Onderzoeksprotocol “STAN versus CTG + MBO”
Divisie Perinatologie en Gynaecologie (afdeling obstetrie)
Onderzoekers: M.E.M.H.Westerhuis, A.Kwee, G.H.A.Visser, K.G.M.Moons
Title
The cost-effectiveness of ST-analysis of the fetal electrocardiogram as compared to fetal
blood sampling for intrapartum monitoring: a randomised controlled trial
Summary:
Background: Cardiotocography (CTG) is worldwide the method for fetal surveillance during
labour. However, CTG alone shows many false positive results and without fetal blood
sampling (FBS) it results in an increase in operative deliveries without an improvement of fetal
outcome. FBS requires additional expertise, is invasive and has often to be repeated during
labour. Two RCTs have shown that a combination of CTG and non-invasive ST-analysis (of
the fetal ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in
both RCTs FBS was still performed in both arms, and it is therefore still unknown if the
observed results were indeed due to the ST-analysis or to the use of FBS in combination with
ST-analysis.
Objective: To quantify costs and effectiveness of non-invasive monitoring (CTG + STanalysis) as compared to normal care (CTG + FBS), in order to judge whether the STanalysis can replace FBS.
Study design: Multicentre randomised controlled trial in eight hospitals.
Study population: Women in labour ( 36 weeks of gestation) with an indication for CTG.
Interventions: Women will be randomised for fetal surveillance with CTG + FBS or CTG + STanalysis.
Outcome measures: Primary outcome is the incidence of serious metabolic acidosis (defined
as pH < 7.05 and BDecf > 12 mmol/l in the umbilical cord artery). Secondary outcome
measures are: instrumental delivery rate, cost-effectiveness, neonatal outcome (Apgar score,
admission to a neonatal ward) and cost-effectiveness of both monitoring strategies across
hospitals.
Power/data analysis: The analysis will follow the intention to treat principle. The incidence of
metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic
acidosis from 3.5 to 1.5 %, using a two sided test with an alpha of 0.05 and a beta of 0.80, in
favour of CTG + ST-analysis, 2400 women have to be randomised (1200 per group).
Economic evaluation: The economic evaluation is designed as cost-effectiveness analysis,
i.e. the ratio of (I) incremental costs and (II) the reduced rate of metabolic acidosis, associated
with the strategies is quantified.
Time Schedule: The total research period is 3 years: a start-up phase of 4 months, an
inclusion period of 26 months and 6 months to realise follow-up, analysis and reporting.
Samenwerking
UMCUtrecht
VUMC
AZM
Maxima MC
TweestedenZH
St Antonius ZH
Jeroen Bosch MC
OLVG
Diakonessenhuis
MEMH Westerhuis/A Kwee/GHA Visser/KGM Moons
SM Bijvoet/HP van Geijn
JG Nijhuis/C.Willekes
M.Porath/BWJ Mol/SG Oei
A Drogtrop/A van Ginkel
E van Beek/GCMGraziosi
R Rijnders
J van Lith
NWE Schuitemaker
1
Problem
The aim of intrapartum fetal monitoring is to identify fetuses at risk for neonatal and long-term
injury due to asphyxia. Although cardiotocography (CTG) is applied on a large scale, this
technique is still subject to debate (1-3). Long-term follow-up studies have shown no or little
benefit of fetal surveillance and intrapartum monitoring results in a significant increase in
operative deliveries (4-6). Fetal blood sampling (FBS) can be used in addition to CTG, but it
requires expertise, is invasive, has to be repeated when CTG abnormalities persist and can
cause complications (7,8). As a consequence, it is not widely applied.(9) In the Netherlands
FBS is available in only 70 % of the hospitals. Because abnormalities in the ST-segment are
related to metabolic acidosis of the fetus, detection of changes in the ST-segment of the fetal
electrocardiogram (ECG), in combination with CTG, is a non-invasive and promising
alternative for FBS.(10,11) Two randomised trials (the Plymouth RCT (2400 cases) and the
Swedish RCT (4966 cases)) indeed have shown a decrease in metabolic acidosis and in
interventions for fetal distress in favour of the CTG plus ECG-group.(12,13) The rate of infants
with encephalopathy in the Swedish RCT was also significantly lower in the CTG + ST group
as compared to the group monitored with CTG only.(14) However, in both RCTs FBS was still
often performed in both arms. Hence, it was not possible to conclude if the observed
improved outcome was indeed due to the monitoring by ST-analysis or because FBS was still
used to guide subsequent management. In the previous ZonMW Doelmatigheidsonderzoek
round, we proposed an observational diagnostic study aiming to determine the diagnostic
value of ST-analysis as compared to FBS. We were advised to study the clinical value of
ST-analysis as compared to FBS using a randomised, follow-up design, rather than an
observational design. Following the suggestions of the ZONMW committee, we now propose
to conduct a randomised trial comparing the (cost-) effectiveness of monitoring using CTG +
ST-analysis with usual care monitoring by CTG+FBS.
Background ST-analysis
The STAN® concept is based on the ability of the ST-interval to reflect the function of the fetal
heart muscle (myocardium) during stress tests. In adult cardiology, ST analysis is performed
to assess and diagnose myocardial insufficiency. During labour, the condition of the fetaus
can be assessed by the routinely available fetal signal, the electrocardiogram. The fetal heart
and brain are equally sensitive or insensitive to oxygen deficiency and, as a result, the
information relating to myocardial function provides an indirect measurement of the condition
of the fetal brain during labour.
The changes in fetal ECG associated with fetal distress are either an increase in T-wave,
quantified by the ratio T-wave to QRS-amplitude (T/QRS), or a biphasic ST-pattern. An
increase in the T-wave (quantified by the T/QRS-ratio) has been associated with a
catecholamine surge, activation of β-adrenoreceptors, myocardial glycogenolysis, and
metabolic acidosis (15-17). A biphasic shape of the ST-segment is related to two situations. It
occurs when the fetal heart is exposed to acute hypoxic stress whereby the fetus has had no
time to respond or when the fetal heart has a reduced capacity to respond due to exposition
to previous stress situations and lacking or already utilized resources. Besides, biphasic STchanges have been associated with disturbances in heart muscle function, infection or
malformations (15-17).
The STAN guidelines are based on an integrated CTG and fetal ECG interpretation.
According to the guidelines of the integrated CTG and fetal ECG monitor, the STAN -monitor,
ST-changes are only thought to be of clinical relevance if they coincide with intermediate or
abnormal CTG traces (Appendix B). In case of a normal CTG, the high sensitivity of the CTG
only, is considered sufficient to ignore abnormalities in the ECG.
What is the disease / condition, subject of this proposal/subgroup of patients
The proposed study evaluates the cost-effectiveness of two strategies for fetal surveillance: a.
conventional monitoring (CTG + FBS) or b. CTG + ST analysis. Women in labour with an
indication for intrapartum fetal surveillance at a gestational age above 36 weeks of gestation
and a singleton fetus in vertex position are included in the study.
