Perinatal morbidity and mortality in early-onset fetal growth restriction: Cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE)

Article (PDF Available)inUltrasound in Obstetrics and Gynecology 42(4):400-8 · October 2013with215 Reads
DOI: 10.1002/uog.13190 · Source: PubMed
  • 1st C Lees
  • 47.73 · University College London
  • 41.73 · Clara Angela Foundation, Witten and Berlin, Germany
  • 38.85 · Academisch Medisch Centrum Universiteit van Amsterdam
Abstract
Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery. We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference < 10(th) percentile and umbilical artery Doppler pulsatility index > 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.
Ultrasound Obstet Gynecol 2013; 42: 400408
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13190
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
1
,N.MARLOW
2
,B.ARABIN
3
,C.M.BILARDO
4
,C.BREZINKA
5
,J.B.DERKS
6
,
J. DUVEKOT
7
, T. FRUSCA
8
,A.DIEMERT
9
, E. FERRAZZI
10
, W. GANZEVOORT
11
,
K. HECHER
9
, P. MARTINELLI
12
,E.OSTERMAYER
13
, A. T. PAPAGEORGHIOU
14
,
D. SCHLEMBACH
15
,K.T.M.SCHNEIDER
13
, B. THILAGANATHAN
14
, T. TODROS
16
,
A. VAN WASSENAER-LEEMHUIS
17
, A. VALCAMONICO
8
,G.H.A.VISSER
18
and
H. WOLF
11
, on behalf of the TRUFFLE Group#
1
Department of Obstetrics & Gynaecology, Rosie Hospital, Cambridge, UK and Department of Obstetrics and Gynecology, KU Leuven,
Belgium;
2
Department of Academic Neonatology, UCL Institute for Women’s Health, London, UK;
3
Department of Perinatology, Isala
Clinics Zwolle, Utrecht, The Netherlands;
4
Fetal Medicine Unit, Department of Obstetrics and Gynaecology, University Medical Centre
Groningen, Groningen, The Netherlands;
5
Obstetrics and Gynecology, Universit
¨
atsklinik f
¨
ur Gyn
¨
akologische Endokrinologie und
Reproduktionsmedizin, Department f
¨
ur Frauenheilkunde, Innsbruck, Austria;
6
Perinatal Center, Wilhelmina Children’s Hospital, Utrecht,
The Netherlands;
7
Division of Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam,
The Netherlands;
8
Maternal-Fetal Medicine Unit, University of Brescia, Brescia, Italy;
9
Department of Obstetrics and Fetal Medicine,
University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
10
Children’s Hospital, Buzzi, University of Milan, Milan, Italy;
11
Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands;
12
Department of Gynecology and
Obstetrics, University Federico II of Naples, Naples, Italy;
13
Section of Perinatal Medicine, Department of Obstetrics and Gynecology,
Technical University, Munich, Germany;
14
Fetal Medicine Unit, St George’s Hospital, London, UK;
15
Department of Obstetrics and
Gynecology, Medical University of Graz, Graz, Austria;
16
Department of Obstetrics & Gynecology, University of Turin, Turin, Italy;
17
Department of Neonatology, Emma Children’s Hospital Academic Medical Centre, Amsterdam, The Netherlands;
18
University Medical
Center, Division of Woman and Baby, Utrecht, The Netherlands
KEYWORDS: CTG; Doppler; ductus venosus; fetal heart; neonatal; outcome; perinatal; short-term variation
ABSTRACT
Objectives Few data exist for counseling and perinatal
management of women after an antenatal diagnosis of
early-onset fetal growth restriction. Yet, the consequences
of preterm delivery and its attendant morbidity for both
mother and baby are far reaching. The objective of this
study was to describe perinatal morbidity and mortality
following early-onset fetal growth restriction based on
time of antenatal diagnosis and delivery.
Methods We report cohort outcomes for a prospective
multicenter randomized management study of fetal
growth restriction (Trial of Randomized Umbilical and
Fetal Flow in Europe (TRUFFLE)) performed in 20
European perinatal centers between 2005 and 2010.
Women with a singleton fetus at 2632 weeks of
gestation, with abdominal circumference < 10
th
percentile
and umbilical artery Doppler pulsatility index > 95
th
Correspondence to: Dr C. Lees, Queen Charlotte’s and Chelsea Hospital, Centre for Fetal Care, Du Cane Road, London W12 0HS, UK
(e-mail: christoph.lees@imperial.nhs.uk)
#The TRUFFLE Group collaborating authors include: H. C. J. Scheepers, M. Spaanderman, S. Calvert, H. Missfelder-Lobos, J. van Eyck,
D. Oepkes, N. Fratelli, F. Prefumo, R. Napolitano, R. Chaoui, G. Maso, G. Ogge, M. Oberto, N. Mensing van Charante
Accepted: 23 July 2013
percentile, were recruited. The main outcome measure
was a composite of fetal or neonatal death or severe
morbidity: survival to discharge with severe brain injury,
bronchopulmonary dysplasia, proven neonatal sepsis or
necrotizing enterocolitis.
Results Five-hundred and three of 542 eligible women
formed the study group. Mean ± SD gestational age at
diagnosis was 29 ± 1.6 weeks and mean ± SD estimated
fetal weight was 881 ± 217 g; 12 (2.4%) babies died
in utero. Gestational age at delivery was 30.7 ± 2.3
weeks, and birth weight was 1013 ± 321 g. Overall,
81% of deliveries were indicated by fetal condition and
97% were by Cesarean section. Of 491 liveborn babies,
outcomes were available for 490 amongst whom there
were 27 (5.5%) deaths and 118 (24%) babies suffered
severe morbidity. These babies were smaller at birth
(867 ± 251 g) and born earlier (29.6 ± 2.0 weeks).
