A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN®) for intrapartum monitoring
BMC Pregnancy and Childbirth
A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN®) for intrapartum monitoring
Erik van Beek 0
Saskia M Bijvoet 7
Addy P Drogtrop 6
Herman P van Geijn 7
Jan MM van
Ben WJ Mol 4 9
Jan G Nijhuis 8
S Guid Oei 9
Martina M Porath 9
Robbert JP Rijnders 2
Nico WE Schuitemaker 10
Ingeborg van der Tweel 11
Gerard HA Visser 3
Christine Willekes 8
Anneke Kwee 3
0 Department of Obstetrics and Gynaecology, Sint Antonius Hospital Nieuwegein , The Netherlands
1 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht , The Netherlands
2 Department of Obstetrics and Gynaecology, Jeroen Bosch Medical Center 's Hertogenbosch , The Netherlands
3 Department of Obstetrics and Gynaecology, University Medical Center Utrecht , The Netherlands
4 Department of Obstetrics and Gynaecology, Academic Medical Center Amsterdam , The Netherlands
5 Department of Obstetrics and Gynaecology, Onze Lieve Vrouwen Gasthuis Amsterdam , The Netherlands
6 Department of Obstetrics and Gynaecology, Tweesteden Hospital Tilburg , The Netherlands
7 Department of Obstetrics and Gynaecology, VU Medical Center Amsterdam , The Netherlands
8 Department of Obstetrics and Gynaecology, Academic Medical Center Maastricht , The Netherlands
9 Department of Obstetrics and Gynaecology, Maxima Medical Center Veldhoven , The Netherlands
10 Department of Obstetrics and Gynaecology , Diakonessenhuis Utrecht , The Netherlands
11 Center for Biostatistics, Utrecht University , The Netherlands
Background: Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, 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. Methods/Design: We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options. Women in labour with a gestational age ≥ 36 weeks and an indication for CTG-monitoring can be included in the trial.
Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with
STanalysis of the fetal ECG.
The primary outcome of the study 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, neonatal outcome (Apgar
score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both
monitoring strategies across hospitals.
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 2.1 %, using a two-sided test with an alpha of 0.05 and
a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the
costeffectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied.
Discussion: This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance
of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the
performance of FBS and in which cases FBS is still needed.
Trial Registration Number: ISRCTN95732366
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 on intrapartum fetal heart
rate monitoring have shown no or little benefit on
neonatal outcome and a significant increase in operative
deliveries [4-6]. Fetal blood sampling (FBS) can be used in
addition to CTG, but requires expertise, is invasive, has to
be repeated when CTG abnormalities persist and may
cause complications [7,8]. As a consequence, it is not
widely applied . In The Netherlands, FBS is available in
only 50 % to 70 % of the hospitals.
Because changes in the ST-segment of the
electrocardiogram (ECG) are related to metabolic acidosis of the fetus,
detection of changes in this part of the fetal ECG, in
combination with CTG, is a non-invasive and promising
alternative for FBS [10,11]. A recent study in more than 600
women showed that ST-changes were present in all cases
with severe metabolic acidosis and that CTG plus
ST-analysis was more specific in detecting fetal acidemia than
CTG alone .
Two large randomised trials comparing CTG and
ST-analysis of the fetal ECG showed a decrease in metabolic
acidosis and interventions for fetal distress in favour of the
CTG plus ECG-group [13,14]. The rate of infants with
encephalopathy was also significantly lower in the CTG
plus ECG-group . However, in both trials FBS was still
frequently performed in both arms. Hence, it remains
difficult to conclude if the observed improved outcome was
indeed due to management to address metabolic acidosis
based on ST-analysis results or on FBS results.
Just before the initiation of the present study a third and
much smaller randomised trial on ST-analysis versus
conventional CTG appeared. This study showed, although
not significant, an opposite effect on the incidence of
neonatal acidemia or metabolic acidosis, compared to
previous trials . The caesarean section and vacuum outlet
rate was comparable in both groups. The only significant
difference was the incidence of FBS, which was much
lower in the ST-analysis group (7.0%) than in the CTG
group (15.6%). The results of this trial further stress the
need for subsequent research.
