Disproportionate Intrauterine Growth Intervention Trial At Term: DIGITAT
BMC Pregnancy and Childbirth
Disproportionate Intrauterine Growth Intervention Trial At Term: DIGITAT
Kim E Boers 12
Denise Bijlenga 11
Ben WJ Mol 9
Saskia LeCessie 17
Erwin Birnie 16
Marielle G van Pampus 15
Rob H Stigter 14
Kitty WM Bloemenkamp 12
Claudia A van Meir 19
Joris AM van der Post 18
Dick J Bekedam 13
Lucy SM Ribbert 7
Addie P Drogtrop 8
Paulien CM van
der Salm 5
Anjoke JM Huisjes 6
Christine Willekes 3
Frans JME Roumen 4
Hubertina CJ Scheepers 1
Karin de Boer 2
Johannes J Duvekot 0
Jim G Thornton 10
Sicco A Scherjon 12
0 Department of Obstetrics and Gynaecology, Erasmus Medical Center Rotterdam , The Netherlands
1 University Medical Center St. Radboud Nijmegen , The Netherlands
2 Rijnstate Hospital Arnhem , The Netherlands
3 Department of Obstetrics and Gynaecology, University Hospital Maastricht , The Netherlands
4 Department of Obstetrics and Gynaecology, Atrium Medical Center Heerlen , The Netherlands
5 Department of Obstetrics and Gynaecology, Meander Medical Center Amersfoort , The Netherlands
6 Department of Obstetrics and Gynaecology, Gelre Hospital Apeldoorn , The Netherlands
7 Department of Obstetrics and Gynaecology, St. Antonius Hospital Nieuwegein , The Netherlands
8 Department of Obstetrics and Gynaecology, TweeSteden Hospital Tilburg , The Netherlands
9 Department of Obstetrics and Gynaecology, Maxima Medical Center Veldhoven , The Netherlands
10 Department of Obstetrics and Gynaecology and Child Health, University of Nottingham, Nottingham City Hospital , UK
11 Department of Social Medicine, Academic Medical Center Amsterdam , The Netherlands
12 Department of Obstetrics and Gynaecology, Leiden University Medical Center , The Netherlands
13 Department of Obstetrics and Gynaecology, OLVG Amsterdam , The Netherlands
14 Department of Obstetrics and Gynaecology, Deventer Hospital , The Netherlands
15 Department of Obstetrics and Gynaecology, University Medical Center Groningen , The Netherlands
16 Department of Public Health Economy, Erasmus Medical Center Rotterdam , The Netherlands
17 Department of Medical Statistics and Bio-informatics, Leiden University Medical Center , Tthe Netherlands
18 Department of Obstetrics and Gynaecology, Academic Medical Center Amsterdam , The Netherlands
19 Department of Obstetrics and Gynaecology, Groene Hart Hospital Gouda , The Netherlands
Background: Around 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality
of life for induction of labour versus expectant management in women with a suspected IUGR fetus
Methods/design: The proposed trial is a multi-centre randomised study in pregnant women who
are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and
41+0 weeks. After informed consent women will be randomly allocated to either induction of
labour or expectant management with maternal and fetal monitoring. Randomisation will be
webbased. The primary outcome measure will be a composite neonatal morbidity and mortality.
Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs.
Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as
assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages
Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference
study will also be performed in the same study population. Health technology assessment with an
economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth
Intervention Trial At Term). The study aims to include 325 patients per arm.
Discussion: This trial will provide evidence for which strategy is superior in terms of neonatal and
maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first
randomised trial for IUGR at term.
Trial registration: Dutch Trial Register and ISRCTN-Register: ISRCTN10363217.
Around 80% of intrauterine growth restricted (IUGR)
infants are born at term . When pregnancy is
complicated by IUGR, there is, whether term or preterm, a clear
association with an increase in neonatal mortality and
neonatal morbidity (short and long term) [2-4]. The long
term morbidity ranges from behavioral problems and
minor developmental delay to spastic cerebral palsy
. However, not all studies, especially after excluding
congenital anomalies, confirm these findings .
Besides fetal asphyxia, meconium aspiration, fetal heart
rate abnormalities and low Apgar score, also more
admittances to and longer stays at neonatal intensive care units
are reported. This might partly be related to a higher
prevalence of hypoglycaemia, neonatal sepsis, hypothermia
and haematological problems as thrombocytopenia and
polycythemia in these neonates [12-14].