Death and severe morbidity were significantly related to
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. OR IG IN AL PA P E R
Short-term outcomes following early FGR 401
gestational age, both at study entry and delivery and also
with the presence of maternal hypertensive morbidity.
The median time to delivery was 13 days for women
without hypertension, 8 days for those with gestational
hypertension, 4 days for pre-eclampsia and 3 days for
HELLP syndrome.
Conclusions Fetal outcome in this study was better than
expected from contemporary reports: perinatal death
was uncommon (8%) and 70% survived without severe
neonatal morbidity. The intervals to delivery, death and
severe morbidity were related to the presence and severity
of maternal hypertensive conditions. Copyright 2013
ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION
The timing of delivery of a baby with early preterm fetal
growth restriction (FGR) poses the obstetrician with a
serious dilemma. To deliver early potentially exposes the
neonate to morbidity associated with immaturity, whereas
to deliver too late risks serious additional morbidity
secondary to critical fetal hypoxia with a worsening of
the fetal condition. There is little information in relation
to risk of intrauterine fetal death or neonatal prognosis
as most studies comprise small or retrospective cohorts
of babies and hence the risks of poor outcome are not
easily generalizable at the time of antenatal diagnosis of
early-onset FGR. Furthermore, those studies that describe
perinatal mortality and morbidity use obstetric and
neonatal parameters that are present immediately before
birth
13
, an obvious confounding attribute of which is
that the parameters themselves may dictate the clinical
urgency for delivery. At the time the diagnosis of early
preterm FGR is made, the gestational age at delivery and
birth weight are, of course, still unknown as the interval
between diagnosis and delivery cannot be predicted.
The technique most frequently used for fetal surveil-
lance and assessment of necessity to deliver is car-
diotocography (CTG). Assessment of the fetal heart rate,
variability and the presence of accelerations and decelera-
tions is performed visually and fetal condition is classified
semi-objectively as ‘reassuring’ or ‘not reassuring’. Com-
puterized analysis of the signal provides an objective
assessment, expressed as short-term variability (STV)
47
.
Although umbilical artery Doppler clearly identifies an
‘at-risk’ fetus, changes in the ductus venosus Doppler
waveform may have a better association with subsequent
neonatal morbidity than that based on umbilical Doppler
abnormality in early preterm FGR
2,3,8,9
.
We recruited women at very preterm gestations
to a European multicenter study on FGR, in which
management was delivery based on the results of ductus
venosus Doppler or CTG-STV monitoring according to
one of three randomized arms and the primary outcome
was infant development at the age of 2 years. When
designing the study, the Trial of Randomized Umbilical
and Fetal Flow in Europe (TRUFFLE) investigators had
detailed discussions regarding the ethical consequences
of the study and hence the three management protocols
were designed in such a way that differences in short-term
outcome between the groups were highly unlikely
10
.
To facilitate counseling and inform clinical manage-
ment, we explored the association between obstetric char-
acteristics and short-term perinatal outcomes in women
who were included in the TRUFFLE study. As long-term
follow-up is not yet complete, randomization allocation
has not been unblinded and therefore is not disclosed.
The study cohort data analysis is for short-term perinatal
outcome and therefore focuses on the questions most per-
tinent to a diagnosis of FGR. These are: how long will it
take until the baby has to be delivered, what factors are
important in prolonging gestation and what is the risk of
severe neonatal morbidity after delivery?
METHODS
Setting
This was a prospective multicenter unblinded manage-
ment trial conducted in 20 European tertiary-care centers
with a fetal medicine unit, in five countries (Austria, Ger-
many, Italy, The Netherlands and the UK). Patients were
included from 2005 to 2010, but not all hospitals started
recruiting at the same time.
Participants
Eligible participants were women over 18 years of age
capable of giving informed consent, with a singleton
pregnancy at 26 + 0to31+ 6 weeks of gestation
diagnosed with FGR. This was defined as fetal abdominal
circumference below the 10
th
percentile according to
local standards and abnormal umbilical artery Doppler
pulsatility index (PI) above the 95
th
percentile based on
local standards, irrespective of the presence of absent or
reversed end-diastolic flow. In all cases, the estimated
fetal weight was > 500 g
11
. Short-term variation after
1 h of CTG tracing had to be > 3.5 ms at 2628 weeks
and > 4 ms at 2931 weeks with ductus venosus PI
< 95
th
percentile
12
. Gestational age was assigned from
measurement of crownrump length prior to 14 weeks
or biparietal diameter between 14 + 0 and 21 + 6
weeks. Women were not eligible if there was known,
planned or impending delivery, major fetal structural
abnormality or invasive prenatal testing showing fetal
karyotype abnormality.
The intervention was delivery of the fetus according to
the criteria of the randomization group, determined by
the CTG criteria of reduced short-term variation, early
abnormalities of the ductus venosus waveform (PI > 95
th
centile) or late ductus venosus changes (absent or negative
A-wave). In all groups, delivery could be undertaken
based on a maternal indication, such as severe pre-
eclampsia, or clear CTG abnormalities, such as recurrent
late decelerations. After 32 + 0 weeks, the timing of
delivery was according to local management protocol.
For all patients, the intention was to deliver within 24 h
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 400408.
402 Lees et al.
after the decision to deliver was made with timing of
maternal steroids according to local protocols. Repeat
doses of steroids were never given.
Outcome variables
The primary outcome for this study was a compos-
ite of fetal or postnatal death (between trial entry in
utero and first discharge home from neonatal services) or
one or more of the following severe morbidities: bron-
chopulmonary dysplasia, severe cerebral germinal matrix
hemorrhage (intraventricular hemorrhage with dilation
of the lateral ventricles (Grade III) or intraparenchymal
hemorrhage (Grade IV)), cystic periventricular leukoma-
lacia, proven neonatal sepsis or necrotizing enterocolitis.