Describe the usual care in the Netherlands for the (sub-) group of patients involved
In the Netherlands women with a medical indication deliver in the hospital. During labour they
are monitored by CTG to detect fetal distress. FBS will be performed in addition to the CTG, if
2
the latter provides an indication to do so. However, only 70 % of the Dutch hospitals perform
FBS due to its technical aspects and in these hospitals it is not applied in a systematic way.
Gynaecologists are responsible for the delivery of pregnant women with a medical indication.
In many hospitals registrars or specially trained midwives under supervision of a
gynaecologist manage these deliveries. The research setting will be the same as in daily
practice; involving gynaecologists, residents as well as midwives working on labour wards.
Describe your motivation for the chosen intervention
In spite of the above-mentioned evidence on the potential improvement in fetal surveillance
using ST-analysis, there is at present still a dilemma for gynaecologists on its clinical value
and cost-effectiveness. First, as mentioned above, the effectiveness of CTG + ST-analysis
without FBS is unknown. Second, ST-analysis requires financial investment, which are at
state considered by many gynaecologists in The Netherlands. Costs are not only related to
the procure of the ST-monitor (34000 Euro per monitor), but are also related to the necessity
of repeated training of labour ward personnel.
In 2000 the University Medical Centre Utrecht (applicants Kwee and Visser) participated in a
EU-project regarding the implementation of ST-analysis. The technique has been applied in
over 600 women. The results of a study within this project showed that ST-changes were
present in all cases with severe metabolic acidosis and that CTG + ST-analysis was more
specific in detecting fetal academia than CTG alone.(18)
In conclusion, ST-analysis is a promising new technique for detecting fetal distress during
labour. However, it is not known whether this technique can be used without FBS. Moreover,
ST-analysis is more costly than conventional fetal monitoring. The present proposal offers a
unique opportunity to address the question if fetal monitoring with CTG + ST-analysis (without
FBS) is more effective than CTG + FBS and provides the possibility of proper costeffectiveness evaluation before widely introducing ST-analysis in clinical practice.
Relevance
Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour.
However, CTG alone shows many false positive results and without fetal blood sampling
(FBS) it results in a significant increase in operative deliveries without improved outcome.
FBS requires additional expertise, is invasive and has to be repeated when CTG
abnormalities persist. Accordingly it has not gained popularity among gynaecologists and
labouring women. Non-invasive ST analysis of fetal ECG recording seems a promising
alternative. Two RCTs have shown that a combination of CTG and ST-analysis reduces the
rates of metabolic acidosis and instrumental delivery. However, in both RCTs FBS was still
performed in both arms, and it is therefore still unknown if the observed decrease in poor
outcome and interventions were indeed due to the ST-analysis or to the use of FBS.
Furthermore, the cost-effectiveness of ST-analysis as compared to routine care using FBS is
yet unknown
How will the results of the proposed study contribute to the resolution of this health care
problem?
The proposed study will reveal the following answers:
1.
The effectiveness of a monitoring strategy using CTG + ST-analysis compared to the
conventional monitoring strategy (CTG + FBS).
2.
The cost-effectiveness of both strategies.
These results will help to resolve an important dilemma in current obstetrical care aiming at
maximal prevention of metabolic acidosis with a minimal instrumental delivery rate.
Are there any studies underway similar to the present study proposal?
As far as we know there are no other studies underway similar to this proposal.
Are there any reports by national advisory boards on the subject of your proposal?
A guideline of the Dutch Society of Obstetrics and Gynaecology (NVOG) regarding fetal
surveillance has recently stated that the use of ST-analysis is still experimental (May 2003).
What is the incidence/prevalence of the targeted (sub-) population
In The Netherlands, 95.000 pregnant women per year are monitored during labour using CTG
3
(19). In 2002, approximately 9.500 (10%) instrumental deliveries were performed in this group
due to fetal distress, and approximately 950 (1%) babies with pH in the umbilical cord artery
below 7.00 have been born.(20) About 10% of the children with a pH below 7.00 will develop
seizures (i.e. 100 children each year), whereas 30 % (30) of these babies will develop long
term neurological problems (21,22). There exist many definitions regarding fetal academia. In
accordance with the two RCTs on the ST-analysis and knowing that cerebral impairment is
very unlikely in case of a more favourable umbilical cord artery pH, we defined metabolic
acidosis as a pH below 7.05 with a BDecf above 12 mmol/l in the umbilical cord artery,
Although data in The Netherlands about the incidence of metabolic acidosis are not available,
the observational study of the UMC Utrecht indicates that the prevalence of metabolic
acidosis in a high risk population (women with an indication for CTG monitoring) may be as
high as 3.5 %.(18)
Estimate the potential effects on health from the intervention(s) that will be evaluated in this
proposal compared to the usual care
The potential effects of the ST-analysis on health include a significant reduction of babies
born with metabolic acidosis and encephalopathy and a reduction of unnecessary
instrumental deliveries. The latter may cause maternal and neonatal morbidity, and even
mortality. It can be inferred from the two RCTs that the rate of metabolic acidosis can be
decreased with 66 % and the instrumental delivery rate with 1 %. As said, these results were
obtained in a population in which FBS was performed and in a population of both low-risk and
high-risk women delivering in a hospital, in contrast to the high-risk population, delivering
under responsibility of a gynaecologist in Dutch hospitals. Furthermore, the effects in
populations in which FBS is not used (30 % of the Dutch hospitals), are likely to be much
larger, since the instrumental delivery rate with CTG alone is much higher than with CTG +
FBS (up to 2-3 times higher).(22) In addition, hospital stay is expected to be shorter, both due
to a decrease in metabolic acidosis and a decrease in instrumental delivery rate.
Estimate the potential effects on costs intervention(s) that will be evaluated in this proposal
compared to the usual care
The results of the study will be applicable to approximately 100.000 women per year in The
Netherlands. A decrease of the instrumental delivery rate from 10 % to 9 % will result in a
reduction of 1.000 instrumental deliveries resulting in a potential saving of €1.000.000. A
reduction of the metabolic acidosis rate from 3.5 to 1.5 % would prevent metabolic acidosis in
2.000 children, resulting in a potential saving of another €1.500.000,-, not even taking into
account any additional costs related to the development of encephalopathy and
consequences in later life.
Objective, research question/assignment:
Objective: to quantify the cost-effectiveness of cardiotocography in combination with noninvasive ST-analysis of the fetal electrocardiogram for fetal monitoring during labour as
compared to usual care including cardiotocography in combination with fetal blood sampling.
Specific Research questions:
1. Is the incidence of developing serious metabolic acidosis (measured in the umbilical cord
artery) decreased with a strategy of fetal monitoring with CTG + ST-analysis, when
compared with
CTG + FBS?
2. Is the number of instrumental deliveries because of fetal distress decreased in the group
monitored with CTG + ST-analysis, when compared with CTG + FBS?
