General Information

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF

1. Algemene gegevens / General Information Projecttitel / Project title Pregnancy-induced hypertension and pre-eclampsia after 36 weeks: induction of labour versus expectant monitoring. A comparison of maternal and neonatal outcome, maternal quality of life and costs? Aanvrager / Applicant Dr. M.G. van Pampus T: 050-3616161 F: E: [email protected] Universitair Medisch Centrum Groningen Obestetrie en Gyneacologie Postbus 30001 9700 RB GRONINGEN Projectleden / Project members Dhr. J.A.M. van der Post (Mede aanvrager) T: 0205669111 F: E: Academisch Medisch Centrum

Obstetrie en Gynaecologie Obstetrie Postbus 22660 1100 DD AMSTERDAM ZUIDOOST Nederland Dr. M.G. van Pampus (Projectleider en penvoerder) T: 050-3616161 F: E: Universitair Medisch Centrum Groningen

Obstetrie en Gyneacologie Postbus 30001 9700 RB GRONINGEN Nederland Dr. S.A. Scherjon (Mede aanvrager)

Aangemaakt door ProjectNet / Generated by ProjectNet: 13-02-2005 22:16

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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF T: 071-5269111 F: E: Leids Universitair Medisch Centrum

Divisie 3 Verloskunde Albinusdreef 2 2333 ZA LEIDEN Nederland Prof. dr. H.W. Bruinse (Mede aanvrager) T: 030-2509111 F: E: Universitair Medisch Centrum Utrecht

Verloskunde Heidelberglaan 100 3584 CX UTRECHT Nederland Dhr. L.C. Bruggeman (Bestuurlijk verantwoordelijke) T: 050-3616161 F: E: Rijksuniversiteit Groningen

Universitair Medisch Centrum Groningen Raad van Bestuur Postbus 196 9700 AD GRONINGEN Nederland Dr. B.W. Mol (Mede projectleider) T: 040-8888000 F: E: Maxima Medisch Centrum

Verloskunde Postbus 7777 5500 MB VELDHOVEN Nederland


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF Prof. dr. P.M.M. Bossuyt (Mede aanvrager) T: 020-5669111 F: E: Academisch Medisch Centrum

Klinische Epidemiologie en Biostatistiek Postbus 22660 1100 DD AMSTERDAM ZUIDOOST Nederland Dr. B.C. Opmeer (Mede aanvrager) T: 020-5669111 F: E: Academisch Medisch Centrum

Klinische Epidemiologie en Biostatistiek Postbus 22660 1100 DD AMSTERDAM ZUIDOOST Nederland Dr. E. Birnie (Mede aanvrager) T: 020-5669111 F: E: Academisch Medisch Centrum

Klinische Methoden & Public Health Sociale Geneeskunde Postbus 22660 1100 DD AMSTERDAM ZUIDOOST Nederland Dr. S le Cessie (Mede aanvrager) T: 071-5269111 F: E: Leids Universitair Medisch Centrum

Medische Statistiek Postbus 9604 2300 RC LEIDEN Nederland


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF Samenwerking / Collaboration TweeSteden Ziekenhuis Verloskunde/ Gynaecologie Dr. Deelenlaan 5 5042 AD TILBURG Catharina Ziekenhuis Postbus 1350 5602 ZA EINDHOVEN Sint Antonius Ziekenhuis Postbus 2500 3430 EM NIEUWEGEIN Onze Lieve Vrouwe Gasthuis Gynaecologie Postbus 95500 1090 HM AMSTERDAM Martini Ziekenhuis Groningen Obstetrie en Gynaecologie Postbus 30033 9700 RM GRONINGEN Gelre Ziekenhuizen Obstetrie en Gynaecologie Postbus 9014 7300 DS APELDOORN Atrium Medisch Centrum Verloskunde en gynaecologie Postbus 4446 6401 CX HEERLEN

2. Projectgegevens / Project information Programma / Programme DoelmatigheidsOnderzoek: deelprogramma Effecten & Kosten / Health Care Efficiency Research Programme: sub-programme Effects & Costs


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF

Subsidieronde / Subsidy round round 2006 - grant applications Datum indienen (via ProjectNet) / Date of application 13-02-2005 22:15 Aandachtsgebieden / Focus Themes: 11 Obstetrics; Themes HTA-methodology:

Projecttype / Project type Onderzoeksproject Samenvatting / Summary OBJECTIVE: 10% to 15% of all pregnancies are complicated by hypertensive disorders, i.e. pregnancy induced hypertension or pre-eclampsia (19.000 women per year in The Netherlands). The large majority of these cases occur at term. There is no causal treatment but termination of pregnancy. In case of pre-term pregnancies complicated by hypertension, conservative management is advocated to as long as the risks for the mother are acceptable. However, there is no consensus whatsoever on the question in such cases at term. Induction of labour might prevent maternal and neonatal complications, but it is also thought to increase the instrumental delivery rate. Nothing is known about the impact of both policies on the psychological well-being of the mother, as well as the costs of both. In The Netherlands in 2002, labour was induced in 9.000 women with pregnancy induced hypertension or pre-eclampsia, whereas labour started spontaneously in 10.000 women. STUDY DESIGN: Multicentre prospective randomised controlled trial. STUDY POPULATION: Women with a singleton pregnancy and pregnancy-induced hypertension or pre-eclampsia with a gestational age between 36 0/7 weeks and 41 0/7 weeks. INTERVENTIONS: Induction of labour, if necessary preceded by artificial cervical ripening versus expectant monitoring. OUTCOME MEASURES: Since we know from large non-randomised data that equality in maternal and neonatal health outcome can be anticipated, this study will have maternal quality of life, quality of recovery and costs as main outcomes. The SF-36 will, among other quality of life measures, be the primary outcome. Of course, maternal and neonatal mortality and morbidity will be measured. POWER/DATA ANALYSIS: The analysis will be by intention to treat. We need two groups of 250 patients to detect relevant differences in the SF-36 (primary outcome). In anticipation of equivalence in quality of life, and maternal and neonatal outcome, the economic analysis will be a cost-minimisation


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF analysis. For each of the two strategies, will calculate costs of perinatal care for mother and child. TIME SCHEDULE: Total study time 36 months. Preparation three months, recruitment 27 months, analysis and report six months. Both data analysis and economic analysis will be performed within the context of a consortium of perinatal centres that are already collaborating in the Zon-MW funded DIGITAT-study (Zon-MW 945-04-558). NEDERLANDSE SAMENVATTING VRAAGSTELLING: 10 tot 15% van alle zwangerschappen wordt gecompliceerd door een vorm van hypertensie in de zwangerschap (19.000 vrouwen per jaar in Nederland). Het merendeel van deze gevallen treedt a terme op. De enige causale therapie is het beëindigen van de zwangerschap. In geval van preeclampsie of zwangerschapshypertensie preterm is een afwachtend beleid effectief gebleken, zo lang het risico voor de moeder acceptabel is. Het is onduidelijk of dit ook geldt voor a terme zwangerschappen met deze complicaties. Inleiden van de baring zou maternale en neonatale complicaties kunnen voorkomen, maar zou ook het aantal instrumentele baringen verhogen. Er is niets bekend over de impact van beide strategieën op het psychische welbevinden van de moeder en de kosten die het met zich meebrengt. In Nederland werd in 2002 bij 9.000 vrouwen met zwangerschapshypertensie of preëclampsie de baring ingeleid terwijl bij 10.000 vrouwen de baring spontaan begon. STUDIE-OPZET: Multicenter prospectief gerandomiseerd onderzoek. POPULATIE: Zwangeren met eenling zwangerschap gecompliceerd door zwangerschapshypertensie of preëclampsie en een zwangerschapsduur tussen 36 0/7 en 41 0/7 week INTERVENTIES: Inleiden van de baring, zo nodig voorafgegaan door het rijpen van de cervix vergeleken met een afwachtend beleid. UITKOMSTMATEN: Omdat uit grote ongerandomiseerde data gebleken is dat zowel de maternale als de neonatale uitkomst hetzelfde zijn na inleiding van de baring of na een afwachtend beleid, zijn de belangrijkste uitkomstmaten de maternale kwaliteit van leven, kwaliteit van herstel en kosten. De SF-36 is de primaire uitkomstmaat. Uiteraard zullen maternale en neonatale mortaliteit en morbiditeit meten, alsmede de wijze van bevallen, gerigistreerd worden. POWER/DATA-ANALYSE: De analyse zal plaatsvinden volgens het intention to treat principe.Er zijn twee groepen van 250 patiënten nodig om relevante verschillen in SF-36 aan te tonen. Anticiperend op gelijkheid in kwaliteit van leven en maternale en neonatale uitkomst zal een kosten-minimisatie analyse plaatsvinden. Voor elke van de twee strategieën zullen de kosten van perinatologische zorg voor moeder en kind berekend worden. TIJDSPLANNING: totale onderzoekstijd 36 maanden. Voorbereidingstijd drie maanden, includeren 27 maanden, datamanagement en economische analyse zes maanden. Zowel de data analyse als economische analyse zullen uitgevoerd worden binnen het een verloskundig consortium, waar binnen op dit moment de DIGTAT studie wordt uitgevoerd (Zon-MW 945-04-558).