Bronchopulmonary dysplasia was defined as a need for
supplemental oxygen to maintain oxygen saturations of
>90% at 36 weeks postmenstrual age; sepsis as positive
blood culture requiring treatment with antibiotics; and
necrotizing enterocolitis as the presence of pneumatosis
or perforation on X-ray or disease identified by laparo-
tomy. Neonatal data were extracted from clinical records
and entered directly into the website study database.
Maternal hypertension was defined as blood pressure
> 140/90 mmHg and proteinuria as > 0.3 g/L on a 24-h
collection of urine. Hypertensive disorders were defined
as chronic if hypertension existed prior to 20 weeks’
gestation or required treatment prior to pregnancy or as
gestational if the onset of hypertension occurred after
20 weeks in the absence of proteinuria. Pre-eclampsia
was defined as hypertension and proteinuria. HELLP
syndrome was defined as alanine aminotransferase
> 70 iu/L with platelets < 100 × 10
9
/L and with evidence
of hemolysis from blood film or lactate dehydrogenase
(LDH) > 600 U/L.
Statistical methods
Groups were compared two-sided for statistical signifi-
cance by ANOVA, the MannWhitney U-test or Pear-
son’s chi-square test, as appropriate. The association of
demographic, clinical and diagnostic parameters at study
inclusion with the composite endpoint was first explored
by univariate analysis. Those parameters that reached
statistical significance in univariate analysis were entered
in a multivariate logistic regression analysis to adjust for
association between parameters and to calculate odds
ratios (ORs). The interval between inclusion and delivery
was explored by KaplanMeier analysis for comparison
of different risk parameters. Logistic regression analysis
was started with all parameters in the model, and the
probability for removal from the model was set at 0.1.
Statistical calculations were performed using Statistical
Package for the Social Sciences (SPSS program, version
20.0; IBM Corp., New York, NY, USA).
Research governance
These data are reported according the STROBE statement
for reporting cohort studies
13
. TRUFFLE was ratified by
the Ethics Committees of all participating units, and all
patients gave written consent for study inclusion. The
protocol underwent review by the Lancet
14
and was pub-
lished online in 2003 with an amendment published in
2007 after revision of the primary outcome: for the ran-
domized study, we estimated that 562 women needed to be
recruited to allow 450 infant assessments at 2 years of age.
The randomized trial was registered with the International
Standard Randomized Controlled Trial Number Register
(ISRCTN56204499)
15
. An independent Data Monitoring
Committee reviewed data for patient safety and performed
interim analyses for efficacy and futility.
RESULTS
Five-hundred and eleven women were recruited of 542
eligible for study inclusion. Thirty-one women were
assessed as eligible for the study but were not entered.
For eight participants in two centers, baseline and follow-
up obstetric and neonatal outcome data were either
substantively incomplete or absent, despite all attempts
at contact; these two centers were excluded from the
analysis. The study cohort therefore comprised 503
women and their fetuses from 20 centers. Demographic
and baseline obstetric characteristics of the women
recruited are shown in Table 1. In one case, neonatal, but
not obstetric, data were missing. Maternal and neonatal
outcome data are presented in Table 2.
Antenatal fetal death occurred in 12 (2.4%) cases. In
five of these, the parents decided against intervention
or withdrew from medical treatment (median gestational
age at inclusion 27 + 2 weeks; range 26 + 1to29+ 1);
estimated fetal weight 707 g (599947 g). The fetal
deaths were unexpected in the other seven (1.3%) cases,
in one following placental abruption.
Four-hundred and ninety babies were liveborn. All
deliveries were medically indicated and 81% were
for fetal indication. Twenty-seven (5.5%) infants died
during the original neonatal admission before they
could be discharged home for the first time; in
two of these, death was caused by an antenatally
undiagnosed lethal congenital abnormality. Table 3
details the major contributors to severe morbidity in
relation to the gestational age at study entry, which were
sepsis (18%) and bronchopulmonary dysplasia (10%).
Relatively infrequent were germinal matrix hemorrhage
(2%) and cystic periventricular leukomalacia (1%). One-
hundred and fifty-seven (31%) babies met the criteria
for the composite outcome of death or severe morbidity.
Table 4 details outcomes in relation to time of delivery;
overall, 345 (70%) of liveborn babies survived without
severe morbidity.
The gestational age at both study entry and delivery
were strongly related to infant outcome (Figures 1 and 2
respectively). Compared with the remaining women,
mothers of babies meeting the criteria for the composite
outcome of death or severe morbidity were recruited
earlier (28 + 3 weeks vs 29 + 3 weeks). At study entry,
estimated fetal weight was lower (798 g vs 918 g)
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 400408.
Short-term outcomes following early FGR 403
Table 1 Demographic, medical, obstetric and diagnostic data at
study entry for all women and those who subsequently had the
composite poor outcome*
Variable
All included
(n = 503)
Death or severe
morbidity
(n = 157)
Maternal age (years) 31 ± 631± 5
Caucasian ethnicity 423 (84) 139 (89)
Nulliparous 319 (63) 107 (68)
Body mass index (kg/m
2
)25± 626± 6‡
Smoking 77 (15) 23 (15)
Diabetes 9 (2) 2 (1)
Chronic hypertension 56 (11) 18 (12)
Renal morbidity 11 (2) 3 (2)
Other medical disease† 91 (18) 31 (20)
Pre-eclampsia-HELLP 195 (39) 70 (45)
Any gestational hypertensive
morbidity
303 (60) 108 (69)‡
Antihypertensive medication 217 (43) 78 (50)‡
Magnesium for pre-eclampsia 48 (10) 16 (10)
GA at entry (weeks + days) 29+0 ± 11§ 28+3 ± 11‡§
Estimated fetal weight (g) 881 ± 217 798 ± 210‡
Data are given as n (%) or mean ± SD. *Composite poor outcome
comprised fetal or neonatal death or severe morbidity
(bronchopulmonary dysplasia (oxygen after gestational age of 36
weeks), germinal matrix hemorrhage (Grade III and Grade IV),
periventricular leukomalacia (Grade II and Grade III), necrotizing
enterocolitis or proven sepsis). †Including liver, thyroid,
thrombo-embolic or autoimmune conditions. ‡P < 0.05. §SD given
in days. GA, gestational age.