3. Is monitoring by CTG + ST-analysis cost-effective?
4
Strategy
Clinical Study
Preliminary studies by applicants on the subject of this proposal
At the University Medical Centre Utrecht we recently performed a relatively small, singlecentre observational diagnostic accuracy study among high-risk women in labour (15). This
study was part of a European Community multi-centre project: a program of dissemination of
knowledge -regarding the STAN-methodology- based on the Centre of Excellence structure.
In this preliminary study all women underwent CTG analysis, fetal ST analysis, and FBS when
indicated. Umbilical cord blood analysis functioned as reference test to determine the true
presence or absence of metabolic acidosis. In two years, 637 women were included. We
found that the sensitivity and specificity of ST analysis were 72 % and 90 %, respectively,
whereas the positive and negative predictive values were 98 % and 18 %. For CTG, the
sensitivity and specificity were 100 % and 18 % and the positive and negative predictive
values were 100 % and 4 % respectively. In 22 % of the women FBS was performed. There
were five cases of severe metabolic acidosis (pH in the umbilical artery < 7.00) that were all
preceded by ST-segment changes, whereas in 3 cases FBS was still negative and unnecessarily- delayed delivery (i.e. false negatives). Addition of fetal ST-analysis to CTG in a
high-risk population resulted in a considerable reduction of the percentage of false negative
(i.e. missing the presence of metabolic acidosis) and false positive (i.e. falsely diagnosing the
presence of metabolic acidosis leading to unnecessary instrumental deliveries) test results.
Study Design
The proposed trial is a pragmatic randomised, multicentre study. The study will be performed
in five level III perinatal centres, which have recently joined research efforts to increase
population size of studies, supplemented with three large regional hospitals.
The cost-effectiveness of fetal monitoring during labour with CTG + ST-analysis is quantified
and compared with the standard monitoring method including CTG + FBS. Eligible patients
will be informed by the attending doctor or midwife. (see Patienteninformatiebrief) In case of
informed consent, essential patient data will be entered in a web-based database program.
This program subsequently randomly allocate the patient to one of the strategies.
Randomisation will be stratified for centre and parity (no previous vaginal delivery versus one
or more previous vaginal deliveries). This on-line system will also be used for the DIGITAT
study (ZonMW grant 945-04-558) and thus already known by most of the participating
centres. Women will be randomly allocated to either monitoring by CTG + FBS or CTG + STanalysis. Women who are offered randomisation, but who decide not to participate in the
study will be monitored and managed confirm routine care including CTG + FBS. The study
will be an open label study, as it is impossible to blind the patients and health care workers
involved for the strategy to which the woman is allocated. Both strategies will be performed
according to strict protocols (see below).
In every centre an independent gynaecologist will be responsible for the study in that centre.
A dedicated research nurse/midwife will monitor the study protocol in each centre by
attending patients meetings and providing feedback on potential protocol violation. This
person will collect data and will be available for more detailed information both for patients
and labour ward personnel.
Resources for training and technical support will be made available by the participating
centres, and not from the funding applied for.
Rationale of the design
ST-analysis is a promising new technique for detecting fetal distress during labour. It is a noninvasive, and thus promising alternative for FBS. Two randomised trials (the Plymouth RCT
(2.400 cases) and the Swedish RCT (4.966 cases)) have shown a decrease in metabolic
acidosis and in interventions for fetal distress in favour of the CTG plus ECG-group.
(12,13)The rate of infants with encephalopathy in the Swedish RCT was also significantly
lower in the CTG + ST group as compared to the group monitored with CTG only.(14)
However, in both RCTs FBS was still often performed in both arms. Hence, it was not
possible to conclude if the observed improved outcome was indeed due to the monitoring by
ST-analysis or because FBS was still used to guide subsequent management.
5
We now propose to conduct a randomised trial comparing the (cost-)effectiveness of
monitoring using CTG + ST-analysis with usual care monitoring by CTG+FBS. In the CTG +
ST-analysis group it is only allowed to perform FBS in case of poor signal quality of the fetal
ECG-signal or in case of a serious abnormal CTG without ST-changes in which one does not
want to decide to perform an intervention. The present proposal offers a unique opportunity to
address the question if fetal monitoring with CTG + ST-analysis (with FBS only in few cases)
is more effective than CTG + FBS, and provides the possibility of proper cost-effectiveness
evaluation before ST-analysis is widely introduced in clinical practice.
Study population
Women will be eligible if they are in labour with a singleton fetus in vertex position, a
gestational age  36 weeks and a medical indication for electronic fetal monitoring. A medical
indication is defined by either a high-risk pregnancy, induction or augmentation of labour,
epidural anaesthesia, meconium stained amniotic fluid or non-reassuring fetal heart rate.
Exclusion criteria are fetus in breech presentation, twin pregnancies and absent informed
consent.
The proposed study concerns a multicentre study in five perinatal centres and three large
regional teaching hospitals, in The Netherlands: Maxima Medical Centre Veldhoven,
Academic Hospital Maastricht, Free University Medical Centre Amsterdam, University Medical
Centre Utrecht, Onze Live Vrouwe Gasthuis Amsterdam. St.Antonius Hospital Nieuwegein,
TweeSteden Hospital Tilburg, Diakonessenhuis Utrecht and Jeroen Bosch Medical Centre
Den Bosch.
Women with a high-risk pregnancy, who will have their out-patient visits under responsibility
of a gynaecologist in the hospital, will get the patient information (about the study) around 36
weeks of gestation, in the outpatient clinic. We will give information on the fact that it is not
always possible to participate in the study, because the STAN-monitor can be occupied in
case another woman has just before been randomised for monitoring by STAN. Therefore we
will ask informed consent when the woman is in labour, when it is actually clear that there is a
STAN-monitor available.
Women, having their prenatal controls under supervision of a midwife and sent to the hospital
during labour, will obviously be informed and asked for informed consent at arrival at the
gynaecologist. We like to note that previous experiences of various members of the study
group with asking women for studies during labour (fetal resuscitation, intrauterine pressure
monitoring), has been very good. Only women (during labour) who are able to read and
understand the patient information and able to give informed consent will be asked to
participate in the study.
Measurements/interventions
Women will be randomly assigned to routine care including fetal monitoring by
cardiotocography with fetal blood sampling (CTG + FBS group) or to the index group including
cardiotocography with ST-analysis (CTG + ST group). (See Appendix A and B). Clinical
management in the CTG + FBS group (routine care) will be guided by guidelines produced by
the FIGO.(23) FBS is recommended in case of a suboptimal or abnormal CTG pattern. In
cases with scalp blood pH lower than 7.20 or preterminal cardiotocograms delivery is
recommended. In the CTG + ST group, clinical management will be supported by
computerised ST waveform assessment and will be guided by the STAN guidelines,
indicating when intervention is recommended.(24, see Appendix B) In case of poor signal
quality of the fetal ECG-signal it is allowed to perform a FBS in the first stage of labour. In
case of an abnormal CTG without ST changes in the first stage it is allowed to perform FBS
after 90 minutes of abnormal recordingwhen the attending doctor does not want to intervene
by caesarean section. Furthermore, when the CTG shows an abnormal pattern at the start of
the recording FBS has to be performed. In the second stage one will perform an instrumental
delivery. FBS in these situations is allowed to prevent serious false-negative cases (neonates
with serious metabolic acidosis).
