NEURO Study: Neonatal neuroimaging with strong negative predictive value for developmental outcomes
1. In multivariate analyses, adverse late cranial ultrasound findings (CUS) were an independent risk factor for full scale IQ scores <70 (FSIQ <70). Adverse late cranial ultrasound findings and adverse findings on MRI were independent risk factors for moderate-to-severe disability (MTSD)
2. The positive predictive value (PPV) for adverse cranial ultrasound (CUS) and MRI findings on FSIQ <70 and MTSD was poor, but the negative predictive value (NPV) was good to excellent for both outcomes.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Extremely preterm (EPT) neonates born <28 weeks' gestation are at increased risk for neurodevelopmental delays later in childhood. The purpose of this study was to evaluate the association between, and the diagnostic value of, adverse findings on neuroimaging and neurodevelopmental outcomes at 6 to 7 years of age. The Neuroimaging and Neurodevelopmental Outcomes (NEURO) study was a subgroup analysis of the larger Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT), a multicenter randomized controlled trial, that studied ventilation and oxygenation strategies in neonates born at 24 weeks' to 27 weeks and 6 days' gestation. In unadjusted analyses, their data showed that adverse findings on early and late CUS, and on MRI, were significantly associated with and higher rates of FSIQ<70 and MTSD. However, in adjusted analyses including perinatal risk factors, only late adverse CUS findings remained as a significant independent risk factor for FSIQ <70, and only adverse MRI and adverse late CUS findings remained as significant independent risk factors for MTSD. The PPV of adverse findings on neuroimaging was poor for FSIQ <70 and MTSD, but the NPV was very good to excellent for both outcomes. Area under the curve estimates improved with the addition of neuroimaging to models with perinatal risk factors, but the confidence intervals had substantial overlap. For clinicians, these data may allow clinicians to offer reassurance in perinatal counseling for neonates without adverse findings on neuroimaging, while it is important to convey the uncertainty of positive studies.
In-Depth [prospective cohort]: The final analysis of this prospective study included 386 children of an original cohort of 480 (83.3% follow-up among survivors) who underwent neonatal neuroimaging and school age follow-up. Of the original cohort, 17 died and 77 were lost to follow-up before the school age assessment. CUS was obtained at an “early” window (4-14 days) and a “late” window (35-42 weeks postmenstrual age, PMA). Adverse early CUS composite findings included grade III-IV intracranial hemorrhage (ICH) or cystic periventricular leukomalacia (cPVL) while adverse late CUS composite findings included cPVL or a porencephalic cyst, and moderate-to-severe ventricular enlargement (VE) unilaterally or bilaterally. Brain MRIs were obtained at 35-42 weeks PMA, within 2 weeks of late CUS, and were evaluated for cerebellar lesions and graded for white matter abnormalities (WMA). School-age assessments were done at 6 to 7 years of age and included an evaluation with the FSIQ of the fourth edition of the Wechsler Intelligence Scale for children (WISC-IV), neurologic testing for cerebral palsy (CP) graded via the gross motor function classification system (GMFCS), and evaluation for vision and hearing loss. Primary outcomes included significant cognitive impairment defined as an FSIQ <70 and moderate-to-severe disability defined as an FSIQ <70, CP with a GMFCS level ≥2, severe hearing impairment, or severe vision impairment.
In unadjusted analyses, the percent of FSIQ <70 was significantly higher in those with adverse findings on early and late CUS compared to those without, as was the percent of neonates with MTSD. For MRI findings, a more severe rating of WMA was associated with a significantly higher rates of FSIQ <70 and MTSD. The percent of FSIQ <70 was also significantly higher in children with a history of cerebellar lesions on MRI compared to those, as was the percent with MTSD. Adverse early CUS findings had a PPV and NPV for FSIQ <70 of 28 and 89, and for MTSD, a PPV and NPV of 42 and 88, respectively. Adverse late CUS findings had a PPV and NPV for FISQ <70 of 58 and 90, and for MTSD, a PPV and NPV of 77 and 89, respectively. Adverse MRI findings had a PPV and NPV for FSIQ <70 of 21 and 90, and a PPV and NPV for MTSD of 29 and 89, respectively. In multivariate models, only adverse findings in late CUS remained as a significant independent risk factor for FSIQ <70. For MTSD, only adverse findings on late CUS and positive cerebellar lesions on MRI remained as independent risk factors. AUCs improved when neuroimaging was added to models with just perinatal risk factors, but 95% CIs were wide: For FSIQ <70, the AUCs for adverse neuroimaging with perinatal risk factors and perinatal risk factors alone were 0.78 (95%CI 0.70-0.86) and 0.68 (95%CI 0.60-0.77). For MTSD, the AUCs for neuroimaging with perinatal risk factors vs. perinatal risk factors alone were 0.75 (95%CI 0.66-0.82) and 0.64 (95%CI 0.56-0.72).
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