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The Growth Restriction Intervention Trial: long-term outcomes in a randomized trial of timing of delivery in fetal growth restriction

Published:November 09, 2010DOI:https://doi.org/10.1016/j.ajog.2010.09.019

      Objective

      The Growth Restriction Intervention Trial found little difference 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.

      Results

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

      Key words

      Of a range of tests of fetal well-being, umbilical artery Doppler flow velocimetry may be used to reduce perinatal mortality in fetal growth restriction.
      • Neilson J.P.
      • Alfirevic Z.
      Doppler ultrasound for fetal assessment in high risk pregnancies.
      • Thornton J.G.
      • Lilford R.J.
      Do we need randomized trials of antenatal tests of fetal well-being?.
      Recent studies have clarified the order in which alterations in the Doppler waveforms (recorded from various vessels), fetal heart rate, and behavioral abnormalities take place.
      • Baschat A.A.
      • Gembruch U.
      • Harman C.R.
      The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens.
      • Hecher K.
      • Bilardo C.M.
      • Stigter R.H.
      • et al.
      Monitoring of fetuses with intrauterine growth restriction: a longitudinal study.
      Fetuses with abnormal Doppler signals
      • Neilson J.P.
      • Alfirevic Z.
      Doppler ultrasound for fetal assessment in high risk pregnancies.
      • Thornton J.G.
      • Lilford R.J.
      Do we need randomized trials of antenatal tests of fetal well-being?.
      • Ley D.
      • Laurin J.
      • Bjerre I.
      • Marsal K.
      Abnormal fetal aortic velocity waveform and minor neurological dysfunction at 7 years of age.
      or with signs of cerebral blood flow redistribution
      • Scherjon S.A.
      • Briët J.
      • Oosting H.
      • Kok J.
      The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in very preterm infants with and without hemodynamic signs of fetal brain-sparing.
      may have impaired cognitive outcomes in middle childhood compared to those without.
      • Walker D.-M.
      • Marlow N.
      Neurocognitive outcomes following fetal growth restriction.
      However, in the absence of randomized trials, those sorts of studies cannot indicate when delivery should take place in response to these changes.
      • Baschat A.A.
      • Gembruch U.
      • Harman C.R.
      The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens.
      • Hecher K.
      • Bilardo C.M.
      • Stigter R.H.
      • et al.
      Monitoring of fetuses with intrauterine growth restriction: a longitudinal study.
      • Baschat A.A.
      Doppler application in the delivery timing of the preterm growth-restricted fetus: another step in the right direction.
      • Ferrazi E.
      • Bozzo M.
      • Rigano S.
      • et al.
      Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth restricted fetus.
      • Veen S.
      • Ens-Dokkum M.H.
      • Schreuder A.M.
      • Verloove-Vanhorick S.P.
      • Brand R.
      • Ruys J.H.
      Impairments, disabilities and handicaps of very pre-term and very-low-birthweight infants at five years of age.
      For Editors' Commentary, see Table of Contents
      Delay could increase exposure to hypoxia and acidosis and affect brain development, but early delivery carries the dangers of prematurity and the associated increased risk of cognitive and behavioral sequelae and cerebral palsy.
      • Saigal S.
      • Doyle L.W.
      An overview of mortality and sequelae of preterm birth from infancy to adulthood.
      • Marlow N.
      Neurocognitive outcome after very preterm birth.
      In situations where there was uncertainty over the appropriate management, the Growth Restriction Intervention Trial (GRIT) was designed to compare early delivery to preempt severe intrauterine 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.
      The GRIT Study Group
      A randomized trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation.
      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 in each group.
      The GRIT Study Group
      Infant well-being at 2 years of age in the Growth Restriction Intervention Trial (GRIT): a multicentered randomized controlled trial.
      Outcome evaluation at 2 years has limited prediction for later cognitive and behavioral sequelae. Given that these later outcomes are associated with poor fetal growth,
      • Walker D.-M.
      • Marlow N.
      Neurocognitive outcomes following fetal growth restriction.
      • Gutbrod T.
      • Wolke D.
      • Soehne B.
      • Ohrt B.
      • Riegel K.
      The effects of gestation and birthweight on the growth and development of very low birthweight small for gestational age infants: a matched group comparison.
      • Teberg A.J.
      • Walther F.J.
      • Pena I.C.
      Mortality, morbidity and outcome of the small-for-gestational age infant.
      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.

      Materials and Methods

      The original trial

      The methods have been fully described in the original trial reports.
      The GRIT Study Group
      A randomized trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation.
      The GRIT Study Group
      Infant well-being at 2 years of age in the Growth Restriction Intervention Trial (GRIT): a multicentered randomized controlled trial.
      In brief, during the recruitment period, November 1993 through March 2001, women with fetal growth restriction between 24-36 completed weeks, where 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 it could safely be delayed no longer. Mode of delivery and monitoring strategies for the defer delivery group was left up to the attending obstetrician.

