Diagnostic utility of cranial ultrasound in predicting clinical outcome in preterm and high-risk term neonates – A prospective cross-sectional study

Inclusion and exclusion criteria

All preterm neonates born before 36 +6 weeks and high-risk term neonates with any of the following risk factors were enrolled in the study.

(a) Neonatal sepsis, (b) birth asphyxia, (c) neonatal encephalopathy including hypoxic-ischaemic encephalopathy (HIE), (d) neonatal seizures, (e) respiratory distress, (f) neonates born out of traumatic/instrumental delivery, (g) suspected metabolic disturbances and (h) antenatally detected congenital malformations of the central nervous system irrespective of gestational age.

Normal-term neonates not fulfilling the above inclusion criteria and all those babies more than 28 days were excluded from the study.

Relevant antenatal history from maternal records was recorded in a standard pro forma. Complete neurological examinations of all the enrolled neonates were recorded. Routine investigations and treatment of all the neonates were done as per existing unit protocols.

Protocol for CUS scans

All enrolled neonates underwent neurosonogram on a GE Voluson machine (GE Healthcare-India) with a multi-frequency transvaginal/transrectal probe. Proper antiseptic precautions were taken while performing the CUS examination, especially in premature neonates. Proper handwashing by the operator and disinfection of the transducer was done to reduce the transmission of fomites. Special attention was taken to avoid hypothermia in the sick neonate. CUS was performed for all preterm neonates on days 1, 3, 7 and 14. In neonates with birth asphyxia, CUS scan was done on days 1, 3, 7 and weekly. In full-term neonates with neurological symptoms, CUS scans were done at the earliest opportunity with any of the inclusion criteria noted during NICU stay. Subsequent scans were based on the findings of the previous scan and the clinical condition of the baby during the NICU stay. All scans were performed through the anterior fontanelle in sagittal and coronal planes. Imaging in the sagittal plane was done in the midline and then both right and left parasagittal areas were evaluated with probe angulation of 15 and 30° on either side. In the coronal plane, an examination was done through the frontal horns of lateral ventricles, Sylvian fissure, third ventricle and occipital horns of lateral ventricles. Additional views were obtained through the posterior and mastoid fontanelle and the squamous temporal bone. Hence, a total of six standard quasi-coronal views and five sagittal views were obtained. Mastoid window views of the cerebellum were not routinely obtained for all neonates. All the initial and follow-up scans were performed by the same radiologist to avoid interobserver variation and images were reviewed by the same radiologist later who did not have any clinical information about the neonates to avoid any intra-observer variation.

The neonates were divided into two groups based on gestational age (<37 weeks and >37 weeks) and birth weight (<2.5 kg and >2.5 kg). The frequency of normal and abnormal CUS findings was compared between the two groups to calculate statistical association. Similarly, abnormal and normal CUS findings were compared between the neonates with APGAR scores of <7 and ≥7. Comparison was also made between neonates with an adverse perinatal risk factor and those without it. The pattern of abnormal CUS findings in all neonates, as per the inclusion criteria mentioned above, was assessed. The immediate outcome was assessed in neonates with various abnormal CUS findings. All neonates were followed till recovery and discharge from the NICU.

Statistical analysis

Data were analysed using the Statistical Package for the Social Sciences (SPSS) version 22.0 (IBM SPSS Statistics, Armonk, NY, USA) software for Windows. Quantitative variables were expressed as mean ± standard deviation and ranges. Categorical variables were shown as frequency and percentage. Differences between the two groups were searched using the Student t-test for quantitative variables and the Chi-square test for categorical variables. P < 0.05 was considered statistically significant.

Demographic data

Thirty-six neonates were enrolled in the study over a 1-year period. Amongst these, 16 (45%) were males and 20 (55%) were females. The mean age of the study population was 35 ±6 weeks. Of these, 24 (67%) were preterm (both early and late preterm) and 12 (33%) were term babies. The mean birth weight of the study population was 1.8 ± 0.67 g. Amongst these, 28/36 (78%) were <2.5 kg (low birth weight) and 8/36 (22%) were more than 2.5 kg. Twenty-one (58%) neonates were born through lower segment caesarean section and 15 (42%) were born by normal vaginal delivery.

Correlation of CUS findings with inclusion criteria

The distribution of abnormal CUS findings in the high-risk neonates as per the inclusion criteria is depicted in Table 1. The abnormal CUS findings were statistically significant in neonates with seizures, respiratory distress and neonatal sepsis.

