MANUSCRIPT CITATION

Hintz S, Barnes P, Bulas D, Slovis T, Finer N, Wrage L, et al.  Neuroimaging and neurodevelopmental outcome in extremely preterm infants.  Pediatrics 2015;135:e32-42. PMID:25554820

REVIEWED BY

Jessica Christiano, MD
Pediatric Resident
Children’s Hospital of Philadelphia

John Flibotte, MD
Assistant Professor of Clinical Pediatrics
Children’s Hospital of Philadelphia

TYPE OF INVESTIGATION

Prognosis

QUESTION

In infants born at gestational age 24-27 completed weeks, how accurately does early cranial ultrasound, late cranial ultrasound, and near-term MRI findings predict neurodevelopmental impairment and significant gross motor impairment or death at 18-22 months corrected age? What’s the relative predictive value of these imaging modalities in predicting outcomes?

METHODS

• Design: Nested Prospective Cohort, where cohort was nested within SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network Randomized Controlled Trials
• Allocation: Observational, does not apply
• Blinding: Three masked central readers, reported neuroimaging results; certified examiners who determined this primary outcome were unaware of treatment allocations or clinical course of the infants
• Follow-up period: 18-22 months’ corrected age
• Setting: 16 Neonatal Research Network Centers between 2005-2009
• Patients:
  • Nested cohort of the SUPPORT Trial (NCT00233324)
  • Inclusion Criteria:
    • 24 to 27 completed gestational weeks
    • Enrolled in SUPPORT
    • MRI was obtained at 35 to 42 weeks’ gestational age, and only infants for whom the MRI was obtained within 2 weeks of late cranial ultrasound (CUS) were included in analysis
• Intervention: The study question focused on the ability of two different modalities of neuroimaging, CUS and MRI, to predict outcomes. In order to evaluate the importance of timing of the CUS, investigators considered both “early” CUS (4-14 days of life) and “late” CUS (35-42 weeks postmenstrual age).  MRI studies were obtained at 35-42 weeks postmenstrual age and within 2 weeks of the late CUS.  Imaging was obtained via local center clinical protocol.

Imaging results were analyzed for the presence or absence of major findings, using a modified central reading form for CUS and central reader form for MRI.  Major findings were defined as follows:

Early CUS major findings: Grade III/IV IVH; cystic PVL

Late CUS major findings: Cystic PVL; porencephalic cysts; moderate (ventricle to brain ratio of 1:3 to 2:3) to severe (>2:3) unilateral or bilateral ventricular enlargement; ventricular shunt

MRI major findings:  Moderate or severe white matter abnormality (WMA) as previously defined by Woodward et al (1); significant cerebellar lesions

US images were read centrally by 2 observers with high inter-rater reliability of Kappa 0.75 for early imaging and 0.88 for late imaging.  All MRI images were read by 1 observer; interrater agreement for moderate-severe WMA scoring of the central reader form used is reported to be 96-98% (1).

• Primary Outcomes:
  1. Neurodevelopmental impairment (NDI) or death
     • NDI defined as Bayley III score <70, moderate-severe CP, GMFCS score > 2, severe hearing impairment, or bilateral severe visual impairment
  2. Significant gross motor impairment or death
     • Gross motor impairment defined as diagnosis of moderate-severe CP or GMFCS score >2
• Secondary Outcomes: Association of imaging findings with cognitive score <85 or <70, any diagnosed CP or moderate-severe CP, NDI or death, unimpaired/mildly impaired versus significant gross motor impairment

• Analysis and Sample Size: Sample size was not calculated due to empiric accrual of all infants in 16 NRN centers participating in SUPPORT who met entry criteria. 480 infants met the inclusion criteria of having late CUS and brain MRI within 2 weeks of each other.  Unadjusted analysis for association between imaging findings and outcomes were performed using standard methods of chi-squared and Fisher’s exact test/ANOVA.

Stepwise linear mixed modeling taking into consideration 4 sets of risk variables was used to construct receiver operator characteristic (ROC) curves to assess predictive value of imaging in NDI or death and significant gross motor impairment or death. The following 4 factors were added in stepwise fashion with calculation/comparison of resulting areas under the curve (AUC) of ROC curves: 1) perinatal and neonatal risk factors; 2) early CUS adverse findings; 3) late CUS adverse findings; 4) MRI adverse findings.

Of note, the perinatal and neonatal risk factors considered in constructing ROC curves for each primary outcome were selected from a predefined list of 12 factors if they had proven association with the outcome when explicitly tested.  For the outcome of NDI or death, the perinatal factors included were race, late sepsis, BPD, and postnatal steroids.  For the outcome of significant gross motor impairment or death, the perinatal factors included were multiple gestation, maternal insurance, race, late sepsis, BPD, and postnatal steroids.

• Patient follow-up: 480 infants were enrolled; 15 infants died before 18 months’ correct age and while no follow-up was obtained for them, they were included in the composite outcomes. 20 children were lost to follow-up; a Bayley III score was obtained for 441 children and neurosensory exam for 445 children.
• Percent included in analysis: Follow-up was 456/480 (95%) for the outcome of NDI or death and 460/480 (96%) for the outcome of significant gross motor impairment or death.