      The current study

      Children delivered to mothers in 5 of the original recruiting countries (Germany, The Netherlands, Italy, Slovenia, and United Kingdom) were followed up. In the United Kingdom, children were flagged by the Office of National Statistics, which provided the name of the family's current general practitioner. The practice was contacted to confirm its current contact details. We maintained contact with the families with annual birthday and Christmas cards, enclosing a change-of-address card. Participants were contacted by mail or telephone and invited to bring the child to an appointment with the psychologist at their school. In The Netherlands, a similar tracing system was used. In Germany, Italy, and Slovenia we relied on the knowledge of the pediatrician who had initially cared for the baby. All parents gave written informed consent, and the study was approved by the North West Region (United Kingdom) Multicenter Research Ethics Committee and the appropriate local committees in the other countries. No attempt was made to follow up participants from Belgium, Cyprus, Czech Republic, Hungary, Greece, Poland, Portugal, and Saudi Arabia. This was because of the small numbers of participants in each country and the difficulty in identifying participants and skilled assessors.
      The original participants had been recruited over a 6-year period, but the present evaluation was carried out over 3 years. As far as possible therefore, the earlier recruits were evaluated first to minimize the age range.
      In the United Kingdom, children were evaluated at school by 1 of 3 psychologists during a single day using a series of directly administered tests (cognition, language, motor) and parent report instruments (behavior and health utility). Teachers also rated children's behavior and completed a comprehensive rating scale of academic attainment. This design for data collection has been previously validated.
      • Johnson S.
      • Hennessy E.
      • Smith R.
      • Trikic R.
      • Wolke D.
      • Marlow N.
      Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study.
      • Wolke D.
      • Samara M.
      • Bracewell M.
      EPICure Study Group
      Specific language difficulties and school achievement in children born at 25 weeks of gestation or less.
      • Wolke D.
      • Rizzo P.
      • Woods S.
      Persistent infant crying and hyperactivity problems in middle childhood.
      In other countries, validated translations and adaptations of the following tests were administered, and assessments were carried out in a variety of settings (clinic/home/school).
      The Kaufman Assessment Battery for Children (ABC)
      • Kaufman A.S.
      • Kaufman N.L.
      Kaufman assessment battery for children (K-ABC).
      is a well-validated assessment of populations of preterm children.
      • Wolke D.
      • Meyer R.
      Cognitive status, language attainment, and pre-reading skills of 6-year-old very preterm children and their peers: the Bavarian longitudinal study.
      • Marlow N.
      • Wolke D.
      • Bracewell M.
      EPICure Study Group
      Neurological and developmental disability at six years of age after extremely preterm birth.
      The mental processing composite (MPC) is a global measure of the child's cognitive ability or generalized IQ (age standardized to mean: 100; SD: 15) and comprises 2 subareas of sequential and simultaneous cognitive processing.
      The Clinical Evaluation of Language Fundamentals–Revised (CELF-R) [UK]
      • Semel D.
      • Wiig W.H.
      • Secord W.
      Clinical evaluation of language fundamentals.
      is a standardized test of language that complements the Kaufman, which evaluates nonlanguage-based cognition. Four CELF-R subtests were selected covering receptive (2 subtests) and expressive (2 subtests) language. Each subtest was standardized to give a mean of 10, SD 3, and a high score representing better language skills. This was only delivered in English-speaking countries.
      The Movement-ABC
      • Henderson S.E.
      • Sugden D.
      Movement assessment battery for children.
      comprises 8 tests of motor impairment grouped as manual dexterity, ball skills, and dynamic balance; these are summed to give an overall impairment score, with higher scores representing greater impairment.
      Teachers rated the scholastic performance of the index and comparison children against the national expected level of attainment for a child of the same age in English, mathematics, science, technology, geography, history, and information technology. This was combined as a Total Academic Achievement Score.
      • Johnson S.
      • Hennessy E.
      • Smith R.
      • Trikic R.
      • Wolke D.
      • Marlow N.
      Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study.
      • Wolke D.
      • Samara M.
      • Bracewell M.
      EPICure Study Group
      Specific language difficulties and school achievement in children born at 25 weeks of gestation or less.
      • Wolke D.
      • Rizzo P.
      • Woods S.
      Persistent infant crying and hyperactivity problems in middle childhood.
      Teachers and parents completed the respective versions of Strength and Difficulties Questionnaire
      • Goodman R.
      The Strengths and Difficulties Questionnaire: a research note.
      from which are derived subscales for emotional symptoms, conduct problems, hyperactivity, peer problems, prosocial behavior, and overall difficulties. Teachers and parents also rated the impact of the behavior, including chronicity, distress, social impairment, and burden to others caused by child behavior.
      • Goodman R.
      Psychometric properties of the strengths and difficulties questionnaire.
      Additional items were included to assess the 2 dimensions of attentional and overactivity/impulsivity problems and school adaptation with the Connors test.
      • Samara M.
      • Marlow N.
      • Wolke D.
      Pervasive behavior problems at 6 years of age in a total-population sample of children born at <=25 weeks of gestation.
      The Health Utilities Index comprises parental reports of the child's health state in respect to hearing, vision, dexterity, and ambulation. These are summated to a utility score, where 1 corresponds to optimal health and 0 represents death. Negative scores are allowed for health states considered worse than death, so the full range of scores runs from –0.34 to 1.0.
      • Verrips E.
      • Vogels T.
      • Saigal S.
      • et al.
      Health-related quality of life for extremely low birth weight adolescents in Canada, Germany, and The Netherlands.
      Apart from the CELF, which was only administered in English-speaking countries, all questionnaires and tests were identical in each country, apart from translation.
      Data were double entered onto a database to avoid entry errors. After data checking and cleaning the database was merged with the original study database for analysis using STATA version 10 (StataCorp, College Station, TX).

