Routine screening cranial ultrasound examinations for the prediction of long term neurodevelopmental outcomes in preterm infants

Since the late 1970s, cranial ultrasound examinations have been performed on preterm infants to provide information about perinatal brain injury for the prediction of long term outcomes (1). Cranial ultrasound examinations and nonultrasound brain imaging techniques, such as magnetic resonance imaging, have also been used for a variety of clinical indications (2–5). Because of recent developments in the technology and process of performing cranial ultrasound examinations (6), and in the classification and understanding of the predictive value of abnormal findings (7–11), it is timely and important to consider the value and process of determining the need for routine screening cranial ultrasound examinations in neonatal intensive care units (NICUs).

OBJECTIVES

The guidelines presented in this statement were prepared to provide caregivers with answers to the questions: Should cranial ultrasound examinations be performed routinely on preterm infants for the prediction of long term neurodevelopmental outcomes? If so, when should cranial ultrasound examinations be performed? Is it possible to predict long term neurodevelopmental outcomes in preterm infants who develop hemorrhagic or ischemic lesions that are documented on routine cranial ultrasound examinations? What actions should be undertaken if infants are found to have hemorrhagic or ischemic brain lesions?

METHODS

A literature review found studies reported in English and French with any of the following keywords: cranial ultrasound, germinal matrix (GM) hemorrhage, intraventricular hemorrhage (IVH), brain injury, ventriculomegaly, echodensity, porencephaly, periventricular leukomalacia and preterm infant. The literature review consisted of a search of MEDLINE from 1976 to 2000 and a review of reference lists of literature identified by the search.

PATHOPHYSIOLOGY OF COMMON ABNORMALITIES

The fetal or preterm infant’s brain is vulnerable to both hemorrhagic and ischemic injury during the late second and early third trimesters (1). This is due to vascular, cellular and anatomical features of the developing brain, and the tendency for preterm infants to experience periods of physiological instability at a time when they have limited cerebral circulatory autoregulation (12). Hemorrhagic lesions (GM and/or IVH) can be restricted to the GM, they can include bleeding into the ventricles (with or without the development of hydrocephalus) or, in the worst cases, they can be found in the brain parenchyma (13). By 32 weeks’ postconceptual age, the GM is found only along the ventricular surface of the caudate nucleus and at its border with the thalamus. It normally involutes by 34 to 36 weeks’ (3,14) postconceptual age. The incidence of GM and/or IVH is infrequent after that time. Hemorrhagic and ischemic injuries often occur together, even though different pathophysiological processes lead to the lesions (15). The vascular structure of the cerebral white matter in mid-to late gestation includes long penetrating arteries that originate from the anterior, middle or posterior cerebral artery (1). The end zones of these arteries are especially prone to hypoperfusion and ischemia, and, thus, there is an increased likelihood of ischemic necrotic damage along the course or end zones of the arteries, or in the periventricular area. Non-hemorrhagic cerebral infarction, ventriculomegaly or cystic lesions, such as periventricular leukomalacia or porencephaly, may evolve from white matter injuries (16–18). Ventriculomegaly that occurs in the absence of IVH is most often secondary to the loss of cerebral white matter that has been damaged or failed to develop normally (19,20).

CLASSIFICATION OF ABNORMAL CRANIAL ULTRASOUND FINDINGS

Different systems have been suggested for the classification (7,8,10,21) and grading (13) of hemorrhagic and ischemic lesions that are detected by neonatal cranial ultrasounds. Grading has traditionally been performed using the system described by Papile et al (13): grade 1 IVH is confined to the GM; grade 2 IVH involves bleeding into the ventricle; in grade 3 IVH, the blood has distended and enlarged the ventricle; and grade 4 hemorrhage refers to bleeding within the brain parenchyma. However, a drawback of this system is that it excludes certain types of hemorrhages, and lacks concordance with the pathophysiology of both severe hemorrhagic and white matter damage (22). A valuable approach to the classification of abnormalities noted by cranial ultrasounds is provided in Table 1 (10). This approach does not specifically include white matter lesions in brain locations other than periventricular areas such as the cerebellum, basal ganglia or brain stem (22); however, it does assist caregivers in interpreting the most common categories of abnormal ultrasound diagnostic findings in preterm infants.

Table 1:

Classification of hemorrhagic and/or ischemic abnormalities detected by cranial ultrasound examinations

Isolated GM and/or IVH Parenchymal echodensities and/or lucencies with or without GM and/or IVH Ventricular enlargement with or without GM and/or IVH

GM/IVH Germinal matrix and/or intraventricular hemorrhage

WHICH INFANTS NEED CRANIAL ULTRASOUND EXAMINATIONS?

Because preterm infants, especially those younger than 32 weeks’ gestation, are prone to both GM and/or IVH and ischemic white matter injuries, routine cranial ultrasound examinations are most valuable for this group (23). The maximum risk of GM and/or IVH is in infants born before 30 weeks’ gestation (24); the incidence of IVH is less than 5% after that time (23,24). However, because occasional abnormalities are detected in infants born after 30 weeks’ gestation, it seems prudent to perform routine cranial ultrasounds on infants born at or before 32 weeks’ gestation.

