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Cranial ultrasound evaluation in term neonates
Early Human Development 143 (2020) 104983
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Cranial ultrasound evaluation in term neonates R. Luciano a b c
a,b,⁎
, I. Bersani
a,1
a
, G. Mancini , G. Vento
a,b
, E. Mercuri
T b,c
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Division of Neonatology Catholic University of Sacred Heart, Rome, Italy Fondazione Policlinico Universitario A. Gemelli IRCCS Rome, Italy, Department of Pediatric Neurology, Catholic University, Rome, Italy
A R T I C LE I N FO
A B S T R A C T
Keywords: Term neonate Cranial ultrasound Brain imaging Intraventricular haemorrhage Sonographic screening
Background: Term neonates (TN) are not routinely submitted to cranial ultrasound scan (CUS), since they are not considered at high risk for developing cerebral lesions. Aims: To investigate the prevalence of cerebral abnormal findings in term neonates (TN), to identify the associated clinical features and to better target neonatal CUS investigations. Study design: Prospective observational study. Subjects: A total number of 1805 healthy TN underwent CUS. 1181 neonates had clinical features supposed to increase the risk for cerebral abnormal findings (study cohort), 624 were controls. Outcome measures: Prevalence of minimal, minor, and major cerebral abnormal findings was analyzed in six different categories of low-risk TN and compared to controls. Results: Variations from normality at the neonatal CUS were observed in 402 TN (22.27%). In half of the cases the ultrasound findings were minimal abnormal findings, while minor abnormal findings were found in 179 TN (9.92%). About 1% of the studied neonates showed major cerebral abnormal findings potentially compromising neurodevelopmental outcome. The prevalence of the observed abnormal findings varied significantly in the different low-risk categories. Conclusions: The clinical features significantly increasing the risk for cerebral anomalies in healthy TN were microcrania, macrocrania, mild neurologic signs, and the detection of mild variations from normal cerebral aspect at the antenatal ultrasound evaluation.
1. Introduction Cranial ultrasound scan (CUS) is the most available and easily repeatable technique for brain imaging during the neonatal period. In contrast with premature neonates, term neonates (TN) are not routinely submitted to CUS at birth, since they are not considered at high risk for developing cerebral lesions. Several studies have however reported that even low risk TN may show abnormal findings when investigated with CUS [1–7]. The prevalence of CUS abnormalities detected in healthy TN is highly variable according to geographic areas, ranging from about 10–20% in the industrialized countries [1–3] up to about 50% in the developing countries [8]. No systematic attempt has been made in the previous studies to investigate whether the imaging abnormalities were
more often associated with specific clinical features. The aim of the present study was to investigate how often some clinical features supposed to increase the risk for cerebral abnormalities were associated with CUS abnormalities in a large population of low risk TN. 2. Patients and methods The study was performed in a 5 years period. During this period a total number of 16606 neonates were born in our institution. A total number of 1805 healthy TN entered the study. A series of consecutive 1181 neonates with clinical features supposed to increase the risk for cerebral abnormal findings were identified and underwent CUS (7.1%
Abbreviations: TN, term neonates; CUS, cranial ultrasound scan; aUS, antenatal ultrasound; CPC, choroid plexus cysts; CM, cisterna magna; SEPC, subependymal pseudocysts; IPV, periventricular hyperdensities; LSV, lenticulostriate vasculopathy; VM, ventriculomegaly; SEH-IVH, subependymal-intraventricular haemorrhage; PVI, periventricular venous infarction; RR, relative risk; CI, confidence interval; AS, Apgar Score ⁎ Corresponding author at: Division of Neonatology, Fondazione Policlinico Universitario A. Gemelli IRCCS-Catholic University of Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy. E-mail addresses: [email protected] (R. Luciano), [email protected] (I. Bersani), [email protected] (G. Mancini), [email protected] (G. Vento), [email protected] (E. Mercuri). 1 Current Address: Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, Rome, Italy. https://doi.org/10.1016/j.earlhumdev.2020.104983 Received 14 October 2019; Received in revised form 8 February 2020; Accepted 10 February 2020 0378-3782/ © 2020 Elsevier B.V. All rights reserved.
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Table 1 Clinical features leading to cranial ultrasound scan evaluation in healthy term neonates. Selected pregnancy complications (no aUS abnormalities)
Assisted reproductive pregnancy Monochorionic twin pregnancy or discordant twins Severe intrauterine growth retardation (birth weight < 3° centile [9]) Maternal autoimmune pathology Mildly enlarged cisterna magna Atrial width of lateral ventricles 8–9 mm Thin corpus callosum or not visualized cavum septum pellucidum Choroid plexus cysts Mild asymptomatic birth asphyxia (1′AS < 4 and 5′AS ≥ 7 or endotracheal intubation for < 5′) Minor birth trauma Head circumference < 3° or > 97° centile [9] Jitteriness Immature head control
Mild intracranial variations from normality at the aUS
Minor peripartum complications Abnormal head circumference Mild neurologic signs
periventricular hyperdensities persisting < 7 days, mildly enlarged cisterna magna (6–8 mm height in the median sagittal scan), posterior horn of lateral ventricles slightly enlarged (1.5–2 cm), full choroid plexus, mild hyperdensities along the lenticulostriate vessels; - Minor cerebral abnormal findings: subependymal pseudocysts (SEPC), persistent homogeneous periventricular hyperdensities (IPV) (i.e. still persisting at the 7 day CUS examination) not evolving in cavitations or ventriculomegaly (VM), lenticulostriate vasculopathy (LSV), ventricular asymmetry or mild ventricular dilatation (anterior horn width 0.3–0.5 cm and/or thalamo-occipital distance > 2 cm), enlarged cisterna magna without cerebellar atrophy or vermis dysgenesia, grade I/II subependymal-intraventricular haemorrhage (SEH-IVH), ≥2 minimal abnormalities; - Major cerebral abnormal findings: stroke or focal lesions, moderate/ severe ventriculomegaly (VM) or evidence of cerebral atrophy, large SEH-IVH (grade III) or periventricular venous infarction (PVI), intracranial congenital malformations.
of live born neonates in our institution during the sampling period). During the same period of time we obtained informed consent from the parents for performing cerebral ultrasound in 624 neonates who had no risk factors according to our protocol. The clinical features leading to CUS evaluation, according with our policy for healthy TN, are listed in Table 1 and grouped in 6 risk categories, namely selected pregnancy complications in absence of antenatal ultrasound (aUS) evidence of cerebral abnormal findings, mild variations from normal cerebral aspect at aUS, minor peripartum complications, microcrania or macrocrania observed at the neonatal routine examination, and mild neonatal neurologic signs. Birth weight and head circumference were evaluated according to the Italian Neonatal Curves [9]. The Hammersmith Neonatal Neurological Examination was routinely utilized for the identification and definition of mild neurologic signs [10]. Another consecutive 624 healthy TN, born during the same period, but without the clinical features listed above, were also submitted to CUS and represent the control group. Informed consent from the parents was obtained for both cohort and control neonates. Exclusion criteria for both groups were prenatal diagnosis of major anomalies of the central nervous system, major birth defects, congenital metabolic disorders, congenital infections, severe birth asphyxia, moderate-severe hypoxic-ischemic encephalopathy, seizures, meningoencephalitis, and severe thrombocytopenia. CUS was performed through the anterior fontanelle within the second day of life and repeated on day 7 of life in case of abnormal findings at the first CUS. Further evaluations were planned thereafter, when indicated, on an individualized schedule according to persistence and typology of the abnormal findings. CUS was always performed or supervised by the same operator (RL). A Philips HD15 Ultrasound system equipped with a 5–7.5 Hz convex probe was used for CUS investigation. Abnormal CUS findings were classified as listed below [11–13].