In this paper we describe the study protocol of a recently
started randomised trial to compare the cost-effectiveness
between conventional CTG versus ST-analysis of the fetal
ECG, in which the use of fetal blood sampling in the
STanalysis group was a priori restricted to well-defined
Rationale for ST-analysis (STAN®)
In adult cardiology, ST-analysis of ECG is performed to
assess and diagnose myocardial insufficiency. The STAN®
concept is similarly based on the association between the
ST-interval of fetal ECG and the function of the fetal
myocardium during stress. The fetal heart and brain are
equally sensitive to oxygen deficiency. As a result, the
information relating to the function of the fetal
myocardium 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
Twave to QRS-amplitude (T/QRS ratio), or a biphasic
STsegment (Figure 1). An increase in T-wave and
subsequently in T/QRS-ratio has been associated with a
catecholamine surge, activation of β-adrenoreceptors,
myocardial glycogenolysis, and metabolic acidosis
[10,11,17]. A biphasic shape of the ST-segment is related
to two situations. First, it may occur when the fetal heart
is exposed to acute hypoxic stress whereby it has had no
time to respond to hypoxia or second, when the fetal heart
has a reduced capacity to respond due to stress situations
and lack of or already utilized resources. Biphasic
STchanges of the fetal ECG have been associated with
disturbances in heart muscle function, infection or
The integrated CTG and fetal ECG monitor, i.e. the
socalled STAN®-monitor, is a device that automatically
analyses the fetal ECG through a scalp electrode applied to the
fetal head . STAN® guidelines are based on an
integrated CTG and fetal ECG interpretation. According to the
STAN® guidelines ST-changes are only thought to be of
clinical relevance if they coincide with intermediate or
abnormal CTG traces (Table 1). In case of a normal or
(pre)terminal CTG, the high sensitivity of the CTG only, is
considered sufficient to ignore abnormalities in the ECG.
In spite of the above-mentioned evidence on the potential
improvement in fetal surveillance using intrapartum
STanalysis [12-14], there is at present still a dilemma for
gynaecologists on its true clinical value (i.e. without the
use of FBS), let alone that its cost-effectiveness is known.
ST-analysis requires financial investment, not only related
to the procure of the ST-monitor (34000 Euro per
monitor), but also related to the necessity of repeated training
of labour ward personnel .
Our randomised trial aims to quantify this
cost-effectiveness of fetal monitoring with CTG plus ST-analysis of the
fetal ECG, as compared to conventional CTG plus FBS.
The primary aim of our randomised trial is to quantify
whether the incidence of metabolic acidosis is decreased
by the use of a strategy of fetal monitoring with CTG plus
ST-analysis of the fetal ECG, compared to usual care
consisting of CTG plus FBS, when indicated.
Secondary aims are to quantify the cost-effectiveness of
CTG in combination with non-invasive ST-analysis of the
fetal ECG for fetal monitoring during labour as compared
to usual care and the differences in incidence of
operational deliveries and performance of FBS across both
EFxigaumrpele1of a STAN-registration with an abnormal CTG and two significant ST-events
Example of a STAN-registration with an abnormal CTG and two significant ST-events. (1 cm/minute).
Baseline heart frequency
* Combination of several intermediary observations will result in an abnormal CTG.
Uncomplicated variable decelerations with a duration of
< 60 sec and a beat loss of < 60 beats/min
Uncomplicated variable decelerations with a duration of
< 60 sec and a beat loss of > 60 beats/min
The trial is a pragmatic randomised diagnostic study. We
have choosen a randomised design because ST-analysis of
the fetal ECG is an example of a new test that might
provide better or other information, potentially leading to
other treatment choices than the existing reference (CTG
plus FBS). In such a situation there is an indication to do
a randomised study rather than a conventional accuracy
study in which ST-analysis is compared to CTG plus FBS,
to quantify its value on patient outcome [20-22]. A design
with randomisation at the moment that the CTG group
and the ST-analysis group provide discordant test results
was not feasible, as this would require randomisation at
the moment of medical emergency .
This study is set in the Dutch Obstetric Consortium, a
collaboration of obstetric clinics in the Netherlands. The
study will be carried out in nine hospitals, including
academic hospitals and non-academic teaching hospitals
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
nonreassuring fetal heart rate.
Exclusion criteria: breech presentation, twin pregnancies,
maternal age < 18 years or absent informed consent.
Procedures, recruitment, randomisation and collection of
Eligible women will receive the patient study information
around 36 weeks of gestation, in the outpatient clinic.
Women, having their prenatal controls under supervision
of a midwife and being referred to the hospital during
labour, will be informed and asked for consent by the
attending doctor or midwife at arrival at the hospital.