      Statistical analysis

      The primary outcome was the Kaufman-ABC MPC scores for survivors. Where this outcome was missing for otherwise evaluated participants, a value was imputed as follows:
      • Marlow N.
      • Wolke D.
      • Bracewell M.
      EPICure Study Group
      Neurological and developmental disability at six years of age after extremely preterm birth.
      if the child was too developmentally impaired to complete the assessment, a value of 40 (the lowest measurable value) was assigned. Otherwise, the predicted value from regressing the measured MPC values on gestational age and, if recorded, Griffiths developmental quotient
      • Griffiths R.
      The Griffiths mental developmental scales from birth to 2 years.
      at 2 years was assigned according to a prespecified analysis protocol. Values were imputed for 5 children: 3 who were too impaired to complete the assessment (1 severe mental retardation; 1 Prader-Willi syndrome; 1 autistic with severe learning difficulties); 1 whose blindness prevented completion; and 1 with only a teacher's assessment at the long-term follow-up visit. No other values were imputed.
      A secondary outcome was the composite endpoint of death or severe disability. For this purpose, severe disability was defined as ≥1 of the following outcomes: severe blindness, severe deafness, cerebral palsy, or Kaufman MPC <70 points.
      • Marlow N.
      • Wolke D.
      • Bracewell M.
      EPICure Study Group
      Neurological and developmental disability at six years of age after extremely preterm birth.
      The analysis strategy was fully described for the original trial.
      • Vail A.
      • Hornbuckle J.
      • Spiegelhalter D.J.
      • Thornton J.G.
      Prospective application of Bayesian monitoring and analysis in an ‘open' randomized clinical trial.
      The primary analysis compared the randomized groups using classic regression to control for end-diastolic frequency (reversed, absent, reduced, normal) and gestational age at randomization. Estimates and their SEs from these classic analyses were used to update prespecified skeptical and enthusiastic prior distributions for Bayesian interpretation.
      • Spiegelhalter D.J.
      • Freedman L.S.
      • Parmar M.K.B.
      Bayesian approaches to randomized trials.
      In brief, the Bayesian approach allows direct consideration of the probability of treatment superiority. Rather than interpret the trial data in isolation, the Bayesian analysis formally allows the trial data to modify an individual's prior beliefs regarding relative treatment effect. For this trial obstetricians' prior beliefs varied widely. We therefore, adopted stylized formulations of prior beliefs to reflect those who were enthusiastic for either treatment and those who were skeptical regarding the existence of any difference.
      • Tin W.
      • Gupta S.
      Optimum oxygen therapy in preterm babies.
      The beliefs are presented as odds ratios with 95% confidence intervals. The trial data are then used to modify these beliefs into a posterior odds ratio with 95% confidence interval.
      For the primary outcome the skeptical prior was that immediate delivery would be unlikely to alter MPC scores by >5 points in those of ≥31 completed weeks' gestation, and by >10 points in those at earlier gestational ages. For the composite endpoint, the skeptical prior was that immediate delivery would be unlikely to more than double or halve the odds ratio.
      Separate analyses for the Kaufman-ABC, Movement-ABC, and composite endpoint were undertaken for the United Kingdom only, and for all countries excluding Italy (because of the low follow-up rate). This long-term follow-up study was not originally planned in the trial for which 2-year outcomes were primary. Original sample size calculations were based on the 2-year assessments. The 95% credibility intervals demonstrate the range of effect size that is consistent with the data.