Classification of CUS findings

Amongst the 36 neonates, CUS was normal in 17 (47%), whereas 19 (52%) had abnormal CUS findings. Amongst the neonates with abnormal CUS findings, 10 (63%) were males and 9 (45%) were females. The details of various abnormal findings are depicted in Table 2. Congenital anomalies and traumatic deliveries were not noted in the enrolled neonates.

Association of CUS findings and gestational age

The distribution of various CUS findings with gestational age is presented in Table 2. Categorisation into early and late preterm was not done. Amongst these preterm neonates, 5 (21%) had HIE changes out of which thalamic hyper-echogenicity was noted in one preterm neonate. Intraventricular haemorrhage (IVH) was the most common 8/24 (34%) CUS abnormality noted in preterm neonates. HIE changes were the most common 5/12 (41%) abnormal CUS findings noted in term neonates. The association of CUS findings with gestational age was not statistically significant in the study.

Association of CUS findings in various perinatal risk factors

In the present study, 28/36 (78%) neonates had various perinatal risk factors. Premature rupture of membrane (PROM) was the most common risk factor. Other risk factors such as gestational diabetes in 6 (16.7%), pregnancy-induced hypertension in 3 (8.3%) and hypothyroidism in 1 (2.8%) were noted. Abnormal CUS findings were noted in 13 (68.4%) neonates with PROM as risk factor. These data were statistically significant with P = 0.019.

HIE

CUS detected several findings suggestive of HIE in the neonates in our study. Abnormally increased brain parenchymal echogenicity consistent with cerebral oedema was noted in 4 (33%) term neonates and 4 (17%) preterm neonates. Thalamic hyper-echogenicity another marker of HIE was seen in 1 (4%) preterm and 1 (8%) term neonate [Table 2]. When the CUS findings were looked for the association with APGAR scores, it was noted that the data were significant for neonates with asphyxia with P = 0.009 detailed in Table 3. As follow-up scans beyond 14 days were not a part of the study, changes consistent with periventricular leukomalacia (PVL) and periventricular cysts were not recorded in the study. Only one neonate with findings of HIE died during the study. The rest 8 either recovered or were discharged as shown in Table 4. We did not use Doppler studies to calculate the resistive index (RI) in HIE neonates.

Germinal matrix- IVH (GMH-IVH)

IVH was the most common CUS finding seen in preterm babies in our study. Amongst the abnormal CUS findings in the neonates, 8 (34%) preterm neonates had GMHIVH and one term baby had GMH. Amongst the eight preterm neonates, 5 (21%) had only GMH, as detailed in Table 2. IVH-GMH was seen in 6 (45%) neonates with birth asphyxia (APGAR <7). The association of APGAR scores for neonates with GMH was statistically significant with P = 0.008 as mentioned in Table 3. The grades of GMH or any ventriculomegaly in the neonates were not recorded in the study. One baby with IVH-GMH died whereas 2 (10%) neonates recovered and 6 (54%) got discharged as depicted in Table 4.

Correlation of CUS findings with various clinical signs and laboratory investigations

Amongst the various clinical signs noted in the enrolled neonates, abnormal cry, poor activity and presence of central cyanosis had statistically significant association with abnormal CUS findings. Amongst the laboratory investigations, it was noted that positive C-reactive protein had a statistically significant association with abnormal CUS findings.

Utility of CUS in neonatal practice

In preterm babies, 25–50% of GMH-IVH cases are clinically asymptomatic and are therefore only detectable by routine imaging.^[2] The Canadian Paediatric Society and The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Science and the American Institute of Ultrasound in Medicine recommend CUS in all preterm neonates born at or before 31 +6 weeks gestation.^[11,12] In high-risk term neonates or any neonate with HIE, CUS is advisable on admission, at 24 h, on detection of any specific neurological issue or clinical indication as per the unit protocol.^[13]

Limitations of CUS versus MRI in imaging the neonatal brain

Although CUS has several advantages, it has some limitations too. The diagnostic accuracy of CUS ranges from 76 to 100% in detecting grade 1 haemorrhagic lesions >5 mm and grade 2–4 haemorrhages.^[2,7] CUS images are dependent on the skill of the operator and the acoustic windows used with limited visualisation of deeper structures and white matter injury. Sequential CUS during the neonatal period detects severely abnormal white matter injury in very preterm infants.^[8,12] MRI around term equivalent age is frequently used to reliably detect white matter injury in very preterm infants.^[8,14]