3. Inhoud / Content Probleemstelling / Problem definition


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF Pregnancy-induced hypertension and pre-eclampsia are common complications of pregnancy. In many cases, the symptoms are mild, consisting only of mild hypertension at term. In other cases however, severe complications such as eclampsia, placental abruption, preterm delivery, HELLP syndrome or intra-uterine death may occur. Hypertensive disorders in pregnancy still make a major contribution to maternal and neonatal mortality; it is the largest single cause of maternal mortality in the Netherlands (1). Approximately 10% to 15% of all pregnancies are complicated by hypertensive disorders. The majority of these cases declare itself after 32 weeks. The only causal treatment of the disease is termination of pregnancy. In case of pre-term pregnancies complicated by pre-eclampsia conservative expectant monitoring is advocated to increase the chance of foetal maturity, as long as the risks for the mother remain acceptable (2,3,4). Expectant management reduces neonatal complications and neonatal stay in the intensive care unit in pre-term pregnancies and is not associated with an increase in maternal complications (3,4). In case of hypertension and/or pre-eclampsia at term, the situation is different as compared to preterm disease. It is unclear whether in this situation expectant management is beneficial for the mother and her baby, since evidence on the subject is lacking. Despite this lack of evidence termination of pregnancy is recommended in most countries outside the Netherlands (3). Recent observational studies indicate that the onset of mild gestational hypertension or mild pre-eclampsia at or near term is associated with minimal to low neonatal and maternal morbidity (4-7). Despite the lack of evidence that would justify intervention, many gynaecologists induce labour in women at term with pregnancy-induced hypertension or pre-eclampsia. Such a policy is thought to increase the risk of assisted vaginal delivery and caesarean section, thus generating additional morbidity and costs (8-10). On the other hand, expectant management might lead to severe pregnancy complications that were mentioned above, i.e. eclampsia, severe hypertension, HELLP syndrome, organ failure or a bad neonatal outcome. The lack of consensus on the subject in The Netherlands is demonstrated by the fact that in 2002 in women with pregnancy induced hypertension and/or pre-eclampsia labour was induced in 9.000 women, whereas labour started spontaneously in 10.000 women. At present, there is no evidence on the effectiveness and efficiency of induction of labour in women with pregnancy induced hypertension or mild pre-eclampsia (nearly) at term as compared to expectant management under regular monitoring. In post term women, randomised trials have indicated that induction of labour does not increase the instrumental delivery rate. However, the fact that the women in those studies were post term, might implicate that myometrial gapjunctions facilitating effective contractions were present. This situation can not be extrapolated to women who are not postterm (11,12). In view of this clinical dilemma, we propose a randomised clinical trial in which induction of labour, if necessary preceded by artificial cervical ripening, is compared to expectant monitoring in women with pregnancy induced hypertension or pre-eclampsia (nearly) at term. The primary outcome will be maternal quality of life. We will also compare maternal and neonatal mortality and morbidity, and maternal quality of recovery, as well as costs. Relevantie / Relevance Data from the national obstetric registration (LVR) indicate no impact of induction of labour versus expectant management on neonatal outcome. In 2002 and 2003, the rate of baby's born with an Apgar score below 7 was 1.3% among women that delivered after a spontaneous onset of labour, versus 1.6% among women in whom labour was induced (OR 1.2 95% CI 1.0 to 1.5). After correction for potential confounders available in the LVR-registration (fetal weight, proteinuria, diastolic blood pressure) this difference became statically insignificant despite the analysis of over 35.000 patients (OR 1.1 95% CI .98 to 1.2). Since this equivalence is also expected from the pathofysiological background of the problem as well as from the medical literature, we anticipate equivalence in neonatal outcome between both strategies (of course, we will look at neonatal and maternal outcome as this should be consistent with


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF earlier findings. If not, this will be important new information not available from other sources!). Thus a choice for one or the other treatment will depend on differences in quality of life and costs. The results of the study will provide insight on whether induction of labour in women with pregnancy induced hypertension or pre-eclampsia (nearly) at term will reduce costs and improve quality of life as compared to expectant monitoring. At present - to our knowledge - no clinical study has been published or undertaken to investigate this issue.Randomised trials in post term women and women with ruptured membranes at term have indicated that the side-effects of induction of labour in this category are limited, but data on term women with pre-eclampsia and pregnancy induced hypertension are lacking (11,12). In The Netherlands, the yearly number of patients with hypertension (RR diastolic above 90 mmHg) without proteinuria at term is 17.000. Moreover, there are 2.000 women with pre-eclampsia at term (Data LVR-2002). The LVR2-data show that among the 10.000 women in whom labour started spontaneously (i.e. those who were managed expectantly), the secondary caesarean section rate was 15% and the vaginal instrumental delivery rate 21%. Among the 9.000 women in whom labour was induced, these rates were 18% and 16%, respectively. As mentioned before neonatal outcome was the same. The health care costs for this group are at least €100 million per year. The study has the power to demonstrate a difference in costs between both policies of €1.000,-. Such a difference, could, one way or the other, lead to a potential cost reduction of €15-€20 million per year in The Netherlands. Thus, a choice for one of the other treatment will depend on differences in quality of life and costs. The results of the study will provide insight on whether induction of labour in women with pregnancy induced hypertension or pre-eclampsia at term will reduce costs and improve quality of life as compared to expectant monitoring. If induction is found to be beneficial, the Dutch Society of Gynaecologists will immediately advise this policy in its guidelines. At present - to our knowledge - no clinical study has been published or undertaken to investigate this issue. Kennisoverdracht, implementatie, bestendiging / Knowledge transfer, implementation, consolidation No major obstacles are to be foreseen as the outcome of the proposed study will lead to more specific recommendations on the policy in women with pregnancy induced hypertension or mild pre-eclampsia at term. The Dutch Society for Obstetrics and Gynaecology will be committed to the outcomes of the study. The results of the project will be incorporated in the guidelines of the NVOG. The study will be performed in eight perinatal centres that already collaborating in the DIGITAT study. As the interventions and outcomes of the DIGITAT protocol are very similar to the present protocol, this will not only stimulate recruitment of patients, but it also implicates that all perinatal centres will be familiar with the study protocol and the result at the end of the study. This is likely to facilitate implementation of the study results, not only in the participating centres, but also in their affiliated clinics. In obstetrics, unique problems in outcome conceptualisation arise from the fact that unlike decisions in other medical domains, here the denominator is not, primarily, the patient herself, but more units at the same time. As a consequence, a single outcome parameter is insufficient to define optimality. Scientists and treating physicians usually circumvent the problems in outcome measurement and decision making by assuming one or the other outcome as negligible or subordinated, or another artificial assumption. This problem will be addressed in a HTA-study additional to the present proposal that has already been


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF granted by ZON-MW (When outcome is a balance. Methods to measure combined utility in obstetrics. Principal investigator prof.dr.G.J.Bonsel). We will provide patient information in Dutch as well as several other languages (Turkish, French, Spanish and English), in order to facilitate inclusion of patients from cultural minorities. Quality of life questionnaires are available in English and French, and we will translate them in to Turkish. Moreoevr, our experience is that most of the pregnant women from ethnic minorities are able to read Dutch questionnaires. By doing so, we will enhance inclusion, and evaluate whether study results can be extrapolated to cultural minorities. This is especially important, since the expectant management strategy requires compliance to the protocol by the patient in order to be safe. Doelstelling / Objective This study will compare induction of labour in women with pre-eclampsia or pregnancy induced hypertension nearly at term in singleton pregnancy, as compared to expectant monitoring. We look at the following outcomes: Maternal quality of life, quality of recovery, as well as pain and anxiety questionnaires. Maternal morbidity: Maternal complications (eclampsia, HELLP syndrome, organ failure), maternal admission (days) Neonatal condition: Bad neonatal outcome will be a composite of a 5-minute Apgar-score below 7 and /or an arterial pH below 7.05 and/ or admission to the NICU. Costs