3. Statistical analysis Descriptive statistics are presented as number and percentages for categorical variables. The prevalence of overall abnormalities as well as minimal, minor, and major cerebral anomalies was evaluated for each risk category and compared to their prevalence in control group neonates. Categorical variables were analyzed with Fischer's exact t-test (GraphPad Software) making a comparison between each low-risk category and controls. The relative risk (RR) and 95% confidence interval (CI) for major cerebral abnormal findings according to the selected risk group categories was evaluated with the X-square test. A two tailed p < 0.05 was considered significant. 4. Results
- Minimal cerebral abnormal findings: small germinolytic cysts or small choroid plexus cysts (CPC), transient homogeneous
A total number of 1805 healthy TN were included in the study
Table 2 Cranial ultrasound findings according to each low risk category. Comparison of each risk category vs controls. Normal CUS Risk categories
N
n (%)
Pregnancy complications without antenatal US abnormalities Mild intracranial variations from normality at the aUS Mild asymptomatic birth asphyxia or minor birth trauma Mild neurologic signs Macrocrania Microcrania Multiple risk factors Controls Total
472 58 111 328 129 52 31 624 1805
396 (83.90) 35^ (60.34) 83§ (74.77) 213^ (64,94) 96* (74,42) 37§ (71.15) 17^ (54.84) 526 §*^ (84.29) 1403 (77.73)
p (risk categories vs controls): °p < 0.05, §p < 0.02, *p < 0.01, ^p < 0.001. 2
Cerebral abnormalities Minimal n (%) 40 (8,46) 11* (18.96) 14 (12,28) 61^ (18,59) 14 (10.77) 6 (11.54) 6° (19,35) 51*^° (8.17) 203 (11.25)
Minor n (%) 36 (7,61) 10* (17,24) 13 (11,4) 49^ (14,94) 15 (11.54) 5 (9.62) 6§ (19,35) 45*^§ (7.21) 179 (9.92)
Major n (%) 0 2* (3,45) 1 (0,88) 5° (1,52) 4* (3.08) 4^ (7.69) 2^ (6,45) 2 *^ ° (0.32) 20 (1.1)
3
14 54 19 9 8 47 199 – 1 1 3 – – 7 – 2 1 1 2 1 7 – 1 – – – – 1 1 1 2 – – 1 5 6 20 4 2 – 11 61 2 12 2 – 4 8 32 5 6 4 1 2 20 55 – 5 5 – – 5 18 – 2 – 1 – – 5
– 4 – 1 – 1 8
ns < 0.001 36 12 – 2 – – – – – – 14 4 4 – 14 3 2 – 2 1 – 2
IPV/LSV Mild VM/ asymmetry n
p = comparison of minor + major anomalies (each risk category vs controls).
Premature neonates are routinely submitted to CUS evaluations
Pregnancy complications (n = 472) Mild antenatal intracranial variations from normality (n = 58) Mild intrapartum complications (n = 111) Mild neurologic signs (n = 328) Macrocrania (n = 129) Microcrania (n = 52) Multiple risk factors (n = 31) Controls (n = 624) Total (n = 1805)
5. Discussion
Large CM n
Table 3 Minor and major CUS anomalies and their distribution in low-risk categories and controls.
SEPC/CPC n
≥2 minimal anomalies n
Minor SEHIVH n
Major SEH-IVH/ PVI n
Stroke n
Atrophy n
Malformations n
Total n
p*
(Table 2). About one third of the studied neonates had no risk factors for cerebral abnormal findings (control group) and about one third underwent CUS because of anomalies observed at routine neonatal examination, namely microcrania or macrocrania and jitteriness or immature head control. In the study cohort (n = 1181), pregnancy complications were registered in 472 cases (40%) and asymptomatic mild intrapartum asphyxia or minor birth trauma in 111 TN (9.40%), whereas a small group of 58 TN (4.91%) was submitted to CUS for mild variations from normal cerebral aspect at the aUS. Thirty-one neonates in the study cohort (2.62%) had multiple risk factors. Variations from normality at the neonatal CUS were observed in 402 TN (22.27%). In half of the cases the ultrasound findings were minimal abnormal findings, while minor abnormal findings were found in 179 TN (9.92%) and major abnormal findings in 20 TN (1.1%). Table 2 summarizes the number and percentage of minimal, minor and major CUS abnormal findings in the studied population divided in risk categories and in controls. No difference was observed comparing TN born from mothers with selected pregnancy complications - but no cerebral abnormal findings at aUS - with control TN. In contrast, prevalence of CUS abnormal findings was significantly higher in comparison with controls, in neonates with mild neurologic signs, microcrania or macrocrania as well as in TN with mild variations from normal cerebral aspect at the aUS. Neonates with mild peripartum complications, when compared to control TN, showed a significant difference in the prevalence of cerebral abnormal findings as a whole but not when the different groups of lesions (either minimal, minor or major) were concerned. Almost half of the neonates with multiple risk factors showed CUS abnormal cerebral findings that were represented by major lesions in 2 cases (6.4%). Interestingly, 23 out of 31(74.2%) neonates with multiple risk factors had minor neurological signs and 3 out of 31(9.7%) in this same category had mild variations on antenatal CUS. Minor and major cerebral abnormal findings are reported in details in Table 3. Cerebral haemorrhages were identified in 66 neonates (3.66% of the overall population and 16.42% of the total number of lesions). A significantly higher prevalence of haemorrhagic lesions in comparison with control TN was found in neonates with mild neurologic signs (6.4% vs 1.92%, p < 0.001) and in neonates with mild birth asphyxia or minor birth trauma (6.3% vs 1.92% p < 0.01). In addition, 35 TN had full choroid plexus (8.71% of the observed cerebral abnormal findings) and 121 CUS findings were represented by SEPC/CPC (30.09% of the total number of lesions), which, in some cases, could be the result of previous small haemorrhages of the germinal matrix or the choroid plexus. White matter hyperdensities or lenticulostriate vasculopathy were observed in 4.43% of our patients, a mild ventricular dilatation or a ventricular asymmetry in 18 TN (1% of the overall population and 4.48% of the abnormalities found in our series). The major cerebral abnormal findings observed in our population were mostly represented by cerebral malformations and atrophy, as shown in Table 3 according to their distribution in the 6 risk categories. Few cases of large SEH-IVH/PVI and stroke were also detected. No major cerebral abnormal findings were found in TN born from mothers with pregnancy complications - but normal aUS - and only one case was observed in TN with asymptomatic birth asphyxia or minor birth trauma. Conversely, TN with microcrania or macrocrania as well as TN with mild neurologic signs and TN with mild variations from normality in the cerebral aspect at aUS, showed a significantly higher prevalence of major cerebral abnormal findings in comparison with control TN. Table 4 shows the RR and the 95% CI for major cerebral abnormal findings in selected risk categories. It resulted as high as 8.43 in presence of microcrania, 6.36 in presence of multiple risk factors and 3.25 in presence of macrocrania.