When a fetus is small for gestational age (SGA), defined
on the basis of a birth weight below the 10th centile, there
is the concern that the fetus might be afflicted by IUGR
. As SGA is defined on the basis of an arbitrary chosen
cutoff birth weight centile, not all infants falling below the
10th centile are abnormally small because of growth
restriction. Many neonates with a birth weight below the
10th centile are representing the normal spectrum of fetal
growth . Variation in birth weight is related to many
factors as maternal height, weight, parity and fetal gender,
but also ethnicity . For that reason optimal growth for
any fetus should be related to the fetus' own individual
optimal growth curve [17-19]. Intrauterine growth
restriction has to be defined on further knowledge such as
Doppler abnormalities as seen in placental perfusion,
eventually in combination with abnormalities in cerebral
perfusion [20,21] and possibly also by neonatal
measurements as the Ponderal Index [22,23].
A reduction of fetal growth is exponentially associated
with a higher perinatal mortality  and morbidity
[25,26]. Doppler umbilical artery studies have shown that
absence of end diastolic velocities, indicative of IUGR
based on severe placental insufficiency is associated with
a higher rate of caesarean deliveries and an increased
incidence of perinatal and neonatal mortality [27-30].
However, a normal umbilical artery Doppler study at term
gestation might be falsely reassuring, while a normal
cerebral artery study might identify the fetus not likely
having a major adverse outcome .
Most of the growth restricted children experience an
accelerated growth, especially of the head circumference,
during the first 6 months after birth . However, this
upward centile crossing or 'catch up growth' is not
complete, even at the age of seven years . Moreover head
circumference seems to correlate with cognitive outcome
Long-term neurological and cognitive development of the
IUGR infant at term have been studied extensively. The
Ponderal Index among IUGR infants, but also among
infants with a normal birth weight, is an independent
predictor of neonatal morbidity: the lower the Ponderal
Index the higher morbidity . Learning difficulties,
defects in speech and mild neurological deficits and
behavioral problems have been reported to occur more in
term neonates born SGA [35,36]. At school ages (78
years) temperamental differences and differences in play
behavior are apparent , most probably contributing to
increased rate of school failure found in IUGR infants.
Long-term morbidity might be resulting from subtle
nutritional insults to the brain in utero. Although the
brain growth spurt, being the most vulnerable period of
the human brain, spans a broad period between mid
pregnancy and 6 months of postnatal age [38,39], it is shown
that growth failure occurring around term shows a strong
association with cognitive disturbances as a poorer mental
and psychomotor development at two years of age .
However, not all studies, even at preschool age show this
trend of increased problems in growth restricted infants
[41,42]. Besides neurodevelopmental consequences it is
now also clear that children who were undernourished
during pregnancy (e.g. born with a birth weight more than
2 SD below the mean birth weight) and especially in combination having had a compensatory growth trajectory during childhood have an increased risk in later life for diabetes, hypertension and cardiovascular diseases .
Given the data from studies concerning the effect of
under-nutrition on the brain and the effects on long-term
cognitive and behavioral outcome, evaluation of the
possible clinical benefit of early induction of delivery,
preempting a detrimental effect of chronic under nutrition
on the fetal brain intervention, is important. By such an
intervention it might be possible to start earlier with a
more optimal feeding, compensating for the poor
intrauterine environment. Induction of labor is very often
common practice in cases of suspected IUGR [44,45]. In
the Netherlands at 33 up to 36 weeks of gestation, 63% of
IUGR pregnancies were induced, whereas from 37 weeks
onwards this percentage is 23%; more than double the
percentage in non-IUGR pregnancies. In a Dutch obstetric
cohort of 14.294 primigravid women with IUGR
pregnancies, 29% of these pregnancies were induced . In these
pregnancies complicated by IUGR, induction of labour
was associated with an increased risk of instrumental
deliveries and emergency caesarean section, but no
difference in neonatal outcome immediately after birth was
At present, there is no uniformity on the management of
women with IUGR at term. Although there is no doubt
that the intra-uterine growth retardated fetus should be
considered as high risk, and should be monitored, there is
no consensus on which diagnostic methods to evaluate
fetal condition and subsequent intervention is best. It is
unclear whether in this situation either induction of
labour or expectant management is beneficial for the
mother and her baby, since evidence on the subject is
For preterm pregnancies complicated by intra-uterine
growth retardation, an international randomised clinical
trial recently showed that expectant management had
little benefit over early delivery with respect to short term
neonatal outcome . However, results of this trial
cannot be extrapolated to the situation at term.
