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Original article
The relationship between ventricular size at 1 month and outcome at 2 years in infants less than 30 weeks’ gestation
  1. Lisa M Fox1,2,
  2. Pauline Choo1,3,
  3. Sheryle R Rogerson1,2,
  4. Alicia J Spittle1,4,
  5. Peter J Anderson4,5,
  6. Lex Doyle1,2,4,
  7. Jeanie L Y Cheong1,2,4
  1. 1Neonatal Services, Royal Women's Hospital, Melbourne, Australia
  2. 2Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia
  3. 3Department of Paediatrics, Hospital Tuanku Ja'afar Seremban, Negeri Sembilan, Malaysia
  4. 4Murdoch Childrens Research Institute, Melbourne, Australia
  5. 5Department of Paediatrics, University of Melbourne, Melbourne, Australia
  1. Correspondence to Dr Lisa M Fox, The Royal Women's Hospital, Locked Bag 300, Parkville, VIC 3052, Australia; lisa.fox{at}thewomens.org.au

Abstract

Background Cranial ultrasound cerebral biometric measurements have been used in preterm neonates, particularly in cases of ventriculomegaly. While cerebral biometric measures using MRI have been found to correlate with long-term outcome, the relationship between cranial ultrasound biometric measures and neurodevelopmental outcome has not been established.

Objective To assess the relationship between ventricular size at 1 month of age using cranial ultrasound and neurodevelopmental outcome at 2 years in very preterm infants.

Method Digital cranial ultrasound images taken between 25 and 35 days of age of 44 infants born at less than 30 weeks’ gestation were analysed independently by two observers. Infants with significant ultrasound abnormalities were excluded. A range of ultrasound linear measures were correlated with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) motor, language and cognitive composite scores at 2 years using linear regression.

Results Larger lateral ventricular sizes (anterior horn width, ventricular height, midbody ventricular height) and larger ventricular-brain biparietal ratios were related to poorer motor composite score at 2 years. A ventricular-brain ratio of less than 0.3 was reassuring with regard to motor outcome. Poorer language composite scores at 2 years were associated with larger midbody ventricular heights. There was little evidence of a relationship with the cognitive composite score.

Conclusions Larger lateral ventricles in the parietal region at a month of age were related to poorer motor development at 2 years. Larger ventricular measurements were also related to slower early language development. The role of cranial ultrasound biometric measures as biomarkers of later outcome in very preterm infants warrants further investigation.

  • ultrasonography
  • infant
  • preterm
  • outcome

https://doi.org/10.1136/archdischild-2013-304374

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    What is already known

    • Diffuse brain injury that results in white matter loss and adversely affects neurodevelopmental outcome is difficult to detect on cranial ultrasound.

    • Linear cerebral biometric measures of brain structures and volumes using MRI at term corrected age correlate with neurodevelopmental outcome in very preterm infants.

    • Cranial ultrasound linear measures of the lateral ventricles at term corrected age correlate with MRI abnormalities.

    What this study adds

    • Ventricular size measured early in the postnatal course using linear ultrasound biometric measures correlate with 2-year neurodevelopmental outcome in very preterm infants.

    • Larger lateral ventricles in the parietal region at 1 month of age are associated with poorer motor outcome at 2 years.

    • These biometric measures have very good interobserver reliability.

    Introduction

    Cranial ultrasound scanning (CUSS) is a useful bedside tool for imaging the neonatal brain. Despite limitations with field of view, grey-white matter differentiation and subtle parenchymal abnormalities, CUSS has an established role in detection of important brain pathology that relates to outcome in preterm infants such as intraventricular haemorrhages (IVH), periventricular haemorrhagic infarctions and cystic periventricular leukomalacia (PVL).1–3

    It is well recognised that these abnormalities detected on CUSS do not reflect all forms of preterm brain injury and that a proportion of very preterm infants have diffuse PVL that is not readily detectable using CUSS. This white matter loss (WML) and subsequent decreased brain volume has been demonstrated using MRI at term equivalent age and been shown to be predictive of developmental delay and cerebral palsy.4 Linear measures of cerebral biometrics using MRI have been found to correlate with cognitive and motor development in very preterm children.5

    Similar cerebral biometrics can be obtained using CUSS. It has been suggested that ventricular dilatation seen on CUSS can reflect WML related to preterm brain injury.6 Various authors have focused on CUSS assessment of WML, either by directly measuring cerebral structures or using increases in extra axial and ventricular spaces as a sign of reduction in brain size within the cranial vault. These studies have largely involved infants assessed at term corrected age.7–10 Woodward et al4 suggested that CUSS at 6 weeks postnatal age was inferior to MRI at term at predicting outcome; however, the CUSS was interpreted only in regard to major IVH or PVL. There are limited data describing early differences in ventricular size using CUSS biometrics and the relationship to neurodevelopmental outcome. We aimed to establish the interobserver reliability of CUSS biometrics measures at 1 month of age in a group of very preterm infants and to explore the relationship of these measures with corrected gestational age and 2-year neurodevelopmental outcome. We were particularly interested in whether these biometric measures related to outcome in very preterm infants without major IVH and PVL in whom neurodevelopmental outcomes in relation to CUSS findings are less well established.

