttkus AK, Noren H, Stupin JH, Blas S, Arulkumaran S, Erkkola R, Hagberg H, Lenstrup C, Visser GHA, Yli B, Rosen KG. Fetal scalp ph and ST analysis of the fetal ECG as adjunct to CTG. A Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 16

17 Subsidieaanvraagformulier / Grant Application Form multi-centre observational study. J Perinat Med, 2004;32: Nijhuis JH, Essed GGM, Van Geyn HP, Visser GHA (eds). Foetale bewaking (Fetal monitoring). Elsevier/Bunge, Maarssen, (with chapters by Visser on antenatal and intrapartum monitoring and on fetal blood sampling) 5. Rijnders RPJ, Mol BWJ, Reuwer PJHM, Drogtrop AP, Vernooy MMA, Visser GHA. Is the correlation between fetal oxygen saturation and blood ph sufficient for the use of fetal pulse oxymetry. J Mat Fet Neon Med 2002;11: Hecker K, Bilardo CM, Stigter RH, Ville Y, Hackeloen BJ, Kok HJ, Senat MV, Visser GHA. Monitoring of fetuses with intrauterine growth restriction: a longitudinal study. Ultrasound Obstet Gynecol 2001;18: Schifrin BS, Harwell R, Rubiustein T, Visser GHA. Maternal heart rate pattern: a confounding factor in intrapartum fetal surveillance. Pren Neon Med 2001;6: Moons KGM, Harrell FE. Sensitivity and specificity should be deemphasized in diagnostic accuracy studies. Acad Radiol 2003;10: Schrecengost JE, LeGallo RD, Boyd JC, Moons KGM, Gonias SL, Rose CE, Bruns DE. Comparison of diagnostic accuracies in outpatients and hospitalized patients of D-dimer testing for the evaluation of suspected pulmonary embolism. Clin Chem 2003;49: Moons KGM, Grobbee DE. Diagnostic studies as multivariable, prediction research. J Epidemiol Community Health 2002;56: Kalkman CJ, Bonsel GJ, Visser K, Moen J, Grobbee DE, Moons KGM. Preoperative prediction of severe postoperative pain. Pain 2003;105: Moons KGM, Biesheuvel CJ, Grobbee DE. Test research versus diagnostic research. Clin Chem Hajenius PJ, Engelsbel S, Mol BWJ, Van der Veen F, Ankum WM, Bossuyt PMM, Hemrika DJ, Lammes FB. Randomised trial of systematic methotrexate versus laparoscopic salpingostomy in tubal pregnancy. Lancet 1997;350: Van der Meulen J, Mol BWJ, Pajkrt E, Van Lith JJM, Voorn W. Use of the disutility ratio for the prenatal screening for Down's syndrome. Br J Obstet Gynaecol 1999;106: Lijmer JG, Mol BWJ, Heisterkamp S, Bonsel GJ, Prins MH, Van der Meulen J, Bossuyt PMM. Empirical evidence of design-related bias in diagnostic studies. JAMA 1999;282: Mol BWJ, Lijmer JG, Van der Meulen J, Pajkrt E, Bilardo CM, Bossuyt PMM. Effect of study design on the association between nuchal translucency measurement and Down syndrome. Obstet Gynecol 1999;94: Graziosi GCM, van der Steeg JW, reuwer PH, Drogtrop AP, Bruinse HW, Mol BWJ. Economic evaluation of misoprostol in the treatment of early pregnancy failure compared to curettage after an expectant management. Hum Rep Kwee A, Graziosi GCM, Schagen van Leeuwen JH, Van Venrooy FH, Bennink D, Mol BWJ, Cohlen BJ, Visser GHA. The effect of immersion on haemodynamic and fetal parameters in uncomplicated pregnancies of nulliparous women. Br J Obstet Gynaecol. 2000;107: Bakker PC, Colenbrander GJ, Verstraeten AA, Van Geijn HP. Quality of intrapartum cardiotocography in twin deliveries. Am J Obstet Gynecol 2004;191: Bakker PC, Colenbrander GJ, Verstraeten AA, Van Geijn HP. The quality of intrapartum fetal heart rate monitoring. Eur J Obstet Gynecol Reprod Biol 2004;116: Papatsonis DN, Van Geijn HP, Bleker OP, Ader HJ, Dekker GA. Hemodynamic and metabolic effects after nifedipine and ritodrine tocolysis. Int J Gynaecol Obstet 2003;82: Mantel R, Van Geijn HP, Ververs IA, Colenbrander GJ, Kostense PJ. Automated analysis of antepartum fetal heart rate in relation to fetal rest-activity states: a longitudinal study of uncomplicated pregnancies using the Sonicaid System Eur J Obstet Gynecol Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 17