ns < 0.001 < 0.01 < 0.02 < 0.01
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Rempen et al., consistently with the results that Heibel et al. [2] obtained in a population of 1000 healthy TN with no perinatal distress. In Haibel's study [2], 90 neonates (9%) were found with CUS abnormal findings, mostly represented by intracranial haemorrhages, SEPC, and CPC. In our study, we identified clear haemorrhagic lesions only in 3.66% of the overall population. In addition, however, 35 TN had full choroid plexus and 121 CUS abnormal findings were represented by SEPC/CPC, which are recognized to be in some cases the result of previous small haemorrhages. Moreover, when the percentage of the haemorrhagic lesions was analyzed in the different risk categories, a significantly higher prevalence of haemorrhagic lesions than controls was found in neonates with mild neurologic signs (6.4% vs 1.92%, p < 0.001) as well as in neonates with mild birth asphyxia or minor birth trauma compared to control TN (6.3% vs 1.92% p < 0.01). Neonates with peripartum complications, although not different from controls in the prevalence of major cerebral lesions, resulted at increased risk when the whole spectrum of lesions was concerned. This finding is partially explained by the threefold risk for haemorrhagic lesions in comparison with control neonates. As a consequence, CUS evaluation in this group might be useful for detection of cerebral bleeding. In a study by Mercuri et al. [3], including 177 apparently healthy neonates with GA ≥36 weeks, the CUS performed between 6 and 48 h of life detected cerebral abnormal findings in 35 neonates (20%), a result that is consistent with the overall prevalence of CUS abnormal findings in our study (22.27%). In 43/177 neonates, an abnormal neurologic examination was recorded and ultrasound abnormal findings were significantly associated with the presence of deviant patterns on clinical neurological examination. This finding is in accordance with
Table 4 Relative risk for major cerebral anomalies in selected risk categories in comparison with controls. Risk categories
RR
95% CI
p
Mild variations at the antenatal US Microcrania Macrocrania Mild neurologic signs Multiple risk factors Mild asymptomatic birth asphyxia or minor birth trauma
3.35 8.43 3.25 1.5 6.36 0.80
0.80–14.09 2.92–24.34 1.09–10.08 0.55–4.10 1.54–26.23 0.11–5.95
0.08 0.00 0.02 0.42 0.0041 0.82
since they are a high-risk population for cerebral abnormal findings. In contrast, only few systematic data exist concerning the prevalence of cerebral abnormal findings in TN [1–7] who undergo CUS at birth in a minority of cases. Moreover, the sonographic patterns of brain damage in TN are different from those detectable among premature infants [14]. In accordance with previous reports [1–7], our results, collected in a large series of patients, highlighted that various cerebral abnormal findings are detectable even in apparently healthy TN. Table 5 summarizes the CUS findings reported in the present study and in the other referenced studies. As far as asymptomatic TN are concerned, Rempen et al. [1], analyzing 673 asymptomatic TN, detected US abnormal findings in 88 of them (13%), a percentage not significantly lower than the 19.43% prevalence of overall abnormal findings in our asymptomatic population, i.e. once excluding neonates with mild neurologic signs. SEH/IVH and ventricular asymmetry were the main findings in the study by Table 5 Findings reported in the different studies. Studies
Population studied
General prevalence of CUS abnormal findings
Prevalence of major abnormal findings
Main findings
Rempen et al. [1]
673 clinically asymptomatic mature newborns
13.1%
–
Heibel [2]
1000 clinically asymptomatic term neonates, with no perinatal distress
9%
–
Mercuri [3]
177 neonates EG 36.3–42 weeks, clinically asymptomatic
20%
Hsu [5]
3186 term neonates with no perinatal distress
6.42%
0.06%
Wang [6]
2309 clinically asymptomatic term neonates without perinatal complications or neurological abnormalities 6771 term neonates
–
0.26%
1.7%
0.19%
1805 term neonates (1181 with risk factors; 624 controls)
22.27%
1.1% (1.5% in TN with risk factors, 0.32% in controls)
Subependymal/intraventricular haemorrhages (5.5%) Sequelae of an old intrauterine bleeding (1.3%) Ventricular asymmetries (5.7%) Choroidal plexus cysts (0.7%) Arachnoidal cysts (0.9%) infratentorial tumour (0.2%) Intracranial haemorrhage (periventricular, choroid plexus and intraventricular) (3.5%) Possible sequelae of bleeding (subependymal and choroid plexus pseudocysts; local dilatation of the lateral ventricles) (3.4%) Morphological aberrations (2.1%) Ischemic lesions, such as periventricular and thalamic densities (8%) Haemorrhagic lesions (6%) Cystic lesions (3.74%) Mild haemorrhage (1.85%) Mild ventricular anomalies (0.75%) Corpus callosum agenesis (0.03%) Significant ventricular dilatation (0.03%) Intracranial haemorrhage (0.13%) Corpus callosum agenesis (0.09%) Middle cerebral artery (MCA) infarct (0.04%) Partial/complete agenesis of corpus callosum (0.04%) Periventricular calcifications (0.01%) Ischemic stroke (0.03%) Hypoxic-ischemic encephalopathy (0.06%) Hydrocephalus (0.01%) Ventriculomegaly (0.01%) Porencephalic cyst (0.01%) Cerebral haemorrhages (3.66%) SEPC/CPC (30.9%) White matter hyperdensities or lenticulostriate vasculopathy (4.43%) Ventricular dilatation or asymmetry (1%) Stroke (0.05%) Atrophy (0.39%) Malformation (0.39%)
Ballardini [7]
Present study
4
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the high prevalence of CUS abnormal findings we observed in the group of neonates included in the study for the presence of mild neurologic signs. As a consequence, CUS within the first days of life should be mandatory in these neonates. Among the neonates included in Mercuri's study [3], 6% had intracranial haemorrhage, 6% ventricular asymmetry, 8% thalamic and white matter hyperdensities, and 8% full choroid plexus, findings that are comparable with our results. Mercuri et al. [3] analyzed the correlation between CUS findings and prenatal and perinatal complications. Prenatal risk factors were found in 29/72 (40%) infants with normal CUS and in 16/23 (61%) with cerebral abnormal findings, with no statistically significant difference. Perinatal risk factors were recorded in 11/72 (15%) neonates with normal CUS and 3/23 (13%) with cerebral anomalies, in this case also without any statistically significant differences. Lesions that could be due to ischemic damage, such as periventricular densities, were seen even in the absence of any antenatal or perinatal risk factors. Consistently with the observations by Mercuri et al. [3], the pregnancy complications we included in the study were not a risk factor for neonatal CUS abnormal findings in our population, unless antenatal US abnormalities were detected. Hsu et al. [5] studied 3186 full term healthy neonates submitted to CUS as screening examination: minor abnormal findings were found in 6.34% infants; major abnormal findings were found in two newborns (0.06%). One neonate with major abnormal findings had some abnormalities on fetal ultrasonography. In our study cohort, a prevalence of 1.5% of major cerebral abnormal findings or malformations potentially compromising neurologic development was found. The prevalence of major abnormal findings was significantly different, compared to controls, according to the different low-risk categories. Our finding of 0.32% in neonates without risk factors (control neonates) is consistent with the prevalence of 0.26% reported in a large population of 2309 apparently healthy TN (GA 37–41 weeks) without perinatal complications or neurological abnormalities, that were subjected to a sonographic screening [6]. Furthermore, this percentage is consistent with that recently reported by Ballardini et al. [7] in a retrospective evaluation of a universal CUS screening in term neonates. Among the 6771 full term neonates examined in this study, 114 (1.7%) had CUS abnormal findings, whereas 6657 were normal or insignificant; 101 of the 114 CUS abnormal findings were minor. Major abnormal findings affected just 13 neonates (0.19% of the whole population). All neonates with major CUS abnormal findings presented at least one risk factor such as microcephaly, abnormal neurological evaluation, prenatal diagnosis of brain abnormal findings [7]. As a consequence, the Authors' conclusion is that universal CUS screening is not recommended in healthy term neonates unless one of those clinical features is identified. All the previous studies reported the incidence of cerebral abnormal findings in the context of a universal CUS screening in the general population of healthy term newborns. Aim of our study was to better target neonatal CUS investigations in healthy term newborns. Accordingly, we selected clinical features potentially associated to cerebral abnormal findings, identifying different low-risk categories among the general population of apparently healthy term neonates. The different low-risk categories were compared to a control group of term healthy neonates without risk factors. A significantly higher risk for cerebral abnormal findings in respect to control term infants was found in some of the identified low-risk categories, namely microcrania and macrocrania, mild neurological signs and antenatal mild intracranial variation from normality. In addition, the RR analysis showed that microcrania, macrocrania and the contemporary presence of multiple risk factors are important markers for major cerebral abnormal findings that can be detected with CUS and thus CUS is not to be missed in these infants. Neonates with mild neurologic signs show not only a significantly higher prevalence of total cerebral abnormal findings but also a significant difference for major cerebral abnormal findings in respect to control neonates with a RR equal to 1.5. We also studied a series of