Plan van aanpak / Strategy STRATEGY: In this prospective equivalence study we aim to compare expectant monitoring to induction of labour in patients with pregnancy induced hypertension or mild pre-eclampsia at term. We hypothesize that we will not find relevant differences between maternal and neonatal outcome in both strategies. This assumption is based on data from the LVR-2 (bad neonatal outcome in both groups around 1.5%, see above), and on the fact that both policies are safe for mother and child in case of term pregnancies. In view of this expected equivalence, we aim to assess maternal quality of life, quality of recovery and costs. PRELIMINARY STUDIES: In the 19.000 women with pregnancy induced hypertension or pre-eclampsia at term in The Netherlands, both expectant monitoring and induction of labour policies have been applied. All participating centres are able to apply both strategies. The LVR-2 data show that among the 10.000 women in whom labour started spontaneously (i.e. were managed expectantly), the secondary caesarean section rate was 15% and the vaginal instrumental delivery rate 21%. Among the 9.000 women in whom labour was induced, these rates were 18% and 16%, respectively. However, these rates are not reliable, since the moment at which the diagnosis was made, was not known in the dataset, and the decision for induction or expectant management was not made at random. Moreover, women with a pre-existing hypertension cannot be identified separately in the LVR-2 database. Therefore, reliable answers to the study questions can only be obtained from the randomised clinical trial that we


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF propose in the present grant application. Members of the study group have experience with randomised studies comparing induction protocols for labour (8, 13) as on studies reporting on quality of life and patient preferences (see Publications Birnie, Bossuyt, Mol). The study will be attached to the Zon-MW funded DIGITAT-study, in which the cost-effectiveness of induction of labour versus expectant management in women pregnant of a small for gestational age child is addressed. The fact that the design of the present study has strong similarities with the DIGITAT-study implicates that scale advantages can be achieved, since the proposed study on PIH and pre-eclampsia will be performed with the DIGITAT-infrastructure. The protocol has, but for a few formal adjustments, been approved by the medical ethical committee of the Academic Hospital Groningen (see addendum). Moreover, in the centres participating in the DIGITAT study, ethical approval will be obtained by a small adjustment of the DIGITAT protocol, which implicates that the time-consuming approval for multicentre studies will be obtained prior to the start of the study. DESIGN: The proposed research concerns a multicentre randomised controlled clinical trial. After inclusion, patient data will be entered in a Webbased database, which will also facilitate randomisation. The expertise for this technology is already available to the study group. Randomisation will be stratified for centre, parity and underlying disease (i.e. hypertension or pre-eclampsia) Women will be randomly allocated to either induction of labour or expectant monitoring. The study will be an open label study, as it is impossible to blind the health care workers and patients involved for the strategy to which the woman is allocated. Cross-over between the two strategies would complicate the interpretation of study result. Although it will not be possible to prevent all cross-overs, both strategies will be performed according to strict criteria (see below). Moreover, in each centre a dedicated research nurse will monitor the study protocol in each centre by attending patient meetings and providing feedback on potential protocol violation. The study will be staffed by research nurses, who will counsel patients and ask informed consent. In every centre an independent gynaecologist will be available for more detailed information both for patients and colleagues. STUDY POPULATION: Term patients with mild pregnancy induced hypertension (diastolic blood pressure of at least 95 mm Hg but below 110 mmHg on two occasions at least 6 hours apart) or mild pre-eclampsia (proteinuria above 300 mg total protein in a 24 hour urine collection but below 5 g total protein in 24 hours) will be eligible for the study. Duration of pregnancy will be between 36+0 and 41+0 weeks. Only women with a singleton pregnancy in a vertex position will be included. Exclusion criteria are treated preexisting hypertension, diabetes mellitus, renal disease, a previous caesarean section, HELLP syndrome, oliguria less than 500 mL in 24 hours, pulmonary oedema or cyanosis, and abnormalities at the CTG. After a patient has given informed consent for participation in the study, vaginal examination will be performed, and cervical length will be measured using transvaginal sonography, both to assess cervical ripeness. Subsequently, the patient will be randomised to either a policy that aims termination of pregnancy (intervention group) or a policy that aims expectant management for spontaneous delivery (expectant group). INTERVENTIONS: In the intervention group, patients will be induced within 24 hours after randomisation. Patients with a cervix that is judged to be 'ripe' at vaginal examination (Bishop score above 6), labour will be induced with amniotomy and, if labour does not start within 1 hour, augmentation with oxytocin. In case the cervix is judged to be 'unripe', cervical ripening will be stimulated with use of intracervical or intravaginal prostaglandins. In case the cervix is judged to be unripe the day after


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF priming, the cervical ripening will be repeated. If the cervix remains unripe, day three will be a rest day. Cervical ripening will be repeated at day four and five. We expect the number of women that need such repeat ripening to be very low (13). All patients in the intervention group will be monitored clinically until after delivery. In the expectant group, patients will be monitored until the onset of spontaneous delivery (see flowchart). Plasma volume expansion will not be applied. Maternal evaluation consists primarily of frequent evaluation of worsening pre-eclampsia. Initial laboratory tests consist of blood tests (platelet count, liver enzymes and renal function) and screening of urine for protein using a dipstick or protein/creatinin ratio (24 hour urine collection for protein is case of positive screening). Subsequent maternal monitoring will contain daily measurement of diastolic and systolic blood pressure, screening for protein in urine every two days, and blood tests twice a week. Foetal monitoring will consist of assessment of foetal movements as reported by the mother, as well as electronic foetal heart rate monitoring once a day. Ultrasound examination for foetal growth and amniotic fluid assessment will be performed each 10 days, and Doppler assessment of the umbilical artery twice a week. In the expectant monitoring group, intervention is recommended in case the diastolic blood pressure is above 110 mmHg, in case the total amount of protein in the urine exceeds 5g/ 24 hours, in case of eclampsia or in case the foetal condition does not justify expectant management (no foetal movements reported by the mother, non-optimal CTG). In case in the expectant group an indication rises for induction of labour, for example prelabour rupture of membranes for > 48 hours or meconium stained liquor, induction of labour is indicated (see flowchart). Reasons for interventions and time interval between randomisation and delivery will be registered. Management of labour will be similar in both groups (see appendix B). OUTCOME PARAMETERS: We will collect the following data: Study-entry: age, ethnic origin, parity, obstetric history, general health history, gestational age, systolic and diastolic blood pressure, normal non-stress test, biometry parameters, pregnancy weight. Patients who do not give informed consent will be treated according to one of the two protocols at the discretion of the attending obstetrician and analysed separately. After explanation of the study and informed consent, but prior to randomisation, we will perform a baseline measurement for quality of life (SF-36 and STAI) and quality of recovery. Moreover, a vaginal examination and a sonographic measurement of the cervical length will be performed prior to randomisation. During admission in the hospital: number of days of antenatal monitoring after study entrance, laboratory findings, ultra sound examinations, complications. Maternal mortality and morbidity will be specified until date of discharge from hospital and six weeks post partum. At delivery: gestational age at birth, mode of delivery, birth weight, condition at birth (Apgar scores, Umbilical artery pH). Quality of life and quality of recovery: Women will complete quality of life questionnaires prior to randomisation, one day after randomization and subsequently after 1 week, 2 weeks, 6 weeks 3 months and 6 months. Since the moment of delivery will differ between the two groups, we will ask the participating women also to complete questionnaires at 1 day an 2 days after delivery. A pain scale will be added to those questionnaires. We hypothesize