and they more frequently suffered from hypertensive
morbidity (gestational hypertension, pre-eclampsia or
HELLP syndrome) (69% vs 56%). The time between
inclusion and delivery was shorter (median 4 days vs
11 days). This median interval was shortest in cases
with fetal death (3 days), slightly longer when severe
neonatal morbidity or neonatal death occurred (4 days)
and significantly longer when severe neonatal morbidity
was absent (11 days). Babies with composite poor
outcome (death or severe morbidity) were more likely
to be delivered at an earlier gestation (29 + 4 weeks vs
31 + 2 weeks), have lower birth weight (867 g vs 1079 g),
have an Apgar score below 7 (15% vs 8%) and lower
umbilical pH (7.23 vs 7.25).
The most important independent determinants of the
composite poor outcome (death or severe morbidity)
were the presence of gestational hypertensive morbidity at
study entry (OR = 1.70; 95% CI, 1.112.62), gestational
age at study entry (OR= 0.80 per week of gestation; 95%
CI, 0.650.99) and estimated fetal weight at study inclu-
sion (OR = 0.84 per 100 g of estimated fetal weight; 95%
CI, 0.720.99). Women with gestational hypertensive
morbidity at inclusion had a significantly shorter median
interval from inclusion to delivery (5 (range, 0.549)
days) than did women without hypertensive morbidity (13
(range, 0.588) days) (Figure 3). The median duration of
this interval was associated with the severity of the hyper-
tensive condition: 8 days for gestational hypertension; 4
days for pre-eclampsia; and 3 days for HELLP syndrome
(Figure 3). The babies of mothers with hypertensive
Table 2 Obstetric and neonatal data at delivery for all women and
for those who subsequently had the composite poor outcome*
Variable
All
included
(n = 503)
Death or
severe
morbidity
(n = 157)
Maternal/pregnancy characteristics
Pre-eclampsia-HELLP 262 (52) 91 (58)
Any hypertensive morbidity 368 (73) 124 (79)†
Antihypertensive medication 262 (52) 92 (59)†
Magnesium for pre-eclampsia 86 (17) 29 (19)
Corticosteroids for fetal
maturation
461 (92) 145 (92)
Interval to delivery (days) 8 (0.588) 4 (0.561)
GA at delivery (weeks + days) 30+5 ± 16‡ 29+4 ± 144†
Delivery indication
Fetal condition 409 (81) 125 (80)
Maternal 64 (13) 20 (13)
Other 30 (6) 12 (8)
Mode of delivery
Cesarean 486 (97) 148 (94)
Vaginal 17 (3) 9 (6)
Fetal death
No intervention planned 5 (1) 5 (3)
Unexpected 7 (1) 7 (4)
Neonatal characteristics
Birth weight (g) 1013 ± 321 867 ± 251†
Male gender 250 (50) 91 (58)†
Apgar score < 7 where liveborn 51 (10) 24 (17)†
Arterial pH (n = 404) 7.25 ± 0.08 7.23 ± 0.08†
Arterial pH
7.0 to < 7.2 64 (16) 35 (29)†
< 7.0 5 (1) 2 (2)†
Data are given as n (%), mean ± SD or median (range).
*Composite poor outcome comprised perinatal death (fetal or
neonatal death) or severe morbidity: bronchopulmonary dysplasia
(oxygen after gestational age of 36 weeks), germinal matrix
hemorrhage (Grade III and Grade IV), periventricular leukomalacia
(Grade II and Grade III), necrotizing enterocolitis or proven sepsis.
P< 0.05. ‡SD given in days. GA, gestational age.
morbidity at study entry were more likely to be delivered
at an earlier gestation (30 + 1 weeks vs 31 + 4 weeks)
and to have a lower birth weight (979 g vs 1063 g).
In the time between study entry and delivery, the
number of women with any gestational hypertensive
condition increased by 13%. At delivery, 368 (73%)
women had a hypertensive condition, of whom 180 (49%)
had pre-eclampsia, 80 (22%) had HELLP syndrome and
two developed eclampsia. Notwithstanding this, only 64
(24%) of the 262 babies with mothers with pre-eclampsia,
HELLP syndrome or eclampsia were delivered solely on
maternal indication.
DISCUSSION
In this prospective multicenter study of 503 women
identified at presentation with a diagnosis of FGR at very
preterm gestational ages, we report low rates of antenatal
and neonatal death. In this very high-risk group, over
two-thirds survive without severe neonatal morbidity.
The proportion surviving with neuromorbidity was low
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 400408.