neonates with the aUS showing mild variations in the fetal cerebral aspect although these variations were not clear anomalies to be regarded as exclusion criteria from the study. These infants showed abnormal findings at the neonatal CUS in about 40% of cases (23 out of 58 neonates in this risk category). Neonatal CUS in these neonates allowed the identification of two major congenital malformations. Accordingly, mild aUS variations from normal cerebral pattern may represent a marker of lesions or congenital anomalies not easily recognizable in utero due to the intrinsic lower accuracy of aUS [15,16]. A series of 102 neonates born from mothers with autoimmune diseases, which are reported to be at risk for CUS abnormal findings [17–19], were analyzed apart from the other observed pregnancy complications. We were unable to demonstrate a different percentage of abnormal CUS findings in comparison with controls (17,65 vs 15,71%). TN with severe asymmetric intrauterine growth retardation (BW < 3° centile but head circumference > 3° centile), which are considered to be at risk for cognitive problems [20], did not show an increased prevalence than controls in CUS abnormal findings (15/121 i.e. 12,4%). As a consequence, we speculate that CUS evaluation is probably not a useful tool in this group of neonates. The prognostic value of the observed findings in TN has been scarcely investigated. In the study by Heibel et al. [2], four patients with intracranial haemorrhage were hemiparetic, and one of them also developed epilepsy, at the 12-month follow-up. In previous studies, we have analyzed a series of neonates with prenatal diagnosis of fetal cerebral haemorrhages [21,22]. According with the exclusion criteria of the present study, these neonates are not included in this report. In Mercuri's study, no major neurological or developmental abnormalities were detectable in the 103 neonates who underwent a 12- and 18month follow-up among the 177 of the original cohort [3,4]. In conclusion, the present study, analyzing a large series of low-risk healthy TN, found about 20% variation from normal CUS pattern, consistently with the data reported in the industrialized countries. Half of the findings were minimal variations from normality and approximately half were minor abnormal findings whose prognostic relevance is not defined at present. More than 1% of the studied neonates showed major cerebral abnormal findings potentially compromising neurologic development. The prevalence of the observed abnormal findings was different, compared to controls, according to the different low-risk categories. The clinical features increasing the risk for cerebral abnormal findings in healthy TN were micro/macrocrania or mild neurologic signs, and mild variations from normality in the cerebral aspect at aUS. These results may help to target the CUS policy in low risk TN, in function of the available resources in the different neonatal units. According to our results, CUS examination should not be performed in healthy term neonates without risk factors and risk categories leading to CUS examination should be restricted to neonates with abnormal head size and mild neurologic signs or neonates with mild variations on antenatal CUS. When considering the effect of restricting the inclusion criteria to these risk categories, half of the neonates (583 neonates) in our study population would not have had criteria to undergo to CUS examination and the percentage of screened neonates would have been reduced to 3.5% of all live births. The prognostic values of the detected abnormal findings should be taken into account. The relative risk calculation for major cerebral abnormalities, as illustrated in Table 4, corroborates the opportunity to perform CUS examination in case of abnormal head size or multiple risk factors. Interestingly, 23 out of 31 (74.2%) neonates with multiple risk factors had minor neurological signs and 3 out of 31(9.7%) in this same category had mild variations on antenatal CUS. Looking at our study population, we should perform 30 CUS examination to find one major cerebral abnormality and a percentage of major cerebral abnormalities equal to 85% could be diagnosed, if we restrict the risk categories as above suggested. Major cerebral abnormal findings arise, obviously, the utmost concern for long-term outcome and should be used to support the need for 5
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long-term follow up. On the contrary, we are still not aware of the clinical relevance that the observed minor abnormal findings entail in this low-risk population of TN. Being not evident from the literature that minor cerebral abnormalities have a causal relationship with long term disabilities, we believe we should concentrate resources in order to detect the cases with relevant abnormalities.
[7]
[8]
[9]
Credit authorship contribution statement [10]
R. Luciano: Conceptualization, Investigation, Formal analysis. I. Bersani: Conceptualization, Investigation, Formal analysis. G. Mancini: Conceptualization, Investigation, Formal analysis. G. Vento: Conceptualization, Investigation, Formal analysis. E. Mercuri: Conceptualization, Investigation, Formal analysis.
[11]
[12]
Declaration of competing interest
[13] [14]
None.
[15]
Acknowledgments We thank the families of patients for their understanding cooperation and the nursing staff for its invaluable support.
[16]
Funding [17]
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[18]
References [19]
[1] A. Rempen, A. Feige, K. Fiedler, Incidence of conspicuous ultrasound findings in the brain in clinically asymptomatic newborn infants, Z. Geburtshilfe Perinatol. 190 (5) (1986) 190–195 Sep-Oct. [2] M. Heibel, R. Heber, D. Bechinger, et al., Early diagnosis of perinatal cerebral lesions in apparently normal full-term newborns by ultrasound of the brain, Neuroradiology 35 (2) (1993) 85–91. [3] E. Mercuri, L. Dubowitz, S.P. Brown, et al., Incidence of cranial ultrasound abnormalities in apparently well neonates on a postnatal ward: correlation with antenatal and perinatal factors and neurological status, Arch. Dis. Child. Fetal Neonatal Ed. 79 (1998) F185–F189, https://doi.org/10.1136/fn.79.3.f185. [4] L. Haataja, E. Mercuri, F. Cowan, et al., Cranial ultrasound abnormalities in full term infants in a postnatal ward: outcome at 12 and 18 months, Arch. Dis. Child. Fetal Neonatal Ed. 82 (2000) F128–F133, https://doi.org/10.1136/fn.82.2.fl28. [5] C.-L. Hsu, et al., Cranial ultrasonographic findings in healthy full-term neonates: a retrospective review, J. Chin. Med. Assoc. 75 (2012) 389e395, https://doi.org/10. 1016/j.jcma.2012.06.007. [6] L.W. Wang, C.C. Huang, T.F. Yeh, Major brain lesions detected on sonographic
[20]
[21]
[22]
6