18 reprod Biol 1997;71: Jonker FH, Van Geijn HP, Chan WW, Rausch WD, Van der Wijden GC, Taverne MA. Characteristics of fetal heart rate changes during the expulsive stage of bovine parturation in relation to fetal outcome. Am J Vet res 1996;57: Van Geijn HP. Developments in CTG analysis. Baillieres Clin Obstet Gynaecol 1996;10: Referenties / References Subsidieaanvraagformulier / Grant Application Form 1. Low JA, Pickersgill H, Killen H, Derrick EJ. The prediction and prevention of intrapartum asphyxia in term pregnancies. Am J Obstet Gynecol 2001:184: Hagberg B, Hagberg G, Beckung E, Uvebant P. Changing panorama of cerebral palsy in Sweden. VIII Prevalence and origin in the birth year period Acta Paediatr Scand 2001;90: Parer JT, King T. Fetal Heart Rate monitoring: Is it salvageable? Am J Obstet Gynecol 2000;182: Hornbuckle J, Vail A, Abrahm KR, Thornton JG. Bayseian interpretation of trials: the example of intrapartum fetal heart rate monitoring. BJOG 2000;107: Nelson KB, Dambrosia JM, Ting TY, et al. Uncertain value of electronic fetal monitoring in predicting cerbral palsy. N Engl J Med 1996;334: Murphy KW, Johnsom P, Moorcroft J, et al. Birth asphyxia and the intrapartum cardiotocograph. Br J Obstet Gynaecol 1990;97: Chawla R, Deppe G, Ahart S, Gleicher N. Hemorrhage after fetal scalp blood sampling. Am J Obstet Gynecol 1984;149: Balfour HH, Bowe ET, James LS. Scalp abscesses following fetal blood sampling or monitoring. J Pediatr 1971;79: Westgate J, Greene K. How well is fetal blood sampling used in clinical practice? Br J Obstet Gynaecol 1994;101: Rosen KG, Dagbjartsson A, Henriksson BA, et al. The relationship between circulating catecholamines and ST-waveform in the fetal lamb electrocardiogram during hypoxia. Am J Obstet Gynecol 1984;149: Westgate JA, Bennet L, Brabyn C, et al. ST waveform changes during repeated umbilical cord occlusions in near-term fetal sheep. Am J Obstet Gynecol 2001;184: Westgate J, Harris M, Curnow JSH, et al. Plymouth randomised trial of cardiotocogram only versus ST waveform plus cardiotocogram for intrapartum monitoring: 2400 cases. Am J Obstet Gynecol 993;169: Amer-Wåhlin I, Hellsten C, Noren H, et al. Cardiotocography only verus cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal monitoring: a Swedish randomised controlled trial. Lancet 2001;358: Noren H, Amer-Wahlin I, Hagberg H, et al. Fetal electrocardiography in labor and neonatal outcome: Data from the Swedish randomised controlled trial on intrapartum fetal monitoring. Am J Obstet Gynecol 2003;188: Kwee A, Van der Horn-van den Beld CW, Veerman J, Dekkers AHS, Visser GHA. STAN S21-monitor for fetal surveillance during labour: an observational study in 637 patients. J Mat Fet Neonat Med,2004;15: Landelijke Verloskundige Registratie (Dutch Perinatal Database):Prismant, Van den Berg PP. Intrapartum surveillance of human fetal oxygenation. Thesis Nijmegen Vandenbussche FPHA. Studies on the clinical significance of fetal blood ph. Thesis Leiden, Enkin M, Keirse MJN, Neilson J et al. Guide to effective care in pregnancy and childbirth. Oxford University Press 2nd edition FIGO. Guidelines for the use of fetal monitoring. Int J Gynaecol Obstet 1987; 25: Rosen KG, Luzietti R. Intapartum fetal monitoring: its basis and current developments. Prenat Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 18

19 Subsidieaanvraagformulier / Grant Application Form Neonat Med 2000;5: Siggaard-Andersen O. An acid base chart for arterial blood with normal and pathofhysiological reference areas. Scand J Clin Lab Invest 1971;27: Whitehead J. The design and analysis of sequential clinical trials. revised 2nd ed. Chichester: Wiley: Van der Tweel I, Schipper M. Sequentiele analyse in klinisch en epidemiologisch onderzoek. Ned Tijdschr Geneesk 2002;146: Oostenbrink JB, Koopmanschap MA, Rutten II. Standardisation of costs: the Dutch manual for costing in economic evaluations. Pharmacoeconomics 2002;20: Neilson JP. fetal electrocardiogram (ECG) for fetal monitoring during labour Cochrane review). In: The Cochrane Library, Issue 4, Chichester, UK, John Wiley & Sons, Ltd. 27. Amer-Wahlin I, Bordahl P, Eikeland T, et al. ST analysis of the fetal electrocardiogram during labor: Nordic observational multicenter study. J Matern Fetal Neonatal Med 2002 Oct;12(4): Dervaitis KL, Poole M, Schmidt G, et al. ST segment analysis of the fetal electrocardiogram plus electronic fetal heart rate monitoring in labor and its relationship to umbilical arterial blood gases. Am J Obstet Gynecol 2004;191: Luttkus AK, Noren H, Stupin JH, et al. Fetal scalp ph and ST analysis of the fetal ECG as andjunct to CTG. A multi-center, observational study. J Perinat Med 2004;32: Financiële gegevens / Financial data Geplande duur in maanden / Planned duration in months 36 maanden / months ZonMw budget Jaar / Year Kostenpost / Cost item Totaal / Total Personeel Materieel Implementatie Apparatuur Overig Totaal / Total Co-financiering / Cofinancing Naam co-financier / Name of cofinancier Bedrag / Amount Status Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 19

20 Subsidieaanvraagformulier / Grant Application Form 5. Bijzondere gegevens / Additional information Vergunningen / Permits Vergunning nodig / Permit required? Vergunning verkregen / Permit obtained? Ja / Yes Nee / No Ja / Yes Nee / No METC/DEC X X WBO X X Biohazards X X Andere vergunningen / Other permits De aanhangende HTA-studie 'When outcome is a balance' is in de vorige doelmatigheidsronde gehonoreerd onder nummer Historie subsidieaanvraag / History grant application Aangemaakt door ProjectNet / Generated by ProjectNet: :17 p. 20