After consent, women are randomised through a
computer-generated randomisation sequence. Stratification will
be applied for centre and parity (no previous vaginal
delivery versus one or more previous vaginal deliveries).
Randomisation will be 1:1 for either monitoring by CTG
plus ST-analysis or CTG plus FBS. Both strategies will be
performed according to strict protocols (see below).
Women who decide not to participate in the study will be
asked for their reasons of refusal. They will be monitored
with CTG and, if indicated, FBS.
In each centre an independent gynaecologist will be
responsible for the centre specific data collection. Per
centre a research nurse or midwife will monitor the protocol
also via patient meetings and feedback on potential
At baseline, demographic, past obstetric and medical
history data will be recorded for all women.
Control group: CTG
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.
CTG-interpretation will be guided by the FIGO guidelines
(Table 1) . Fetal blood sampling is recommended in
case of an intermediate or abnormal CTG.
If the pH of the first FBS 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 the consecutive CTG pattern on
discretion of the attending doctor or midwife.
Intervention group: CTG and ST-analysis
In women randomised to the intervention group, a scalp
electrode will be applied to the fetal head and connected
to the STAN®-monitor. This electrode will allow both
standard fetal heart rate monitoring (CTG) as well as
STanalysis of the fetal ECG. The CTG will be classified as
normal, intermediate, abnormal or preterminal according
to the FIGO-guidelines for fetal heart rate monitoring
(Table 1) . Clinical management will be supported by
computerised ST waveform assessment and will be guided
by the STAN®-guidelines, indicating when intervention is
recommended . The ST log automatically alerts the
attending doctor or midwife if a significant ST-event
occurs. Delivery is recommended when there are
significant ST-changes unless the cause of fetal distress can be
alleviated (Table 2).
Preferably, FBS will not be performed in this group. This,
however, does not suffice in all cases. The aim is to keep
the performance of FBS as low as possible, limited to three
well-defined situations: 1) poor signal quality of the fetal
ECG in combination with an abnormal CTG; 2)
STAN®registration starts with an abnormal CTG; 3) 60 to 90
minutes of abnormal CTG recording during first stage of
labour without ST-events and the attending doctor
decides not to intervene by caesarean section. In the
second stage of labour it is advised to perform an
instrumental delivery (if possible) in case of the before mentioned
Furthermore, we will also consider the incidence of FBS in
both groups as secondary outcome.
Children who were admitted to the neonatal intensive
care or high care after delivery because of birth asphyxia or
other delivery trauma, will be checked upon at 6 months
Secondary outcome measures
Secondary outcomes are:
1. Instrumental delivery rate because of fetal distress, failure to progress or a combination of the two
2. Neonatal outcome defined as Apgar scores < 4 after 1 minute and/or < 7 after 5 minutes
3. Need for admission to neonatal medium or intensive care unit
4. Incidence of performance of FBS in both groups
5. Cost-effectiveness of both monitoring strategies in general and across hospitals.
Although in the two previous randomised trials the
incidence of metabolic acidosis decreased from 1.5 % to 0.5
% in favour of the CTG + ST-analysis group [13,14], we
assume that the incidence of metabolic acidosis in our
higher-risk population (women delivering in the hospital
with a medical indication/risk factor) is higher and
estimated on 3.5 %, as found in our preliminary study .
Based upon the numbers of the largest clinical trial with a
relative risk of 0.5 the required sample size would then
yield 2400 cases (1200 per arm), using an alpha of 0.05
(2-sided) and a power of 0.80 . However, soon after
the start of our study a third randomised clinical trial
appeared, although much smaller and non-significant,
Episodic T/QRS-rise (duration < 10 min)
Baseline T/QRS-rise (duration ≥ 10 min)
Biphasic ST (a component of the ST-segment
below the baseline)
Increase > 0.15 from baseline
Increase > 0.10 from baseline
Continuous >5 min or >2 episodes 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.