From each woman, we will systematically (by protocol) document demographics and medical
history, as well as CTG analysis, fetal ST-analyis and FBS results. Finally, the umbilical cord
artery results, the performance of an instrumental delivery and neonatal outcome until
discharge from the hospital will be documented. (see Appendix C)
Long term neonatal outcome is no endpoint of the study because the expectation of children
with impaired neurological outcome will be only 1 in a group of 2400 women. Assuming a rate
6
of 1 % neonates born wit severe metabolic acidosis (pH below 7.00), one would expect that of
these 24 neonates 10 % (=2.4) will develop seizures and of these children 30 % (= about 1)
will develop neurological problems in later life. (20,21) Therefore we focus on short-term
neonatal outcome.
CTG and FBS.
In women randomised to the control group, a scalp electrode will be applied to the fetal head
and connected to the conventional CTG-monitor conform routine practice of CTG monitoring.
If the pH of the first measurement is below 7,20 delivery is recommended unless the cause of
fetal distress can be alleviated. If the pH is between 7,20 and 7,25 FBS will be repeated after
30 minutes. If the pH is above 7,25 FBS is repeated according to CTG pattern according to
the attending doctor or midwife.
The number of failed FBS will be recorded.
CTG and ST-analysis.
In women randomised to the index group, a scalp electrode will be applied to the fetal head
and connected to the STAN-monitor conform routine practice of CTG monitoring. This
electrode will allow both standard fetal heart rate monitoring (CTG) as well as ST-analysis.
The CTG will be classified as normal, intermediate, abnormal or preterminal according to the
FIGO-guidelines for fetal heart rate monitoring (23). The ST log automatically alerts the
attending doctor or midwife if a significant ST-event occurs (21). Delivery is recommended
when there are significant ST-changes (see appendix B) unless the cause of fetal distress
can be alleviated.
It is only allowed to perform FBS in the CTG + ST-analysis arm in case of poor signal quality
of the fetal ECG in combination with an intermediate or abnormal fetal heart rate pattern in the
first stage. Furthermore, FBS is allowed in case of an abnormal CTG without ST-changes
when the doctor does not want to perform a caesarean section (because of the CTG), but
needs further information (pH FBS) to prevent a serious false negative case.From our
preliminary study, we know that in 10 % of cases the fetal ECG had a poor signal quality (18).
This percentage can be lowered by more appropriate placing and replacing of the electrodes.
Furthermore, this is only of clinical value when the CTG is intermediate or abnormal. In our
study 30 % of the CTG’s in the first stage were not normal. We estimate that in maximally 3 %
of cases there will exist a situation of poor signal quality and an intermediate or abnormal
CTG, indicating FBS.
In both study arms the doctor will be always responsible for the mother and fetus and can
decide on any moment to perform an intervention, independent of the results of FBS as well
as ST-analysis.
Outcome parameters
Primary Outcome:
Presence or absence of serious metabolic acidosis defined as a pH < 7.05 and a BDecf > 12
mmol/l in the umbilical cord artery (25)
Secondary outcome:
1. Instrumental delivery rate for the following indications: fetal distress, failure to progress or
a combination.
2. Cost-effectiveness of both strategies: see below
3. Neonatal outcome defined by low Apgar scores, defined as < 4 after 1 minute and/or < 7
after 5 minutes
4. Need for admission to the neonatal medium or intensive care unit
5. Cost-effectiveness of both monitoring strategies across hospitals, particularly, comparing
academic and non-academic hospitals.
Power analysis
The aim of the present trial is to determine the difference in cost-effectiveness of CTG + STanalysis versus the standard treatment including CTG + FBS for intrapartum fetal monitoring.
The analysis will follow the intention to treat principle. For the primary outcome, difference in
incidence in metabolic acidosis across both groups, the relative risk estimate (95% CI) will be
7
estimated. The same analysis will be done for the dichotomous secondary outcomes. For
cost-effectiveness analysis see below.
The sample size calculation is based on the primary endpoint: metabolic acidosis in the
umbilical cord artery. Although in the two randomised trials the incidence of metabolic
acidosis decreased from 1.5 % to 0.5 % in favour of the CTG + ST-analysis group (12,13), we
assume that the incidence of metabolic acidosis in our high-risk population (women delivering
in the hospital with a medical indication) is higher and estimated on 3.5 %, as found in our
preliminary study (18). A similar relative reduction of metabolic acidosis in our study would
imply a reduction from 3.5 to 1.15 %, in favour of the CTG + ST-analysis arm. To be more
conservative, assuming a reduction of 3.5 % to 1.5 %, 2106 women should be randomised
(1053 per arm), using an alpha of 0.05 (2-sided) and a power of 0.80. Accounting for 10%
loss to follow-up, the study would require inclusion of 2400 women in order to obtain 2106
analysable cases.
We will plan to perform after each 300 included subjects a group-sequential-analysis to
determine whether enough evidence is gathered and the trial could be stopped before all
patients are randomised (26,27).
All cases with a serious metabolic acidosis and/or neonates admitted to the neonatal
intensive care will be reported to the scientific committee, consisting of an independent
gynaecologist, neonatologist and epidemiologist. This committee can decide to stop the trial
when there are significantly more neonates with severe asphyxia in one arm of the study.
Feasibility of recruitment
Based on the experience of our previous study, per year 200 parturients per monitor can be
recorded. Six hundred thirty seven women were included in 26 months, with one monitor
during 12 months and two monitors during the remaining 14 months (18). This means that per
STAN-monitor 400 women per year can be randomised (200 in the CTG + FBS arm and 200
in the CTG + ST-analysis arm). To be conservative we assume that per monitor 250 women
will be randomised.
To recruit the required 2400 women 11 STAN-monitors will be needed. The participating
centres have in total 14 monitors (UMCU 3 monitors, VUMC 5 monitors, AZM 1 monitor, MMC
1 monitor, OLVG 1 monitor, Diakonessenhuis 1 monitor, St Antonius Hospital 1 monitor,
TweeSteden hospital 1 monitor and Jeroen Bosch Medicentrum 1 monitor) who will be able to
recruit 480 women per monitor in two years. The required number of 2400 women can be
recruited. We refer to the letters of intention to participate in this study. See appendix D for
detailed patient inflow.
Data-analysis and presentation/synthesis
The analysis will be done by intention to treat. The experimental and standard policy will be
compared. Relative risks and 95 % confidence intervals will be calculated for the relevant
outcome measures. The analysis will be stratified for centre and parity (no previous vaginal
deliveries versus 1 or more previous vaginal deliveries).
Moreover, for each of the two strategies (CTG+ST-analysis or CTG+FBS), accuracy can be
determined with the umbilical cord pH and blood gasses as reference testing. Fetal
monitoring is performed to detect fetal hypoxia, which is an indication for instrumental
delivery. The primary aim is not to miss cases of fetal hypoxia (false negatives) as they may
lead to neonatal complications, but on the other hand also avoid unnecessary instrumental
deliveries (false positives) as they may lead to maternal as well as neonatal morbidity.