Recommendation: Routine screening cranial ultrasound examinations are recommended for all infants born at 32 weeks’ gestation or earlier.

WHEN SHOULD CRANIAL ULTRASOUND EXAMINATIONS BE PERFORMED?

Among infants who developed GM and/or IVH, at least one-third of the infants had echodensities as early as 1 h after birth, indicating an antenatal or immediate postnatal onset (25,26). Approximately 50% of GM and/or IVH occurred in the first 6 to 8 h after birth (27). Most IVHs are evident by the third day (25,28), but they can develop at any time during the first two weeks of life. It has been suggested that cranial ultrasounds performed near two weeks of age provide the most complete and reliable diagnoses of hemorrhagic lesions (9). A concern with delaying cranial ultrasounds until two weeks after birth is that early onset IVHs may be of more ominous prognostic value than later onset IVHs (29); however, if only one ultrasound examination is to be performed to predict long term neurodevelopmental outcomes, the most appropriate time is two weeks after birth.

White matter abnormalities, which may manifest as echodensities, ventriculomegaly or cystic changes, may be present at birth but they often appear later (30). Cystic periventricular leukomalacia of antenatal onset is evident by two weeks of age (31). The evolution of postnatally acquired periventricular leukomalacia has been described as a period of initial congestion (manifest as echodensities), followed by relative normalization, followed by the development of echolucency or cysts and, finally, cyst resolution occurs with the development of ventricular enlargement (16). This sequence may not be completed until three months of age or later, but most cysts are evident within 60 days of birth (30).

Caregivers of very low birth weight infants who have multiple early complications may prefer to have diagnostic cranial ultrasound examinations performed by the third day of life. An ultrasound at this time provides important input for both short term and long term clinical management (29). Repeated ultrasounds should be performed, as clinically indicated, in infants with identified brain injuries.

Recommendation: Routine cranial ultrasound examinations are recommended at about the second and the sixth weeks of life to predict long term outcomes; early ultrasound examinations allow diagnosis of hemorrhagic lesions, and later ultrasound examinations can detect cystic lesions or ventriculomegaly.

PREDICTIVE VALUE OF ABNORMALITIES DETECTED BY CRANIAL ULTRASOUNDS

Periventricular brain damage, whether it is hemorrhagic, ischemic or both, can be associated with abnormalities in neurodevelopmental outcome (11,32,33). Some of the earlier reports focused on infant outcomes associated with isolated GM and/or IVH, but in most cases, infants with such lesions were not disabled (8). The outcome abnormalities found in GM and/or IVH with white matter damage, however, can range from subtle cognitive abnormalities to borderline or severe mental retardation (34,35). Motor abnormalities are reported often, particularly in association with disabilities such as cerebral palsy (10,21,36,37), mental retardation (2), or visual or hearing disturbances (38).

The sensitivity of cranial ultrasound examinations as predictors of later neurodevelopmental abnormalities has been reported as 16% at one and two weeks after birth, increasing to 53% at six weeks and 58% if performed when a child is at term-corrected age (39). The specificity of cranial ultrasound examinations has been 99% to 100% in all age groups (39). The presence of cysts has been reported as a predictor of cerebral palsy, with a sensitivity of 67% and a specificity of 96% (36). In most reports, estimates of the negative predictive value of cranial ultrasound examinations are consistent in that repeated normal examinations predict that an infant is unlikely to have cerebral palsy (33,36).

The specific location of cystic periventricular brain damage has been reported to be of predictive value in some but not all studies (17,40,41). Cysts are located most often at the level of the optic radiations adjacent to the trigone and at the level of the frontal white matter near the foramen of Monro. Descending fibres from the motor cortex are generally located superior and lateral to the lateral ventricles, and those fibres that are most closely related to lower extremity function are adjacent to the lateral ventricles. Therefore, leukomalacia in those areas is linked to the development of spastic diplegia. Quantitative measurements of cystic periventricular leukomalacia are difficult to accomplish by ultrasound. Quantitative measurements have included the diameters of the largest cyst or cystic region and the total cerebral mantle thickness. Parasagittal measurements of the antero-posterior dimension of cystic periventricular leukomalacia may best predict which infants will have quadriplegia, and the more severe cognitive and sensory impairments (41). Psychiatric abnormalities, including disruptive disorders, attention deficit/hyperactivity disorder, anxiety disorder or tics (42), have been reported in infants with GM and/or IVH and white matter damage.

Prenatally diagnosed isolated ventriculomegaly, in the absence of associated anomalies, is not a strong predictor of cognitive or motor abnormalities (43). However, ventricular enlargement that is detected postnatally may be more ominous in infants who develop posthemorrhagic hydrocephalus that requires shunting and in infants who develop ventriculomegaly without posthemorrhagic hydrocephalus.

