The association of neonatal morbidity with long-term neurological outcome in infants who were growth restricted and preterm at birth: secondary analyses from TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe)

BJOG. 2017 Jun;124(7):1072-1078. doi: 10.1111/1471-0528.14511. Epub 2017 Feb 3.


Objective: To study the relationship between neonatal morbidity (NNM) and two-year neurodevelopmental impairment (NDI) in surviving children after early fetal growth restriction (FGR).

Design: Secondary analysis of a European randomised trial (TRUFFLE) of delivery for very preterm fetuses dependent on venous Doppler or cardiotocographic criteria.

Setting: Tertiary perinatal centres, participants in TRUFFLE.

Population: 402 surviving children after early FGR.

Methods: Prospective data were collection from the recognition of FGR until the corrected age of two years. We studied the association between NNM and NDI, retaining trial allocation in all statistical models. NNM included any of bronchopulmonary dysplasia, brain injury, sepsis or necrotising enterocolitis. NDI was a composite of Bayley cognitive score < 85, cerebral palsy or severe sensory impairment.

Main outcome measure: NDI in relation to NNM.

Results: NNM occurred in 104 cases (26%) and was more frequent in 17 of 39 infants with NDI (44%) than in the 87 of 363 infants with normal outcome (24%) [odds ratio 2.5 (95% CI, 1.3-4.8); P = 0.01]. In 22 of 39 NDI cases (56%) there was no preceding NNM. NNM was inversely related to gestational age, but NDI did not vary by gestational age. In multivariable analyses, cerebral ultrasound abnormalities were most strongly associated with NDI, together with trial group allocation, birthweight ratio, infant sex and Apgar score.

Conclusions: With the exception of cerebral ultrasound abnormalities, commonly used NNMs are poor markers of later NDI and should not be used as surrogate outcomes for NDI.

Tweetable abstract: Neonatal morbidities cannot be used as surrogate outcomes for neurodevelopmental impairment.

Keywords: Fetal growth restriction; neonatal morbidity; neurodevelopmental impairment; prediction.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Europe / epidemiology
  • Female
  • Fetal Growth Retardation / epidemiology*
  • Humans
  • Infant
  • Infant, Extremely Premature / growth & development*
  • Infant, Newborn
  • Infant, Premature, Diseases / epidemiology*
  • Male
  • Neurodevelopmental Disorders / epidemiology*
  • Neurodevelopmental Disorders / etiology
  • Pregnancy
  • Premature Birth
  • Prospective Studies
  • Risk Factors
  • Ultrasonography, Prenatal