Economic evaluation
General considerations
The aim of the economic evaluation is to compare the optimality of two intrapartum diagnostic
strategies in terms of costs and health effects: a. CTG+ST-analysis (experimental strategy),
versus b. CTG+FBS (reference strategy), in singleton pregnant women with a gestational age
of at least 36 weeks for whom intrapartum fetal monitoring is indicated.
8
Generally, the CTG+ST is preferred to conventional CTG+FBS if the incremental health
effects of CTG+ST compared to CTG+FBS outweigh the incremental costs of the
experimental strategy compared to CTG+FBS. Specifically, data on diagnostic accuray of the
strategies CTG+ST-analysis and CTG+FBS (pH in umbilical artery as gold standard), as well
as data on neonatal outcome and costs of the true positive (TP), true negative (TN), false
positive (FP) and false negative (FN) subgroups allow a comparison of costs and health
effects of the experimental diagnostic strategy (CTG+ST) versus CTG+FBS.
Given the superiority design of the clinical study, the economic evaluation is primarily
designed as a costs-effectiveness analysis (CEA): the optimal strategy is the one with the
most favourable trade-off between avoided adverse neonatal outcome (fetal
distress/metabolic acidosis) and cost differences.
For each of the diagnostic strategies, costs and outcomes are analysed according to
intention- to-treat and described with appropriate statistical measures/tests. The sensitivity of
costs and health outcomes for various model parameters is tested by sensitivity analysis and
sampling techniques and visualised in ICER-graphs and acceptability curves. Scenarios for
relevant subgroups are added.
If differences in diagnostic accuracy imply differences in poor neonatal outcome and/or
caesarean section rates, a long-term analysis is performed using a decision analytic
approach. Discounting is applied only if the time horizon of analysis exceeds 12 months.
Cost analysis
The process of care is distinguished into two cost stages (delivery/childbirth stage, postnatal
stage) and three cost categories (direct medical costs [all costs in the health care sector],
direct non-medical costs [costs outside the health care sector that are affected by health
status or health care], and indirect costs [productivity costs, costs of sick leave]). For each
stage and each cost category, costs are measured as the volumes of resources used
multiplied with appropriate valuations (e.g. cost-per-unit estimates, reimbursement fees,
national reference prices).
Cost volumes in the childbirth stage consists of direct medical costs (all interventions and
types of maternal and fetal monitoring during childbirth, e.g. CTG, FBS, ‘rescue’ FBS, STanalysis, lab tests, care/costs associated with intrapartum complications; type of delivery) and
includes the costs of training (education and interpretation associated with ST-analysis and
learning). Direct non-medical and indirect costs in that stage may relate to the women’s
partners and families.
Cost volumes in the postnatal stage consist of maternal care (hospitalisation) and neonatal
care (admission to NICU/neonatalogy ward, outpatient vists) and possibly primary care after
discharge. If neonatal health at birth or at discharge is suboptimal, additional direct medical,
direct non-medical and/or indirect costs may occur. Hence for these infants, resource use of
infants and/or parents is measured during 6 months after childbirth.
Volumes of health care resource use are recorded prospectively alongside the clinical study
in all participating centres as part of the CRF. Resource use outside hospitals is recorded by
means of questionnaires or interviews. Valuations of direct medical resources are estimated
as cost per unit estimates comprising ‘true’ economic costs, i.e. including shares of fixed
costs and hospital overheads. Cost per unit is estimated for at least one teaching and one
non-teaching hospital. An analysis based on reimbursement fees/DBCs is added. Direct
medical volumes outside the hospital and direct non-medical volumes are valued using
national reference prices (28). Indirect costs are quantified according to the friction cost
method. Study specific costs are excluded from analysis.
Patient outcome analysis
Patient outcome in this study comprises the health effects that accrue to pregnant
women/mothers, neonates/infants, as well as women’s/parent’s preferences for the diagnostic
strategies.
Expectedly, CTG+ST compared to CTG+FBS is thought to reduce the false positive and false
negative rates and thereby to reduce the rate of metabolic acidosis and the rate of
instrumental deliveries, the latter reducing the unfavourable maternal and neonatal health
consequences (maternal and neonatal morbdity).
Neonatal outcome is quantified as presence/absence of metabolic acidosis (see primary
outcome section for exact definition). If neonatal health at birth or at discharge is
compromised, postnatal follow-up of infants at 6 and 12 months will take place.
9
Short-term maternal morbidity is measured as the rate of mild and severe complications
during childbirth and in the postnatal stage; and the type of delivery (instrumental delivery/CS)
during the childbirth stage.
A study of women’s/parent’s preferences for each of the diagnostic strategies using trade-off
techniques is added, as well as a study on the relative weight of maternal health and neonatal
outcome in preferences and trade-offs. These will be studied as part of the HTA-Methodology
study “When outcome is a balance”.
Systematic review
Search terms:
-population:
-intervention:
-Comparison/control:
-Outcome:
labour, fetal ECG, ST-analysis, CTG, FBS, Outcome
women in labour
ST-analysis, fetal ECG
cardiotocography eventually with FBS
neonatal outcome: metabolic acidosis, encephalopathy
maternal outcome: instrumental delivery rate
-methodological filters: human study, randomised controlled trial or observational
study using STAN-monitor (type 8801 or S21)
Databases used and number of manuscripts retrieved
Medline and Cochrane library (29).
Seven manuscripts retrieved in which the current method of ST-analysis with the STANmonitor was used. (2 RCT, 1 follow-up study and 4 observational studies) (12-14,18, 30-32).
Selection procedure, validity assessment
In fact this systematic review was already performed by JP Neilson in the Cochrane Library
(29). This meta-analysis dates from February 2003 and includes two RCT’s based on STanalysis and 1 RCT based on the PR-interval. The latter one is excluded in our review. The
development of ST-analysis has a long history, with the first clinical observation in 1979.
Thereafter followed years of technical developments leading up to a model for automatic ST
waveform assessment. First, the STAN 8801-monitor was used in the Plymouth RCT
published in 1994 (12). The second model, STANS21-monitor was used in the observational
studies and the Swedish RCT and is the model available at this moment (13-14,18,30-32) We
only included the studies with the STAN 8801-monitor and STANS21-monitor, because
these used automatic assessment of the ST-segment, what is used in the proposed study.
Results (primary outcome parameter/secondary outcome parameter/economic evaluation)
There are two randomised trials (Plymouth RCT and Swedish RCT) comparing CTG only with
CTG + ST analysis, in total including 7400 women (12,13). FBS was performed at discretion
of the doctor in both trials. The use of ST-waveform analysis was associated with fewer
babies with severe metabolic acidosis (cord pH less than 7.05 and base deficit greater than
12 mmol/l) (relative risk (RR) 0.44, 95 % confidence interval (CI) 0.26-0.75, data from 6672
babies). This was achieved along with fewer fetal scalp samples during labour (RR 0.86, 95
% CI 0.76-0.97) and fewer operative deliveries (RR 0.89, 95 % CI 0.82-0.97). A follow-up
study of the Swedish RCT showed a significant reduction of babies with encephalopathy from
0.33 (8/2447) in the cardiotocography-only group to 0.04 % (1/2519) in the cardiotocography
+ ST group (14).
