Research

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OBSTETRICS

The Growth Restriction Intervention Trial: long-term

outcomes in a randomized trial of timing
of delivery in fetal growth restriction
Dawn-Marie Walker, PhD; Neil Marlow, DMFMedSci; Lisa Upstone, DClinPsy; Harriet Gross, PhD;
Janet Hornbuckle, MD, MB, MRCOG; Andy Vail, MSc; Dieter Wolke, PhD; Jim G. Thornton, MD, FRCOG
OBJECTIVE: The Growth Restriction Intervention Trial found little differ-

RESULTS: Of 376 babies, 302 (80%) had known outcome: either dead

ence in overall mortality or 2-year outcomes associated with immediate

or deferred delivery following signs of impaired fetal health in the presence of growth restriction when the obstetrician was unsure whether to
deliver. Because early childhood assessments have limited predictive
value, we reevaluated them.
STUDY DESIGN: Children were tested with standardized school-based
evaluations of cognition, language, motor performance, and behavior.
Analysis and interpretation were Bayesian.

or evaluated at age 6-13 years. Numbers of children dead, or with severe disability: 21 (14%) immediate and 25 (17%) deferred groups.
Among survivors, the mean (SD) cognition scores were 95 (15) and 96
(14); motor scores were 8.9 (7.0) and 8.7 (6.7); and parent-assessed
behavior scores were 10.5 (7.1) and 10.5 (6.9), respectively, for the 2
groups.
CONCLUSION: Clinically significant differences between immediate
and deferred delivery were not found.

Cite this article as: Walker D-M, Marlow N, Upstone L, et al. The Growth Restriction Intervention Trial: long-term outcomes in a randomized trial of timing of
delivery in fetal growth restriction. Am J Obstet Gynecol 2011;204:34.e1-9.

B ACKGROUND AND O BJECTIVE

Fetuses with abnormal Doppler signals
or with signs of cerebral blood flow redistribution may have impaired cognitive outcomes in middle childhood compared to those without. However, in the
absence of randomized trials, such studies cannot indicate when delivery should
take place in response to these changes.
The Growth Restriction Intervention
Trial (GRIT) was designed to compare
early delivery to preempt severe intra-

uterine hypoxia with delaying delivery to

gain maturity. Trial allocation resulted
in an average 4-day difference in delivery
between the groups. Within the delayed
delivery group there were more intrauterine deaths but fewer neonatal deaths
compared to immediate delivery, but little difference overall. At 2 years of age,
the frequency of disability tended to be
higher in the immediate delivery group,

but no major differences between the 2

groups were seen. In particular, the Griffiths developmental scores at 2 years of
age were similar.
We have reevaluated children of
mothers entered into GRIT at early
school age to determine whether early or
deferred delivery in fetal growth restriction with Doppler waveform abnormalities alters longer-term cognitive, language, motor, or behavioral outcomes.

M ATERIALS AND M ETHODS

From the Departments of Community Health Sciences (Dr Walker) and Human
Development (Mr Marlow, and Drs Upstone, Gross, and Thornton), University of
Nottingham, Nottingham, UK; the Research and Development Support Unit, University of
Manchester, Manchester, UK (Mr Vail); and the Department of Psychology, University of
Warwick, Warwick (Dr Wolke), United Kingdom; and the Department of Womens and
Infants Health, University of Western Australia, Perth, Australia (Dr Hornbuckle).
Presented at the 56th Annual Scientific Meeting of the Society of Gynecological Investigation,
Glasgow, Scotland, United Kingdom, March 18-21, 2009.
Sponsored by the United Kingdom Medical Research Council, which had no involvement with the
study design, collection analysis, or interpretation of the data, the writing of the report, or the
decision to submit the manuscript.
Acknowledgments and the countries, centers, and principal local investigators of the Growth
Restriction Intervention Trial study group who participated in the 6- to 9-year follow-up are listed
with the full-length article at www.AJOG.org.
0002-9378/free 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.09.019