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF differences on the emotional and anxiety scales prior to delivery, and differences in physical scales after delivery (due to differences in instrumental delivery rates). The questionnaires will contain the SF-36, EuroQoL, state anxiety (STAT) as well as a questionnaire on quality of recovery. The latter has been developed by Myles et al, and is currently validated for pregnant women (14). This validation will be finished prior to the study (Kluivers Brolmann, Bruinvels and Mol, personal communication). Furthermore, patients preferences will be assessed. A representative sample of the participating women will be interviewed 3 months after randomisation. They will be asked for their preference for expectant management as compared to induction of labour, taking into account their own condition as well as that of the child. Measurement of preferences will be done in close collaboration with the investigators of the HTA-methodology, that was granted by ZonMW in 2004 ((When outcome is a balance. Methods to measure combined utility in obstetrics. Principal investigator prof dr. G.J. Bonsel). Both Dr. Birnie and Dr. Mol are participants are participants in that study. Neonate: Neonatal admission (type and days), neonatal mortality and morbidity will be specified until date of discharge from hospital and six weeks post partum. In case at 6 weeks after birth, the child does not score perfect, the neonate will be followed for 6 months using the composite outcome score (15). Since we know from large-non-randomised data that equality in maternal and neonatal outcome can be anticipated, this study will have maternal quality of life and costs as main outcomes. Secondary outcomes will be severe maternal morbidity, neonatal mortality or neonatal morbidity. Bad neonatal outcome will be defined as a 5-minute Apgar score below 7, an umbilical artery pH below 7.05 or admission to the neonatal intensive care. We will collect baseline characteristics, data on the course of pregnancy and delivery, and data on neonatal outcome. In case at 6 weeks after birth, the child does not score perfect, the neonate will be followed for six months using the composite outcome score (15). We will also register the use of medical resources as well as non-medical costs such as travel expenses. SAMPLE SIZE CALCULATIONS: The initial analysis will be performed by intention to treat. We will consider the SF-36 as primary endpoint. In order to detect a 5-point difference in the Physical Component Summary scale and Mental Component Summary scale after 1 week as relevant, we will need two groups of 250 patients to find a relevant difference (alpha .05; beta .80; SD 20). As the measurements at multiple time points allow for repeated measures analysis, this sample size will be sufficient for testing effects over time, including overall difference and trends. In view of the inpredictability of other quality of life measures, we feel that such a sample is adequate to detect other relevant differences. In case of equivalent maternal and neonatal outcome, the study will be cost-minimisation analysis. If we assume the cost of spontaneous labour to be €1.000, the costs of instrumental delivery to be €10.000 (composite of instrumental vaginal delivery and caesarean section) and the costs of expectant management to be €900 per patient, and if we assume that in the group in whom spontaneous labour is awaited the instrumental delivery rate is 15%, than the instrumental delivery rate should be 25% in the induction of labour group to reach a break-even point in the costs of the two approaches. DATA ANALYSIS AND PRESENTATION: The initial analysis will be performed by intention to treat. We will consider the SF-36 as primary endpoint. The analysis will be done by intention to treat, and stratified for centre, parity and for underlying disease (pre-eclampsia or pregnancy induced hypertension). Quality


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF of life as well as pain scores will be analysed using repeated measures analysis of variance. Relative risks and 95% confidence intervals will be calculated for the relevant outcome measures. ECONOMIC EVALUATION: General considerations: The aim of the economic evaluation is to compare the costs and health effects of (A) induction of labour (conventional management strategy) versus (B) expectant maternal and foetal monitoring (experimental strategy), in (nearly) at term pregnant women with either mild hypertension or mild pre-eclampsia. Generally, expectant monitoring is preferred to induction of labour if the incremental (health) effects of expectant monitoring compared to induction of labour outweigh the incremental costs of expectant monitoring compared to induction of labour. As the clinical study is designed as an equivalence study, the primary economic evaluation is a cost-minimisation analysis (CMA): the optimal strategy is the one with lowest costs. The sensitivity of costs and health outcomes for various parameters is tested in sensitivity analysis and visualised in ICER-graphs and acceptability curves. Scenario analyses for relevant subgroups (e.g. parity, underlying disease, etc.) are added. If caesarean section rates differ between the strategies, a long term analysis of costs and outcome is performed using a decision analytic approach. Cost analysis: The process of care is distinguished into three cost stages (antenatal stage, delivery/childbirth, 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 of the pregnant woman and her partner [costs of sick leave]). For each stage and each cost category, costs are measured as the volumes of resources used multiplied with appropriate valuations (cost-per-unit estimates, fees, national reference prices). Cost volumes in the antenatal stage consist of direct medical costs (e.g. home/hospital care, outpatient visits, foetal monitoring [FHR monitoring, ultrasound, Doppler] and maternal monitoring [various labtests; hospital care]). Direct non-medical and indirect costs in that stage may occur if role patterns or household routines shift. Costs during childbirth are dominated by the course of childbirth and type of delivery. Cost volumes in the postnatal stage consist of maternal care (hospitalisation etc.) and neonatal care (admission to NICU/neonatology ward, outpatient visits) and primary care. If neonatal health at discharge is suboptimal, further direct medical, direct non-medical and indirect costs may occur. Hence, for these infants, resource use of infants and/or parents is measured during 12 months after childbirth. Volumes of health care resource use are measured prospectively alongside the clinical study in all participating centres as part of the CRF. Health resource use outside the hospital is recorded by questionnaires. 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 units are estimated for at least teaching and one non-teaching hospital. An analysis based on reimbursement fees is added. Direct medical volumes outside the hospital and direct non-medical volumes are valued using national reference prices [16]. Indirect costs are quantified but remain unvalued. Study-specific costs are excluded from analysis. Patient outcome analysis: The decision problem at hand comprises the health effects of pregnant women/mothers and of neonates/infants and women's/parent's preferences for the management strategies. Short-term maternal morbidity is measured as the rate of mild and severe complications in the antenatal and postnatal stages; and the type of delivery (instrumental delivery/caesarean section) during the childbirth stage. Mid-term maternal health effects are measured with conventional health status


p. 13

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF questionnaires (MOS-SF36, EuroQoL, STAT), including record of complications and complaints, at 2 and 6 months after childbirth. If neonatal health at discharge is compromised, parents' burden is measured at the same intervals. As we anticipate equivalence between maternal and neonatal outcome, the economic analysis is expected to be a cost-minimisation analysis. SYSTEMATIC REVIEW: Search terms: hypertension pregnancy-induced (MeSH)AND labor, induced (MeSH)245 hits, 13 pages Population: pregnant women with pre-eclampsia or pregnancy-induced hypertension Intervention: induction of labour Comparison/control: expectant management Outcome: maternal and neonatal outcome, maternal quality of life Methodological filters: Clinical queries, therapy, sensitive setting: 144 hits, 8 pages. Limit to English, human, female. Randomized control trials, 9 hits. There is no randomised controlled trial in women with pre-eclampsia at term. A search with pregnancy toxemias and expectant management and induction revealed 1 study of Sibai et al. This study addressed women with preterm pregnancies. Pregnant toxemias AND expectant management AND term: 27 hits, but non in pre-eclampsia at term. Databases used and number of manuscripts retrieved: There is no relevant literature about the management of pre-eclampsia at term. Studies are limited to preterm preeclampsia. Summary and conclusion: The proposed randomised controlled trial has never been published in the peer reviewed literature. In view of the foreign policy on this issue, performance of such a study is not to be expected from abroad. HTA-methodology study? When outcome is a balance. Two measures to combined utility to support clinical and economic analysis in obstetrics and fertility. Principal investigator G.J. Bonsel. Funded in the ZonMW programme 2004 TIME SCHEDULE: Duration of the study three year. We will need a run-in period of three months for the study set up. Twenty seven months for inclusion of the required number of cases. Six months for follow-up data collection and report of results. The study will be performed in the same infrastructure in which the DIGITAT study is already performed. In view this infrastructure, the requested budget of this study will be lower than the requested budget of the previous application, since the cooperation will result in scale benefits.