screening of apparently normal term neonates, Neuroradiology 46 (5) (2004) 368–373, https://doi.org/10.1007/s00234-003-1160-4. E. Ballardini, et al., Universal head ultrasound screening in full-term neonates: a retrospective analysis of 6771 infants, Pediatr. Neurol. 71 (2017) 14–17, https:// doi.org/10.1016/j.pediatrneurol.2017.03.012. C.F. Hagmann, N.J. Robertson, D. Acolet, et al., Cranial ultrasound findings in well newborn Ugandan infants, Arch. Dis. Child. Fetal Neonatal Ed. 95 (5) (2010) F338–F344, https://doi.org/10.1136/adc.2009.174607. E. Bertino, E. Spada, L. Occhi, et al., Neonatal anthropometric charts: the Italian neonatal study compared with other European studies, J. Pediatr. Gastroenterol. Nutr. 51 (3) (2010) 353–361, https://doi.org/10.1097/MPG.0b013e3181da213e. L.M.S. Dubowitz, V. Dubowitz, E. Mercuri, The Neurological Assessment of the Preterm and Full-term Newborn Infant Clinics in Developmental Medicine, 148 Mac Keith Press, London, 1999. M.J. Brouwer, L.S. de Vries, F. Groenendaal, et al., New reference values for the neonatal cerebral ventricles, Radiology 262 (2012) 224–233, https://doi.org/10. 1148/radiol.11110334. L. Goodwin, R.G. Quisling, The neonatal cisterna magna: ultrasonic evaluation, Radiology 149 (1983) 691–695, https://doi.org/10.1148/radiology.149.3. 6647845. P. Govaert, L.S. de Vries, An Atlas of Neonatal Brain Sonography Clinics in Developmental Medicine, Mac Keith Press, London, 2010, pp. 182–183. A. Yikilmaz, G.A. Taylor, Cranial sonography in term and near-term infants, Pediatr. Radiol. (6) (2008) 605–616, https://doi.org/10.1007/s00247-007-0692-x. A. Gagnon, R.D. Wilson, V.M. Allen, F. Audibert, C. Blight, J.A. Brock, V.A. Désilets, J.A. Johnson, S. Langlois, L. Murphy-Kaulbeck, P. Wyatt, Society of Obstetricians and Gynaecologists of Canada, Evaluation of prenatally diagnosed structural congenital anomalies, J. Obstet. Gynaecol. Can. 31 (9) (2009) 875–881 Sep. 882-9. G.M. Senapati, D. Levine, C. Smith, J.A. Estroff, C.E. Barnewolt, R.L. Robertson, T.Y. Poussaint, T.S. Mehta, X.Q. Werdich, D. Pier, H.A. Feldman, C.D. Robson, Frequency and cause of disagreements in imaging diagnosis in children with ventriculomegaly diagnosed prenatally, Ultrasound Obstet. Gynecol. 36 (5) (2010) 582–595 Nov. A.A. Zuppa, F. Gallini, D. De Luca, R. Luciano, S. Frezza, P.L. de Turris, G. Tortorolo, Cerebral ultrasound findings in neonatal lupus syndrome, Biol. Neonate 86 (2004) 230–234, https://doi.org/10.1159/000079820. M. Motta, C. Zambelloni, C. Rodriguez-Perez, A. Angeli, A. Lojacono, A. Tincani, G. Chirico, Cerebral ultrasound abnormalities in infants born to mothers with autoimmune disease, Arch. Dis. Child. Fetal Neonatal Ed. 96 (5) (2011) F355–F358, https://doi.org/10.1136/adc.2010.195099 Sep. Mazzucchelli, et al., Maternal and neonatal outcomes in pregnant women with autoimmune diseases in Pavia, Italy, BMC Pediatr. 15 (2015) 217, https://doi.org/ 10.1186/s12887-015-0532-3. T. Arcangeli, B. Thilaganathan, R. Hooper, K.S. Khan, A. Bhide, Neurodevelopmental delay in small babies at term: a systematic review, Ultrasound Obstet. Gynecol. 40 (2012) 267–275, https://doi.org/10.1002/uog.11112. R. Luciano, G. Baranello, L. Masini, D. Ricci, F. Gallini, S. Ciotti, D. Leone, F. Serrao, M. De Santis, E. Zecca, A. Zuppa, C. Romagnoli, C. Di Rocco, F. Guzzetta, E. Mercuri, Antenatal post-hemorrhagic ventriculomegaly: a prospective follow-up study, Neuropediatrics 38 (3) (2007) 137–142, https://doi.org/10.1055/s-2007985366 Jun. D. Ricci, R. Luciano, G. Baranello, C. Veredice, L. Cesarini, F. Bianco, M. Pane, F. Gallini, G. Vasco, I. Savarese, A. Zuppa, L. Masini, C. Di Rocco, C. Romagnoli, F. Guzzetta, E. Mercuri, Visual development in prenatal post-haemorrhagic ventricular dilatation, Arch. Dis. Child. Fetal Neonatal Ed. 92 (4) (2007) F255–F258, https://doi.org/10.1136/adc.2006.101485 Jul.
Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Cranial ultrasound evaluation in term neonates R. Luciano a b c
a,b,⁎
, I. Bersani
a,1
a
, G. Mancini , G. Vento
a,b
, E. Mercuri
T b,c
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Division of Neonatology Catholic University of Sacred Heart, Rome, Italy Fondazione Policlinico Universitario A. Gemelli IRCCS Rome, Italy, Department of Pediatric Neurology, Catholic University, Rome, Italy
A R T I C LE I N FO
A B S T R A C T
Keywords: Term neonate Cranial ultrasound Brain imaging Intraventricular haemorrhage Sonographic screening
Background: Term neonates (TN) are not routinely submitted to cranial ultrasound scan (CUS), since they are not considered at high risk for developing cerebral lesions. Aims: To investigate the prevalence of cerebral abnormal findings in term neonates (TN), to identify the associated clinical features and to better target neonatal CUS investigations. Study design: Prospective observational study. Subjects: A total number of 1805 healthy TN underwent CUS. 1181 neonates had clinical features supposed to increase the risk for cerebral abnormal findings (study cohort), 624 were controls. Outcome measures: Prevalence of minimal, minor, and major cerebral abnormal findings was analyzed in six different categories of low-risk TN and compared to controls. Results: Variations from normality at the neonatal CUS were observed in 402 TN (22.27%). In half of the cases the ultrasound findings were minimal abnormal findings, while minor abnormal findings were found in 179 TN (9.92%). About 1% of the studied neonates showed major cerebral abnormal findings potentially compromising neurodevelopmental outcome. The prevalence of the observed abnormal findings varied significantly in the different low-risk categories. Conclusions: The clinical features significantly increasing the risk for cerebral anomalies in healthy TN were microcrania, macrocrania, mild neurologic signs, and the detection of mild variations from normal cerebral aspect at the antenatal ultrasound evaluation.
1. Introduction Cranial ultrasound scan (CUS) is the most available and easily repeatable technique for brain imaging during the neonatal period. In contrast with premature neonates, term neonates (TN) are not routinely submitted to CUS at birth, since they are not considered at high risk for developing cerebral lesions. Several studies have however reported that even low risk TN may show abnormal findings when investigated with CUS [1–7]. The prevalence of CUS abnormalities detected in healthy TN is highly variable according to geographic areas, ranging from about 10–20% in the industrialized countries [1–3] up to about 50% in the developing countries [8]. No systematic attempt has been made in the previous studies to investigate whether the imaging abnormalities were
more often associated with specific clinical features. The aim of the present study was to investigate how often some clinical features supposed to increase the risk for cerebral abnormalities were associated with CUS abnormalities in a large population of low risk TN. 2. Patients and methods The study was performed in a 5 years period. During this period a total number of 16606 neonates were born in our institution. A total number of 1805 healthy TN entered the study. A series of consecutive 1181 neonates with clinical features supposed to increase the risk for cerebral abnormal findings were identified and underwent CUS (7.1%
Abbreviations: TN, term neonates; CUS, cranial ultrasound scan; aUS, antenatal ultrasound; CPC, choroid plexus cysts; CM, cisterna magna; SEPC, subependymal pseudocysts; IPV, periventricular hyperdensities; LSV, lenticulostriate vasculopathy; VM, ventriculomegaly; SEH-IVH, subependymal-intraventricular haemorrhage; PVI, periventricular venous infarction; RR, relative risk; CI, confidence interval; AS, Apgar Score ⁎ Corresponding author at: Division of Neonatology, Fondazione Policlinico Universitario A. Gemelli IRCCS-Catholic University of Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy. E-mail addresses: [email protected] (R. Luciano), [email protected] (I. Bersani), [email protected] (G. Mancini), [email protected] (G. Vento), [email protected] (E. Mercuri). 1 Current Address: Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, Rome, Italy. https://doi.org/10.1016/j.earlhumdev.2020.104983 Received 14 October 2019; Received in revised form 8 February 2020; Accepted 10 February 2020 0378-3782/ © 2020 Elsevier B.V. All rights reserved.
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Table 1 Clinical features leading to cranial ultrasound scan evaluation in healthy term neonates. Selected pregnancy complications (no aUS abnormalities)
Assisted reproductive pregnancy Monochorionic twin pregnancy or discordant twins Severe intrauterine growth retardation (birth weight < 3° centile [9]) Maternal autoimmune pathology Mildly enlarged cisterna magna Atrial width of lateral ventricles 8–9 mm Thin corpus callosum or not visualized cavum septum pellucidum Choroid plexus cysts Mild asymptomatic birth asphyxia (1′AS < 4 and 5′AS ≥ 7 or endotracheal intubation for < 5′) Minor birth trauma Head circumference < 3° or > 97° centile [9] Jitteriness Immature head control
Mild intracranial variations from normality at the aUS
Minor peripartum complications Abnormal head circumference Mild neurologic signs
periventricular hyperdensities persisting < 7 days, mildly enlarged cisterna magna (6–8 mm height in the median sagittal scan), posterior horn of lateral ventricles slightly enlarged (1.5–2 cm), full choroid plexus, mild hyperdensities along the lenticulostriate vessels; - Minor cerebral abnormal findings: subependymal pseudocysts (SEPC), persistent homogeneous periventricular hyperdensities (IPV) (i.e. still persisting at the 7 day CUS examination) not evolving in cavitations or ventriculomegaly (VM), lenticulostriate vasculopathy (LSV), ventricular asymmetry or mild ventricular dilatation (anterior horn width 0.3–0.5 cm and/or thalamo-occipital distance > 2 cm), enlarged cisterna magna without cerebellar atrophy or vermis dysgenesia, grade I/II subependymal-intraventricular haemorrhage (SEH-IVH), ≥2 minimal abnormalities; - Major cerebral abnormal findings: stroke or focal lesions, moderate/ severe ventriculomegaly (VM) or evidence of cerebral atrophy, large SEH-IVH (grade III) or periventricular venous infarction (PVI), intracranial congenital malformations.