    Methods

    Participants

    Very preterm infants cared for at the Royal Women's Hospital, Melbourne, who were <30 weeks’ gestational age at birth and enrolled in a randomised controlled trial of developmental care at home between January 2005 and January 2007 were eligible for this study if they had a cranial ultrasound scan performed between 25 and 35 days after birth. The intervention of developmental care did not significantly improve cognitive, language or motor developmental scores at 2 years.11 Ethics approval was obtained from the Royal Women's Hospital's Human Research Ethics Committee.

    Cranial ultrasound scans

    The cranial ultrasound images were obtained between 25 and 35 days after birth using a General Electric LOGIQ 9 ultrasound scanner (GE Healthcare Technologies, Waukesha, Wisconsin, USA) with an 8 MHz curvilinear transducer via the anterior fontanelle as part of routine clinical care. Measurements were calculated postacquisition from stored digital images by two independent examiners who were unaware of the clinical details and outcome—one experienced sonographer and one trainee with over 1 year's cranial ultrasound experience. The following CUSS biometrics were measured in two standard cranial ultrasound planes:

    First plane—coronal, at the level of the third ventricle (figure 1):

    1. Lateral ventricle anterior horn width—distance between the ventricle walls.12

    2. Lateral ventricular index—distance between the most lateral wall of the each ventricle and falx.13

    3. Lateral ventricular transverse width—combined width of both lateral ventricles.14

    4. Biparietal diameter–internal diameter of the skull at the level of the Sylvian fissure.14

    Figure 1
    Figure 1

    Coronal view. (A) anterior horn width, (B) ventricular index, (C) ventricular transverse width, (D) biparietal diameter.

    Ventricular-brain ratio (lateral ventricle transverse width divided by the biparietal diameter) was calculated from measures C and D.14

    Second plane—parasagittal (figure 2):

    1. Ventricle height—vertical diameter of the anterior horn of the lateral ventricle at the apex of the thalamus corresponding to the level of the foramen of Monro.15

    2. Ventricle midbody height—diameter of the body of the lateral ventricle.7

    Figure 2
    Figure 2

    Parasagittal view. (A) ventricular height, (B) midbody height.

    Neurodevelopmental outcome

    The children were assessed at 2 years of age (adjusted for prematurity) using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) by examiners blinded to the clinical and sonographic details.16 Ninety-three per cent of the assessments were performed by a single assessor; the remaining 7% were performed by two other assessors. The motor (fine and gross motor), language (receptive and expressive communication) and cognitive scales were administered. The variables of interest in this study were the cognitive, language and motor composite scores, which have a mean of 100 and SD of 15.

    Statistics

    Data were analysed using STATA V.12 (StatCorp, Texas, USA). Participant characteristics were compared using t tests or χ2 analyses. Interobserver reliability for the individual biometric measurements was calculated using the intraclass correlation coefficient (ICC). An ICC of >0.70 was considered to demonstrate strong agreement between examiners. Linear regression was performed to establish the relationship between CUSS biometrics and corrected gestational age at time of scan. Linear regression was used to establish the relationship between CUSS biometrics and Bayley-III motor, language and cognitive scores, first in a univariable analysis, and then adjusted for gestational age at birth, corrected age at scan and sex.

    Results

    Of the 120 infants enrolled in the randomised controlled trial, 68 had CUSS that fulfilled our study criteria. The other infants had scans outside of the predefined 10-day study period or had been transferred elsewhere before day 25. Two infants withdrew from the study at their parent's request and two died before 2 years of age. Six infants with major cranial ultrasound abnormalities (large IVH with ventricular dilatation, parenchymal haemorrhagic infarction or PVL) were excluded. Digital images were not available for 14 infants; thus, 44 infants were included in the study (figure 3).

    Figure 3
    Figure 3

    Study population.

    The perinatal characteristics of the study sample are shown in table 1, along with the remainder of the cohort.

    View this table:
    Table 1

    Clinical characteristics

    Twelve infants (27%) were born at 23–25 weeks’ gestation, 19 (43%) at 26–27 weeks and 13 (30%) at 28–29 weeks.