Expertise, voorgaande activiteiten en producten / Expertise, prior activities and products Maria G. van Pampus was trained as a gynaecologist at the AMC in Amsterdam. During her residency, she was involved in clinical studies on pre-eclampsia and HELLP syndrome, which resulted in a PhD


p. 14

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF thesis in 1999 entitled The HELLP syndrome: clinical course, underlying disorders and long-term follow-up. Currently she is working as a perinatologist in the AZG in Groningen. She is (co)-author of 20 publications in peer reviewed journals. Ben 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 more than 100 international publications. Over the last years, he has supervised four PhD theses on the evaluation of abnormal vaginal bleeding, diagnosis and treatment of fetal lung maturity, treatment of dysfunctional uterine bleeding and medical treatment of miscarriage, respectively. He is currently working as a perinatologist in the Maxima Medical Centre in Veldhoven. He coordinated the Dutch OFO-project, in which 40 fertility clinics in The Netherlands are collaborating, resulting in inclusion of the 6.000 subfertile couples 6 months prior to the end of the recruitment period. Together with Rene Eijckemans he coordinated uniformation of the used outcome measures and the costs between 6 projects in the ZonMW program fertility disorders. A study proposal entitled: Use of probabilistic decision rules in Obstetrics and Gynaecology was granted in the VIDI program of NWO. His total amount of non-commercial grants obtained exceeds € 1.000.000,. Patrick M.M. Bossuyt (clinical epidemiologist) has been involved in several OG-projects, resulting in publications in leading international journals. He is chair of the guideline programme of the AMC, and in this function been involved in implementation since many years. He has a vast experience with measurement of quality of life in HTA-studies. Erwin Birnie (health economist) has been involved in ZonMW funded projects, in which he was responsible for the economic analysis. He is co-author of 20 peer-reviewed publications. Publicaties / Publications Key Publications: Van Pampus MG, Dekker GA, Wolf H et al. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gyn 1999;180: 1146-1150. Van Pampus MG, Koopman MMW, Wolf H et al. Lipoprotein (a) concentrations in women with a history of severe preeclampsia; a case control study. Thromb Haemost 1999;82: 10-3. Van Pampus MG, Wolf H, Ilsen A et al. Maternal outcome following temporising management of the (H)ELLP syndrome. Hypertens Pregnancy 2000;20: 211-20. Van Pampus MG, Wolf H, Mayruhu G et al. Long-term follow-up in patients with a history of (HELLP) syndrome. Hypertens Pregnancy 2001;20: 15-25. Van Pampus MG, Wolf H, Koopman MMW et al. Prothrombin 20210 AG mutation and Factor V leiden mutation in patients with a history of severe pre-eclampsia and (H)ELLP syndrome. Hypertens Pregnancy 2001;20: 292-298. 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;350:774-779. Lijmer JG, Mol BWJ, Heisterkamp S, et al. Empirical evidence of design-related bias in diagnostic studies. JAMA 1999;282:1061-6.


p. 15

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF Oei SG, Mol BWJ, De Kleine MJK, et al. Nifedipine versus ritodrine for suppression of preterm labour; a meta-analysis. Acta Obstet Gyn Scand. 1999;78:783-8. Oei SG, Jongmans L, Mol BWJ. Randomised trial of administration of prostaglandin E2 gel for induction of labour in the morning or the evening. J Perinat Med 2000;27:20-5. Graziosi GCM, Mol BWJ, Bruinse HW. Women's preferences for misoprostol in case of early pregnancy failure. Eur J Obstet Gynecol. In Press Graziosi GCM, Bruinse HW, Reuwer PJH, Van Kessel PH, Mol BWJ. Misoprostol versus curettage in women with early pregnancy failure: impact on women?s health ?related quality of life. A randomised controlled trial. Human Reprod. In press Bongers MY, Bourdrez P, Mol BWJ, Heintz APM, Brölmann HAM. Bipolar radiofrequency endometrial ablation versus balloon endometrial ablation in dysfunctional uterine bleeding: impact on patients? health related quality of life. Fertil Steril. In press. Bourdrez P, Bongers MY, Mol BWJ. Treatment of dysfunctional uterine bleeding: patient preferences for endometrial ablation, levonorgestrel-releasing intra uterine device or hysterectomy. Fertil Steril 2004;82-160-6.

Locadia M, Bossuyt PM, Stalmeier PF, Sprangers MA, van Dongen CJ, Middeldorp S, Bank I, van der Meer J, Hamulyak K, Prins MH. Treatment of venous thromboembolism with vitamin K antagonists: patients' health state valuations and treatment preferences. Thromb Haemost. 2004 ;92:1336-41. van Wely M, Bayram N, Bossuyt PM, van der Veen F. Laparoscopic electrocautery of the ovaries versus recombinant FSH in clomiphene citrate-resistant polycystic ovary syndrome. Impact on women's health-related quality of life. Hum Reprod. 2004;19:2244-50. van Wely M, Bayram N, van der Veen F, Bossuyt PM. An economic comparison of a laparoscopic electrocautery strategy and ovulation induction with recombinant FSH in women with clomiphene citrate-resistant polycystic ovary syndrome. Hum Reprod. 2004;19:1741-5. van der Schaaf IC, Brilstra EH, Rinkel GJ, Bossuyt PM, van Gijn J. Quality of life, anxiety, and depression in patients with an untreated intracranial aneurysm or arteriovenous malformation. Stroke. 2002;33:440-3 Nieuwkerk PT, Hajenius PJ, Ankum WM, Van der Veen F, Wijker W, Bossuyt PM. Systemic methotrexate therapy versus laparoscopic salpingostomy in patients with tubal pregnancy. Part I. Impact on patients' health-related quality of life. Fertil Steril. 1998;70:511-7. Monincx WM, Birnie E, Zondervan HA, Bleker OP, Bonsel GJ.Maternal health, antenatal and at 8 weeks after delivery, in home versus in-hospital fetal monitoring in high-risk pregnancies. Eur J Obstet Gynecol Reprod Biol. 2001 ;94:197-204. Birnie E, Monincx WM, Zondervan HA, Bossuyt PM, Bonsel GJ. Cost-minimization analysis of domiciliary antenatal fetal monitoring in high-risk pregnancies. Obstet Gynecol. 1997;89:925-9.


p. 16

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF Birnie E, Monincx WM, Zondervan HA, Bossuyt PM, Bonsel GJ. Comparing treatment valuations between and within subjects in clinical trials: does it make a difference? J Clin Epidemiol. 2000;53:39-45.

Referenties / References References: 1. Schuitemaker NWE, Van Roosmalen J, Dekker GA et al. Confidential enquiry into maternal deaths in The Netherlands 1983-1992. Eur J Obstet Gynecol.1998;79:57-62. 2. Van Pampus MG, Wolf H, Westenberg SM et al.Maternal and perinatal outcome after expectant management of the HELLP syndrome compared with pre-eclampsia without HELLP syndrome. Eur J Obstet Gynaecol Reprod Biol 1998;76:31-6. 3. Sibai BM, Mercer BM, Schiff E et al.Aggressive versus expectant management of severe pre-eclampsia at 28 to 32 weeks gestation: a randomised controlled trial. Am J Obstet Gynecol 1994;171(3):818-22. 4. Odendaal HJ, Pattinson RC, Bam R et al. Aggressive or expectant management for patients with severe pre-eclampsia between 28-34 weeks gestation: A randomized controlled trial. Obstet Gyn 1990;76:1070-75. 5. Redman CW, Roberts JM. Management of pre-eclampsia. Lancet 1993;341:1451-1454. 6. Sibai BM, Diagnosis and management of gestational hypertension and preeclampsia.Obstet Gyn 2003;102:181-92. 7. Sibai BM, Caritis S, Hauth J. What we have learned about peeclampsia. Seminars in Perinatology 2003;27: 239-46. 8. Van Gemund N, Hardeman A, Scherjon SA, Kanhai HHH. Intervention rates after elective induction of labor compared with a spontaneous onset; a matched cohort study. Gynecol Obstet Invest 2003;56(3):133-8. 9. Cammu H, Martens G, Ruyssinck G, Amy JJ. Outcome after elective labor induction in nulliparous women: a matched control study. Am J Obstet Gynecol 2002;186(2) 240-4. 10. Maslow AS, Sweeny AL. Elective induction of labor as a risk factor for cesarean delivery among low-risk women at term. Obstet Gynecol 2000;95 (6) 917-22. 11. Hannah ME, Hannah WJ, Hellmann J et al. Induction of labor as compared with serial antenatal monitoring in post-term pregnancy. A randomized controlled trial. The Canadian Multicenter Post-term Pregnancy Trial Group. N.Engl J med. 1992;326:1587-92. 12. Hannah ME, Ohlsson A, Farine D et al. Induction of labor compared with expectant management for prelabor rupture of the membranes at term. TERMPROM Study Group. N Engl J med.1996;334:1005-10. 13. Oei SG, Jongmans L, Mol BWJ. Randomised trial of administration of prostaglandin E2 gel for


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF induction of labour in the morning or the evening. J Perinat Med 2000;27:20-5. 14. Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability of a postoperative quality of recovery score: the QoR-40. BJ Anaesthesia 2000;84: 11-15. 15. Verma A, Okun NB, Maguire TO, Mitchell BF. Morbidity Assessment Index for Newborns: A composite tool for measuring newborn health. Am J Obstet Gynecol 1999;181: 701-08. 16. Oostenbrink JB, Koopmanschap MA, Rutten FFH. Handleiding voor kostenonderzoek. Methoden en richtlijnen voor economische evaluaties in de gezondheidszorg. CVZ 2000