      Results

      The derivation of the study population is shown in Figure 1. Outcome was known for 302/376 (80%) children of mothers entered into the study and for 78% (269/343) survivors. Follow-up rates varied by country: Germany, 10/16 (63%); Italy, 25/101 (25%); The Netherlands, 51/71 (72%); Slovenia, 20/22 (91%); and United Kingdom, 188/234 (80%). Follow-up in survivors occurred at a median (range) age of 9.2 (6.8 to 12.5) years in the immediate delivery group and 9.4 (6.8 to 13.7) years in the deferred delivery group. Because the achieved follow-up rate in Italy was so low (25%), all Italian babies were excluded from the primary analysis.
      Figure thumbnail gr1
      FIGURE 1Flowchart of trial profile indicating derivation of study population
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.
      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 (Table 1).
      TABLE 1Death and severe disability at school age
      Gestational ageOutcomeImmediateDeferred
      OverallDeath or disability21/153 (14%)25/149 (17%)
      Dead14 (9%)19 (13%)
      Severe disability7 (5%)6 (4%)
      24-30 wkDeath or disability15/60 (25%)19/52 (37%)
      Dead9 (15%)16 (31%)
      Severe disability6 (10%)3 (6%)
      31-36 wkDeath or disability6/93 (6%)6/97 (6%)
      Dead3 (3%)5 (5%)
      Severe disability3 (3%)1 (1%)
      Disability classified as one of cerebral palsy, IQ <70, deafness, or blindness.
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.
      The frequency of key variables was compared between children who were alive and followed up, recorded as alive at 2 years but did not respond to contacts, or refused and therefore were not evaluated, and children from nonparticipant countries who were alive at 2 years (Table 2). There was a higher mortality 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 had better developmental outcomes recorded at 2 years.
      TABLE 2Characteristics by follow-up status of surviving children
      CharacteristicAlive and followed up (n = 269)Alive but not evaluated (n = 74)Children from nonparticipant countries alive at 2 y (n = 179)
      Included 2 participants with unrecorded end-diastolic frequency and 1 lost to follow-up before delivery.
      Maternal age, yMean (SD)28 (5.7)27 (5.9)29 (5.6)
      Gestational age, wk24-3087 (32%)23 (31%)47 (26%)
      31-36182 (68%)51 (69%)132 (74%)
      End-diastolic frequencyReversed16 (6%)5 (7%)4 (2%)
      Absent95 (35%)28 (38%)42 (24%)
      Reduced87 (32%)22 (30%)63 (36%)
      Normal71 (26%)19 (26%)68 (38%)
      SexMale118 (44%)36 (49%)90 (51%)
      Female151 (56%)38 (51%)88 (49%)
      Group allocationImmediate139 (52%)40 (54%)89 (50%)
      Deferred130 (48%)34 (46%)90 (50%)
      Status at 2 yNo severe disability252 (94%)66 (89%)156 (87%)
      Severe disability16 (6%)7 (9%)10 (6%)
      Unknown1 (0%)1 (1%)13 (7%)
      Griffiths quotient at 2 y>85231 (86%)44 (59%)134 (75%)
      71-8523 (9%)14 (19%)13 (7%)
      ≤7010 (4%)6 (8%)7 (4%)
      Unknown5 (2%)10 (14%)25 (14%)
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.
      a Included 2 participants with unrecorded end-diastolic frequency and 1 lost to follow-up before delivery.
      Among children evaluated at school age, the prevalence of a range of study baseline variables was similar in those allocated to either study group (Table 3). Participants in the immediate delivery arm contained a slightly higher proportion with severe disability at 2-year follow-up compared to deferred delivery.
      TABLE 3Characteristics by study group of surviving children attending long-term follow-up
      CharacteristicLevelImmediate (n = 139)Deferred (n = 130)
      CountryUnited Kingdom98 (71%)90 (69%)
      The Netherlands29 (21%)22 (17%)
      Slovenia9 (6%)11 (8%)
      Germany3 (2%)7 (5%)
      Gestational age, wk24-3051 (37%)36 (28%)
      31-3688 (63%)94 (72%)
      End-diastolic frequencyReversed7 (5%)9 (7%)
      Absent52 (37%)43 (33%)
      Reduced45 (32%)42 (32%)
      Normal35 (25%)36 (28%)
      Clinically assessed fetal growth restrictionPresent117 (84%)112 (86%)
      Status at 2 ySevere disability present10 (7%)6 (5%)
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.
      The distribution of Kaufman-ABC MPC scores for the 2 trial groups divided into those randomized >30 and <30 weeks is shown in Figure 2.
      Figure thumbnail gr2
      FIGURE 2Distribution of Kaufman Assessment Battery for Children mental processing composite
      Values were imputed for 5 children: 3 who were too impaired to complete assessment (1 severe mental retardation; 1 Prader-Willi syndrome; 1 autistic with severe learning difficulties); 1 whose blindness prevented completion; and 1 with only teacher's assessment at long-term follow-up visit.
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.
      Mean differences and their associated SEs for the scales evaluated in survivors are shown in Table 4. For these outcomes only the adjusted mean differences, or the log odds ratios, together with their SEs, are presented. We provide no P values, because this was not a frequentist analysis. We do not provide a Bayesian interpretation, because no priors were predefined for these outcomes.
      TABLE 4Scales 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-ABC
      The higher the score, the better their ability;
       MPC26995 (15)96 (14)−1.0 (1.71)
       Sequential26396 (14)95 (13)
       Simultaneous26497 (13)98 (13)
      CELF
      The higher the score, the better their ability;
       Concepts2347.4 (2.8)7.5 (3.1)−0.1 (0.38)
       Sentences1857.8 (3.6)8.0 (3.8)−0.2 (0.54)
       Classes1857.5 (3.1)7.9 (3.2)−0.4 (0.47)
       Recall1858.0 (3.2)7.8 (2.9)0.2 (0.46)
      Total Academic Achievement Score
      The higher the score, the better their ability;
      (teacher) below average (<2.5)
      20835 (31%)32 (34%)−0.14 (0.30)
      Movement-ABC
      The lower the score, the better their ability.
       Total impairment score2648.9 (7.0)8.7 (6.7)0.1 (0.82)
       Dexterity2644.2 (3.1)4.3 (2.9)
       Ball skills2642.6 (2.6)2.3 (2.6)
       Balance2642.2 (3.1)2.2 (3.1)
      SDQ overall behavior scores
      The lower the score, the better their ability.
       Parent17110.5 (7.1)10.5 (6.9)0.0 (1.08)
       Teacher17510.7 (7.8)10.5 (7.1)0.4 (1.15)
      SDQ attention deficit disorder
      The lower the score, the better their ability.
       Parent (score ≥10)1597 (9%)8 (10%)−0.17 (0.55)
       Teacher (score ≥10)16616 (18%)7 (9%)0.70 (0.49)
      School adaptation scale
      The higher the score, the better their ability;
       Parent (score ≥3)16019 (24%)22 (28%)−0.21 (0.37)
       Teacher (score ≥3)16524 (27%)17 (23%)0.20 (0.37)
      HUI-3 overall utility score
      The higher the score, the better their ability;
      (<1)
      22644 (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 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.
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.
      a The higher the score, the better their ability;
      b The lower the score, the better their ability.
      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 (Movement-ABC), and the number of children reaching caseness for behavior, attention deficit disorder, and health utility. Since obstetricians may wonder if the effect of early delivery varied by gestational age, we reported results stratified this way (Figure 2). We also analyzed results stratified into gestational age/Doppler levels, as in our previous report,
      The GRIT Study Group
      Infant well-being at 2 years of age in the Growth Restriction Intervention Trial (GRIT): a multicentered randomized controlled trial.
      but numbers in those groups were very small and no important differences were seen (data not shown).
      In view of the low rates of follow-up in some countries, we reanalyzed the results using just United Kingdom data (not shown). We found similar findings to those reported.