404 Lees et al.
Table 3 Perinatal mortality and severe morbidity according to gestational age at study entry
Gestational age at study entry
Variable 2627 weeks 2829 weeks 3031 weeks Total
n 133 204 166 503
Fetal death
No intervention 4 (3) 1 (1) 0 5 (1)
Unexpected 3 (2) 4 (2) 0 7 (1)
Live birth* 126 (95) 198 (97)* 166 (100) 490 (97)
Neonatal death 15 (12) 10 (5) 2 (1) 27 (6)
Deathwithcongenitalanomaly 0202
Overall mortality 22 (17) 15 (7) 2 (1) 39 (8)
Survival if liveborn 111 (88) 188 (94) 164 (98) 463 (95)
Neonatal morbidity
Ventilated 90 (71) 76 (38) 38 (23) 204 (42)
Oxygen 79 (77) 128 (65) 72 (43) 297 (61)
BPD
>28 days 54 (43) 31 (16) 6 (4) 91 (19)
>36 weeks† 34 (27) 13 (7) 2 (1) 49 (10)
Sepsis
Clinical suspicion 30 (24) 26 (13) 11 (7) 67 (14)
Proven† 27 (21) 35 (18) 25 (15) 87 (18)
NEC
Pneumatosis† 4 (3) 3 (2) 0 (0) 7 (1)
Perforation† 3 (2) 5 (3) 1 (1) 9 (2)
GMH Grade III or IV† 6 (5) 5 (3) 1 (1) 12 (2)
PVL Grade II or III† 2 (2) 1 (1) 2 (1) 5 (1)
Death following severe morbidity† 14 (11) 8 (4) 2 (1) 24 (5)
Adjusted age at discharge relative to EDD (days)‡ +12 (22 to 68) 4(39 to 170) 10 (37 to 64) 9(39 to 170)
Severe morbidity (% of survivors)† 46 (37) 44 (22) 28 (17) 118 (24)
Survival without severe morbidity (% of all study entrants) 65 (49) 144 (71) 136 (82) 345 (69)
Data are given as n, n (%) or median (range). Percentages for neonatal mortality and morbidity were calculated from total number of
liveborn infants. *One case with missing neonatal data was not included. †Severe morbidity: BPD (oxygen after gestational age of 36
weeks), GMH (Grade III or IV), PVL (Grade II or III), NEC or proven sepsis. ‡Adjusted age at discharge calculated from expected date of
delivery at 40 weeks’ gestation. BPD, bronchopulmonary dysplasia; EDD, expected date of delivery; GMH, germinal matrix hemorrhage;
NEC, necrotizing enterocolitis or proven sepsis; PVL, cystic periventricular leukomalacia.
(3%); most severe neonatal morbidity was caused by
acquired infection or by bronchopulmonary dysplasia.
All fetuses in this study had evidence of significant FGR
but were eligible for care if delivery was to be indicated.
There was standardization of management strategies up
to 32 weeks of gestation.
Overall, 8% of babies died after a diagnosis of FGR,
with approximately one-third of deaths occurring before
delivery and two-thirds occurring in the neonatal period.
Antepartum deaths were caused either by a decision for
non-intervention, because the prognosis was considered
too poor (five of 12 cases), or were unanticipated. This is
perhaps not unexpected as the study population comprises
a very preterm group at high risk of intrauterine hypoxia,
in whom sudden fetal death is thought to be common.
As might be expected and is reported in other studies
1,16
,
the vast majority of women had a Cesarean delivery.
Male babies rather than female babies were more likely to
meet the criteria for composite morbidity in a 3:2 ratio,
consistent with the known male vulnerability to neonatal
mortality and morbidity at low gestational ages
17,18
.
The major determinant of adverse outcome was
maternal hypertension, the presence of which short-
ened the interval from antenatal diagnosis of FGR to
delivery. Women with HELLP syndrome were delivered
earliest, followed by those with pre-eclampsia and
gestational hypertension. It has been suggested that
the interval between the first occurrence of umbilical
Doppler abnormalities and fetal heart-rate changes
19,20
or subsequent fetal Doppler deterioration
21
is shorter in
FGR with maternal hypertension or pre-eclampsia. Thus,
in the context of maternal hypertensive disease, it is the
proportion of maternal indication deliveries that increase.
These findings, although intuitive, provide evidence to
underpin the close monitoring of maternal blood pressure
and proteinuria that is mandated when a diagnosis of
early-onset FGR is made.
The prospective study against which these data can
be meaningfully compared is the multicenter Growth
Restriction Intervention Trial (GRIT)
16
. Five-hundred
and forty-eight women with ‘compromised’ pregnancies
were recruited at 2436 weeks’ gestation from 69 hos-
pitals in 13 European countries between 1996 and 2002;
outcomes on 487 liveborn babies were reported. They
were randomly allocated to early (median 0.9 days from
randomization) or late (median 4.9 days from random-
ization) delivery; most babies were affected by FGR. The
overall outcomes for neonatal morbidity and mortality
were similar between the immediate and deferred delivery
groups with the median delivery gestation being 32 weeks,
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 400408.
