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OBSTETRICS

The Growth Restriction Intervention Trial: long-term

outcomes in a randomized trial of timing

of delivery in fetal growth restrictionDawn-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-

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

or deferred delivery following signs of impaired fetal health in the pres-

ence 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.

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

or evaluated at age 6-13 years. Numbers of children dead, or with se-

vere 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 immediateand 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.

BACKGROUND AND OBJECTIVEFetuses with abnormal Doppler signalsor with signs of cerebral blood flow re-distribution may have impaired cogni-tive outcomes in middlechildhood com-pared to those without. However, in theabsence of randomized trials, such stud-ies cannot indicate when delivery shouldtake place in response to these changes.

The Growth Restriction InterventionTrial (GRIT) was designed to compareearly delivery to preempt severe intra-

uterine hypoxia with delaying delivery to

gain maturity. Trial allocation resulted

in an average 4-day difference in deliverybetween the groups. Within the delayed

delivery group there were more intra-

uterine deaths but fewer neonatal deathscompared to immediate delivery, but lit-

tle difference overall. At 2 years of age,

the frequency of disability tended to behigher in the immediate delivery group,

but no major differences between the 2groups were seen. In particular, the Grif-fiths developmental scores at 2 years ofage were similar.

We have reevaluated children ofmothers entered into GRIT at earlyschool age to determine whether early ordeferred delivery in fetal growth restric-tion with Doppler waveform abnormal-ities alters longer-term cognitive, lan-guage, motor, or behavioral outcomes.

MATERIALS AND METHODSDuring the recruitment period, Novem-ber 1993 through March 2001, womenwith fetal growth restriction at 24-36completed weeks in whom an umbilical

artery Doppler waveform had been re-corded, and the responsible clinician wasuncertain whether to deliver the babyimmediately, wererandomlyallocatedtoeither deliver now or defer deliveryuntil delivery could safely be delayed nolonger. Children delivered to mothers in5 of the original recruiting countries(Germany, The Netherlands, Italy, Slov-enia, and United Kingdom) were fol-lowed up. No attempt was made to fol-low up participants from Belgium,

Cyprus, Czech Republic, Hungary,Greece, Poland, Portugal, or Saudi Ara-

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 andInfants 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

Research www.AJOG.org

34 American Journal of Obstetrics &Gynecology JANUARY 2011

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bia because of the small numbers of par-ticipants in each country. The originalparticipants had been recruited over a6-year period, but the present evaluationwas carried out over 3 years.

The Kaufman Assessment Battery forChildren (ABC) is a well-validated as-sessment of populations of preterm chil-dren. 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 8tests of motor impairment. Teachersrated scholastic performance, whichwas combined as a Total AcademicAchievement Score.

Teachers and parents completed therespective versions of the Strength and

Difficulties Questionnaire. Additionalitems were included to assess the 2 di-

mensions of attentional and overactiv-ity/impulsivity problems and school ad-aptation with the Connors test.

The Health Utilities Index comprisesparental reports of the childs healthstate with respect to hearing, vision, dex-terity, and ambulation. Apart from theCELF, which was administered only inEnglish-speaking countries, all question-

naires and tests were identical in eachcountry apart from translation.

TABLE

Scales evaluated in survivors at school-age follow-up

Scale (cutoff value) nImmediate, mean(SD) or n (%)

Deferred, mean(SD) or n (%)

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

Kaufman-ABCa 1.0 (1.71).......................................................................................................................................................................................................................................................................................................................................................................

MPC 269 95 (15) 96 (14).......................................................................................................................................................................................................................................................................................................................................................................

Sequential 263 96 (14) 95 (13).......................................................................................................................................................................................................................................................................................................................................................................

Simultaneous 264 97 (13) 98 (13)................................................................................................................................................................................................................................................................................................................................................................................

CELFa.......................................................................................................................................................................................................................................................................................................................................................................

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)................................................................................................................................................................................................................................................................................................................................................................................

Total Academic Achievement Scorea (teacher)

below average (

2.5)

208 35 (31%) 32 (34%) 0.14 (0.30)

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

Movement-ABCb 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)................................................................................................................................................................................................................................................................................................................................................................................