      Bayesian interpretation

      The lack of difference seen for odds of death/severe disability (Table 1) 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 (Figure 3). In Figure 3, the data on death or severe disability for all of the follow-up participants are shown as an odds ratio and used to modify these prior beliefs into 3 posterior beliefs.
      Figure thumbnail gr3
      FIGURE 3Death/Severe disability and prior beliefs
      Effect of trial data for odds of death/severe disability on prior beliefs that were enthusiastic for immediate delivery, skeptical concerning group differences, and enthusiastic for deferred delivery. Higher values (>1.0) favor deferred delivery.
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.
      Similarly, the evidence from the trial should temper the beliefs of those who anticipated large differences in Kaufman-ABC scores between survivors (Figure 4). Figure 4, A, shows the effect of the trial data in Kaufman scores. Figure 4, B, shows the data for participants randomized <30 weeks and Figure 4, C, for those randomized >30 weeks.
      Figure thumbnail gr4
      FIGURE 4Kaufman-ABC scores
      Effect of trial data for mean difference in Kaufman scores on prior beliefs regarding A, overall ability and gestational age B, 24-30 and C, 31-36 weeks at randomization. Lower values (<0) favor deferred delivery.
      ABC, Assessment Battery for Children.
      Walker. GRIT: long-term outcomes in an RCT of timing of delivery in fetal growth restriction. Am J Obstet Gynecol 2011.