In published reports, details are often lacking regarding the timing, type, severity and laterality of abnormalities noted on cranial ultrasound examinations. In addition, in some reports, long term outcome assessments are recorded in broad outcome categories that may interfere with precise interpretation. Some investigators have not reported other neonatal and postneonatal factors that can influence outcome (44,45), making it difficult to isolate the impact of the abnormalities noted on cranial ultrasounds.

Recommendation: Routine cranial ultrasound examinations can provide a relatively sensitive and highly specific means of predicting the presence or absence of later neurodevelopmental abnormalities in preterm infants.

HOW SHOULD CRANIAL ULTRASOUND EXAMINATIONS BE PERFORMED?

Advances in cranial ultrasonography have led to the improved visualization of hemorrhagic or ischemic lesions, with minimal risk to infants. The availability of real-time imaging and the use of the anterior fontanelle as an ultrasonographic ‘window’ were major developments in the application of neonatal ultrasonography (3). Although ultrasonographic approaches vary, ultrasound scans are done through the anterior fontanelle using sequential coronal and parasaggital projections; the posterior fontanelle is used for a detailed depiction of periventricular white matter or the presence of small amounts of blood in the lateral ventricles (15,46). It has been suggested that a scan performed through the mastoid fontanelle provides optimal visualization of the posterior fossa structures (6,47); however, a scan through the mastoid fontanelle is not performed routinely.

Pinto et al (48) studied the interobserver variability in the interpretation of abnormalities of the GM, ventricles and parenchyma; concordance among readers was the lowest for GM hemorrhages and the highest for parenchymal hemorrhages and echodensities. The American Institute of Ultrasound in Medicine and the American College of Radiology (49) have published guidelines for ultrasound examination of the brains of paediatric patients.

Recommendation: Caregivers should be aware that there will be differences in the diagnosis and interpretation of cranial ultrasound examinations according to the available ultrasound technology and expertise.

BENEFITS, HARMS AND COSTS

Cranial ultrasound examinations can provide a safe and effective screening and diagnostic test of GM and/or IVH or ischemic periventricular white matter damage in preterm infants. However, whenever testing is performed early in life for the purpose of predicting long term neurodevelopmental outcomes, the caregiver should be aware of the likelihood of false positive and false negative results when communicating test results and the risk of later problems to the parents of each infant. If the timing of the cranial ultrasound examination is not optimal or if there are technical concerns, uncertainty increases about the predictive value of the results. In fact, uncertainty is intrinsic in all predictions that are made in relation to the long term outcome of preterm infants (50). The possibility of increasing parental anxiety or distress by presenting results that are actually false positives, or minimizing the risks of long term neurodevelopmental sequelae on the basis of false negative results, provide examples of the potential harm related to routine cranial ultrasound examinations.

The major benefits of testing are to direct families of affected infants toward the most appropriate follow-up facilities to promote early diagnosis and intervention for chronic neurodevelopmental sequelae of hemorrhagic or ischemic brain injury, and to foster ongoing research activities that are aimed at ensuring the best possible outcomes for all infants. Costs that have been considered are related to the performance of cranial ultrasounds, such as the ultrasound hardware, human resources and possible infant health risks, which are minimal, and parental anxiety associated with erroneous or delayed results. One must be cognizant of the costs related to follow-up diagnostic and treatment activities, which may occur at an earlier age than would have been the case if routine cranial ultrasound examinations were not performed. It is hoped that the recommendations in this statement encourage the most cost effective use of routine cranial ultrasound examinations in preterm infants.

Recommendation: The potential benefits and harmful consequences of misinterpreting cranial ultrasound examinations should be communicated to parents whose infants are undergoing the testing. Infants who have hemorrhagic lesions or any white matter or cystic lesions evident on cranial ultrasound examinations require close, systematic follow-up after their discharge from NICUs to facilitate the timely initiation of interventions.

SUMMARY OF RECOMMENDATIONS

• Routine screening cranial ultrasound examinations are recommended for all infants born at 32 weeks’ gestation or earlier.

• Routine cranial ultrasound examinations are recommended at about the second and the sixth weeks of life to predict long term outcomes; early ultrasound examinations allow diagnosis of hemorrhagic lesions, and later ultrasound examinations can detect cystic lesions or ventriculomegaly.

• Routine cranial ultrasound examinations can provide a relatively sensitive and highly specific means of predicting the presence or absence of later neurodevelopmental abnormalities in preterm infants.

• Caregivers should be aware that there will be differences in the diagnosis and interpretation of cranial ultrasound examinations according to the available ultrasound technology and expertise.

• The potential benefits and harmful consequences of misinterpreting cranial ultrasound examinations should be communicated to parents whose infants are undergoing the testing. Infants who have hemorrhagic lesions or any white matter or cystic lesions evident on cranial ultrasound examinations require close, systematic follow-up after their discharge from NICUs to facilitate the timely initiation of interventions.