4. Financiële gegevens / Financial data Geplande duur in maanden / Planned duration in months 36 maanden / months ZonMw budget Jaar / Year Kostenpost / Cost item Personeel

1

2

3

4

5

6

7

8

Totaal / Total

110

111

96

0

0

0

0

0

317

Materieel

0

0

0

0

0

0

0

0

0

Implementatie

0

0

5

0

0

0

0

0

5

Apparatuur

0

0

0

0

0

0

0

0

0

Overig

0

0

0

0

0

0

0

0

0

110

111

101

0

0

0

0

0

322

Totaal / Total

Co-financiering / Cofinancing Naam co-financier / Name of cofinancier Universitair Medisch Centrum GroningenLaboratorium voor verloskunde en Gynaecologie GRONINGEN

Bedrag / Amount Status

30.000 Toegekend

5. Bijzondere gegevens / Additional information


p. 18

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF Vergunningen / Permits Vergunning nodig / Permit required? Ja / Yes METC/DEC

Vergunning verkregen / Permit obtained? Nee / No

X

Ja / Yes

Nee / No

X

WBO

X

X

Biohazards

X

X

Andere vergunningen / Other permits

Historie subsidieaanvraag / History grant application Deze aanvraag is eerder ingediend bij het programma / This grant application has previously been submitted to the ZonMw programme: Preventie 1 deelp. 2: Effectiviteit- en/of doelmatigheidsonderzoek Projectnummer / Project number: 945-04-561


p. 19

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3280 DEFINITIEF Ondertekening / Signatures Naam Penvoerder-projectleider:

Naam bestuurlijk verantwoordelijke:

M.G. van Pampus

L.C. Bruggeman

Plaats en datum:

Plaats en datum:

Handtekening:

Handtekening:

-----------------------------------------

-----------------------------------------


p. 20

Appendix C Datum 30 januari 2005 Onderwerp onderzoek pre-eclampsie Geachte mevrouw, U bent in ons ziekenhuis onder behandeling in verband met het doormaken van een zwangerschap met hoge bloeddruk (hypertensie), zwangerschapsvergiftiging (preëclampsie) en/of het HELLP syndroom. Zoals in alle academische ziekenhuizen wordt ook in het ……..ziekenhuis medisch-wetenschappelijk onderzoek gedaan. Dit onderzoek kan gericht zijn op het vinden van betere methoden om een ziekte vast te stellen of te behandelen, of op het verwerven van meer inzicht in de werking van het lichaam en ziekteprocessen. Dergelijk onderzoek is alleen mogelijk met de medewerking van ‘proefpersonen’, hetzij patiënten of gezonde vrijwilligers. Graag vragen wij uw hulp om aan een onderzoek mee te werken. In deze brief willen wij u graag informatie geven over het doel van het onderzoek waarvoor u in aanmerking komt, de te gebruiken onderzoeksprocedure en de voor- en nadelen ervan. Deelname aan het onderzoek is vrijwillig. Als u deze informatie gelezen hebt en hierover nog vragen hebt kunt u die met de onderzoeker bespreken. Als u vindt dat u voldoende informatie hebt kunt u beslissen of u aan het onderzoek wilt deelnemen. Onderzoek De soort behandeling van vrouwen met hoge bloeddruk in de zwangerschap of zwangerschapsvergiftiging is afhankelijk wanneer deze problemen zich in de zwangerschap voordoen. Is dit vroeg in de zwangerschap, dan zal men onder optimale bewaking proberen de zwangerschap voor te laten bestaan, teneinde de gevolgen van het te vroeg geboren zijn van uw baby, zoveel mogelijk te beperken. Dit is lang niet altijd mogelijk en soms moet de zwangerschap dan ook beëindigd worden omdat de baby in nood is of de conditie van de moeder langer wachten niet toestaat. Als een zwangere echter bijna uitgerekend is, kiest men vaak voor het beëindigen van de zwangerschap uit voorzorg. Het is echter helemaal niet duidelijk of dit voor de moeder en/of voor de baby beter is. Het beëindigen van de zwangerschap gaat door middel van het opwekken van weeën. Uit andere onderzoekingen is gebleken dat vrouwen die ingeleid worden om andere redenen een groter kans hebben op een kunstverlossing, zoals een vacuüm of een keizersnede. Wordt en afwachtend beleid onder bewaking gevolgd, dan is er theoretisch een grotere kans op complicaties, echter in de praktijk is dit niet aangetoond. Om te onderzoeken of het inleiden van de bevalling beter is dan het opnemen en zorgvuldig bewaken van de moeder en het ongeboren kind, worden in een aantal ziekenhuizen een onderzoek uitgevoerd. In totaal worden XXX vrouwen met hoge bloeddruk of zwangerschapsvergiftiging en die tenminste 36 + 0 weken zwanger zijn gevraagd aan het onderzoek mee te werken. Als de baarmoeder nog niet rijp genoeg is om de vliezen te breken, dan wordt vaginale gel gegeven. Is de baarmoeder wel rijp, dan worden de vliezen gebroken en wordt er een infuus gegeven met een weeënopwekkend middel. Zoals gezegd is er een iets grotere kans op een kunstverlossing of keizersnede doordat de baring onvoldoende vordert of doordat er foetale nood optreedt. Het onderzoek waarvoor uw deelname wordt gevraagd In het huidige onderzoek worden twee behandelingen met elkaar vergeleken. Als u meedoet aan het onderzoek, dan wordt u aangemeld bij een landelijk meldingspunt. Hier wordt een lot getrokken. Dit lot bepaalt de behandeling die u krijgt. De ene groep wordt behandeld met een afwachtend beleid, dat wil zeggen dat er geen inleiding plaatsvindt, tenzij dat om medische redenen noodzakelijk is en dat uw conditie en die van de baby nauwgezet in de gaten wordt gehouden. Mocht dit niet langer verantwoord zijn, dan zullen we geen enkel risico nemen en tot de bevalling overgaan. Create PDF with PDF4U. If you wish to remove this line, please click here to purchase the full version

De andere groep wordt ingeleid. Is dit niet mogelijk door middel van het breken van de vliezen, dan wordt eerst vaginale gel ingebracht. Zes weken na het onderzoek wordt gekeken hoe het met u en de baby gaat. De resultaten van de twee groepen zullen uiteindelijk vergeleken worden. Bedenktijd Natuurlijk zult u tijd nodig hebben om erover na te denken of u aan dit onderzoek wilt meewerken. Ook zult u er waarschijnlijk met anderen over willen praten. Hiervoor krijgt u uiteraard de gelegenheid. Vertrouwelijkheid van de gegevens De gegevens die in het kader van dit onderzoek over u verzameld worden, zullen vertrouwelijk worden behandeld. De gegevens worden op aparte formulieren ingevuld, waarop alleen een nummer voorkomt, niet uw naam en persoonlijke gegevens. De gegevens worden dus anoniem verwerkt. In publicaties zal uw naam niet terug te vinden zijn. Verzekering De ….heeft een verzekering afgesloten die eventuele schade door deelname aan dit onderzoek dekt. Nadere informatie hierover kunt u krijgen bij de onderzoeker. Vrijwilligheid van deelname U bent er geheel vrij in al of niet aan dit onderzoek mee te doen. Verder heeft u te allen tijde, ook wanneer u schriftelijk heeft verklaard te willen deelnemen, het recht om zonder opgave van redenen af te zien van verdere deelname aan het onderzoek. Deze beslissing zal geen nadelige gevolgen hebben op uw verdere behandeling en geen invloed hebben op de zorg en aandacht, waarop u in ons ziekenhuis recht hebt. Ook uw behandelend arts kan het in uw belang achten het onderzoek voortijdig te beëindigen. Hij/zij zal dit dan met u bespreken. Indien u er niets voor voelt om met het onderzoek mee te doen zal de gebruikelijke therapie of handelwijze gevolgd worden. Mocht in de periode dat u aan het onderzoek deelneemt nieuwe informatie bekend worden die van invloed kan zijn op uw bereidheid om mee te werken, dan zullen wij u hiervan zo spoedig mogelijk op de hoogte stellen, zodat u uw beslissing kunt heroverwegen. Nadere informatie Mocht u na het lezen van de brief, voor of tijdens het onderzoek nog nadere informatie willen ontvangen of komen er nog vragen bij u op dan kunt u altijd contact opnemen met de uitvoerder van het onderzoek in dit ziekenhuis, …….., telefonisch te bereiken via ………. Indien u nadere informatie wenst onafhankelijk van de uitvoerder van het onderzoek dan kunt u contact opnemen met …………….telefonisch te bereiken op ….. Ondertekening toestemmingsverklaring Als u besluit mee te werken aan het onderzoek zullen wij u vragen een formulier te ondertekenen. Met deze toestemmingsverklaring (‘Informed consent’) bevestigt u uw voornemen om aan het onderzoek mee te werken. U blijft de vrijheid behouden om wegens voor u relevante redenen uw medewerking te stoppen. De onderzoeker zal het formulier eveneens ondertekenen en bevestigt dat hij/zij u heeft geïnformeerd over het onderzoek, deze informatiebrief heeft overhandigd en bereid is om waar mogelijk in te gaan op nog opkomende vragen. Met vriendelijke groeten, Namens de onderzoeksgroep, Dr. M.G. van Pampus, gynaecoloog Create PDF with PDF4U. If you wish to remove this line, please click here to purchase the full version