Short-term outcomes following early FGR 405
Table 4 Perinatal mortality and severe morbidity amongst live births according to gestational age at delivery
Gestational age at birth
2627 weeks 2829 weeks 3031 weeks 3233 weeks 34 weeks Total
n* 43 131 169* 103 44 490
Neonatal death 8 (19) 12 (9) 5 (3) 1 (1) 1 (2) 27 (6)
Deathwithcongenital
anomaly
0 (0) 0 (0) 0 (0) 1 (1) 1 (2) 2 (1)
Survival 35 (81) 119 (91) 164 (97) 102 (99) 43 (98) 463 (94)
Neonatal morbidity
Ventilated 41 (95) 84 (64) 57 (34) 16 (16) 6 (14) 204 (42)
Oxygen 39 (91) 108 (82) 101 (60) 39 (38) 10 (23) 297 (61)
BPD
>28 days 27 (63) 49 (37) 13 (8) 1 (1) 1 (2) 91 (19)
>36 weeks† 16 (37) 25 (19) 6 (4) 1 (1) 1 (2) 49 (10)
Sepsis
Clinical suspicion 10 (23) 27 (21) 22 (13) 7 (7) 1 (2) 67 (14)
Proven† 14 (33) 31 (24) 28 (17) 10 (10) 4 (9) 87 (18)
NEC
Pneumatosis† 0 4 (3) 2 (1) 0 1 (2) 7 (1)
Perforation† 0 5 (4) 2 (1) 1 (1) 1 (2) 9 (2)
GMH Grade III or IV† 3 (7) 7 (5) 2 (1) 0 0 12 (2)
PVL Grade II or III† 2 (5) 0 2 (1) 1 (1) 0 5 (1)
Died following
severe morbidity†
8 (19) 11 (8) 5 (3) 0 ()0()24(5)
Adjusted age at
discharge relative
to EDD (days)‡
+12 (22 to 68) 4(39 to 170) 10 (37 to 64) 12 (28 to 51) 8(31 to 81) 9(39 to 170)
Severe morbidity† 22 (51) 46 (35) 33 (20) 12 (12) 5 (11) 118 (24)
Survival without severe
morbidity
13 (30) 73 (56) 131 (78) 90 (87) 38 (86) 345 (70)
Data are given as n, n (%) or median (range). *One case with missing neonatal data not included. †Severe morbidity: BPD (oxygen after
gestational age of 36 weeks), GMH (Grade III or IV), PVL (Grade II or III), NEC or proven sepsis. ‡Adjusted age at discharge calculated
from expected date of delivery at 40 weeks’ gestation. BPD, bronchopulmonary dysplasia; EDD, expected date of delivery; GMH, germinal
matrix hemorrhage; NEC, necrotizing enterocolitis or proven sepsis; PVL, cystic periventricular leukomalacia.
and birth weight of 1200 g for the immediate delivery
group and 1400 g for the deferred delivery group. Over-
all, 36 (7%) babies died in the neonatal period and the
proportion with intraventricular hemorrhage was 15%,
5% had cystic periventricular leukomalacia and 6.1%
had necrotizing enterocolitis; neither bronchopulmonary
dysplasia nor sepsis was reported separately. These mor-
bidities were therefore more common in the GRIT babies
compared with the TRUFFLE cohort, although in our
study babies were born on average just over 1 week earlier
and were approximately 300 g lighter, and thus may be
considered to be at higher risk. GRIT found no differences
between the early or delayed delivery groups in terms of
perinatal death, or 2-year
22
or school-age outcomes
23
.
However, antenatal surveillance was not standardized: it
is reasonable to hypothesize that by improving antenatal
surveillance, as in TRUFFLE, a reduction in antenatal
mortality might be achieved without worsening neonatal
outcome.
Another, more recent, study from American and
European centers compared outcomes in which ductus
venosus Doppler was normal vs abnormal in 604 severely
FGR babies born before 33 weeks’ gestation (median
gestational age = 29 weeks) and admitted to the neonatal
unit
2
. Importantly, and in contrast to TRUFFLE, cases
were not collected prospectively from the point of
antenatal diagnosis. The babies were born, on average,
1 week earlier than in TRUFFLE and weighed slightly
less, but it is reasonable to compare gestation-specific
outcomes. If FGR is diagnosed at 2627 weeks, we
report that 17% of babies die before or after birth
and 19% die if delivery occurs at 2627 weeks, which
contrasts with the previous report of 43% for delivery at
26 weeks. By contrast, after 30 weeks, we found that FGR
is associated with mortality lower than 3%, in contrast to
the previously reported mortality, of 17%, after delivery
at 30 weeks
2
.
A study of 180 babies with birth weight < 10
th
per-
centile, < 34 weeks and with abnormal umbilical Doppler,
delivered between 1997 and 2004 in one of the larger
units subsequently recruiting to TRUFFLE, and immedi-
ately prior to TRUFFLE commencing recruitment, offers
further comparison. The mean gestational age at delivery
was 30.2 weeks and mean birth weight was 875 g
24
.The
overall mortality in that study was 14% and severe mor-
bidity 28.3% compared to 5% and 25%, respectively, in
this report; the definition of severe morbidity was similar
but also included retinopathy of prematurity.
In this context, it is interesting to note the recently
reported outcomes from EPICure 2 for appropriately
grown babies born in 2006; at 26 weeks, 78% survived
and 50% survived without major neonatal morbidity
18
.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 400408.
406 Lees et al.
n 57 76 94 109
93
73
100
80
60
40
Percent
20
0
26 27 28
Gestational age at inclusion (weeks)
29 30 31
Figure 1 Outcome for fetuses according to gestational age at
inclusion. ‘n’ indicates total number of infants represented in each
bar (one case is missing). Severe morbidity is defined as
bronchopulmonary dysplasia (36 weeks), germinal matrix
hemorrhage of Grade III or IV, cystic periventricular leukomalacia
of more than Grade I, proven sepsis or necrotizing enterocolitis.
, No severe morbidity; , severe morbidity; , neonatal death;
, fetal death.
This contrasts with our findings at 2627 weeks of
81% survival but only 30% survival without severe
morbidity. In EPICure 2, the birth weight standard
deviation score was a predictor for bronchopulmonary
dysplasia and for retinopathy of prematurity, but not
for mortality, which seems consistent with these findings.
The similarity in mortality for studies that were almost
exactly contemporary, but one reporting on FGR and the
other not, suggests that growth restriction may specifically
modify morbidity risk.
A consensus antenatal monitoring and delivery proto-
col was used for women entered into TRUFFLE with close
fetal monitoring involving CTG and Doppler parameters.
As a result of this, 97% of women in TRUFFLE had
Cesarean deliveries, compared with 98% and 85% in the
cohorts reported by Baschat
2
and GRIT
16
, respectively.
