We evaluated the relationship between neonatal cranial ultrasound findings and standardized developmental assessments in extremely low gestational age neonates. As have others, we found that cranial ultrasound abnormalities are more strongly associated with delayed development of skills assessed with the PDI than those assessed with the MDI5,19–21
and that ventriculomegaly and echolucency are the ultrasound findings associated most strongly with delayed infant development.9,22
Among ultrasound diagnoses, cystic PVL and PVHI are associated most strongly with developmental delay,5,12,13
although bilateral cerebellar hemorrhage, found in 1% of our cohort, may be comparably predictive of adverse outcome. The lower predictive value of echodensity is to be expected, because the reliability of cranial ultrasound interpretations used in our study was lower for echodensity (κ
= 0.3), as compared with IVH, ventriculomegaly, and echolucency (κ
The frequency of an MDI of <70 described here (26%) is similar to that observed in a cohort born at 23 to 27 weeks,23
and the rate that we observed among infants without ultrasound abnormalities (23%) is similar to that of a cohort with a birth weight of 401 to 1000 g.24
We found evidence that the risk of developmental delay varies with laterality, location, and extent of white matter abnormalities. For example, bilateral echolucency was associated more strongly with delayed development than unilateral echolucency.3,25,26
Unexpected are our findings that unilateral ventriculomegaly is as strongly associated with low PDI as is bilateral ventriculomegaly and that unilateral echodensity is as strongly associated with low BSID-II scores as is bilateral echodensity.
Others have found that ultrasound abnormalities are associated with a twofold to fourfold increase in the risk of low BSID-II scores5
and mental retardation.27
These include the findings of ventriculomegaly and echolucency, which most often are seen after the initial scan9,10,28,29
; the diagnosis of PVHI, which often is present on scans performed in the first weeks of life30–32
; and cystic PVL, which typically is not present until several weeks after birth.9,28,29
In the only study we found that assessed whether the hemispheric side of white matter lesions influences developmental outcome, intelligence quotients were higher and visual motor integration was better at 8 years of age among children born preterm who had right-sided cerebral lesions as compared with those with left-sided lesions.25
In the current study, infants with right-sided echolucency had better scores for PDI, but those with right-sided echodensity had worse scores for MDI. Most likely these right-left differences are because of random variation.
In this study, unilateral ventriculomegaly seen on early ultrasound (ie, the first 14 days) was more predictive of low BSID-II than was bilateral ventriculomegaly. In contrast, fetuses with unilateral33
or bilateral ventriculomegaly34
typically have normal developmental outcome.
The stronger association between cranial ultrasound abnormalities and a PDI of <70, as compared with an MDI of <70, might relate, in part, to the greater contribution of periventricular brain structures, such as corticospinal tracts, to functions assessed with the PDI, such as perceptual-motor integration, sensory integration, and quality of movement.18
On the other hand, substantial white matter is located in associative areas, which influence cognitive abilities, such as those assessed with the MDI (eg, memory, problem-solving skills, and language development). In addition, children who have early imaging evidence of periventricular white matter damage also have reduced cortical volume.35
This has been attributed to damage to myelin-producing cells36
and neurons, which migrate to the cortex through injured white matter.37
Such damage might be more diffuse and widespread with ventriculomegaly and more focal with echolucency.
The importance of the cerebellum in cognitive development is supported by studies correlating cerebellar size and scores on cognitive testing38
and studies of developmental outcome after cerebellar hemorrhage.39,40
After the advent of neonatal intensive care, cerebellar hemorrhage was described in autopsy studies of preterm infants.41
After ultrasound imaging improved, this lesion could be identified in surviving infants.39,40
As have others,42
we found that ~3 of every 4 infants with cerebellar hemorrhage had delayed psychomotor development and that more than half had delayed mental development.