of live born neonates in our institution during the sampling period). During the same period of time we obtained informed consent from the parents for performing cerebral ultrasound in 624 neonates who had no risk factors according to our protocol. The clinical features leading to CUS evaluation, according with our policy for healthy TN, are listed in Table 1 and grouped in 6 risk categories, namely selected pregnancy complications in absence of antenatal ultrasound (aUS) evidence of cerebral abnormal findings, mild variations from normal cerebral aspect at aUS, minor peripartum complications, microcrania or macrocrania observed at the neonatal routine examination, and mild neonatal neurologic signs. Birth weight and head circumference were evaluated according to the Italian Neonatal Curves [9]. The Hammersmith Neonatal Neurological Examination was routinely utilized for the identification and definition of mild neurologic signs [10]. Another consecutive 624 healthy TN, born during the same period, but without the clinical features listed above, were also submitted to CUS and represent the control group. Informed consent from the parents was obtained for both cohort and control neonates. Exclusion criteria for both groups were prenatal diagnosis of major anomalies of the central nervous system, major birth defects, congenital metabolic disorders, congenital infections, severe birth asphyxia, moderate-severe hypoxic-ischemic encephalopathy, seizures, meningoencephalitis, and severe thrombocytopenia. CUS was performed through the anterior fontanelle within the second day of life and repeated on day 7 of life in case of abnormal findings at the first CUS. Further evaluations were planned thereafter, when indicated, on an individualized schedule according to persistence and typology of the abnormal findings. CUS was always performed or supervised by the same operator (RL). A Philips HD15 Ultrasound system equipped with a 5–7.5 Hz convex probe was used for CUS investigation. Abnormal CUS findings were classified as listed below [11–13].
3. Statistical analysis Descriptive statistics are presented as number and percentages for categorical variables. The prevalence of overall abnormalities as well as minimal, minor, and major cerebral anomalies was evaluated for each risk category and compared to their prevalence in control group neonates. Categorical variables were analyzed with Fischer's exact t-test (GraphPad Software) making a comparison between each low-risk category and controls. The relative risk (RR) and 95% confidence interval (CI) for major cerebral abnormal findings according to the selected risk group categories was evaluated with the X-square test. A two tailed p < 0.05 was considered significant. 4. Results
- Minimal cerebral abnormal findings: small germinolytic cysts or small choroid plexus cysts (CPC), transient homogeneous
A total number of 1805 healthy TN were included in the study
Table 2 Cranial ultrasound findings according to each low risk category. Comparison of each risk category vs controls. Normal CUS Risk categories
N
n (%)
Pregnancy complications without antenatal US abnormalities Mild intracranial variations from normality at the aUS Mild asymptomatic birth asphyxia or minor birth trauma Mild neurologic signs Macrocrania Microcrania Multiple risk factors Controls Total
472 58 111 328 129 52 31 624 1805
396 (83.90) 35^ (60.34) 83§ (74.77) 213^ (64,94) 96* (74,42) 37§ (71.15) 17^ (54.84) 526 §*^ (84.29) 1403 (77.73)
p (risk categories vs controls): °p < 0.05, §p < 0.02, *p < 0.01, ^p < 0.001. 2
Cerebral abnormalities Minimal n (%) 40 (8,46) 11* (18.96) 14 (12,28) 61^ (18,59) 14 (10.77) 6 (11.54) 6° (19,35) 51*^° (8.17) 203 (11.25)
Minor n (%) 36 (7,61) 10* (17,24) 13 (11,4) 49^ (14,94) 15 (11.54) 5 (9.62) 6§ (19,35) 45*^§ (7.21) 179 (9.92)
Major n (%) 0 2* (3,45) 1 (0,88) 5° (1,52) 4* (3.08) 4^ (7.69) 2^ (6,45) 2 *^ ° (0.32) 20 (1.1)
3
14 54 19 9 8 47 199 – 1 1 3 – – 7 – 2 1 1 2 1 7 – 1 – – – – 1 1 1 2 – – 1 5 6 20 4 2 – 11 61 2 12 2 – 4 8 32 5 6 4 1 2 20 55 – 5 5 – – 5 18 – 2 – 1 – – 5
– 4 – 1 – 1 8
ns < 0.001 36 12 – 2 – – – – – – 14 4 4 – 14 3 2 – 2 1 – 2
IPV/LSV Mild VM/ asymmetry n
p = comparison of minor + major anomalies (each risk category vs controls).
Premature neonates are routinely submitted to CUS evaluations
Pregnancy complications (n = 472) Mild antenatal intracranial variations from normality (n = 58) Mild intrapartum complications (n = 111) Mild neurologic signs (n = 328) Macrocrania (n = 129) Microcrania (n = 52) Multiple risk factors (n = 31) Controls (n = 624) Total (n = 1805)
5. Discussion
Large CM n
Table 3 Minor and major CUS anomalies and their distribution in low-risk categories and controls.
SEPC/CPC n
≥2 minimal anomalies n
Minor SEHIVH n
Major SEH-IVH/ PVI n
Stroke n
Atrophy n
Malformations n
Total n
p*
(Table 2). About one third of the studied neonates had no risk factors for cerebral abnormal findings (control group) and about one third underwent CUS because of anomalies observed at routine neonatal examination, namely microcrania or macrocrania and jitteriness or immature head control. In the study cohort (n = 1181), pregnancy complications were registered in 472 cases (40%) and asymptomatic mild intrapartum asphyxia or minor birth trauma in 111 TN (9.40%), whereas a small group of 58 TN (4.91%) was submitted to CUS for mild variations from normal cerebral aspect at the aUS. Thirty-one neonates in the study cohort (2.62%) had multiple risk factors. Variations from normality at the neonatal CUS were observed in 402 TN (22.27%). In half of the cases the ultrasound findings were minimal abnormal findings, while minor abnormal findings were found in 179 TN (9.92%) and major abnormal findings in 20 TN (1.1%). Table 2 summarizes the number and percentage of minimal, minor and major CUS abnormal findings in the studied population divided in risk categories and in controls. No difference was observed comparing TN born from mothers with selected pregnancy complications - but no cerebral abnormal findings at aUS - with control TN. In contrast, prevalence of CUS abnormal findings was significantly higher in comparison with controls, in neonates with mild neurologic signs, microcrania or macrocrania as well as in TN with mild variations from normal cerebral aspect at the aUS. Neonates with mild peripartum complications, when compared to control TN, showed a significant difference in the prevalence of cerebral abnormal findings as a whole but not when the different groups of lesions (either minimal, minor or major) were concerned. Almost half of the neonates with multiple risk factors showed CUS abnormal cerebral findings that were represented by major lesions in 2 cases (6.4%). Interestingly, 23 out of 31(74.2%) neonates with multiple risk factors had minor neurological signs and 3 out of 31(9.7%) in this same category had mild variations on antenatal CUS. Minor and major cerebral abnormal findings are reported in details in Table 3. Cerebral haemorrhages were identified in 66 neonates (3.66% of the overall population and 16.42% of the total number of lesions). A significantly higher prevalence of haemorrhagic lesions in comparison with control TN was found in neonates with mild neurologic signs (6.4% vs 1.92%, p < 0.001) and in neonates with mild birth asphyxia or minor birth trauma (6.3% vs 1.92% p < 0.01). In addition, 35 TN had full choroid plexus (8.71% of the observed cerebral abnormal findings) and 121 CUS findings were represented by SEPC/CPC (30.09% of the total number of lesions), which, in some cases, could be the result of previous small haemorrhages of the germinal matrix or the choroid plexus. White matter hyperdensities or lenticulostriate vasculopathy were observed in 4.43% of our patients, a mild ventricular dilatation or a ventricular asymmetry in 18 TN (1% of the overall population and 4.48% of the abnormalities found in our series). The major cerebral abnormal findings observed in our population were mostly represented by cerebral malformations and atrophy, as shown in Table 3 according to their distribution in the 6 risk categories. Few cases of large SEH-IVH/PVI and stroke were also detected. No major cerebral abnormal findings were found in TN born from mothers with pregnancy complications - but normal aUS - and only one case was observed in TN with asymptomatic birth asphyxia or minor birth trauma. Conversely, TN with microcrania or macrocrania as well as TN with mild neurologic signs and TN with mild variations from normality in the cerebral aspect at aUS, showed a significantly higher prevalence of major cerebral abnormal findings in comparison with control TN. Table 4 shows the RR and the 95% CI for major cerebral abnormal findings in selected risk categories. It resulted as high as 8.43 in presence of microcrania, 6.36 in presence of multiple risk factors and 3.25 in presence of macrocrania.