Diagnostic utility of CUS in preterm neonates

The study observed that the pattern of CUS findings differs between preterm and high-risk term neonates. While there is some overlap in injury patterns, GMH-IVH was more common in preterm neonates, whereas HIE changes were more often seen in high-risk term neonates according to the findings in several studies.^[12,13,15] GMH-IVH is strongly associated with gestational age and is frequently seen in neonates born before 30 weeks, as the germinal matrix is most prominent at 25 weeks and regresses by 36 weeks. Premature neonates are more susceptible to GMH-IVH due to the fragility of blood vessels and fluctuating cerebral blood flow during critical illness. Most haemorrhages occur within the first 24 h and over 90% get detected within the first 3 days of life. After the 1^st week, the incidence of haemorrhage decreases due to increased tissue oxygenation.^[12] The Papile grading system for GMH-IVH, based on the bleeding extent and ventricular involvement, remains widely used.^[16]

Diagnostic utility of CUS in term/high-risk term neonates

CUS is a valuable first-line imaging tool for assessing high-risk term infants or those with neonatal encephalopathy, commonly caused by conditions such as HIE, seizures, infections and metabolic disorders.^[1] In HIE, brain injury typically presents in two main patterns: Watershed injury, causing diffuse cerebral oedema (seen as effacement of sulcal markings and a slit-like appearance of the ventricles) and basal ganglia/thalamic injury, seen as thalamic hyper-echogenicity in acute, profound hypoxia-ischaemia. Doppler studies of the anterior cerebral artery (ACA) can help detect rebound increases in cerebral blood flow, providing additional evidence of brain insult.^[13] Cranial US can identify intracranial haemorrhages, cysts, calcifications and structural malformations, but its ability to detect smaller or complex brain injuries, especially in watershed areas or posterior fossa, is limited. While CUS is useful for initial screenings, MRI remains the gold standard for detailed evaluation.^[7,10,14] MRI, performed between days 3 and 5 after birth and repeated after 14 days or after rewarming in hypothermic infants, offers a more detailed assessment of brain injury and severity, which is essential for long-term neurodevelopmental prognosis.^[13]

Comparison of CUS findings to various studies in the literature

Kaushal et al.^[17] conducted a cross-sectional study on 120 neonates (60 preterm and 60 high-risk term) using CUS and Doppler to screen symptomatic neonates. They found that IVH-GMH was the most common abnormal finding in preterm neonates (46%), while periventricular and subcortical cysts were most common in high-risk term neonates. The findings in preterm neonates are like our study, but the CUS findings in term neonates differ. We could notice HIE changes more commonly in high-risk term babies. The study highlighted the importance of combining Doppler with CUS to improve the detection of subtle abnormalities in symptomatic neonates. The comparison of sensitivity between NSG and Doppler, as well as NSG combined with Doppler, was statistically significant in preterm neonates with hypotonia and seizures (P = 0.0442). Similar significant data (P = 0.0399) were found in high-risk term neonates. We did not include Doppler findings in our study which could be the limitation in our study.

Sherwani et al.^[18] conducted a prospective study on 200 neonates, including preterm (<34 weeks), high-risk late preterm (34–36 weeks) and high-risk term neonates, with risk factors such as birth asphyxia, seizures, HIE, respiratory distress syndrome, sepsis, birth trauma, congenital malformations and metabolic disturbances. They identified abnormal CUS findings in 76 neonates (38%). The most common abnormality was GMH-IVH in 36.8% of cases, followed by Cerebral edem a (CE) (18.4%), Thalamic hyper echogenicity (THE) (13.1%), PVL (5.2%) and congenital anomalies (10.5%). All these findings are like our study except that we did not have any case of congenital anomaly or birth trauma. Statistically significant associations were found between abnormal CUS findings and factors such as birth weight <2000 g, prematurity, APGAR score <7 and adverse perinatal foetal and maternal factors (P < 0.05). We also noticed a statistically significant association between CUS findings and <7 APGAR scores in neonates with HIE. Clinically, poor cry, poor activity, abnormal tone and the presence of cyanosis were also significantly associated with abnormal CUS findings which were like our findings.