If ultrasound detected all, or most, white matter damage, we would expect the risk of low BSID-II scores to be higher with bilateral, as compared with unilateral, ventriculomegaly and with bilateral, as compared with unilateral, echodensity; but we observed neither. In addition, the risk of low BSID-II scores did not increase in a graded fashion with an increasing extent of unilateral echolucency. Finally, as reported by others,24
we found that approximately one quarter of extremely premature infants with normal ultrasounds have BSID-II scores <70.
The most parsimonious explanation for these findings is that ultrasound detects only a fraction of the total white matter damage. Support for this hypothesis, referred to as the “tip-of-the-iceberg” hypothesis,36
comes from studies correlating ultrasound findings with either MRI43,44
or postmortem examination.45
In addition, ~50% of infants who develop cerebral palsy have ultrasound abnormality.7,46,47
A likely explanation for our finding that echodensity and echolucency were found predominantly in zones located superior to the lateral ventricles and were infrequently seen in zones closest to the temporal lobes and zones closest to the occipital lobes is better visualization of the superior aspects of the brain when using an ultrasound through the anterior fontanelle.
Perhaps the main limitation of this study was our dependence on ultrasound to identify white matter damage. Early MRI does a much better job, especially of detecting diffuse white matter damage.48–50
Thus, the study might have misclassified some scans as not showing white matter damage, when, indeed, an MRI would have identified white matter damage.
Strengths of this study include the large sample51
based on gestational age rather than birth weight,52
efforts to minimize interobserver disagreements about ultrasound findings,16
efforts to standardize the administration of the BSID-II and minimize examiners’ knowledge of the infants’ clinical histories, and the high proportion of infants with ultrasounds obtained after the first month of life, when white matter damage may be seen for the first time.9
Finally, to classify study participants who were not testable with the BSID, we used proxy measures of developmental status in an effort to decrease bias (ie, “missing clinical data bias”53
The most important implication of our study is that clinicians can use ultrasound markers of white matter damage (ventriculomegaly, echodensity, and echolucency4,36,45,54
) as predictors of developmental impairment.13,25,27,55
Children with these markers can be targeted for early intervention to improve developmental outcome.56,57
This use of ultrasound is part of the basis for the Practice Parameter for Neuroimaging of the Neonate in 2002,41
which recommends cranial ultrasound screening for infants born before 30 weeks’ gestation, at 7 to 14 days, and again at 36 to 40 weeks. In a study of very preterm infants, the sensitivity of major ultrasound abnormalities (ie, Papile grade III hemorrhage, echodensity, echolucency, and basal ganglia lesions) for prediction of cerebral palsy was 95% and the specificity was 99%.9
The sensitivity and specificity are lower for the prediction of other developmental impairments, particularly nonmotor impairments. In a multicenter study of 2103 infants, the sensitivity, specificity, and likelihood ratio positive for cystic PVL for identifying infants with a PDI of <70 were, respectively, 0.30, 0.80, and 6.00,58
as compared with the values reported here for echolucency (0.14, 0.96, and 3.50). Similar likelihood ratios for the prediction of a PDI of <70 were reported from studies of an index of chronic physiologic instability59
and the Nursery Neurobiological Risk Score.60
Thus, when the clinical goal is prediction of low scores on the BSID-II, other clinical information may be complementary to,59
or even more valuable than,58
cranial ultrasonography. Alternative methods, such as MRI48,49
or more frequent scanning with ultrasound,9
might improve the predictive value of neuroimaging. Nonetheless, the information provided here can be used cautiously to counsel parents and plan for developmental services for infants at high risk.
What’s Known on This Subject
In low birth weight and preterm newborns, cranial ultrasound abnormalities indicative of white matter damage are the strongest predictors of cerebral palsy and developmental delays.
What This Study Adds
The association of cerebral white matter damage and developmental impairments applies to extremely low gestational age newborns. The association is stronger for motor, as compared with mental, development. Cerebellar hemorrhage is strongly associated with delayed mental and motor development.