The Nordic observational study describes 574 cases (30). The cases were managed on the
basis of CTG information and FBS, although ST-information was available. All fifteen cases of
intrapartum hypoxia (metabolic acidosis or neuromuscular neonatal symptoms) were
identified by ST-analysis. This means a sensitivity of 100 %. The specificity was 95 %. A total
of 47 FBS were taken from 36 fetuses. Four of these had a pH < 7.20, and all these cases
displayed ST-changes before the sampling.
Our own observational study (described in more detail above, section preliminary studies by
applicants of this proposal) includes 637 women (18). Conclusion of the study was that ST
changes were present in all five cases with severe metabolic acidosis (umbilical artery pH <
7.00) and in 46 % of cases with mild metabolic acidosis (pH between 7.00 and 7.05).
10
Furthermore, CTG + ST-analysis was more specific in detecting fetal academia than CTG
alone.
The study of Dervaitis describes 143 women, managed on the basis of CTG information and
blinded for the ST-information (31). Afterwards, CTG was combined with the ST-information
and when applying the STAN clinical guidelines they found a sensitivity of 43 %, specificity of
74 %, negative predictive value of 96 % and a positive predictive value of 8 % for metabolic
acidosis. However metabolic acidosis was defined as an umbilical cord artery pH < 7.15 and
base deficit > 12 mmol/l and no neonates with a metabolic acidosis as defined in the other
studies and our proposal (pH below 7.05 with base deficit more than 12 mmol/l) was born.
Luttkus evaluated 911 cases (part of the EU multi centre study) where a scalp pH was
obtained, including 53 cases with cord artery academia (pH < 7.06) (32). Forty-three fetuses
were identified by CTG + ST as being in need for intervention 31 (25-46) minutes before
delivery. In five, no indications were given and in another five there were inadequate data.
They conclude that cardiotocography plus ST-analysis provides accurate information about
intrapartum hypoxia similar to that obtained by scalp pH.
There are no data about economic evaluation.
Summary and Conclusion
The findings of the two RCT’s support the use of fetal ST-analysis when a decision has been
made to undertake continuous fetal heart rate monitoring during labour (12,13). Both rates of
metabolic acidosis and instrumental deliveries can be lowered using CTG + ST-analysis
instead of CTG alone. This is underlined by three of the four observational studies (18,31,32)
The only study showing a poor positive predictive and low sensitivity used another definition
of metabolic acidosis and did not include neonates with metabolic acidosis as defined for this
proposal (30). However, there are no data about using ST-analysis without fetal blood
sampling and the cost-effectiveness of ST-analysis.
Time schedule
Month 1-4: run-in period for the study set-up
Month 5-30: inclusion of women
Month 31-36: data analysis and reporting
11
Record of research achievement
Drs. A.Kwee is involved in research in obstetrics, with a focus on fetal monitoring during
labour and instrumental delivery rates and complications. She has participated in a
multicentre project, supported by a EU grant, based on the Centre of Excellence structure, to
implement the STAN-methodology in the UMC Utrecht (September 2000). A paper on the use
of the STAN has recently been published. In 2005 she will finish her thesis on the abovementioned subjects.
Prof.Dr G.H.A. Visser has a longstanding experience with fetal monitoring and is one of the
editors of the Dutch book on fetal monitoring. Recently he and his group have tested another
new new monitoring technique during labour (pulsoxymetry), which appeared not ready for
implementation into daily clinical practice. He was also involved in the above mentioned EUstudy regarding implementation of the ST-analysis.
Dr K.G.M. Moons has a vast experience in clinical epidemiology. His research comprised
both theoretical and applied (empirical) research, in close collaboration with national and
international universities and hospitals. Recently, he has obtained several
ZONMW/VAZ/Ontwikkelingsgeneeskunde research grants, including a personal VIDI-grant to
study advanced methods for diagnostic evaluations. Furthermore, he, for example, conducted
studies on the cost–effectiveness of routine diagnostic management in children with neck
stiffness and with fever without apparent focus (OG-97-041), on methods for design and
analysis of diagnostic research (NWO 904-66-112), and on defining an optimal strategy for
diagnosis of heart failure (NWO 945-02-014).
Dr B.W.J. Mol (clinical epidemiologist and gynaecologist) has been involved in many projects
in the field of Obstetrics and Gynaecology, and is (co-) author of >100 international
publications. His thesis, which focussed on the evaluation of diagnostic and prognostic tests
in subfertility, was awarded with the Jan Swammerdam prize. Over the last three years, he
has supervised three doctorates on the evaluation of abnormal vaginal bleeding, diagnosis
and treatment of fetal lung maturity, and treatment of dysfunctional uterine bleeding,
respectively.
In 2002, he has initiated the Dutch OFO-project, a study that aims to evaluate the
effectiveness and cost-effectiveness of the basic fertility work-up. In this study, which is
supported by ZON-MW, about 40 fertility clinics in The Netherlands are collaborating, and the
aimed 6000 subfertile couples have been included 6 months prior to the aimed recruitment
period. A study proposal entitled: Use of probabilistic decision rules in Obstetrics and
Gynaecology was granted in the VIDI program of ZonMW. The total amount of grants
obtained exceeds € 1.000.000.
Prof. dr H.P. van Geijn did his training in Obstetrics and Gynaecology at the University of
Nijmegen, the Netherlands. Next he moved in 1978 to Columbus Ohio, USA, for a fellowship
in Maternal-Fetal Medicine at the Ohio State University (head: Prof dr FP Zuspan). In 1980
he entered the staff of Obstetrics and Gynaecology at the Vrije Universiteit Medical Center
(VUmc), Amsterdam, the Netherlands. He fulfilled since then various positions in this
department. Currently he is Head of the Department of Obstetrics and Gynaecology and
Director of the Residency Training Programme.
He is a member of the Dutch Society of Obstetrics and Gynaecology, FIGO study group
Assessment of New Technologies in Obstetrics and Gynaecology, and the Board of the
International Society ‘The Fetus as a Patient’. Earlier he has been Projectleader of European
Concerted actions on Fetal Surveillance for 10 years.
His research interests include perinatal medicine, fetal surveillance, preterm delivery and
maternal vascular diseases and stress. He has published over 160 papers in international
peer-review journals, edited two books and published a substantial number of book chapters.
As an invited speaker in international meetings he regularly addresses various aspects of the
topics Fetal Monitoring, Preterm Delivery and Maternal Diseases.
12
Publications
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Kwee A, Van der Hoorn-van den Beld CW, Veerman J, Dekkers AHS, Visser GHA.
STAN S21-monitor for fetal surveillance during labour: an observational study in 637
patients. J Mat Fet Neonat Med 2004;15:400-407.