      Comment

      The present long-term follow-up of the children originally randomly assigned to immediate or delayed delivery in 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 delay delivery group, and of early neonatal deaths in the immediate delivery group (previously reported)
      The GRIT Study Group
      A randomized trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation.
      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, and it is possible that the plasticity of the developing brain overcame any imbalances that remained.
      The main strength of the present study is that it is the only randomized trial of timed delivery for fetal growth restriction. Since participants were analyzed in their groups as allocated and subgroup analysis was restricted to data items collected before trial entry, there was no bias from obstetricians altering delivery timing in response to subtle risk factors. The follow-up rate of 70% is considerably lower than the 95% achieved at 2 years but not untypical for face-to-face follow-up after 9 years. One of the reasons for the lower follow-up rate in the present study is that at the 2-year follow-up point the ethics committees permitted relatively intrusive methods, such as repeated telephone calls and home visits, on the grounds that parents had originally consented to this duration of follow-up. We also included outcome data at 2 years from brief telephone contact with parents or general practitioners. By the time of the present study, although we had been tracking the whereabouts of the children with annual birthday and Christmas cards, we no longer had explicit permission for follow-up assessments. We were therefore, constrained to limit our follow-up to those parents who responded to a limited number of telephone or postal invitations and attended the appointments offered. Another strength is that we used well-validated tools to measure the various outcomes at 6-9 years.
      • Johnson S.
      • Hennessy E.
      • Smith R.
      • Trikic R.
      • Wolke D.
      • Marlow N.
      Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study.
      • Wolke D.
      • Samara M.
      • Bracewell M.
      EPICure Study Group
      Specific language difficulties and school achievement in children born at 25 weeks of gestation or less.
      • Wolke D.
      • Rizzo P.
      • Woods S.
      Persistent infant crying and hyperactivity problems in middle childhood.
      • Kaufman A.S.
      • Kaufman N.L.
      Kaufman assessment battery for children (K-ABC).
      • Semel D.
      • Wiig W.H.
      • Secord W.
      Clinical evaluation of language fundamentals.
      • Henderson S.E.
      • Sugden D.
      Movement assessment battery for children.
      • Goodman R.
      Psychometric properties of the strengths and difficulties questionnaire.
      Our data comparing evaluated and dropout children on trial baseline and 2-year data (Table 2) provide conflicting evidence on the likelihood of differential follow-up. Trial baseline data were similar between the 2 groups. In contrast, by 2 years of age the followed-up babies were less likely to have low Griffiths developmental quotient (13% vs 27%) and less likely to have severe disability (6% vs 9%). This confirms that dropouts are likely to have had higher rates of disabilities at 6-9 years but follow-up in the 2 trial groups was similar, and there was unlikely to be systematic bias in 1 group for follow-up evaluations. Similar findings have been observed in other follow-up studies of preterm babies.
      • Johnson S.
      • Hennessy E.
      • Smith R.
      • Trikic R.
      • Wolke D.
      • Marlow N.
      Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study.
      • Tin W.
      • Gupta S.
      Optimum oxygen therapy in preterm babies.
      • Wolke D.
      • Söhne B.
      • Ohrt B.
      • Riegel K.
      Follow-up of preterm children: important to document dropouts.
      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, which agrees with other small-for-gestational-age cohort studies
      • Gutbrod T.
      • Wolke D.
      • Soehne B.
      • Ohrt B.
      • Riegel K.
      The effects of gestation and birthweight on the growth and development of very low birthweight small for gestational age infants: a matched group comparison.
      • Teberg A.J.
      • Walther F.J.
      • Pena I.C.
      Mortality, morbidity and outcome of the small-for-gestational age infant.
      but conflicts with cohort studies of flow velocity abnormalities.
      • Ley D.
      • Laurin J.
      • Bjerre I.
      • Marsal K.
      Abnormal fetal aortic velocity waveform and minor neurological dysfunction at 7 years of age.
      • Scherjon S.A.
      • Briët J.
      • Oosting H.
      • Kok J.
      The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in very preterm infants with and without hemodynamic signs of fetal brain-sparing.
      However, the test used has relatively old standardization norms and thus, absolute scores may underestimate the cognitive deficit.
      • Marlow N.
      • Wolke D.
      • Bracewell M.
      EPICure Study Group
      Neurological and developmental disability at six years of age after extremely preterm birth.
      In particular, 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, within the setting of this trial. We cannot of course, rule out the possibility that early delivery benefitted those babies where the obstetric opinion was that immediate delivery was preferable
      • Gardosi J.
      GRIT: concern about external validity.
      or not indicated, since such women were not included in the original trial, which was based on uncertainty. This was unavoidable at the time, given the wide range of delivery timing practices in place 10 years ago, and limits the external validity of GRIT, but the lack of other randomized trial data indicates that evidence to support change in practice is still awaited.
      Our finding of no excess of motor disability in the early delivery group contrasts with many observational studies, which report preterm delivery as a strong independent risk factor for cerebral palsy and for less severe motor impairments.
      • Marlow N.
      • Wolke D.
      • Bracewell M.
      EPICure Study Group
      Neurological and developmental disability at six years of age after extremely preterm birth.
      Scores achieved are in keeping with those reported in other preterm populations, and it seems likely that the 4-day delay in delivery timing was not sufficient to produce detectable improvements in scores. Similarly the behavioral scores are well balanced between the 2 groups, and overall parent-reported health utilities were similarly distributed between the 2 groups and similar proportions had impaired health utility. The lack of difference seen is consistent with other studies, eg, Baschat et al,
      • Baschat A.A.
      • Viscardi R.M.
      • Hussey-Gardner B.
      • Hashmi N.
      • Harman C.
      Infant neurodevelopment following fetal growth restriction: relationship with antepartum surveillance parameters.
      Fouron et al,
      • Fouron J.C.
      • Gosselin J.
      • Amiel-Tison C.
      • et al.
      Correlation between prenatal velocity waveforms in the aortic isthmus and neurodevelopmental outcome between the ages of 2 and 4 years.
      and Eixarch et al,
      • Eixarch E.
      • Meler E.
      • Iraola A.
      • et al.
      Neurodevelopmental outcome in 2-year-old infants who were small-for-gestational age term fetuses with cerebral blood flow redistribution.
      which showed the placental dysfunction prior to delivery had the greatest impact on neurodevelopment.
      The pragmatic nature of the original trial, identifying a range of uncertainty over the timing of delivery without specifying precise fetal health parameters at entry or timing of delivery, was integral to the design of the trial. It has been criticized in that we have been unable to rule out benefit from either early delivery, when the obstetric opinion was that delivery was necessary
      • Gardosi J.
      GRIT: concern about external validity.
      or indeed where delay in delivery was beneficial. As yet no trial of such practice has been completed, although the Trial of Umbilical and Fetal Flow in Europe is currently ongoing; it evaluates timed delivery based on predetermined delivery criteria. The original 2-year outcomes suggested minor benefits from delayed delivery in the “zone of uncertainty,” but these have not been borne out using more robust outcomes measurable during middle childhood. It would appear that the judgment about timing of delivery made by recruiting obstetricians impacts little on longer-term outcomes.