A multicentre longitudinal study by Campbell et al.^[6] provides valuable insights into the long-term neurodevelopmental outcomes of extremely preterm infants, particularly those born at 23–27 weeks of gestation. The study followed 1,506 extremely low gestational age neonates, out of which 1,198 survived. Amongst the survivors, 889 neonates had undergone CUS during the early neonatal period. Weapons of mass destruction (WMD) in the absence of IVH were found to be associated with a higher risk of cognitive impairment, cerebral palsy and epilepsy by the time the children reached 10 years of age. The association between WMD and adverse long-term outcomes (cognitive impairment, cerebral palsy and epilepsy) was also present when WMD was accompanied by IVH. Interestingly, isolated IVH (without WMD) was not significantly associated with the neurodevelopmental outcomes, suggesting that WMD may be a more critical marker for long-term impairments. Although 11% of the participants were lost to follow-up, which can be a source of potential bias, it is important that the study still showed significant trends amongst those who were followed to 10 years of age. While CUS abnormalities indicative of WMD were found to be predictive of neurodevelopmental impairments, the study also highlighted that CUS might not detect all cases of WMD. MRI was noted to be more sensitive than CUS in identifying WMD, suggesting that MRI may be a more reliable diagnostic tool for early brain injury in preterm infants. As we did not have any follow-up data, our study was not comparable to the data derived from this study.

Diwakar et al.^[19] conducted a prospective study on 100 premature neonates (<32 weeks gestational age, birth weight 1,500–1,800 g) and found abnormal CUS results in 30 neonates. CUS was performed on days 1, 3 and 7, with follow-up scans at 2 weeks, 1 month, 2 months and 3 months to assess intracranial abnormalities. Abnormal neurological findings persisted in 20% of neonates during follow-up, while the rest were lost to follow-up. The abnormal CUS findings included healthcare personnel (12 cases), IVH (6), CE (6), PVL (2), cystic lesions (2), congenital anomalies (1) and ventricular septa (1). The findings in the study were different from our study as this was only on preterm babies and had follow-up data. The neonatal mortality rate was 16%. MRI was performed in 10% of cases, and abnormalities were detected in all of them. This emphasises the need for follow-up CUS in neonates born prematurely as the findings evolve in these babies. MRI is always needed at term in these babies to give clarity on the neurological outcome.

Rao et al.^[20] conducted a prospective study in the NICU of a tertiary care hospital, observing abnormal CUS findings in 36 out of 104 neonates (34.6%). Of the neonates, 74 were preterm (71.2%) and 30 were term (28.8%). The abnormal CUS findings included diffuse CE (19.2%), Grade I IVH (5.8%), Grade II IVH (3.8%), Grade III IVH (1%), PVL (3.8%) and basal ganglia hyperintensity (1.9%). These findings were like our study except for the fact that we did not categorise the IVH into different grades. All neonates also underwent RI measurement using colour Doppler within 72 h of birth. Low RI (<0.6) was observed in 30.8% of the ACA and 45.3% of the middle cerebral artery (MCA). Follow-up neurological assessments at 6 months revealed that neonates with low RI in the ACA and MCA had worse neurological outcomes, with statistically significant results. The positive likelihood ratio for low RI in the MCA was higher than for neurosonogram findings. This was an additional finding in this study as our study did not include any Doppler measurements on the neonates and we did not have any follow-up which could be the limitation in our study.

Fumagalli et al.^[21] conducted a prospective study on 1,172 late preterm neonates (34–36 +6 weeks) from a single centre, screening them for abnormal CUS findings at birth and at 5 weeks. Periventricular echogenicity (PVE) was found in 19.6% of neonates, with 91.3% of cases resolving by the ⁵th week. This is significant data from the follow-up of the neonates which is missing in our study due to the lack of follow-up. The study demonstrated that factors such as gestational age, APGAR score <5 at 5 min and comorbidities (e.g., hypoglycaemia, HIE, necrotising enterocolitis, sepsis) were predictors of abnormal CUS at 5 weeks. Multivariate analysis revealed that the predictive accuracy for abnormal CUS was fair when considering gestational age, APGAR score and comorbidities. However, accuracy improved to excellent when CUS findings at birth (classified as normal, mild or severe abnormal, including PVE) were also included.

Limitations of our study

CUS findings are highly operator-dependent. It has limited value in visualising deeper and peripheral structures and detecting white matter injury. Confirmation with MRI or another radiologist could have given a better picture. The study lacked follow-up data on participants, which prevented assessment of the progression or resolution of white matter lesions in preterm neonates with abnormal CUS findings. Doppler measurements, such as RI, were not used, which could have enhanced the understanding of neonates with asphyxia and HIE. In addition, the small sample size was a major limitation of our study. This study gives scope for future studies with a long-term follow-up which can give better insights into the neurodevelopmental outcome in newborns with abnormal CUS findings.