Outcome in relation to mode of delivery was not reported
in GRIT, but this suggests that, for some deliveries, a
less interventional approach may be reflected in worse
neonatal outcomes. The proportion delivered by Cesarean
section will also be related to indication for delivery
and we have shown a close relationship of the timing
of delivery to the maternal hypertensive condition and a
higher likelihood of maternal indication for delivery with
greater severity of the hypertensive disorder, which for
GRIT would not have been the case.
This study has several important strengths. Women
were recruited prospectively from 2005 to 2010, hence
n 11 32 64 67 93 76 74 29 44
100
80
60
40
Percent
20
0
26 28 29
Gestational age at delivery (weeks)
31 32
34
27 30 33
Figure 2 Outcome of live births (n = 490) according to gestational
age at delivery. ‘n’ indicates total number of infants represented in
each bar (one case is missing). Severe morbidity is defined as
bronchopulmonary dysplasia (36 weeks), germinal matrix
hemorrhage of Grade III or IV, cystic periventricular leukomalacia
of more than Grade I, proven sepsis or necrotizing enterocolitis.
, No severe morbidity; , severe morbidity; , neonatal death.
reflecting contemporary neonatal medicine and obstetric
practice. The entry criteria reflected the ultrasound
and Doppler findings most commonly used to describe
‘genuine’ FGR as the babies were both small and showed
evidence of fetoplacental impairment with raised umbil-
ical artery PI. Indeed, only two babies were subsequently
found to have major congenital abnormalities. Thus, the
results are broadly generalizable to those women referred
for specialist follow up of early-onset FGR between 26
and 32 weeks. Although the trigger for delivery was one
of three different arms, this was randomly allocated and
all three arms reflect practice current both at the inception
of the study and now. Ascertainment of outcome was
high, reflecting the philosophy of the group, whose
investigators met on average twice per year from 2002
to 2012. The investigators achieved a high measure of
agreement for a common monitoring policy, despite their
own preferences in practice, met stringent criteria for the
use of Doppler assessments and were co-located with a
specialist neonatal facility whose specialists collaborated
closely in the study. In only eight pregnancies were we
unable to acquire outcome data; exclusion of all cases
from these two centers prevented a possible selection bias.
A potential criticism is that women were randomized
to one of three management arms and we report the
outcomes of the entire cohort. However, as the three
randomized arms reflect closely current fetal medicine
practice, reporting the aggregated data is an appropriate
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2013; 42: 400408.
Short-term outcomes following early FGR 407
1.0
0.8
0.6
0.4
Cumulative delivered
0.2
0.0
040
Interval: inclusion-to-delivery (days)
60
100
20 80
Figure 3 KaplanMeier analysis of interval between inclusion and
delivery, presented separately for women with and those without
hypertensive morbidity on inclusion. Differences between groups
were statistically significant.
, HELLP; , pre-eclampsia;
, gestational hypertension; , no hypertensive morbidity.
reflection of outcomes expected in day-to-day clinical
practice. We do not disclose outcome by randomized
group in advance of reporting the primary outcome to
avoid any possible influence on practice in the interim.
Our aim in this paper is rather, given the paucity of
prospective reports of outcome in FGR restriction for large
cohorts, to describe perinatal outcomes in contemporary
practice.
In summary, we describe somewhat better than
expected perinatal outcomes in this high-risk group of
fetuses, which are likely to be attributable to developments
both in neonatal care and in antenatal monitoring.
Delivery at 26 weeks of gestation still carries significant
mortality and morbidity, similar to that in national birth
cohorts, and the converse is true for delivery after 30
weeks. Maternal hypertension, in particular its severity,
shortens the interval to delivery and influences neonatal
outcome negatively. These data provide contemporary
information to support counseling in respect of short-term
outcomes for women at the time of antenatal diagnosis
and separately at delivery.
ACKNOWLEDGMENTS
Data-monitoring group: Professors J. Thornton (UK),
H. Valensise (Italy), J. Kingdom (Canada) and K. Marsal
(Sweden). Data and analysis: Dr H. Wolf had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis. Sources of funding: in The Netherlands
the randomized trial of timing of delivery in early
preterm fetal growth restriction was based on early and
late fetal Doppler venous changes vs cardiotocography.
TRUFFLE (Trial of Umbilical and Fetal Flow in Europe),
was supported by Grant Number 94506556, ZonMw,
PostBox 93245, 2509 AE Den Haag, The Netherlands. In
other countries, the study was not funded. A contribution
was made to study funding from the Dr Gesienhofer
Stiftungspreis, Munich, Germany. ICMJE declaration:
the corresponding author has no involvement with a
commercial organization that may have an interest in
this research or any non-financial association with any
entity that may be relevant. The corresponding author is
supported by the National Institute for Health Research
(NIHR) Biomedical Research Centre based at Imperial
College Healthcare NHS Trust and Imperial College
London. The views expressed are those of the author(s)
and not necessarily those of the NHS, the NIHR or the
Department of Health.
