Long-Term Follow-up of Very Preterm Infants

Abstract & Commentary

Synopsis: Individuals who were born very preterm (< 32 weeks) had higher rates of neurocognitive and behavioral problems than controls when studied in adolescence. More brain lesions were demonstrated by MRI than had been noted by neonatal cerebral ultrasonography.

Source: Stewart AL, et al. Brain structure and neurocognitive and behavioral function in adolescents who were born very premature. Lancet 1999;353:1653-1657.

Infants who are born very prematurely (< 32 weeks of gestation) are known to be at risk for neurocognitive handicaps in later life. The neurodevelopmental prognosis can be predicted by neonatal ultrasonography, but little is known about their function in later life. A cohort of 105 infants born before 33 weeks of gestation in 1979-1980 who had neonatal ultrasonograms were studied prospectively at 1, 4, and 8 years. At ages 14-15 years, 72 of these infants who remained in the United Kingdom (cases), and 21 age-matched controls who were born full term underwent brain MRIs as well as neurological, cognitive, and behavioral assessments. Of the 72 cases, 40 (55%) had unequivocally abnormal MRIs and an additional 15 had equivocally abnormal scans. Of the 21 controls, one (5%) had abnormal and five had equivocally abnormal MRI scans. Abnormalities of the ventricles, corpus callosum, and white matter were common in the cases. More brain lesions were identified by MRIs than had been noted by neonatal ultrasonography. The cases had significantly more reading, adjustment, and neurological impairments than controls, and their degree of behavioral impairment was significantly related to MRI abnormality.

Comment by Laura Ment, MD, FAAP

Preterm (PT) birth results in significant developmental disability, and several recent reports have suggested that cognitive outcome may be directly related to gestational age at birth. Neonates of less than 1250 g birth weight now represent almost 2% of all live births in the United States, and the survival rates of these infants approaches 85-90%. In conjunction with reports of increased survival, however, are troublesome data concerning long-term handicaps in these very low birth weight infants who often are critically ill in the first weeks and months of life.1 Bhushan reported an increase in cerebral palsy, which he attributed to the increasing prevalence of PT birth,2 and two studies have independently demonstrated that the incidence of cognitive deficits in this population has not changed over the past decade.3,4 Depending on the birth weights of the patient cohort examined and the years in which they were born, the incidence of major neurodevelopmental handicaps in very preterm infants ranges from 12-32%.5,6 In addition, it is these PT infants in whom high incidences of behavioral and school difficulties are now emerging. At age 8 years, more than half require special assistance in school, almost one-fifth are educated in designated special education classrooms, and 16% have repeated at least one grade.l,6 Such data suggest that strategies for identifying causes of disability in this population of patients are essential.

The study of Stewart and her colleagues is an extremely important one, therefore, because it begins for the first time to explore the structure-function relationship in the developing preterm brain. Stewart et al performed long-term follow-up studies of a group of very preterm infants who had neonatal cranial ultrasounds. Serial neurodevelopmental assessments were done on surviving study children, and MRI scans were performed on 72 children at age 14-15 years. These children were compared with 21 age-matched children born at term who served as controls. Both cases and controls were evaluated with cognitive, behavioral, and standard neurologic examinations.

MRI studies were considered to be normal in only 17 of the 72 (24%) preterm subjects; studies were equivocal in 15 (21%) and abnormal in 40 children (55%). For the term control children, studies were normal in 15 (71%), equivocal in five (24%), and abnormal in one (5%). The most common MRI abnormalities reported were ventricular dilatation, thinning or atrophy of the posterior body of the corpus callosum, and abnormal white matter signal; overall, 36 of the 72 (50%) preterm subjects had abnormalities of cortical white matter on MRI. In addition, although the specificity of neonatal cranial ultrasonography for predicting abnormal MRI at age 14-15 years was 94%, the sensitivity of this measure was only 22%. Those children who had neonatal ventriculomegaly were most likely to have abnormal MRI studies 14 years later.

For outcome assessment, preterm subjects were grouped into those with normal, equivocal, and abnormal MRI scans. Overall, preterm subjects were at much higher risk than term children for cognitive and neurologic abnormalities but Stewart et al were unable to detect significant differences in the incidences of cognitive, visual motor, or neurologic abnormalities between the preterm children with normal, equivocal, or abnormal MRI studies. Only the Rutter behavioral scores showed a clear association with abnormal cerebral MRI.

Stewart et al have made an important contribution to the understanding of the influence of preterm birth on cognitive outcome in adolescence. They have demonstrated what many investigators have long suspected but were unable to prove: children born prematurely are at high risk for structural CNS abnormalities. In this, the close of the NIH Decade of the Brain, these studies provide important baseline data. Future MRI studies will surely include diffusion-weighted imaging (DWI) analysis of axonal development and myelination 13 and 1H spectroscopic determinations of regional N-acetyl aspartate levels to approximate neuronal counts and synapse number. Finally, functional MRI (fMRI) studies may permit the exploration of the structure/function relationship in the developing brain.7 (Dr. Ment is Professor of Pediatrics and Neurology at the Yale University School of Medicine.)

References

1. McCormick MC, et al. Very low birth weight children: Behavior problems and school difficulty in a national sample. J Pediatr 1990;117:687-693.

2. Whitaker AG, et al. Neonatal cranial ultrasound abnormalities in low birth weight infants: Relation to cognitive outcomes at six years of age. Pediatrics 1996; 98:719-729.

3. Bhushan V, et al. Impact of improved survival of very low birth weight infants of recent secular trends in the prevalence of cerebral palsy. Pediatrics 1993;91: 1094-1100.

4. Piecuch R, et al. Outcome of extremely low birth weight infants (500-999 grams) over a 12-year period. Pediatrics 1997;100:633-639.

5. Hall A, et al. School attainment, cognitive ability and motor function in a total Scottish very-low-birthweight population at eight years: A controlled study. Dev Med Child Neurol 1995;37:1037-1050.

6. Klebanov P, et al. Classroom behavior of very low birth weight elementary school children. Pediatrics 1994; 94:700-708.

7. Peterson BS, et al. An fMRI study of Stroop word-color interference: Evidence for cingulate subregions subserving multiple distributed attentional systems. Biol Psychiatry 1999; in press.

True statements about long-term follow-up of surviving children who were born very preterm include all of the following except:

a. The reported incidence of major neurologic handicaps ranges from 12-20%.

b. More than half of these individuals require special assistance in school.

c. The frequency of abnormal MRIs can be accurately predicted by neonatal ultrasonography.

d. Half of these individuals have cortical white matter abnormalities on MRI.