ns < 0.001 < 0.01 < 0.02 < 0.01
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Rempen et al., consistently with the results that Heibel et al. [2] obtained in a population of 1000 healthy TN with no perinatal distress. In Haibel's study [2], 90 neonates (9%) were found with CUS abnormal findings, mostly represented by intracranial haemorrhages, SEPC, and CPC. In our study, we identified clear haemorrhagic lesions only in 3.66% of the overall population. In addition, however, 35 TN had full choroid plexus and 121 CUS abnormal findings were represented by SEPC/CPC, which are recognized to be in some cases the result of previous small haemorrhages. Moreover, when the percentage of the haemorrhagic lesions was analyzed in the different risk categories, a significantly higher prevalence of haemorrhagic lesions than controls was found in neonates with mild neurologic signs (6.4% vs 1.92%, p < 0.001) as well as in neonates with mild birth asphyxia or minor birth trauma compared to control TN (6.3% vs 1.92% p < 0.01). Neonates with peripartum complications, although not different from controls in the prevalence of major cerebral lesions, resulted at increased risk when the whole spectrum of lesions was concerned. This finding is partially explained by the threefold risk for haemorrhagic lesions in comparison with control neonates. As a consequence, CUS evaluation in this group might be useful for detection of cerebral bleeding. In a study by Mercuri et al. [3], including 177 apparently healthy neonates with GA ≥36 weeks, the CUS performed between 6 and 48 h of life detected cerebral abnormal findings in 35 neonates (20%), a result that is consistent with the overall prevalence of CUS abnormal findings in our study (22.27%). In 43/177 neonates, an abnormal neurologic examination was recorded and ultrasound abnormal findings were significantly associated with the presence of deviant patterns on clinical neurological examination. This finding is in accordance with
Table 4 Relative risk for major cerebral anomalies in selected risk categories in comparison with controls. Risk categories
RR
95% CI
p
Mild variations at the antenatal US Microcrania Macrocrania Mild neurologic signs Multiple risk factors Mild asymptomatic birth asphyxia or minor birth trauma
3.35 8.43 3.25 1.5 6.36 0.80
0.80–14.09 2.92–24.34 1.09–10.08 0.55–4.10 1.54–26.23 0.11–5.95
0.08 0.00 0.02 0.42 0.0041 0.82
since they are a high-risk population for cerebral abnormal findings. In contrast, only few systematic data exist concerning the prevalence of cerebral abnormal findings in TN [1–7] who undergo CUS at birth in a minority of cases. Moreover, the sonographic patterns of brain damage in TN are different from those detectable among premature infants [14]. In accordance with previous reports [1–7], our results, collected in a large series of patients, highlighted that various cerebral abnormal findings are detectable even in apparently healthy TN. Table 5 summarizes the CUS findings reported in the present study and in the other referenced studies. As far as asymptomatic TN are concerned, Rempen et al. [1], analyzing 673 asymptomatic TN, detected US abnormal findings in 88 of them (13%), a percentage not significantly lower than the 19.43% prevalence of overall abnormal findings in our asymptomatic population, i.e. once excluding neonates with mild neurologic signs. SEH/IVH and ventricular asymmetry were the main findings in the study by Table 5 Findings reported in the different studies. Studies
Population studied
General prevalence of CUS abnormal findings
Prevalence of major abnormal findings
Main findings
Rempen et al. [1]
673 clinically asymptomatic mature newborns
13.1%
–
Heibel [2]
1000 clinically asymptomatic term neonates, with no perinatal distress
9%
–
Mercuri [3]
177 neonates EG 36.3–42 weeks, clinically asymptomatic
20%
Hsu [5]
3186 term neonates with no perinatal distress
6.42%
0.06%
Wang [6]
2309 clinically asymptomatic term neonates without perinatal complications or neurological abnormalities 6771 term neonates
–
0.26%
1.7%
0.19%
1805 term neonates (1181 with risk factors; 624 controls)
22.27%
1.1% (1.5% in TN with risk factors, 0.32% in controls)
Subependymal/intraventricular haemorrhages (5.5%) Sequelae of an old intrauterine bleeding (1.3%) Ventricular asymmetries (5.7%) Choroidal plexus cysts (0.7%) Arachnoidal cysts (0.9%) infratentorial tumour (0.2%) Intracranial haemorrhage (periventricular, choroid plexus and intraventricular) (3.5%) Possible sequelae of bleeding (subependymal and choroid plexus pseudocysts; local dilatation of the lateral ventricles) (3.4%) Morphological aberrations (2.1%) Ischemic lesions, such as periventricular and thalamic densities (8%) Haemorrhagic lesions (6%) Cystic lesions (3.74%) Mild haemorrhage (1.85%) Mild ventricular anomalies (0.75%) Corpus callosum agenesis (0.03%) Significant ventricular dilatation (0.03%) Intracranial haemorrhage (0.13%) Corpus callosum agenesis (0.09%) Middle cerebral artery (MCA) infarct (0.04%) Partial/complete agenesis of corpus callosum (0.04%) Periventricular calcifications (0.01%) Ischemic stroke (0.03%) Hypoxic-ischemic encephalopathy (0.06%) Hydrocephalus (0.01%) Ventriculomegaly (0.01%) Porencephalic cyst (0.01%) Cerebral haemorrhages (3.66%) SEPC/CPC (30.9%) White matter hyperdensities or lenticulostriate vasculopathy (4.43%) Ventricular dilatation or asymmetry (1%) Stroke (0.05%) Atrophy (0.39%) Malformation (0.39%)
Ballardini [7]
Present study
4
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the high prevalence of CUS abnormal findings we observed in the group of neonates included in the study for the presence of mild neurologic signs. As a consequence, CUS within the first days of life should be mandatory in these neonates. Among the neonates included in Mercuri's study [3], 6% had intracranial haemorrhage, 6% ventricular asymmetry, 8% thalamic and white matter hyperdensities, and 8% full choroid plexus, findings that are comparable with our results. Mercuri et al. [3] analyzed the correlation between CUS findings and prenatal and perinatal complications. Prenatal risk factors were found in 29/72 (40%) infants with normal CUS and in 16/23 (61%) with cerebral abnormal findings, with no statistically significant difference. Perinatal risk factors were recorded in 11/72 (15%) neonates with normal CUS and 3/23 (13%) with cerebral anomalies, in this case also without any statistically significant differences. Lesions that could be due to ischemic damage, such as periventricular densities, were seen even in the absence of any antenatal or perinatal risk factors. Consistently with the observations by Mercuri et al. [3], the pregnancy complications we included in the study were not a risk factor for neonatal CUS abnormal findings in our population, unless antenatal US abnormalities were detected. Hsu et al. [5] studied 3186 full term healthy neonates submitted to CUS as screening examination: minor abnormal findings were found in 6.34% infants; major abnormal findings were found in two newborns (0.06%). One neonate with major abnormal findings had some abnormalities on fetal ultrasonography. In our study cohort, a prevalence of 1.5% of major cerebral abnormal findings or malformations potentially compromising neurologic development was found. The prevalence of major abnormal findings was significantly different, compared to controls, according to the different low-risk categories. Our finding of 0.32% in neonates without risk factors (control neonates) is consistent with the prevalence of 0.26% reported in a large population of 2309 apparently healthy TN (GA 37–41 weeks) without perinatal complications or neurological abnormalities, that were subjected to a sonographic screening [6]. Furthermore, this percentage is consistent with that recently reported by Ballardini et al. [7] in a retrospective evaluation of a universal CUS screening in term neonates. Among the 6771 full term neonates examined in this study, 114 (1.7%) had CUS abnormal findings, whereas 6657 were normal or insignificant; 101 of the 114 CUS abnormal findings were minor. Major abnormal findings affected just 13 neonates (0.19% of the whole