Informed consent Toestemmingsformulier voor deelname aan het wetenschappelijk onderzoek: Hoge bloeddruk in de zwangerschap en zwangerschapsvergiftiging: inleiden of afwachten onder zorgvuldig observeren. Een vergelijking van uitkomsten van moeders en kinderen, kwaliteit van leven en kosten Pregnancy-induced hypertension and pre-eclampsia at term: induction of labour versus expectant monitoring. A comparison of maternal and neonatal outcome, maternal quality of life and costs?

- Ik ben naar tevredenheid over het onderzoek geïnformeerd. Ik heb de schriftelijke informatie goed gelezen. Ik ben in de gelegenheid gesteld om vragen over het onderzoek te stellen. Mijn vragen zijn naar tevredenheid beantwoord. Ik heb goed over deelname aan het onderzoek kunnen nadenken. Ik heb het recht mijn toestemming op ieder moment weer in te trekken zonder dat ik daarvoor een reden behoef op te geven. - Ik stem toe met deelname aan het onderzoek. Naam : Geboortedatum

:

Handtekening

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Datum:

- Ondergetekende verklaart dat de hierboven genoemde persoon zowel schriftelijk als mondeling over het bovenvermelde onderzoek geïnformeerd is. Hij/zij verklaart tevens dat een voortijdige beëindiging van de deelname door bovengenoemde persoon van geen enkele zal zijn op de zorg die hem of haar toekomt. Naam : Functie

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Handtekening

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Datum:

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Date: Subject: preeclampsia research project At this moment you are being treated for a pregnancy with high blood pressure (hypertension), pregnancy intoxication (preeclampsia). As in all University hospitals this hospital ............. is also doing medical-scientific research. This research can be based on finding better methods to diagnose or treat an illness or gathering more insight into the working of the human body and processes of illness. Such research is only possible with the co-operation of test subjects, either patients or healthy volunteers. Therefore we would like to ask you to cooperate in a research project. In this letter we would like to give you information on the purpose of the research project that is eligible for you, the research procedure that will be used and its advantages and disadvantages. Participation in the study is voluntarily. If you have any questions after reading this information, you can discuss these with the research worker. If you are covinced that you have had enough information on the research project please decide whether or not you would like to participate in this project. Research project The manner of treatment for women with high blood pressure induced by pregnancy or pregnancy intoxication is dependent on when this problem manifestates during pregnancy. If these problems occur in early pregnancy, we will try to continue pregnancy under optimal monitoring, to minimise the effects of too early delivery of your baby. Unfortunately this is not always possible and sometimes the pregnancy has to be ended because the baby is in danger or because the condition of the mother no longer tolerates further waiting. If a pregnant women is however nearly due often ending of pregnancy is planned precautiously. It is however not yet obvious if this is best for the mother and her baby. Ending of pregnancy is started by inducing contractions. On the other hand other studies have concluded that inducing pregnancy for other reasons gives a greater chance of vaginal instrumental delivery, like a vacuum or a caesarean section. To investigate if inducing labour is better than admission to hospital and extensive monitoring of mother and the unborn child, research is being performed in several hospitals. XXX women in total with high blood pressure or pregnancy intoxication of at least 36 + 0 weeks of gestation will be asked to participate in the research project. The research project for which your participation is being asked In the former research project two manners of treatment are being compared. If you decide to participate in the research project you will be enlisted at a national report centre. At this centre a lot will be drawn. This lot decides which manner of treatment you will get. One of the groups will be treated with expectative management, involving admission to hospital with close monitoring of your condition and that of your baby. If this condition is no longer acceptable we will not take any risk and progress to labour. In the other group labour will be induced. If this is not possible by breaking the membranes we will insert a vaginal gel first.

Six weeks after the research project we will examine how you and your baby are doing. The results of the two treatment groups will be compared in the end. Time for reflection You will of course need time to think the matter of participation in the research project over and will probably want to discuss this with others. You will have the possibility to do this. Confidential information The information collected about your pregnancy during the research period will be handled confidentially. The data will be written on special forms with only a number, not your name


or any personal information. The data will be handled anonymously. You will not find your name in scientific papers.

Insurance The .........will take out an insurance that will cover any possible loss due to participation in the research project. You can get further information on this insurance from the researcher worker. Voluntary participation You are completely free in the decision of participation in this research project. Besides this you always have the right, even when you have declared written participation in the form, to give up further participation in the research project without any reason. This decision will not have any negative influence on your further treatment and will not have any influence on the care and attention you are entitled to in our hospital. The doctor who is treating you can also decide to end participation in the research project earlier, for your best interest. He/she will in this situation discuss this with you. If you decide not to participate in the research project you will get standard treatment and/or therapy. If during the research period you are participating in, new information is released that can have influence on your decision in participation, we will inform you as soon as possible so that you can reconsider your choice. Further information If you would like to have any further information or if you have any questions after reading this letter, before or after the research project you can always contact .......... research worker in this hospital for this research project, telephone .....................

If you would like to have further information from someone independent of the research worker of this project you can contact .................. telephone................... Signing the declaration of agreement If you decide to participate in the research project we will ask you to sign a form. With this declaration of agreement (informed consent) you confirm your intention of participation in the research project. You keep the right to end participation in case of a for you relevant reason. De researche worker will also sign the form and confirm that he/she has informed you about the research project, has given you this patientinformation and is willing where possible to answer any rising questions. Kind regards, On behalf of the researchgroup, Dr. M.G.van Pampus


Pregnancy-induced hypertension and pre-eclampsia at term: induction of labour versus expectant monitoring. A comparison of maternal and neonatal outcome, maternal quality of life and costs? Agreement form for participation in the scientific research project: -I have satisfactorily been informed about the research project. I have read the written information thoroughly. I have had the possibility to ask questions about the research project. My questions have been answered satisfactorily. I have giving the matter of participation considerable thought. I have the right to withdraw my permission at any moment without having to give a reason. -I am fully aware that the most important risk of participation in this research project is slight skin irritation in exceptional cases. -I am also fully aware that if a serious physical abnormality is discovered, this could have consequences when taking out an insurance. I don’t object to this being passed on to my general practitioner. -I agree to participating in this research project Name: Date of birth: Signature:

Date:

-Undersigned declares that the above mentioned person is informed in writing as well as by word of mouth about the above mentioned research project. He/she also declares that a premature ending of participation by the above mentioned person will not have any influence what so ever on the health care that he or she is entitled to.

