Elsevier

The Lancet

Volume 385, Issue 9983, 30 May–5 June 2015, Pages 2162-2172
The Lancet

Articles
2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial

https://doi.org/10.1016/S0140-6736(14)62049-3Get rights and content

Summary

Background

No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction. We aimed to assess whether changes in the fetal ductus venosus Doppler waveform (DV) could be used as indications for delivery instead of cardiotocography short-term variation (STV).

Methods

In this prospective, European multicentre, unblinded, randomised study, we included women with singleton fetuses at 26–32 weeks of gestation who had very preterm fetal growth restriction (ie, low abdominal circumference [<10th percentile] and a high umbilical artery Doppler pulsatility index [>95th percentile]). We randomly allocated women 1:1:1, with randomly sized blocks and stratified by participating centre and gestational age (<29 weeks vs ≥29 weeks), to three timing of delivery plans, which differed according to antenatal monitoring strategies: reduced cardiotocograph fetal heart rate STV (CTG STV), early DV changes (pulsatility index >95th percentile; DV p95), or late DV changes (A wave [the deflection within the venous waveform signifying atrial contraction] at or below baseline; DV no A). The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85, at 2 years of age. We assessed outcomes in surviving infants with known outcomes at 2 years. We did an intention to treat study for all participants for whom we had data. Safety outcomes were deaths in utero and neonatal deaths and were assessed in all randomly allocated women. This study is registered with ISRCTN, number 56204499.

Findings

Between Jan 1, 2005 and Oct 1, 2010, 503 of 542 eligible women were randomly allocated to monitoring groups (166 to CTG STV, 167 to DV p95, and 170 to DV no A). The median gestational age at delivery was 30·7 weeks (IQR 29·1–32·1) and mean birthweight was 1019 g (SD 322). The proportion of infants surviving without neuroimpairment did not differ between the CTG STV (111 [77%] of 144 infants with known outcome), DV p95 (119 [84%] of 142), and DV no A (133 [85%] of 157) groups (ptrend=0·09). 12 fetuses (2%) died in utero and 27 (6%) neonatal deaths occurred. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes (133 [95%] of 140, 95%, 95% CI 90–98) were free of neuroimpairment when compared with those randomly assigned to CTG (111 [85%] of 131, 95% CI 78–90; p=0.005), but this was accompanied by a non-significant increase in perinatal and infant mortality.

Interpretation

Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age.

Funding

ZonMw, The Netherlands and Dr Hans Ludwig Geisenhofer Foundation, Germany.

Introduction

When a fetus is diagnosed with early onset growth restriction, the main priority for the obstetrician, fetal medicine specialist, neonatologist, and parent is for the fetus to be delivered in optimum condition and survive the neonatal period. Nevertheless, outcomes in later life relating to neurodisability are of potentially greater importance than survival, are rarely reported, and cannot be inferred from whether or not complications occur in the neonatal period.1 Most studies of early onset fetal growth restriction have focused on short-term neonatal outcomes2, 3, 4 and only one, the GRIT study,5 was both randomised and reported infant follow-up at 2 years and the age at which the infant began school. The GRIT study randomly allocated women to early or delayed delivery when signs of fetal compromise were present, but the obstetrician was in equipoise as to whether delivery was indicated. Neonatal outcomes,6 childhood morbidity at 2 years,7 and at morbidity at school age8 did not show benefit for either group, thus not further informing management.

Several methods exist for surveillance of the at-risk fetus—eg, cardiotocography, arterial and venous Doppler examination, and biophysical profiles.9 The temporal sequence of these changes is variable,10 but generally, the more severe the growth restriction is, the more pronounced the Doppler changes are.11 No consensus exists for what is the best way to monitor growth restriction, what is the most appropriate trigger for delivery, and no trials of the importance of different criteria for delivery exist. In the preterm growth restricted fetus, the decision to deliver is usually made only when signs of substantial worsening of the fetal condition are observed by visual or qualitative assessment of a cardiotocograph tracing or changes in biophysical status because these changes correlate with fetal hypoxaemia.12 One prospective cohort study13 comparing short-term variation of fetal heart rate, Doppler of the umbilical artery, middle cerebral artery, and ductus venosus in early preterm pregnancies complicated by fetal growth restriction concluded that the abnormal ductus venosus pulsatility index was the best discriminating variable for neonatal outcome.

We therefore postulated that changes in the fetal ductus venosus Doppler waveform, which generally develop after those in the umbilical artery, might be used as indications for delivery instead of cardiotocograph short-term variation. To test this hypothesis, we designed a three group randomised trial to establish whether the assessment of the ductus venosus waveform could be a better method than cardiotocograph with short-term variation calculation alone to trigger delivery of the very preterm (before 32 week) growth restricted fetus.

Section snippets

Study design and participants

The Trial of Umbilical and Fetal Flow in Europe (TRUFFLE) study was a prospective, multicentre, randomised management trial done in 20 European tertiary care centres with a fetal medicine unit in five countries (Germany, Italy, the Netherlands, Austria, and the UK). Participants were included from Jan 1, 2005, to Oct 1, 2010, but not all hospitals started recruiting at the same time.14 Women were recruited by investigators with expertise in fetal assessment using secure web based randomisation.

Results

511 women were included in the study, of whom eight were subsequently excluded because they were entered in two centres from which no delivery or outcome data could be obtained (figure 1, table 1). 461 infants (92%) were alive at 2 years and complete follow-up data were available from 402 (87%; table 1). At delivery, 362 (72%) of 503 women had a hypertensive condition (table 2). Antenatal corticosteroids were given to 461 (92%) of women (table 2).

The median gestation at delivery was 30·7 weeks

Discussion

To our knowledge, this study is the first multicentre, randomised management trial to report outcomes in a large cohort of women whose fetuses had early onset growth restriction, being both small for gestational age and with evidence of fetoplacental insufficiency based on raised umbilical artery Doppler impedance (panel). Women were enrolled before giving birth and managed according to one of three prespecified management strategies. The proportion of infants who survived without

References (32)

  • J Unterscheider et al.

    Optimising the definition of intrauterine growth restriction: the multicenter prospective PORTO Study

    Am J Obstet Gynecol

    (2013)
  • JG Thornton

    When do obstetricians recommend delivery for a high-risk preterm growth-retarded fetus? The GRIT Study Group. Growth Restriction Intervention Trial

    Eur J Obstet Gynecol Reprod Biol

    (1996)
  • JG Thornton et al.

    Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial

    Lancet

    (2004)
  • A randomised trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation

    BJOG

    (2003)
  • DM Walker 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)
  • K Hecher et al.

    Monitoring of fetuses with intrauterine growth restriction: a longitudinal study

    Ultrasound Obstet Gynecol

    (2001)
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