      Acknowledgments

      Study Manager: Heather Palmer (Nottingham);
      Co-principal investigators: Jim Thornton, Neil Marlow, Dieter Wolke (United Kingdom);
      Psychologists: Dawn-Marie Walker, Lisa Upstone, Harriet Gross (United Kingdom); Anja Kahnt (Germany); Vislava Velikonja (Slovenia); Sara Mazzotti, Elisa Mani (Italy); Petra Barneveld, Marit Bierman (Netherlands)
      Trial Steering Committee: A. Grant (chair), P. Steer, D. Torgeson, S. Kitzinger, J. Hornbuckle, P. Steer, A. Salt, L. Murray
      The GRIT study group: countries, centers, and principal local investigators who participated in the 6- to 9-year follow-up.
      Obstetricians:
      Germany: (Universitat Munchen) K. T. M. Schneider.
      Italy: (Ferretti, G. Turin) T. Todros; (Fatebenefratelli, Rome) D. Arduini; (Ospedale Salesi, Ancona) A. Tranquilli; (Ospedale Valduce, Como) A. C. Tenore; (Universita Degli Studi Di Milano-Bicocca, Monza) N. Roncaglia; (University of Brescia) T. Frusca.
      The Netherlands: Swaab, H, AZ Groningen, M. J. N. Weinans; AZ Leiden, J. van Roosmalen; De Heel, Zaandam, J. W. van der Slikke; (Free University, Amsterdam) H. van Geijn; Kennemer Gasthius Lokatie Deo, Haarlem, P. J. M. Pernet; (Amsterdam Medical Centre) H. Wolf; AZ Utrecht, R. H. Stigter.
      Slovenia: Ljubljana, Z Novak-Antolic.
      United Kingdom: (Aberdeen) P. Danielian; Redditch, S. D. Jenkinson; (Arrowe Park, Wirral) C. R. Welch; (Birmingham Heartlands) C. Griffin; (Birmingham Women's) H. Gee; (Bradford Royal Infirmary) D. Tuffnell; (Chesterfield) J. Cresswell; (Dewsbury) T. Tariq; (Dryburn) B. Sengupta; (Forth Park, Kirkcaldy) G. Tydeman; (Northallerton) M. K. Kumarendran; (Good Hope Sutton Coldfield) D. Churchill; (St Thomas' London) S. Bewley; (Hammersmith, London) L. Fusi; (Hull) S. W. Lindow; (Ipswich) W. Johal; (Jessop, Sheffield) F. M. Fairlie; (Kent and Canterbury) K. Neales; (Leeds General) G. Mason, R. J. Lilford; (Leicester General) I. Scudamore; (Leicester Royal) J. Konje; (Liverpool Women's) S. A. Walkinshaw; (Luton and Dunstable) M. Griffiths; (Abergavenny) A. Dawson; Ninewells, (Dundee) G. Mires; (North Staffordshire Maternity) R. Johanson; (Northern General) Sheffield, R. B. Fraser; (Ormskirk) P. Hendy Ibbs; (Peterborough) S. A. Steel; (Queens Medical Centre, Nottingham) M. Ramsay; (Inverclyde) J. B. Robins; (Winchester) M. J. Heard; (Bath) H. M. Tonge; (St Georges, London) I. T. Manyonda; (St James, Leeds) J. Walker; (St Mary's Manchester) M. Maresh; (St Mary's Isle of Wight) A. Yoong; (St Michael's Bristol) P. Soothill; (Sunderland) H. Cameron; (Treliske, Truro) D. Byrne; (Heath Cardiff) B. Beattie; (West Cumberland) S. Bober.