SDQ overall behavior scoresb.......................................................................................................................................................................................................................................................................................................................................................................

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)................................................................................................................................................................................................................................................................................................................................................................................

SDQ attention deficit disorderb.......................................................................................................................................................................................................................................................................................................................................................................

Parent (score 10) 159 7 (9%) 8 (10%) 0.17 (0.55).......................................................................................................................................................................................................................................................................................................................................................................

Teacher (score 10) 166 16 (18%) 7 (9%) 0.70 (0.49)................................................................................................................................................................................................................................................................................................................................................................................

School adaptation scalea.......................................................................................................................................................................................................................................................................................................................................................................

Parent (score 3) 160 19 (24%) 22 (28%) 0.21 (0.37).......................................................................................................................................................................................................................................................................................................................................................................

Teacher (score 3) 165 24 (27%) 17 (23%) 0.20 (0.37)................................................................................................................................................................................................................................................................................................................................................................................

HUI-3 overall utility scorea (1) 226 44 (38%) 52 (47%) 0.45 (0.29)................................................................................................................................................................................................................................................................................................................................................................................

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 regressionestimates 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 andDifficulties 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.

www.AJOG.org Obstetrics Research

JANUARY 2011 American Journal of Obstetrics &Gynecology 35

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The primary outcome was the Kauf-man-ABC mental processing compositescores for survivors. A secondary out-come was the composite endpoint ofdeath or severe disability.

Bayesian analysis formally allows the

trial data to modify an individuals priorbeliefs regarding relative treatment ef-fect. Forthis trial,obstetricians prior be-liefs varied widely.

RESULTSOutcome was known for 302/376 (80%)children of mothers entered into thestudy and for 269/343 (78%) survivors.The proportions of participants who haddied or were known to be severely dis-abled were similar between the allocated

groups within each gestational age bandand overall. Mortality rates were higherby 2 years in the nonparticipant coun-tries, but 2-year participant survivorswere similar in terms of trial baselinecharacteristics to those not followed up.Participants in the immediate deliveryarm contained a slightly higher propor-tion with severe disability at 2-year fol-low-up compared to deferred delivery.

There were only small differences be-tween the children in each study group

over the range of performance measures(Kaufman-ABC, CELF, Total AcademicAchievement Score), impairment scores

(Movement-ABC), and the number ofchildren reaching case status for behav-ior, attention deficit disorder, and healthutility (Table).

The lack of difference seen for odds ofdeath/severe disability should convince

enthusiasts for either immediate or de-ferred delivery that within this trial set-ting, real differences in this compositeendpoint are unlikely to be large. The ev-idence from the trial should temper thebeliefs of those whoanticipated large dif-ferences in Kaufman-ABC scores be-tween survivors.

COMMENTTheGRIT study hasessentiallyshownno

measurable differences in motoror intel-lectual disabilities between the groups.This is despite the considerable potentialfor damage from both arms of the trial:early delivery, with allthe risks of prema-turity, and delayed delivery, with therisks of prolonged hypoxemia in utero.The excess of stillbirths in the delayeddelivery group and of early neonataldeaths in the immediate delivery group(previously reported) is evidence thatsuch damage occurred. The lack of dif-

ference in outcomes at 6-9 years of ageindicates that such damage is largely bal-anced out. It is possible that the plasticity

of the developing brain overcame any

imbalances that remained.Ourfinding of cognitivescores close to

the standardization range in both groupstends to argue against severe growth re-striction as an independent cause of

lower intelligence. The finding of no dif-ference in cognitiveor language scoresorin educational attainment between thegroups argues against the idea that anyharm from chronic hypoxemia can be

modified by timed early delivery.Our finding of no excess of motor dis-

ability in the early delivery group con-trasts with many observational studiesthat report preterm delivery as a strongindependent riskfactor for cerebral palsy

and for less severe motor impairments.

The 4-day delay in delivery timing wasnot sufficient to produce detectable im-provements in scores. The behavioralscores are well balanced between the 2

groups. Overall parent-reported healthutilities were similarly distributed.

CLINICAL IMPLICATIONS

Timing delivery cannot improvebrain development.

Obstetricians should delay deliveryas long as possible, concurrent withavoiding fetal death. f

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