UOG Journal Club: October 2013 Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE) C. Lees, N. Marlow, B. Arabin, C. M. Bilardo, C. Brezinka, J. B. Derks, J. Duvekot, T. Frusca, A. Diemert, E. Ferrazzi, W. Ganzevoort, K. Hecher, P. Martinelli, E. Ostermayer, A. T. Papageorghiou, D. Schlembach, K. T. M. Schneider, B. Thilaganathan, T. Todros, A. van Wassenaer-Leemhuis, A. Valcamonico, G. H. A. Visser and H. Wolf Link to the free-access article: http://onlinelibrary.wiley.com/doi/10.1002/uog.13190/abstract

1. UOG Journal Club: October 2013
Perinatal morbidity and mortality in early-onset fetal growth
restriction: cohort outcomes of the trial of randomized umbilical and
fetal flow in Europe (TRUFFLE)
C. Lees, N. Marlow, B. Arabin et al.
on behalf of the TRUFFLE group.
Volume 42, Issue 4, Date: October 2013, pages 400-408.
Journal Club slides prepared by
Dr Katherine Goetzinger
(UOG Editor for Trainees)

2. Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
• There is little data available to guide decision-making for timing of
delivery in the early preterm growth-restricted fetus (FGR)
• Currently, physicians must balance the risks of prematurity,
intrauterine fetal death (IUD) and chronic fetal hypoxia to determine
timing of delivery
• Cardiotocography (CTG) and umbilical artery Doppler studies are
currently the most commonly used techniques to stratify fetal risk in
cases of FGR
• However, changes in the ductus venosus (DV) Doppler waveform
may have a stronger association with neonatal morbidity in early
preterm FGR and therefore, impact clinical decision-making

3. Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
Trial of Randomized Umbilical and Fetal Flow in
Europe (TRUFFLE)
• A European multicenter study designed to investigate the optimal
timing of delivery in preterm FGR based on DV Doppler versus CTG-
short term variability (STV)
• Primary outcome: infant development at the age of 2 years
• Long-term follow up is not yet complete; therefore randomization
allocation remains unblinded and undisclosed
• Short-term perinatal outcome data from the study cohort is available
and may be used to to guide counseling and clinical management of
pregnancies complicated by preterm FGR

4. To explore the association between obstetric
characteristics and short-term perinatal outcomes in
women with early-onset preterm fetal growth restriction
What is the length of time from diagnosis to delivery?
Which factors are important in prolonging gestation?
What is the risk of severe neonatal morbidity?
Objective
Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013

5. Inclusion Criteria
•Singleton gestations between 26+0
to 31+6
weeks
•FGR: Abdominal circumference <10th
percentile + abnormal umbilical
artery Doppler studies
•Short-term variation on CTG & DV pulsatility index (PI) <95th
percentile
Intervention
Delivery of the fetus was based on one of three randomization arms
•CTG criteria of reduced short-term variation
•Early changes in DV waveform (PI >95th
percentile)
•Late changes in DV waveform (absent or negative A-wave)
Methodology
Prospective randomized management trial
Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013

6. Primary Outcome
•Composite of fetal/postnatal death or any of the following:
• Bronchopulmonary dysplasia (BPD), grade 3/4 intraventricular
hemorrhage (IVH), periventricular leukomalacia (PVL), proven
neonatal sepsis, necrotizing enterocolitis
Analysis
• Association between demographic, clinical, and diagnostic
parameters with the composite endpoint
• Univariate and multivariate logistic regression analysis
• Interval between inclusion and delivery
• Kaplan-Meier analysis
Methodology
Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013

7. Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
Results
Eligible for study inclusion
(n=542)
Study cohort
(n=503)
Antenatal fetal death
(n=12)
Not entered into study
(n=31)
Incomplete follow up data
(n=8)
Composite outcome of death or severe morbidity
(n=157)
Neonatal death prior to
discharge
(n=27)

8. Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
26-27 wks
(n=133)
28-29 wks
(n=204)
30-31 wks
(n=166)
Total
(n=503)
Neonatal Death 12% 5% 1% 6%
BPD 27% 7% 1% 10%
Proven Sepsis 21% 18% 15% 18%
NEC with
pneumatosis
3% 2% 0% 1%
NEC with perforation 2% 3% 1% 2%
IVH Grade 3/4 5% 3% 1% 2%
PVL Grade 2/3 2% 1% 1% 1%
Intact Survival 49% 71% 82% 69%
Perinatal morbidity & mortality by
gestational age at study entry

9. Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
Perinatal morbidity & mortality by gestational age at
the Time of Delivery
Babies with the composite
outcome were more likely to:
• Be delivered earlier
294/7
vs 312/7
weeks
• Have a lower birth weight
867g vs 1079g
• Have an Apgar score <7
15% vs 8%
• Have a lower umbilical artery pH
7.23 vs 7.25

10. Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
Determinants of the composite outcome of
perinatal death or severe morbidity
Variable
OR
(95% CI)
Gestational hypertensive morbidity
at study entry
1.70
(1.11-2.62)
Gestational age at study entry
(per week gestation)
0.80
(0.65-0.99)
Estimated fetal weight at study entry
(per 100 grams)
0.84
(0.72-0.99)

11. Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
Interval from study entry to delivery
Women with gestational
hypertensive morbidity at study
entry had a significantly shorter
median interval from inclusion to
delivery
5 days (0.5-49)
vs.
13 days (0.5-88)
This duration was associated
with the severity of the
hypertensive condition

12. Conclusions
• Early-onset preterm FGR is associated with a low rate of perinatal
mortality as well as a low rate of severe short-term morbidity in survivors
• These findings may reflect improvement in both neonatal care and
antenatal monitoring in contemporary practice
• Maternal hypertension shortens the interval from diagnosis to delivery
and is a major determinant of adverse neonatal outcome
• This highlights the importance of close monitoring of maternal blood
pressure and proteinuria once an initial diagnosis of FGR is made
• Data from this study can be used for counseling on short-term outcomes
both at the time of antenatal diagnosis of FGR and at the time of delivery
Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013

13. • Prospective data collection
from the time of diagnosis
• Low loss to follow up rate
• Standardized antenatal
surveillance and delivery
strategies
• Definition of “genuine” FGR
incorporating both fetal size
and evidence of feto-placental
impairment
Strengths
Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
• Outcomes reported for the
entire cohort rather than for
each intervention arm
• Use of primary composite
outcome
• Short-term outcomes only
• Extremely high rate of
Cesarean delivery
• Generalizability
Limitations

14. Discussion Points
Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:
Cohort Outcomes of TRUFFLE
Lees et al., UOG 2013
• What is the appropriate antenatal surveillance strategy in early-onset preterm
FGR?
• What is the optimal trigger for delivery in these patients?
• How might have the results of this study changed if the reporting of short-
term outcomes was based on randomization arm rather than the entire
cohort?
• Considering the extremely high Cesarean delivery rate in this study, what is
the optimal mode of delivery in early-onset preterm FGR? Does gestational
age alter mode of delivery?
• Can results from this study be generalized to FGR diagnosed at or after 32
weeks?
• Will results from this study change your counseling of patients affected by
early-onset preterm FGR?