    Seven infants had minor focal pathology that appeared to have no impact on ventricular size: one had a unilateral cerebellar hemisphere haemorrhage and six had small germinal matrix/intraventricular haemorrhages (GM/IVH) without ventricular dilatation seen on imaging in the first week that had largely or completely resolved by the time of the study scan.

    Interobserver reliability of ultrasound measures

    The ICCs for interobserver reliability between examiners are shown in table 2. Most measures correlated well between examiners. The ventricular index measures, particularly the right, had lower ICCs compared with the other measures and have therefore been excluded from further analysis.

    View this table:
    Table 2

    Interobserver reliability of ultrasound measures between examiners

    Given the good reliability between the examiners, the measures reported below are the mean of the measurements taken by the two examiners.

    Size of the ventricles and the Bayley-III score

    The measurements of the ventricles and the Bayley scores of the study cohort are given in table 3.

    View this table:
    Table 3

    CUSS measures and Bayley-III composite scores

    Relationship between CUSS measures and corrected gestational age at time of scan

    The ventricular transverse width and the biparietal diameter increased with increasing age at the time of the scan; the other measures did not (table 4).

    View this table:
    Table 4

    Relationship between USS biometrics at 1 month and gestational age at scan

    Relationship between CUSS biometric measures and 2-year outcome

    Larger lateral ventricular sizes (anterior horn width, ventricular height, midbody ventricular height) were related to poorer motor development as assessed on the Bayley-III at 2 years (figure 4). There was a reduction in motor scores of a mean (SE) of 3.3 (1.2, right side) and 3.5 (1.3, left side), respectively, for every 1-mm increase in midbody height measurements at 28 days (p value for both ≤0.01).

    Figure 4
    Figure 4

    Relationship between cranial ultrasound measurements and composite motor scores on the Bayley-III developmental assessment. The x-axis shows composite score difference for every 1-mm change in ultrasound measurement. The analysis was adjusted for gestational age at birth, corrected age at scan and sex.

    Conclusions remained unchanged for all US measures when fine and gross motor scores were analysed separately, with the exception of the right anterior horn width and the ventricular-brain ratio, where the relationship was weak and failed to reach statistical significance with fine motor scores only.

    Language scores were lower with larger left midbody ventricular height (figure 5). There was little evidence of a relationship between cognitive development and CUSS measurements (figure 6).

    Figure 5
    Figure 5

    Relationship between cranial ultrasound measurements and composite language scores on the Bayley-III developmental assessment. The x-axis shows composite score difference for every 1-mm change in ultrasound measurement. The analysis was adjusted for gestational age at birth, corrected age at scan and sex.

    Figure 6
    Figure 6

    Relationship between cranial ultrasound measurements and composite cognitive scores on the Bayley-III developmental assessment. The x-axis shows composite score difference for every 1-mm change in ultrasound measurement. The analysis was adjusted for gestational age at birth, corrected age at scan and sex.

    The correlations between larger left midbody height measurements and lower language (coefficient −5, r2=0.18, p value= 0.011) and motor (coefficient −3.5, r2=0.18, p value=0.010) scores are illustrated in figure 7.

    Figure 7
    Figure 7

    Relationship between left midbody height measurements and language and motor score on the Bayley-III developmental assessment.

    Ventricular-brain ratio also correlated with motor development, with lower motor scores associated with increasing ventricular ratio (coefficient −181, r2=0.25, p value 0.002) (figure 8). A ventricular-brain ratio less than 0.3 was not associated with poorer motor outcome in this cohort.

    Figure 8
    Figure 8

    Relationship between ventricular ratio measurements and motor score on the Bayley-III developmental assessment.

    Discussion

    This study demonstrates that brain growth measurements from as early as 1 month of age in very preterm infants correlate with neurodevelopmental outcome at 2 years. These observations suggest that the altered brain growth of preterm infants can be detected even in those without significant sonographically detectable focal intracranial pathology. We are not aware of any other reports of biometric measures at this age that assess the relationship with 2-year outcome.

    A plausible explanation for the association between midbody height and motor and language development could be that the ventricles have expanded in this area to compensate for the localised WML of the corticospinal tracts which are adjacent to this portion of the lateral ventricle, thus altering the shape of the ventricle. Cognition is dependent on diffuse neural networks and somewhat surprisingly ventricular dilatation at this time point was not related to cognitive development. The formation and function of the ventricular system remain poorly understood, and explanations remain speculative.