      References

        • Neilson J.P.
        • Alfirevic Z.
        Doppler ultrasound for fetal assessment in high risk pregnancies.
        Cochrane Database Syst Rev. 2002; 2 (CD000073)
        • Thornton J.G.
        • Lilford R.J.
        Do we need randomized trials of antenatal tests of fetal well-being?.
        Br J Obstet Gynaecol. 1993; 100: 197-200
        • Baschat A.A.
        • Gembruch U.
        • Harman C.R.
        The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens.
        Ultrasound Obstet Gynecol. 2001; 18: 571-577
        • Hecher K.
        • Bilardo C.M.
        • Stigter R.H.
        • et al.
        Monitoring of fetuses with intrauterine growth restriction: a longitudinal study.
        Ultrasound Obstet Gynecol. 2001; 18: 564-570
        • Ley D.
        • Laurin J.
        • Bjerre I.
        • Marsal K.
        Abnormal fetal aortic velocity waveform and minor neurological dysfunction at 7 years of age.
        Ultrasound Obstet Gynecol. 1996; 8: 152-159
        • Scherjon S.A.
        • Briët J.
        • Oosting H.
        • Kok J.
        The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in very preterm infants with and without hemodynamic signs of fetal brain-sparing.
        Pediatrics. 2000; 105: 385-391
        • Walker D.-M.
        • Marlow N.
        Neurocognitive outcomes following fetal growth restriction.
        Arch Dis Child Fetal Neonatal Ed. 2008; 93: F322-F325
        • Baschat A.A.
        Doppler application in the delivery timing of the preterm growth-restricted fetus: another step in the right direction.
        Ultrasound Obstet Gynecol. 2004; 23: 111-118
        • Ferrazi E.
        • Bozzo M.
        • Rigano S.
        • et al.
        Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth restricted fetus.
        Ultrasound Obstet Gynecol. 2002; 19: 140-146
        • Veen S.
        • Ens-Dokkum M.H.
        • Schreuder A.M.
        • Verloove-Vanhorick S.P.
        • Brand R.
        • Ruys J.H.
        Impairments, disabilities and handicaps of very pre-term and very-low-birthweight infants at five years of age.
        Lancet. 1991; 338: 33-36
        • Saigal S.
        • Doyle L.W.
        An overview of mortality and sequelae of preterm birth from infancy to adulthood.
        Lancet. 2008; 19: 261-269
        • Marlow N.
        Neurocognitive outcome after very preterm birth.
        Arch Dis Child Fetal Neonatal Ed. 2004; 89: F224-F228
        • The GRIT Study Group
        A randomized trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation.
        BJOG. 2003; 110: 27-32
        • The GRIT Study Group
        Infant well-being at 2 years of age in the Growth Restriction Intervention Trial (GRIT): a multicentered randomized controlled trial.
        Lancet. 2004; 364: 513-519
        • Gutbrod T.
        • Wolke D.
        • Soehne B.
        • Ohrt B.
        • Riegel K.
        The effects of gestation and birthweight on the growth and development of very low birthweight small for gestational age infants: a matched group comparison.
        Arch Dis Child Fetal Neonatal Ed. 2000; 82: F208-F214
        • Teberg A.J.
        • Walther F.J.
        • Pena I.C.
        Mortality, morbidity and outcome of the small-for-gestational age infant.
        Semin Perinatol. 1988; 12: 84-94
        • Johnson S.
        • Hennessy E.
        • Smith R.
        • Trikic R.
        • Wolke D.
        • Marlow N.
        Academic attainment and special educational needs in extremely preterm children at 11 years of age: the EPICure study.
        Arch Dis Child Fetal Neonatal Ed. 2009; 94: F283-F289
        • Wolke D.
        • Samara M.
        • Bracewell M.
        • EPICure Study Group
        Specific language difficulties and school achievement in children born at 25 weeks of gestation or less.
        J Pediatr. 2008; 152: 256-262
        • Wolke D.
        • Rizzo P.
        • Woods S.
        Persistent infant crying and hyperactivity problems in middle childhood.
        Pediatrics. 2002; 109: 1054-1060
        • Kaufman A.S.
        • Kaufman N.L.
        Kaufman assessment battery for children (K-ABC).
        American Guidance Service, Circle Pines, MN1993
        • Wolke D.
        • Meyer R.
        Cognitive status, language attainment, and pre-reading skills of 6-year-old very preterm children and their peers: the Bavarian longitudinal study.
        Med Child Neurol. 1999; 41: 94-109
        • Marlow N.
        • Wolke D.
        • Bracewell M.
        • EPICure Study Group
        Neurological and developmental disability at six years of age after extremely preterm birth.
        N Engl J Med. 2005; 352: 9-19
        • Semel D.
        • Wiig W.H.
        • Secord W.
        Clinical evaluation of language fundamentals.
        3rd ed. Psychological Association, San Antonio, TX1995
        • Henderson S.E.
        • Sugden D.
        Movement assessment battery for children.
        Psychological Corp, London1992
        • Goodman R.
        The Strengths and Difficulties Questionnaire: a research note.
        J Child Psychology and Psychiatry. 1997; 38: 581-586
        • Goodman R.
        Psychometric properties of the strengths and difficulties questionnaire.
        J Am Acad Child Adolesc Psychiatry. 2001; 40: 1337-1345
        • Samara M.
        • Marlow N.
        • Wolke D.
        Pervasive behavior problems at 6 years of age in a total-population sample of children born at <=25 weeks of gestation.
        Pediatrics. 2008; 122: 562-573
        • Verrips E.
        • Vogels T.
        • Saigal S.
        • et al.
        Health-related quality of life for extremely low birth weight adolescents in Canada, Germany, and The Netherlands.
        Pediatrics. 2008; 122: 556-561
        • Griffiths R.
        The Griffiths mental developmental scales from birth to 2 years.
        Test Agency, Oxford1996
        • Vail A.
        • Hornbuckle J.
        • Spiegelhalter D.J.
        • Thornton J.G.
        Prospective application of Bayesian monitoring and analysis in an ‘open' randomized clinical trial.
        Stat Med. 2001; 20: 3777-3787
        • Spiegelhalter D.J.
        • Freedman L.S.
        • Parmar M.K.B.
        Bayesian approaches to randomized trials.
        J R Stat Soc (Series A). 1994; 157: 357-387
        • Tin W.
        • Gupta S.
        Optimum oxygen therapy in preterm babies.
        Arch Dis Child Fetal Neonatal Ed. 2007; 92: F143-F147
        • Wolke D.
        • Söhne B.
        • Ohrt B.
        • Riegel K.
        Follow-up of preterm children: important to document dropouts.
        Lancet. 1995; 345: 447
        • Gardosi J.
        GRIT: concern about external validity.
        Lancet. 2004; 365: 384
        • Baschat A.A.
        • Viscardi R.M.
        • Hussey-Gardner B.
        • Hashmi N.
        • Harman C.
        Infant neurodevelopment following fetal growth restriction: relationship with antepartum surveillance parameters.
        Ultrasound Obstet Gynecol. 2009; 33: 44-50
        • Fouron J.C.
        • Gosselin J.
        • Amiel-Tison C.
        • et al.
        Correlation between prenatal velocity waveforms in the aortic isthmus and neurodevelopmental outcome between the ages of 2 and 4 years.
        Am J Obstet Gynecol. 2001; 184: 630-636
        • Eixarch E.
        • Meler E.
        • Iraola A.
        • et al.
        Neurodevelopmental outcome in 2-year-old infants who were small-for-gestational age term fetuses with cerebral blood flow redistribution.
        Ultrasound Obstet Gynecol. 2008; 32: 894-899