but yielding an opposite effect . A meta-analysis of the
three clinical trials showed the varying relative risks of 0.5,
0.4 and 2.4 . Hence, to be conservative we used the
meta-analysis overall relative risk of 0.6 for our power
calculation, implying a reduction of metabolic acidosis, in
favour of ST-analysis, from 3.5% to 2.1%. With an alpha
of 0.05, a two-sided test – given conflicting results in the
literature – and a power of 0.80, about 4638 women
should be randomised (2319 per arm). Accounting for
10% loss to follow-up, the study requires inclusion of
about 5100 women in order to obtain 4638 analysable
The analysis of the primary endpoint will follow the
intention to treat principle. Since this is a randomised
trial, we would anticipate minimal differences in baseline
characteristics. The relative risk with 95% confidence
interval of metabolic acidosis in the CTG plus ST-analysis
group compared to the CTG (plus FBS) group will be
calculated, accounting for the stratified randomisation by
centre and parity. Relative risks and 95% confidence
intervals will also be calculated for the dichotomous secondary
outcomes, i.e. instrumental delivery rate, neonatal
outcome, need for neonatal admission and incidence of
performance of FBS across both groups.
The following planned subgroup analyses will be
performed: analysis according to risk pregnancies such as
women with insulin dependent diabetes mellitus, fever
during delivery and start of a STAN®-registration with an
Missing data rarely occur at random. Simply excluding
subjects with missing values thus not only lead to loss of
statistical power but also to biased study results. To
decrease bias and increase statistical efficiency we will
therefore impute missing values rather than perform
complete case analysis only. This will be done using single and
multiple imputation methods [28-30].
The economic evaluation is primarily a cost-effectiveness
analysis (CEA) to find the optimal strategy as the one with
the most favourable trade-off between avoided adverse
neonatal outcome (fetal distress/metabolic acidosis) and
difference in cost.
For this purpose, the process of care is distinguished into
two cost stages (delivery/childbirth stage and postnatal
stage) and three cost categories (direct medical costs [all
costs in the health care sector, such as type of intervention
and maternal and fetal monitoring, lab tests, costs
associated with intrapartum complications, costs of training,
maternal and neonatal care in the postnatal stage], 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]).
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. Direct medical volumes outside
the hospital and direct non-medical volumes are valued
using national reference prices . Indirect costs are
quantified according to the friction cost method. Study
specific costs are excluded from analysis.
As we anticipate a reduction of metabolic acidosis with
the use of CTG plus ST-analysis compared to CTG plus
FBS, the economic analysis is planned to be a
cost-effectiveness analysis. We will use bootstrap sampling to
calculate 95% confidence intervals around the
costeffectiveness ratios. Sensitivity analysis will be used to
explore the effect of variation of several key factors.
Age at delivery (yrs)
Previous ceasarean section
Gestational age at delivery (wks)
Prolonged pregnancy (> 42 gestational wks)
Induction of labour
Meconium-stained amniotic fluid
n = 254
n = 246
Baseline obstetric characteristics of first 500 randomised
Baseline obstetric characteristics of the first 500 enrolled
patients in the study are shown in table 3.
Ethical considerations and Safety Committee
The study protocol has been approved by the Medical
Ethical Committee of the University Medical Center Utrecht,
Utrecht, The Netherlands (05/157-K). Written informed
consent will be obtained from each participating patient.
Serious Adverse Events (SAE) are defined as "metabolic
acidosis (arterial pH < 7.00 and BDecf >12 mmol/L) and
admission to a Neonatal Intensive Care Unit (NICU)" or
"an Apgar score < 7 after 5 minutes and admission to a
NICU". Given the conflicting results in the literature, all
SAE's will be reported to the Data Safety Monitoring
of an independent gynaecologist,
neonatologist, epidemiologist and a biostatistician. This
committee will consider the reported incidence of SAE's at
regular intervals to determine whether there are
significantly more serious adverse events in the STAN-group
and, if so, whether the study should be discontinued. For
this purpose the computer program PEST, version 4, will
This study is the first randomised trial to quantify the
costeffectiveness of ST-analysis of the fetal ECG during labour
and the first to achieve data about the use of ST-analysis
with fetal blood sampling performed only in well-defined
circumstances. This study aims to provide additional
evidence on the true clinical value of intrapartum ST-analysis
and also the clinical indications in which fetal blood
sampling still might be necessary in addition to ST-analysis.
CTG – cardiotocogram
ECG – electrocardiogram
FBS – fetal blood sampling
STAN – ST ANalysis
NICU – neonatal intensive care unit
The author(s) declare that they have no competing
AK, BM, GV, IT, KM, and MW were involved in conception
and design of the study. AK, KM and MW drafted the
manThis study is subsidized by ZonMW, the Dutch Organisation for Health
Research and Development (Grant number: 945-06-557).
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