For Editors Commentary, see Table of Contents

34

American Journal of Obstetrics & Gynecology JANUARY 2011

During the recruitment period, November 1993 through March 2001, women
with fetal growth restriction at 24-36
completed weeks in whom an umbilical
artery Doppler waveform had been recorded, and the responsible clinician was
uncertain whether to deliver the baby
immediately, were randomly allocated to
either deliver now or defer delivery
until delivery could safely be delayed no
longer. Children delivered to mothers in
5 of the original recruiting countries
(Germany, The Netherlands, Italy, Slovenia, and United Kingdom) were followed up. No attempt was made to follow up participants from Belgium,
Cyprus, Czech Republic, Hungary,
Greece, Poland, Portugal, or Saudi Ara-

Obstetrics

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Research

TABLE

Scales evaluated in survivors at school-age follow-up

Scale (cutoff value)

Immediate, mean
(SD) or n (%)

Deferred, mean
(SD) or n (%)

Adjusted difference,
mean (SE) or log OR
(SE)
1.0 (1.71)

Kaufman-ABC

.......................................................................................................................................................................................................................................................................................................................................................................

MPC

269

95 (15)

96 (14)

Sequential

263

96 (14)

95 (13)

Simultaneous

264

97 (13)

98 (13)

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a

CELF

.......................................................................................................................................................................................................................................................................................................................................................................

Concepts

234

7.4 (2.8)

7.5 (3.1)

0.1 (0.38)

Sentences

185

7.8 (3.6)

8.0 (3.8)

0.2 (0.54)

Classes

185

7.5 (3.1)

7.9 (3.2)

0.4 (0.47)

Recall

185

8.0 (3.2)

7.8 (2.9)

0.2 (0.46)

208

35 (31%)

32 (34%)

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a

Total Academic Achievement Score (teacher)

below average (2.5)

0.14 (0.30)

................................................................................................................................................................................................................................................................................................................................................................................
b

Movement-ABC

0.1 (0.82)

.......................................................................................................................................................................................................................................................................................................................................................................

Total impairment score

264

8.9 (7.0)

8.7 (6.7)

Dexterity

264

4.2 (3.1)

4.3 (2.9)

Ball skills

264

2.6 (2.6)

2.3 (2.6)

Balance

264

2.2 (3.1)

2.2 (3.1)

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
b

SDQ overall behavior scores

.......................................................................................................................................................................................................................................................................................................................................................................

Parent

171

10.5 (7.1)

10.5 (6.9)

0.0 (1.08)

Teacher

175

10.7 (7.8)

10.5 (7.1)

0.4 (1.15)

.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
b

SDQ attention deficit disorder

.......................................................................................................................................................................................................................................................................................................................................................................

Parent (score 10)

159

7 (9%)

8 (10%)

Teacher (score 10)

166

16 (18%)

7 (9%)

0.17 (0.55)

.......................................................................................................................................................................................................................................................................................................................................................................

0.70 (0.49)

................................................................................................................................................................................................................................................................................................................................................................................
a

School adaptation scale

.......................................................................................................................................................................................................................................................................................................................................................................

Parent (score 3)

160

19 (24%)

22 (28%)

0.21 (0.37)

Teacher (score 3)

165

24 (27%)

17 (23%)

0.20 (0.37)

226

44 (38%)

52 (47%)

0.45 (0.29)

.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a

HUI-3 overall utility score (1)

................................................................................................................................................................................................................................................................................................................................................................................

Data presented are mean (SD) of scales or number (%) of children reaching caseness thresholds. For group difference, linear regression estimates are presented for former and logistic regression
estimates for latter, each adjusted for end-diastolic frequency and gestational age at randomization.
ABC, Assessment Battery for Children; CELF, Clinical Evaluation of Language Fundamentals; HUI-3, Health Utilities Index; MPC, mental processing composite; OR, odds ratio; SDQ, Strength and
Difficulties Questionnaire.
a

The higher the score, the better their ability; b The lower the score, the better their ability.

Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.

bia because of the small numbers of participants in each country. The original
participants had been recruited over a
6-year period, but the present evaluation
was carried out over 3 years.
The Kaufman Assessment Battery for
Children (ABC) is a well-validated assessment of populations of preterm children. The mental processing composite
is a global measure of cognitive ability.
The Clinical Evaluation of Language

FundamentalsRevised (CELF-R) [UK]

is a standardized test of language.
The Movement-ABC comprises 8
tests of motor impairment. Teachers
rated scholastic performance, which
was combined as a Total Academic
Achievement Score.
Teachers and parents completed the
respective versions of the Strength and
Difficulties Questionnaire. Additional
items were included to assess the 2 di-

mensions of attentional and overactivity/impulsivity problems and school adaptation with the Connors test.
The Health Utilities Index comprises
parental reports of the childs health
state with respect to hearing, vision, dexterity, and ambulation. Apart from the
CELF, which was administered only in
English-speaking countries, all questionnaires and tests were identical in each
country apart from translation.

JANUARY 2011 American Journal of Obstetrics & Gynecology

35

Research

Obstetrics

The primary outcome was the Kaufman-ABC mental processing composite

scores for survivors. A secondary outcome was the composite endpoint of
death or severe disability.
Bayesian analysis formally allows the
trial data to modify an individuals prior
beliefs regarding relative treatment effect. For this trial, obstetricians prior beliefs varied widely.

R ESULTS
Outcome was known for 302/376 (80%)
children of mothers entered into the
study and for 269/343 (78%) survivors.
The proportions of participants who had
died or were known to be severely disabled were similar between the allocated
groups within each gestational age band
and overall. Mortality rates were higher
by 2 years in the nonparticipant countries, but 2-year participant survivors
were similar in terms of trial baseline
characteristics to those not followed up.
Participants in the immediate delivery
arm contained a slightly higher proportion with severe disability at 2-year follow-up compared to deferred delivery.
There were only small differences between the children in each study group
over the range of performance measures
(Kaufman-ABC, CELF, Total Academic
Achievement Score), impairment scores

36

www.AJOG.org
(Movement-ABC), and the number of
children reaching case status for behavior, attention deficit disorder, and health
utility (Table).
The lack of difference seen for odds of
death/severe disability should convince
enthusiasts for either immediate or deferred delivery that within this trial setting, real differences in this composite
endpoint are unlikely to be large. The evidence from the trial should temper the
beliefs of those who anticipated large differences in Kaufman-ABC scores between survivors.

C OMMENT
The GRIT study has essentially shown no
measurable differences in motor or intellectual disabilities between the groups.
This is despite the considerable potential
for damage from both arms of the trial:
early delivery, with all the risks of prematurity, and delayed delivery, with the
risks of prolonged hypoxemia in utero.
The excess of stillbirths in the delayed
delivery group and of early neonatal
deaths in the immediate delivery group
(previously reported) is evidence that
such damage occurred. The lack of difference in outcomes at 6-9 years of age
indicates that such damage is largely balanced out. It is possible that the plasticity

American Journal of Obstetrics & Gynecology JANUARY 2011

of the developing brain overcame any

imbalances that remained.
Our finding of cognitive scores close to
the standardization range in both groups
tends to argue against severe growth restriction as an independent cause of
lower intelligence. The finding of no difference in cognitive or language scores or
in educational attainment between the
groups argues against the idea that any
harm from chronic hypoxemia can be
modified by timed early delivery.
Our finding of no excess of motor disability in the early delivery group contrasts with many observational studies
that report preterm delivery as a strong
independent risk factor for cerebral palsy
and for less severe motor impairments.
The 4-day delay in delivery timing was
not sufficient to produce detectable improvements in scores. The behavioral
scores are well balanced between the 2
groups. Overall parent-reported health
utilities were similarly distributed.

CLINICAL IMPLICATIONS

Timing delivery cannot improve

brain development.
Obstetricians should delay delivery
as long as possible, concurrent with
f
avoiding fetal death.