MAIN RESULTS

Independent associations of neuroimaging findings and patient outcomes were presented in Table 6 and tested within full and limited models– these models defined by which imaging results were included. Notable findings included:

In a full model (all types of imaging included):

1. Significant association of adverse late CUS findings with NDI or death (OR 9.8) as well as significant gross motor impairment or death (OR 10.9)
2. Significant association of cerebellar lesions on MRI with both NDI or death (OR 3.0) and significant gross motor impairment or death (OR 5.2)

In limited models (only some imaging included):

1. Excluding late CUS, MRI with moderate or severe WMA and MRI with significant cerebellar lesions were significantly associated with NDI or death (OR 2.4 and 2.7, respectively) and significant gross motor impairment or death (OR 2.8 and 4.5, respectively)
2. Excluding MRI, adverse late CUS findings were significantly associated with NDI or death (OR 11.9) and significant gross motor impairment or death (OR 13.2)

The authors presented their results in Table 7, as follows:

The authors did not present data for traditional measures of diagnostic testing such as sensitivity, specificity, positive predictive value and negative predictive value.

CONCLUSION

In this large prospective nested cohort study, Hintz et al present data from 480 extremely preterm infants in the post-surfactant era and demonstrate that late CUS is more reliable than early CUS in predicting neurodevelopmental outcomes.  Early CUS was not predictive of future neurodevelopmental outcomes in any of the multivariable models.  The ability to predict outcomes is only mildly enhanced with the addition of MRI to late ultrasound results.  In environments where MRI is not easily available, late CUS alone may be sufficient in predicting prognosis.

COMMENTARY

Neurodevelopmental outcomes are a crucial part of prognosis and are pivotal in on-going conversations between neonatologists and parents (4,5).  Recent studies show greater predictive value in near-term cranial ultrasound (CUS) and MRI versus traditional CUS performed in the first few weeks of life (3,4,5).  MRI detects white matter injury more accurately while US detects intraventricular hemorrhages, ventriculomegaly, and cystic periventricular leukomalacia (1,2,5).  However, studies have found former preterm infants with developmental impairments despite normal NICU ultrasounds, and, importantly, others have reported transient findings of cystic periventricular leukomalacia (resolving by near-term) is associated with developmental impairments (5,7,8).

The NEURO prospective study by Hintz et al analyzed the predictive ability of early CUS, near-term CUS, and near-term MRI in a cohort of 480 extremely preterm neonates, born at 24-27 weeks (9).  Negative outcomes were defined as neurodevelopmental impairment, significant gross motor impairment, or death.  The authors provided multivariable modeling to consider perinatal and neonatal demographic and clinical risk factors.  Results were presented as OR and AUC of ROC curves.  Further statistical calculations of tables 2-5 show sensitivity and specificity of 0.27 and 0.92, respectively, for the association between major findings in early CUS and negative outcomes of neurodevelopmental impairment or death, compared to sensitivity of 0.28 and specificity of 0.97 for major findings in late CUS.  The calculated sensitivity and specificity of MRI WMA is similar to that reported by Woodward et al in 2006 (92% vs 84% and 23% vs 34%, respectively), demonstrating that MRI has potential for higher sensitivity than CUS (1).  The major findings of the NEURO study were that early CUS is not predictive of future neurodevelopmental outcomes, despite taking into account perinatal and neonatal demographic and clinical risk factors.  The ability to predict outcomes is only mildly enhanced by the addition of MRI to late CUS.  Therefore, in environments where MRI is not easily available, late CUS may be sufficient in predicting prognosis.

The strengths of the NEURO study included large population size, blinded imaging evaluations, required temporal proximity of late CUS and MRI.  Limitations included that CUS were obtained by local center protocol with possibility for technical inconsistencies, and there were low rates of adverse outcomes, leading to wide confidence intervals.  While multivariable modeling taking into account neonatal risk factors scrutinizes results, a drawback is potential over-analysis.

Near-term CUS and MRI has been shown to be more reliable alternatives to early CUS in predicting outcomes, but imaging is only mildly effective in formulating predictions of neurodevelopmental outcomes in extremely premature neonates (1,5,6).  There is still considerable uncertainty regardless of imaging modality or combination of imaging modalities used.  Studies have shown that MRI before discharge is too early to detect posterior limb internal capsule myelination abnormalities, which have been shown to be associated with gross motor deficits (2,3).  Extending outcomes to include cognitive and behavioral difficulties of school-age ex-premature neonates will detect deficits not fully appreciated on Bayley or GMFCS testing (5,6).

REFERENCES

1. Woodward L, Anderson P, Austin N, Howard K, Inder T. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006;355(7):685–694.
2. de Vries L, van Haastert I, Benders M, Groenendaal F. Myth: cerebral palsy cannot be predicted by neonatal brain imaging. Seminars in Fetal and Neonatal Medicine 2011;16(5):279–287.
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6. O’Shea TM, Allred EN, Kuban KCK, et al. ELGAN Study Investigators. Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants.  J Child Neurol.  2012;27(1):22-29.
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8. Sarkar S, Shankaran S, Laptook A, Sood B, Do B, Stoll B, et al. Screening cranial imaging at multiple time points improves cystic periventricular leukomalacia detection. Am J Perinatol 2015;32(10): 973-979.
9. Hintz S, Barnes P, Bulas D, Slovis T, Finer N, Wrage L, et al. Neuroimaging and neurodevelopmental outcome in extremely preterm infants.  Pediatrics 2015;135:e32-42.