    The infants in the ultrasound scanning sample were younger and lighter at birth than the remainder of the cohort. This likely reflects the neonatal unit practice that infants are transferred to level II units once they are mature enough; thus, the infants born at older gestational ages are less likely to still be in our unit at a month of age. Although most neonatal morbidity was more common in the study sample, in keeping with their relative immaturity, the differences were not statistically significant. This is likely due to the relatively small sample size.

    The interobserver reliability in this study was very good for most measures and provides some reassurance that these measures can be made accurately and reproducibly in what is an inherently subjective methodology. The interobserver reliability is an important feature of any biometric measurement. Measures that are not reliably reproducible have limited clinical value. Accuracy, and consequently reproducibility, may decrease for a number of reasons. Indistinct structural margins or measurements that are small enough to be at the margins of resolution of the modality as well as the inherent error of hand–eye coordination may contribute to variability. This can be seen by the poor reproducibility of the ventricular index measures. It can be difficult to ascertain the midline due to the cavum septum pellucidi. In addition, the anterior horn of the right ventricle is often smaller than the left and the usual shape of the ventricles in the coronal plane where the lateral walls are essentially in opposition to each other can make the lateral margin difficult to determine. This may explain the reduced reliability between examiners in this study. We have shown previously that reproducibility of measures of cerebral structures is high when margins are clear.18

    Horsch et al9 demonstrated that linear measures of various cerebral structures using CUSS correlated well with MRI abnormalities in 72 extremely preterm infants with paired assessments performed at term. Ment described 11 preterm infants with moderate or severe ventriculomegaly (defined as midbody enlargement of the lateral ventricles as seen in the parasagittal plane) on CUSS at term—55% of whom had an IQ <70 at 4.5 years of age. Nearly half of these infants had had a severe IVH.7 Contrary to our cohort of infants with no other detectable brain injury in which there was a relationship between the ventricular-brain ratio and motor outcome, Maunu et al8 examined the ventricular-brain ratios and ventricular horn widths of 225 very low birthweight infants at term and found there was no association between isolated ventricular dilatation and adverse outcome. They concluded, however, that the ventricular-brain ratio in particular was a sensitive and specific indicator of adverse outcome in those with other brain pathology.8

    This study has several strengths. We used measures previously described by others which more easily enables comparison with other observations reported in the literature. The focus on 2-year outcome is very important as much of the previous literature has focused on comparison to MRI. There are little data available that provide information regarding long-term outcome in relation to these measures, particularly when assessed prior to term.

    The major limitation of this study is the relatively small numbers of infants. Many infants are transferred to local hospitals prior to a month of age and thus images are not available. The digital imaging system used in the hospital was relatively new at the time of this study and not all images were able to be retrieved. The inclusion of infants with minor GM/IVH may be a limitation on that we cannot be absolutely certain they did not have a small amount of dilatation related to the IVH. We included these infants in our study as determining minor GM/IVH from normal can be difficult and the lesions had almost all resolved by the time of the study scan without any evidence of obstructive hydrocephalus.

    This study provides evidence that alterations of brain growth that relate to neurodevelopmental outcome may be observed using simple ultrasonographic techniques early in the postnatal course of very preterm infants who do not have significant detectable brain injury such as large GM/IVH or PVL. Although neuroimaging modalities such as MRI are more sensitive than cranial ultrasound in some aspects of brain structural assessment in the newborn, access to an MRI is limited. Establishing biometric measures on cranial ultrasound that are robustly reproducible has an important role in clinical care of very preterm infants as ultrasound is widely available to centres caring for newborns.

    Further research is required to elaborate on these findings with a view to refining the role of early ultrasonographic biometric measurements in the detection of brain injury related to neurodevelopmental outcome in very preterm infants.

    Conclusions

    Larger lateral ventricles in relation to brain size are related to motor development at 2 years. There is also a relationship between larger ventricular measurements and language development. These changes appear to be detectable early in the postnatal course. Techniques that allow serial assessment of the trajectories of brain growth in very preterm infants may be useful in assessing the impact of postnatal interventions on the preterm brain. These measures may also provide additional information in refining the assessment and targeting of high risk preterm newborns for neurodevelopmental surveillance.

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    View Abstract

    Footnotes

    • Contributors LMF, SRR and JLYC initiated and designed the study. LMF, PC and AJS participated in data collection. LMF, PJA, LD and JLYC participated in data interpretation. All authors contributed to drafting and revising the manuscript. JLYC provided data analysis and supervision of the study.

    • Funding Supported by Project Grant #284512 from the National Health and Medical Research Council of Australia

    • Competing interests None.

    • Ethics approval Royal Women's Hospital Human Research Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.