TRUFFLE GROUP COLLABORATING
AUTHORS
H. C. J. Scheepers, Department of Obstetrics and Gynae-
cology, Maastricht University Medical Centre, Maas-
tricht, The Netherlands
M. Spaanderman, Radboud University Nijmegen Medical
Centre, Nijmegen, The Netherlands
S. Calvert, Neonatal Unit, St George’s Hospital, London,
UK
H. Missfelder-Lobos, Addenbrooke’s Hospital, Cam-
bridge, UK
J. van Eyck, Department of Obstetrics and Gynaecology,
Isala Clinics, Zwolle, The Netherlands
D. Oepkes, Department of Obstetrics, Leiden University
Medical Center, Leiden, The Netherlands
N. Fratelli, MaternalFetal Medicine Unit, University of
Brescia, Brescia, Italy
F. Prefumo, MaternalFetal Medicine Unit, University of
Brescia, Brescia, Italy
R. Napolitano, Department of Gynecology and Obstet-
rics, University Federico II of Naples, Naples, Italy
R. Chaoui, Center for Prenatal Diagnosis and Human
Genetics, Friedrichstrasse, Berlin, Germany
G. Maso, Department of Obstetrics and Gynaecology,
IRCCS Burlo Garofolo, University of Trieste, Trieste,
Italy
G. Ogge, Department of Obstetrics and Gynaecology,
University of Turin, Turin, Italy
M. Oberto, Department of Obstetrics and Gynaecology,
University of Turin, Turin, Italy
N. Mensing van Charante, Department of Obstetrics and
Gynecology, Academic Medical Center, Amsterdam, The
Netherlands
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    • "In our study, 98% of women who delivered before the 34th week of gestation had a cesarean section. This value was similar to the percentile reported in the TRUFFLE study [46]. Fetal pH at birth and the Apgar score were both in the range of normality (Table 1). "
    [Show abstract] [Hide abstract] ABSTRACT: Aim of the study: Analyzing velocimetric (umbilical artery, UA; ductus venosus, DV; middle cerebral artery, MCA) and computerized cardiotocographic (cCTG) (fetal heart rate, FHR; short term variability, STV; approximate entropy, ApEn) parameters in intrauterine growth restriction, IUGR, in order to detect early signs of fetal compromise. POPULATION STUDY: 375 pregnant women assisted from the 28th week of amenorrhea to delivery and monitored through cCTG and Doppler ultrasound investigation. The patients were divided into three groups according to the age of gestation at the time of delivery, before the 34th week, from 34th to 37th week, and after the 37th week. Data were analyzed in relation to the days before delivery and according to the physiology or pathology of velocimetry. Statistical analysis was performed through the t-test, chi-square test, and Pearson correlation test (P < 0.05). Our results evidenced an earlier alteration of UA, DV, and MCA. The analysis between cCTG and velocimetric parameters (the last distinguished into physiological and pathological values) suggests a possible relation between cCTG alterations and Doppler ones. The present study emphasizes the need for an antenatal testing in IUGR fetuses using multiple surveillance modalities to enhance prediction of neonatal outcome.
    Full-text · Article · Dec 2014
    • "Dans une série prospective multicentrique de 604 foetus RCIU de moins de 33 SA, Baschat et al. retrouvent des taux de mortalité de 8,6 % chez les foetus nés à 31 SA et de 2,6 % pour ceux nés à 32 SA [8]. Dans l'analyse de la cohorte TRUFFLE, dans laquelle tous les foetus ont été inclus sur l'existence d'un RCIU au moins associé à des anomalies des Doppler ombilicaux, la mortalité néonatale est de 3 % à 30—31 SA et devient nulle à 32—33 SA (n = 103) ainsi qu'à 34 SA et plus (n = 44), hors malformations congénitales [9]. Ces chiffres semblent démontrer qu'en dehors des situations où une extraction a été décidée en raison d'anomalies du Doppler veineux ou du RCF, le risque périnatal est modéré même en cas d'altérations des flux ombilicaux (augmentation de l'index de pulsatilité, onde diastolique nulle ou reverse). "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this paper is to review available data regarding the management of delivery in intra uterine growth retarded fetuses and try to get recommendations for clinical obstetrical practice. Bibliographic research performed by consulting PubMed database and recommendations from scientific societies with the following words: small for gestational age, intra-uterine growth restriction, fetal growth restriction, very low birth weight infants, as well as mode of delivery, induction of labor, cesarean section and operative delivery. The diagnosis of severe IUGR justifies the orientation of the patient to a referral centre with all necessary resources for very low birth weight or premature infants Administration of corticosteroids for fetal maturation (before 34 WG) and a possible neuroprotective treatment by with magnesium sulphate (before 32-33 WG) should be discussed. Although elective caesarean section is common, there is no current evidence supporting the use of systematic cesarean section, especially when the woman is in labor. Induction of labor, even with unfavorable cervix is possible under continuous FHR monitoring, in favorable obstetric situations and in the absence of severe fetal hemodynamic disturbances. Instrumental delivery and routine episiotomy are not recommended. For caesarean section under spinal anesthesia, an adequate anesthetic management must ensure the maintenance of basal blood pressure. Compared with appropriate for gestational age fetus, IUGR fetus is at increased risk of metabolic acidosis or perinatal asphyxia during delivery.
    Full-text · Article · Nov 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Objective The purpose of this paper is to review available data regarding the management of delivery in intra uterine growth retarded fetuses and try to get recommendations for clinical obstetrical practice. Materials and methods Bibliographic research performed by consulting PubMed database and recommendations from scientific societies with the following words: small for gestational age, intra-uterine growth restriction, fetal growth restriction, very low birth weight infants, as well as mode of delivery, induction of labor, cesarean section and operative delivery. Results The diagnosis of severe IUGR justifies the orientation of the patient to a referral centre with all necessary resources for very low birth weight or premature infants Administration of corticosteroids for fetal maturation (before 34 WG) and a possible neuroprotective treatment by with magnesium sulphate (before 32–33 WG) should be discussed. Although elective caesarean section is common, there is no current evidence supporting the use of systematic cesarean section, especially when the woman is in labor. Induction of labor, even with unfavorable cervix is possible under continuous FHR monitoring, in favorable obstetric situations and in the absence of severe fetal hemodynamic disturbances. Instrumental delivery and routine episiotomy are not recommended. For caesarean section under spinal anesthesia, an adequate anesthetic management must ensure the maintenance of basal blood pressure. Conclusion Compared with appropriate for gestational age fetus, IUGR fetus is at increased risk of metabolic acidosis or perinatal asphyxia during delivery.
    Full-text · Article · Jan 2013
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