Name: Position: Signature:

Date:



Appendix A Clinical instructions Inclusion criteria: Pregnant women gestational age > 36+0 week until 41+0 weeks Blood pressure (Korotkoff phase V) ≥ 140/95 on more than two occasions at least 6 hours apart . Eventually combined with proteinuria (≥ 300 mg total protein in a 24 hour urine collection or, if this is not available, 2+ proteinuria by dipstick Exclusion criteria: Treated hypertension before pregnancy, diabetes mellitus, renal disease, previous caesarean section, HELLP syndrome, oliguria < 500 mL in 24 hours, cerebral or visual disturbances, pulmonary edema or cyanosis, non vertex position Randomisation

Expectant management (n=250) * Monitoring until onset spontaneous delivery * Maternal monitoring: blood pressure, proteinuria, platelet count, Liver enzymes, renal function Uric acid * Fetal monitoring: fetal heart rate monitoring, fetal movements * Ultra sound examination fetal growth, amniotic fluid each 10 days * Doppler a umbilicalis twice a week * No plasma volume expansion * Intervention: maternal reasons - diastolic blood pressure >=110 mm Hg - eclampsia - rupture of membranes > 48 hours or with meconium stained liquor - HELLP syndrome

-

-

Intervention (n=250) * Cervical ripeness Bishop > 6: induction amniotomy and if necessary augmentation with oxytocin * If Bishop score < 6: cervical ripening with prostaglandins: Start with Prepidil 0.5 mg intracervical. after 4 hours Prostin 1 mg intravaginal, in case of minimal reaction another Prostin 2 mg

proteinuria > 5g/L

fetal reasons - fetal condition does not justify expectant management anymore


Appendix B Bishop score 0

1

2

3

Dilataton of cervix

0

1-2

3-4

5-6

Effacement cervix

0-30%

40-50%

60-70%

>80%

Consistency cervix

Firm

medium

soft

Position cervix

Posterior

central

anterior

Station of foetal head in relation to spines

3 cm above

2 cm above

1-0 cm above

1-2 cm below

Intervention group: Bishop score > 6: amniotomy, augmentation with oxytocin Bishop score < 6: cervical ripening by use of prostaglandines Start with Prepidil 0.5 mg intracervical after 4 hours Prostin 1 mg intravaginal in case of minimal reaction another Prostin 2 mg

Indication instrumental delivery: Caesarean section: fetal distress without possibility for fetal blood sample or failure to progress first stage Obstructed labor second stage Fetal distress: fetal blood sample ph < 7.20.


Women with term pregnancy (36+0 to 41+0 weeks) AND Mild PIH (95mmHg ≤ Diastolic RR < 110 mmHg) OR Mild PE (95mmHg ≤ Diastolic RR < 110 mmHg) and 0.3 g ≤ proteinuria < 5 g

Assessment of exclusion criteria

diabetes mellitus, renal disease, a previous caesarean section, HELLP syndrome, oliguria < 500 mL in 24 hours, pulmonary edema or cyanosis, and abnormalities at the CTG

Informded consent?

No

Yes Vaginal examination Cervical length measurement QoL Questionnaires Randomisation: webbased stratification for parity centre PE or PIH

Randomi sation N=250

Induction of labour Treat according to local protocol

BS ≤ 6

N=250

Expectant monitoring

BS > 6

Cervical

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Daily RR measurement Daily CTG Urine check for protein every 2 days Blood test twice a week

BEGROTINGSOVERZICHT DOELMATIGHEIDSONDERZOEK Projectnaam: Pregnancy-induced hypertension and pre-eclampsia after 36 weeks: induction of labour versus expectant monitoring. A comparison of maternal and neonatal outcome, maternal quality of life and costs? Jaar 1 €

Jaar 2 €

Jaar 3 €

Totaal €

1 Personele kosten 2 Materiele kosten 3 Apparatuur kosten 4 Overige kosten

110.227 0 0 0

111.653 0 0 0

100.196 0 0 0

322.077 -

Totale lasten

110.227

111.653

100.196

322.077

9920

29181

5 Bijdragen

Saldo

9535

9726

292.896


Projectnaam: Pregnancy-induced hypertension and pre-eclampsia after 36 weeks: induction of labour versus expectant monitoring. A comparison of maternal and neonatal outcome, maternal quality of life and costs? 1.a PERSONELE KOSTEN JAAR 1 (start eind 2004): nr

Functie

Schaal

1 Res. Nurse Data base 2 manager 3 Health economist 4 Coordinator 5 Statistician Research 6 physician 7 8 9 ..

Formatie (perc. per jaar)

Bruto

Overhevelings Werkgevers- Subtotaal

salaris (413) 57600

toeslag (4222)

bijdragen (422) 21312

Opslag op

personeelskosten 16% 78912 12626

Totaal

€ 91538

8

2

8 11 14 14

0,1 0 0,1 0

2400 0 6000 0

888 0 2220 0

3288 0 8220 0

526 0 1315 0

3814 0 9535 0

11

0,1

3360

1243,2

4603 0 0 0 0 95023

737 0 0 0 0 15204

5340 0 0 0 0 110227

Totaal 1.b PERSONELE KOSTEN JAAR 2: nr

Functie

1 Res. Nurse Data base 2 manager 3 Health economist 4 Coordinator 5 Statistician 6 Research

Schaal

Formatie (perc. per jaar)

Bruto

Overhevelings Werkgevers- Subtotaal toeslag (4222)

8

2

salaris (413) 58752

8 11 14 14 11

0,1 0 0,1 0 0,1

2448 0 6120 0 2937,6

bijdragen (422) 21738,24 905,76 0 2264,4 0 1086,912


Opslag op

personeelskosten 16% 80490 12878 3354 0 8384 0 4025

537 0 1342 0 644

Totaal

€ 93369 3890 0 9726 0 4668

physician 7 8 9 ..

0 0 0 0 96253

Totaal

0 0 0 0 15400

0 0 0 0 111653

1.c PERSONELE KOSTEN JAAR 3: nr

Functie

1 Res. Nurse Data base 2 manager 3 Health economist 4 Coordinator 5 Statistician Research 6 physician 7 8 9 ..

Schaal

Formatie (perc. per jaar) 8

Bruto

Overhevelings Werkgevers- Subtotaal

salaris toeslag (413) (4222) 1,3 19476,288

bijdragen (422) 7206,22656

Opslag op

personeelskosten 16% 26683 4269

Totaal

€ 30952

8 11 14 14

0,1 0,1 0,1 0,05

2496,96 2996,352 6242,4 1872,72

923,8752 1108,65024 2309,688 692,9064

3421 4105 8552 2566

547 657 1368 411

3968 4762 9920 2976

11

1

29963,52

11086,5024

41050 0 0 0 0 86376

6568 0 0 0 0 13820

47618 0 0 0 0 100196

Totaal


Projectnaam: Pregnancy-induced hypertension and pre-eclampsia after 36 weeks: induction of labour versus expectant monitoring. A comparison of maternal and neonatal outcome, maternal quality of life and costs? 2.a MATERIELE KOSTEN JAAR 1 (start eind 2004) Bij verrichting (COTG nr….)

Aantal

Databasemanufacturing

Tarief 1

Totaal 0 0 0 0 0

0

Totaal 2.b MATERIELE KOSTEN JAAR 2 Bij verrichting (COTG nr….)

Aantal

Database-onderhoud

Tarief 0

Totaal 0 0 0 0 0

3000

Totaal 2.c MATERIELE KOSTEN JAAR 3 Bij verrichting (COTG nr….) Database-onderhoud

Aantal

Tarief 0

Totaal

3000

Totaal


0 0 0 0 0

Projectnaam: Pregnancy-induced hypertension and pre-eclampsia after 36 weeks: induction of labour versus expectant monitoring. A comparison of maternal and neonatal outcome, maternal quality of life and costs? 5.a BIJDRAGEN JAAR 1 (start eind 2004)

5.a.1

5.a.2

Eigen bijdrage instelling -ziekenhuis -universiteit Bijdragen derden

0 0 9535 0

Totaal

9535

5.b BIJDRAGEN JAAR 2

5.b.1

5.b.2


0 0 9726 0

Totaal

9726

5.c BIJDRAGEN JAAR 3

5.b.1

5.b.2


0 0 9920 0

Totaal

9920


Motivation for the requested funds: Recruitment of patients will be performed by reserach nurses who will work in the participating centres. These nurses will also monitor patients through the study, enter data in the web-based database, and collect the questionnaires on quality of life. A central database manager will be responsible for the validation of entered data. This person will provide feedback on the research nurse about data-quality. As the database will be similar to that used in the DIGITAT-studu, scale advantages can be reached here, we only request an appointment for .1 fte. A health economist will collect data for the cost-analaysis and perform the cost-analysis. As costs of volumes will be largely equal to those collecetd in the DIGITAT-study, we only ask for an economist in the last year. A statistician will advise the database manager. In the last year, this person will do the analysis. A junior researcher (resident gynaecology) will write publications about the study, and will give presentations. This person will attend project meetings, keep up with the literature, and will be dedicated full time to the project in the last year. A coordinators, payed the AZG, will supervise the project.











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