The lack of consensus on the subject in the Netherlands is
demonstrated by the fact that in 2002 in women with a
SGA child, labour was induced in 32% of these women,
whereas labour started spontaneously in 56% of these
women, the remaining 11% had an elective caesarean
section. These data are based on actual birth weight, and the
clinical situation is even more complicated by the fact that
the antenatal diagnosis of a SGA child is often difficult to
make and easily missed in clinical practice.
In view of this clinical dilemma, we propose a
randomised clinical trial in which induction of labour is
compared with expectant monitoring in women with a
suspected IUGR child at term. We will compare maternal
outcome, neonatal outcome and maternal quality of life,
as well as costs. Moreover, we will collect, in both
randomisation arms, data of the diagnostic tests used in fetal
surveillance, i.e. fetal heart rate pattern, sonographic
measurement of the amniotic fluid index and Doppler
measurement of the umbilical artery and the fetal medial
cerebral artery in women.
This trial is embedded in the Dutch Obstetric
Consortium, a collaboration of obstetric hospitals in the
Netherlands. Approximately 40 hospitals, including all 10
university hospitals, teaching hospitals and district
hospitals will participate in this trial.
All women with a singleton pregnancy, with a child in
cephalic presentation, with suspicion of IUGR (Fetal
Abdominal Circumference < 10th centile, Estimated Fetal
Weight < 10th percentile as defined by local protocols), or
decreased relative growth though still > 10th centile, e.a.
from 70th centile to 40th centile) are eligible. Gestational
age should be between 36+0 weeks and 41+0 weeks.
Women with a history of caesarean section, serious
congenital defects, ruptured membranes, renal diseases,
diabetes mellitus, or positive HIV serology will be excluded.
Procedures, recruitment, randomisation and collection of
All women with a singleton pregnancy who present at one
of the participating clinics will be referred to an
obstetrician or a specifically appointed research nurse/midwife
for counselling. Eligible women receive participant
information. After written consent, they are randomised by
means of a web-based application. Stratification will be
applied for previous vaginal birth (nullipara versus
multipara) and for centre. Randomisation will be in a 1:1 ratio
for induction of labour or expectant management.
Patients that withhold consent for randomisation are
asked permission for data collection on pregnancy
outcome. Participation to the quality of life study and
longterm follow up (Child Behavioural Check Lists-CBCL and
Ages and Stages Questionnaire-ASQ) is asked separately.
Baseline demographic, past obstetric and medical
histories will be recorded for all women. Cervical length will be
measured at the time of randomisation. The quality of life
questionnaires are filled out before randomization, after
randomization, 6 weeks postpartum and 6 months
postpartum. The questionnaires contain the Hospital Anxiety
and Depression Scale (HADS), EuroQoL 5D3L, Short
Form (SF-36), Symptom Check List (SCL-90), and
questions on background characteristics, intervention
preparedness, risk perception and experience with the current
When randomised to the induction arm, induction of
labor must start within 48 hours after randomisation.
Induction of labor can be proceded according to local
protocol (among other things cervical ripening with
prostaglandin-gel or tablets or with amniotomy, with or without
the use of oxytocin). When allocated to the expectant
management group patients will not be induced unless
the fetal or maternal condition deteriorates and this is for
the attending obstetrician a reason for induction. The
patients will be observed, e.g. with fetal and maternal
monitoring according to local practice, until labour starts
spontaneously. However, monitoring must at least
include measurement of the umbilical artery Doppler
waveform, fetal heart rate tracing, blood pressure and
urine analysis for albuminuria weekly. Doppler studies of
the medial cerebral artery are optional. Reasons for
interventions and time interval between randomisation and
labour will be collected.
Follow up of women and infants
All details of delivery, maternal and fetal assessments and
admittance during pregnancy are recorded in the case
record form that is accessible at the website. In case of
admittance of the child to the neonatal intensive care unit,
details of this admittance are also recorded.
Long-term follow up of children will be done by recording
growth after birth as measured at the local infant follow
The primary outcome measure will be a bad composite
neonatal outcome. Adverse neonatal outcome will be
defined as death before hospital discharge, a 5-minute
Apgar score < 7, an umbilical artery pH < 7.05 or
admission to the neonatal intensive care. Secondary outcome
measures are mode of delivery and time until delivery,
length of admittance at the neonatal intensive care,
maternal morbidity, hospitalisation of the mother for fetal and
maternal surveillance, quality of life, and costs. In the
present proposal, no funding is asked for long term
follow-up of the child, yet. However, if additional funding
can be obtained children's behavioural-, and neuro
development will assessed by administering with a postal
enquiry the Child Behaviour Checklist-CBCL and Ages
and Stages Questionnaire- ASQ by their parents after 2
Sample size calculations
The study is designed as an equivalence study, whereby
both treatments will have the same incidence of the
primary outcome measure of combined bad neonatal
outcome. This incidence is assumed to be 6% . The null
hypothesis is that both treatments will not be equivalent.
