Subsidieaanvraag HYPITAT - Studies

Transcription

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:
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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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
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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DEFINITIEF
Prof. dr. P.M.M. Bossuyt (Mede aanvrager)
T: 020-5669111
F:
E:
Klinische Epidemiologie en Biostatistiek
Postbus 22660
Nederland
Dr. B.C. Opmeer (Mede aanvrager)
T: 020-5669111
F:
E:
Klinische Epidemiologie en Biostatistiek
Postbus 22660
Nederland
Dr. E. Birnie (Mede aanvrager)
T: 020-5669111
F:
E:
Klinische Methoden & Public Health
Sociale Geneeskunde
Postbus 22660
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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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
Postbus 30033
9700 RM GRONINGEN
Gelre Ziekenhuizen
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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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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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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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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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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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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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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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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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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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
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
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
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
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
p. 17
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
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
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.
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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
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
:
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
:
Handtekening
:
Datum:
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
Create PDF with PDF4U. If you wish to remove thisripening
line, please click here to purchase the full version
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.
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
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
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
salaris
toeslag
(413)
(4222)
1,3 19476,288
bijdragen
(422)
7206,22656
Opslag op
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.
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
nr….)
Aantal
Database-onderhoud
Tarief
0
Totaal
0
0
0
0
0
3000
Totaal
2.c MATERIELE KOSTEN JAAR 3
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.
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
Eigen bijdrage
instelling
-ziekenhuis
-universiteit
Bijdragen derden
0
0
9726
0
Totaal
9726
5.c BIJDRAGEN JAAR 3
5.b.1
5.b.2
Eigen bijdrage
instelling
-ziekenhuis
-universiteit
Bijdragen derden
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.

Subsidieaanvraag HYPITAT - Studies

Transcription

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