Dekkers AHS, Kwee A, Van Wijk HPJ, Van der Hoorn-van den Beld CW, Veerman J,
Visser GHA. Occurrence of non-significant ST-changes in CTG + ECG recordings
with the STAN S21-monitor during labour. Submitted.
Luttkus AK, Noren H, Stupin JH, Blas S, Arulkumaran S, Erkkola R, Hagberg H,
Lenstrup C, Visser GHA, Yli B, Rosen KG. Fetal scalp pH and ST analysis of the
fetal ECG as adjunct to CTG. A multi-centre observational study. J Perinat Med,
2004;32:486-494.
Nijhuis JH, Essed GGM, Van Geyn HP, Visser GHA (eds). Foetale bewaking (Fetal
monitoring). Elsevier/Bunge, Maarssen, 1998. (with chapters by Visser on
antenatal and intrapartum monitoring and on fetal blood sampling)
Rijnders RPJ, Mol BWJ, Reuwer PJHM, Drogtrop AP, Vernooy MMA, Visser GHA. Is
the correlation between fetal oxygen saturation and blood pH sufficient for the use of
fetal pulse oxymetry. J Mat Fet Neon Med 2002;11:80-83.
Hecker K, Bilardo CM, Stigter RH, Ville Y, Hackeloen BJ, Kok HJ, Senat MV, Visser
GHA. Monitoring of fetuses with intrauterine growth restriction: a longitudinal study.
Ultrasound Obstet Gynecol 2001;18:564-70.
Schifrin BS, Harwell R, Rubiustein T, Visser GHA. Maternal heart rate pattern: a
confounding factor in intrapartum fetal surveillance. Pren Neon Med 2001;6:75-82.
Moons KGM, Harrell FE. Sensitivity and specificity should be deemphasized in
diagnostic accuracy studies. Acad Radiol 2003;10:670-672.
Schrecengost JE, LeGallo RD, Boyd JC, Moons KGM, Gonias SL, Rose CE, Bruns
DE. Comparison of diagnostic accuracies in outpatients and hospitalized patients of
D-dimer testing for the evaluation of suspected pulmonary embolism. Clin Chem
2003;49:1483-90.
Moons KGM, Grobbee DE. Diagnostic studies as multivariable, prediction research. J
Epidemiol Community Health 2002;56:337-8.
Kalkman CJ, Bonsel GJ, Visser K, Moen J, Grobbee DE, Moons KGM. Preoperative
prediction of severe postoperative pain. Pain 2003;105:415-423.
Moons KGM, Biesheuvel CJ, Grobbee DE. Test research versus diagnostic
research. Clin Chem 2004.
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.
Van der Meulen J, Mol BWJ, Pajkrt E, Van Lith JJM, Voorn W. Use of the disutility
ratio for the prenatal screening for Down’s syndrome. Br J Obstet Gynaecol
1999;106:108-15.
Lijmer JG, Mol BWJ, Heisterkamp S, Bonsel GJ, Prins MH, Van der Meulen J,
Bossuyt PMM. Empirical evidence of design-related bias in diagnostic studies. JAMA
1999;282:1061-6.
Mol BWJ, Lijmer JG, Van der Meulen J, Pajkrt E, Bilardo CM, Bossuyt PMM. Effect of
study design on the association between nuchal translucency measurement and
Down syndrome. Obstet Gynecol 1999;94:864-9.
Graziosi GCM, van der Steeg JW, reuwer PH, Drogtrop AP, Bruinse HW, Mol BWJ.
Economic evaluation of misoprostol oin the treatment of early pregnancy failure
compared to curettage after an expectant management. Hum Rep 2004.
Kwee A, Graziosi GCM, Schagen van Leeuwen JH, Van Venrooy FH, Bennink D,
Mol BWJ, Cohlen BJ, Visser GHA. The effect of immersion on haemodynamic and
fetal parameters in uncomplicated pregnancies of nulliparous women. Br J Obstet
Gynaecol. 2000;107:663-8.
Bakker PC, Colenbrander GJ, Verstraeten AA, Van Geijn HP. Quality of intrapartum
cardiotocography in twin deliveries. Am J Obstet Gynecol 2004;191:2114-9.
Bakker PC, Colenbrander GJ, Verstraeten AA, Van Geijn HP. The quality of
intrapartum fetal heart rate monitoring. Eur J Obstet Gynecol Reprod boil
2004;116:22-7.
Papatsonis DN, Van Geijn HP, Bleker OP, Ader HJ, Dekker GA. Hemodynamic and
13
22.
23.
24.
metabolic effects after nifedipine and ritodrine tocolysis. Int J Gynaecol Obstet
2003;82:5-10.
Mantel R, Van Geijn HP, Ververs IA, Colenbrander GJ, Kostense PJ. Automated
analysis of antepartum fetal heart rate in relation to fetal rest-activity states: a
longitudinal study of uncomplicated pregnancies using the Sonicaid System 8000. Eur
J Obstet Gynecol reprod Biol 1997;71:41-51.
Jonker FH, Van Geijn HP, Chan WW, Rausch WD, Van der Wijden GC, Taverne MA.
Characteristics of fetal heart rate changes during the expulsive stage of bovine
parturation in relation to fetal outcome. Am J Vet res 1996;57:1373-81.
Van Geijn HP. Developments in CTG analysis. Baillieres Clin Obstet Gynaecol
1996;10:185-209.
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palsy in Sweden. VIII Prevalence and origin in the birth year period 1991-94. Acta
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Parer JT, King T. Fetal Heart Rate monitoring: Is it salvageable? Am J Obstet
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Murphy KW, Johnsom P, Moorcroft J, et al. Birth asphyxia and the intrapartum
cardiotocograph. Br J Obstet Gynaecol 1990;97:470-9.
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Chawla R, Deppe G, Ahart S, Gleicher N. Hemorrhage after fetal scalp blood
sampling. Am J Obstet Gynecol 1984;149:92.
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Balfour HH, Bowe ET, James LS. Scalp abscesses following fetal blood sampling or
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Westgate J, Greene K. How well is fetal blood sampling used in clinical practice? Br J
Obstet Gynaecol 1994;101:250-1.
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Rosen KG, Dagbjartsson A, Henriksson BA, et al. The relationship between
circulating catecholamines and ST-waveform in the fetal lamb electrocardiogram
during hypoxia. Am J Obstet Gynecol 1984;149:190-5.
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Westgate JA, Bennet L, Brabyn C, et al . ST waveform changes during repeated
umbilical cord occlusions in near-term fetal sheep. Am J Obstet Gynecol
2001;184:743-51.
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Westgate J, Harris M, Curnow JSH, et al. Plymouth randomised trial of
cardiotocogram only versus ST waveform plus cardiotocogram for intrapartum
monitoring: 2400 cases. Am J Obstet Gynecol 993;169:1151-60.