To detect equivalence with a power of 80% a sample size
in both groups of 325 will be needed (PASS SOFTWARE).
The margin of equivalence, given in terms of the
difference, extends from -5.5 % to +5.5 %. The actual difference
is 0 %. The calculations assume that two, one-sided Z tests
are used. The significance level of the test is 0.05.
Data will initially be analysed according to the intention
to treat method. The main outcome variable, 'bad
neonatal outcome', will be assessed by calculating rates in the
two groups, relative risks and 95% confidence intervals as
well as numbers needed to treat.
Time to delivery will be evaluated by Kaplan-Meier
estimates, with account for differing durations of gestation at
entry, and will be tested with the log rank test. The other
secondary outcome measures will be approached
similarly to the primary outcome measure. The analysis will be
stratified for parity and centre.
will be able to evaluate which pregnancies are at risk for a
poor neonatal outcome.
Non response and inclusion bias
As non-response for follow up is overrepresented in
certain outcome-related risk categories such as in non-native
mothers, mothers with lower educational level and in
mothers with boys, statistical methods that use
imputation of missing data have to be applied . To prevent
inclusion bias all patients who were asked but decline
randomisation, will be asked for permission to collect data
on pregnancy outcome and further follow up according to
the same schedule as the randomised patients.
The aim of the economic evaluation is to compare
optimality, in terms of costs and health effects, of both
strategies. As the clinical study is based on equivalence design
we hypothesize that there will be no relevant difference
between maternal and neonatal outcome in the two
strategies. The economic evaluation will be in the form of a
cost-effectiveness analysis (CEA), in which the optimal
strategy is defined as the strategy with the largest health
gain at the smallest costs.
This study has been approved by the ethics committee of
the Leiden University Medical Centre (Ref. No. P04.210).
There is uncertainty about the management of IUGR at
term, whether to leave the child in utero until
spontaneous labour starts, or to prevent undernutrition by
prolonged pregnancy in a poor intra-uterine environment by
inducing labour. This latter treatment modality will most
probably be at the cost of an increase in instrumental
deliveries . As optimal management of a pregnancy at
term suspected to be complicated by IUGR remains
unclear, it is a challenge to develop criteria for inducing
delivery. An increase in fetal surveillance in these
pregnancies (with normal umbilical artery studies) is thought to
be associated with more inductions of labour and a
shortening of gestational age . Neonatal morbidity (and
mortality) is low in term SGA neonates , nevertheless
these neonates cannot be considered just "healthy small
Although our primary aim is to study pregnancies
complicated by IUGR, the inclusion criteria are obviously based
on a suspicion of a SGA child, as we include women with
a fetus with a Fetal Abdominal Circumference < 10th
centile or an Estimated Fetal Weight < 10th centile. By
patient's characteristics, such as ethnicity, maternal and
paternal length as well as tests results as the amount of
amniotic fluid or the Doppler of the arteria umblicalis, we
In summary, at the present, there is controversy as to
which strategy is the best when IUGR at term is suspected.
Whether to induce labour or to await spontaneous labour
under strict fetal and maternal monitoring remains
debatable because of a lack of evidence. Patients' management
partly depends on the attending doctor and on local
protocols. To resolve these issues, we will compare both
strategies in the multi centre randomised trial DIGITAT. In a
pilot study carried out in one of the participating
hospitals, we examined the feasibility of the DIGITAT-trial.
Preliminary data from this small pilot show that the interval
between randomisation and labour was 2 weeks shorter
and birth-weight was 100 grams less in the pregnancies
that were directly terminated by induction . The
results of the present DIGITAT-trial are expected in 2009.
IUGR Intrauterine growth retardation
SGA Small for gestational age
CBCL Child Behavioural Check List
ASQ Ages and Stages Questionnaire
NICU Neonatal Intensive Care Unit
SS, JvdP, BWM and JGT were involved in conception and
design of the study. KEB and SS drafted the manuscript.
All authors have read and given final approval of the final
This study is funded by ZonMW grant 945-04-558.
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