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Amer-Wåhlin I, Hellsten C, Noren H, et al. Cardiotocography only verus
cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal
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Noren H, Amer-Wahlin I, Hagberg H, et al. Fetal electrocardiography in labor and
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Hökegård KH, Karlsson K, Kjellmer I, Rosen KG. ECG changes in the fetal
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Rosen KG, Dagbjartsson A, Henriksson BA, Lagercrantz H, Kjellmer I. The
relationship between circulating catecholamines and ST-waveform in the fetal
lamb electrocardiogram during hypoxia. Am J Obstet Gynecol 1984;149:19017.
Westgate JA, Bennet L, Brabyn C, Williams CE, Gunn AJ. ST waveform
changes during repeated umbilical cord occlusions in near-term fetal sheep.
Am J Obstet Gynecol 2001;184:743-51.
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patients. J Mat Fet Neonat Med,2004;15:400-7.
Landelijke Verloskundige Registratie (Dutch Perinatal Database):Prismant,2000.
Van den Berg PP. Intrapartum surveillance of human fetal oxygenation. Thesis
Nijmegen 1995.
Vandenbussche FPHA. Studies on the clinical significance of fetal blood pH. Thesis
Leiden, 1999.
Enkin M, Keirse MJN, Neilson J et al. Guide to effective care in pregnancy and
childbirth. Oxford University Press 2nd edition 1995.
FIGO. Guidelines for the use of fetal monitoring. Int J Gynaecol Obstet 1987; 25: 15967.
Rosen KG, Luzietti R. Intapartum fetal monitoring: its basis and current
developments. Prenat Neonat Med 2000;5:155-68.
Siggaard-Andersen O. An acid base chart for arterial blood with normal and
pathofhysiological reference areas. Scand J Clin Lab Invest 1971;27:239-45.
Whitehead J. The design and analysis of sequential clinical trials. revised 2 nd ed.
Chichester: Wiley:1997.
van der Tweel I, Schipper M. Sequentiele analyse in klinisch en epidemiologisch
onderzoek. Ned Tijdschr Geneesk 2002;146:2348-52.
Oostenbrink JB, Koopmanschap MA, Rutten II. Standardisation of costs: the Dutch
manual for costing in economic evaluations. Pharmacoeconomics 2002;20:443-54.
Neilson JP. fetal electrocardiogram (ECG) for fetal monitoring during labour
(Cochrane review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK, John
Wiley & Sons, Ltd.
Amer-Wahlin I, Bordahl P, Eikeland T, et al. ST analysis of the fetal
electrocardiogram during labor: Nordic observational multicenter study. J Matern
Fetal Neonatal Med 2002 Oct;12(4):260-6.
Dervaitis KL, Poole M, Schmidt G, et al. ST segment analysis of the fetal
electrocardiogram plus electronic fetal heart rate monitoring in labor and its
relationship to umbilical arterial blood gases. Am J Obstet Gynecol 2004;191:879-84.
Luttkus AK, Noren H, Stupin JH, et al. Fetal scalp pH and ST analysis of the fetal
ECG as andjunct to CTG. A multi-center, observational study. J Perinat Med
2004;32:486-94.
Bijlagen:
-Flowchart (Appendix A)
-Short protocol (Appendix B
15
STAN FLOW CHART
Vrouwen in partu  36 weken en
een medische indicatie
(N=4400)
CTG
+
MBO
CTG
+
STAN
RANDOMISATIE
Geen actie
CTG
normaal
CTG suboptimaal
CTG abnormaal
CTG (pre)terminaal
Interventie
abnormaa
l
MBO
arm
pH  7.25
pH  7.20
en
 7.25
Herhaal op
advies/discretie van de
arts
Volg
protocol
weer
Herhaal
binnen 30
minuten
STAN
arm
pH < 7.20
Interventie of
opheffen van een
oorzaak
Indien start registratie
met (sub-) of
abnormaal CTG
Uitgangs
MBO:
indien goed
Geen
significante
STevents*
Wel
significante
ST events
Interventie of
opheffen van
een oorzaak
Volg
protocol
weer
Uitdrijving:
Suboptimaal CTG: interventie bij significant event
Abnormaal CTG: interventie bij elk event
Twijfel over sub- of abnormaal: classificeer als abnormaal
*interventie overwegen (partus of MBO) bij > 60-90 min. abnormaal CTG zonder ST-events
Registratie van uitkomsten
Wijze van bevallen (bij kunstverlossing reden opgeven!), navelstrenggassen (meteen klemmen!),
Apgarscore, aantal dagen opname moeder en neonaat, neonatale follow-up indien metabole acidose.
16
Appendix B
Protocol ST-analyse versus MBO
Inclusie:
-vrouwen in partu met een éénling in hoofdligging
-zwangerschapsduur  36 + 0 weken
-indicatie voor CTG-bewaking
-gebroken vliezen of reden om de vliezen te breken
Randomisatie: MBO-arm of STAN-arm
Protocol:
-schedelectrode plaatsen
-aansluiten aan STAN® S21/S31-monitor of conventioneel CTG
-ECG-signaal controleren en indien nodig verbeteren
-CTG beoordelen volgens FIGO-criteria (zie kaartje)
CTG
Normaal
Suboptimaalabnormaal*
(pre)-terminaal
Aktie
Geen verdere interventies
MBO verrichten of foetaal ECG beoordelen
MBO
pH < 7.20
Aktie
termineren, tenzij CTG verbeterd of een oorzaak kan
worden weggenomen
MBO na 30 minuten herhalen
MBO herhalen ter beoordeling aan arts
pH  7.20 en < 7.25
pH  7.25
direkt intervenieren
MBO (in CTG + ST-arm)
- alleen in ontsluitingsfase toegestaan als:
-onvoldoende signaalkwaliteit foetaal ECG in combinatie met
suboptimaal of abnormaal CTG.
-bij aanlsuiten CTG abnormaal patroon
-bij aansluiten CTG suboptimaal patroon en twijfel over foetale conditie
-abnormaal CTG zonder ST-veranderingen, waarbij de arts geen
sectio wil verrichten, maar toch meer informatie nodig heeft over de
foetale conditie (ip na 90 minuten)
Kunstverlossing vanwege foetale nood
-significante ST-veranderingen (zie onder)
-pH < 7.20 bij MBO
-(pre-)terminaal CTG
-als de arts het nodig vindt
Post partum
-navelstrenggassen (arterieel en veneus) afnemen
-Apgarscore noteren
-CRF invullen
17
Stan® clinical guidelines; ST-changes that prompted clinical intervention
Intermediate CTG
Abnormal CTG
Episodic T/QRS-rise
(duration < 10 min)
Increase > 0,15 from baseline
Increase > 0,10 from baseline
Baseline T/QRS-rise
(duration  10 min)
Increase > 0,10 from baseline
Increase > 0,05 from baseline
Biphasic ST
(a component of the STsegment below the baseline)
Continuous >5 min or >2
episodes of coupled Biphasic
ST type 2 or 3
Continuous >2 min or >1
episode of coupled Biphasic
ST type 2 or 3
The ST log requires 20 minutes recording for automatic ST analysis to start. A
decrease in signal quality with insufficient number of T/QRS measurements requires
manual data analysis.
18