population). All neonates with major CUS abnormal findings presented at least one risk factor such as microcephaly, abnormal neurological evaluation, prenatal diagnosis of brain abnormal findings [7]. As a consequence, the Authors' conclusion is that universal CUS screening is not recommended in healthy term neonates unless one of those clinical features is identified. All the previous studies reported the incidence of cerebral abnormal findings in the context of a universal CUS screening in the general population of healthy term newborns. Aim of our study was to better target neonatal CUS investigations in healthy term newborns. Accordingly, we selected clinical features potentially associated to cerebral abnormal findings, identifying different low-risk categories among the general population of apparently healthy term neonates. The different low-risk categories were compared to a control group of term healthy neonates without risk factors. A significantly higher risk for cerebral abnormal findings in respect to control term infants was found in some of the identified low-risk categories, namely microcrania and macrocrania, mild neurological signs and antenatal mild intracranial variation from normality. In addition, the RR analysis showed that microcrania, macrocrania and the contemporary presence of multiple risk factors are important markers for major cerebral abnormal findings that can be detected with CUS and thus CUS is not to be missed in these infants. Neonates with mild neurologic signs show not only a significantly higher prevalence of total cerebral abnormal findings but also a significant difference for major cerebral abnormal findings in respect to control neonates with a RR equal to 1.5. We also studied a series of
neonates with the aUS showing mild variations in the fetal cerebral aspect although these variations were not clear anomalies to be regarded as exclusion criteria from the study. These infants showed abnormal findings at the neonatal CUS in about 40% of cases (23 out of 58 neonates in this risk category). Neonatal CUS in these neonates allowed the identification of two major congenital malformations. Accordingly, mild aUS variations from normal cerebral pattern may represent a marker of lesions or congenital anomalies not easily recognizable in utero due to the intrinsic lower accuracy of aUS [15,16]. A series of 102 neonates born from mothers with autoimmune diseases, which are reported to be at risk for CUS abnormal findings [17–19], were analyzed apart from the other observed pregnancy complications. We were unable to demonstrate a different percentage of abnormal CUS findings in comparison with controls (17,65 vs 15,71%). TN with severe asymmetric intrauterine growth retardation (BW < 3° centile but head circumference > 3° centile), which are considered to be at risk for cognitive problems [20], did not show an increased prevalence than controls in CUS abnormal findings (15/121 i.e. 12,4%). As a consequence, we speculate that CUS evaluation is probably not a useful tool in this group of neonates. The prognostic value of the observed findings in TN has been scarcely investigated. In the study by Heibel et al. [2], four patients with intracranial haemorrhage were hemiparetic, and one of them also developed epilepsy, at the 12-month follow-up. In previous studies, we have analyzed a series of neonates with prenatal diagnosis of fetal cerebral haemorrhages [21,22]. According with the exclusion criteria of the present study, these neonates are not included in this report. In Mercuri's study, no major neurological or developmental abnormalities were detectable in the 103 neonates who underwent a 12- and 18month follow-up among the 177 of the original cohort [3,4]. In conclusion, the present study, analyzing a large series of low-risk healthy TN, found about 20% variation from normal CUS pattern, consistently with the data reported in the industrialized countries. Half of the findings were minimal variations from normality and approximately half were minor abnormal findings whose prognostic relevance is not defined at present. More than 1% of the studied neonates showed major cerebral abnormal findings potentially compromising neurologic development. The prevalence of the observed abnormal findings was different, compared to controls, according to the different low-risk categories. The clinical features increasing the risk for cerebral abnormal findings in healthy TN were micro/macrocrania or mild neurologic signs, and mild variations from normality in the cerebral aspect at aUS. These results may help to target the CUS policy in low risk TN, in function of the available resources in the different neonatal units. According to our results, CUS examination should not be performed in healthy term neonates without risk factors and risk categories leading to CUS examination should be restricted to neonates with abnormal head size and mild neurologic signs or neonates with mild variations on antenatal CUS. When considering the effect of restricting the inclusion criteria to these risk categories, half of the neonates (583 neonates) in our study population would not have had criteria to undergo to CUS examination and the percentage of screened neonates would have been reduced to 3.5% of all live births. The prognostic values of the detected abnormal findings should be taken into account. The relative risk calculation for major cerebral abnormalities, as illustrated in Table 4, corroborates the opportunity to perform CUS examination in case of abnormal head size or multiple risk factors. Interestingly, 23 out of 31 (74.2%) neonates with multiple risk factors had minor neurological signs and 3 out of 31(9.7%) in this same category had mild variations on antenatal CUS. Looking at our study population, we should perform 30 CUS examination to find one major cerebral abnormality and a percentage of major cerebral abnormalities equal to 85% could be diagnosed, if we restrict the risk categories as above suggested. Major cerebral abnormal findings arise, obviously, the utmost concern for long-term outcome and should be used to support the need for 5
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long-term follow up. On the contrary, we are still not aware of the clinical relevance that the observed minor abnormal findings entail in this low-risk population of TN. Being not evident from the literature that minor cerebral abnormalities have a causal relationship with long term disabilities, we believe we should concentrate resources in order to detect the cases with relevant abnormalities.
[7]
[8]
[9]
Credit authorship contribution statement [10]
R. Luciano: Conceptualization, Investigation, Formal analysis. I. Bersani: Conceptualization, Investigation, Formal analysis. G. Mancini: Conceptualization, Investigation, Formal analysis. G. Vento: Conceptualization, Investigation, Formal analysis. E. Mercuri: Conceptualization, Investigation, Formal analysis.
[11]
[12]
Declaration of competing interest
[13] [14]
None.
[15]
Acknowledgments We thank the families of patients for their understanding cooperation and the nursing staff for its invaluable support.
[16]
Funding [17]
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
[18]
References [19]
[1] A. Rempen, A. Feige, K. Fiedler, Incidence of conspicuous ultrasound findings in the brain in clinically asymptomatic newborn infants, Z. Geburtshilfe Perinatol. 190 (5) (1986) 190–195 Sep-Oct. [2] M. Heibel, R. Heber, D. Bechinger, et al., Early diagnosis of perinatal cerebral lesions in apparently normal full-term newborns by ultrasound of the brain, Neuroradiology 35 (2) (1993) 85–91. [3] E. Mercuri, L. Dubowitz, S.P. Brown, et al., Incidence of cranial ultrasound abnormalities in apparently well neonates on a postnatal ward: correlation with antenatal and perinatal factors and neurological status, Arch. Dis. Child. Fetal Neonatal Ed. 79 (1998) F185–F189, https://doi.org/10.1136/fn.79.3.f185. [4] L. Haataja, E. Mercuri, F. Cowan, et al., Cranial ultrasound abnormalities in full term infants in a postnatal ward: outcome at 12 and 18 months, Arch. Dis. Child. Fetal Neonatal Ed. 82 (2000) F128–F133, https://doi.org/10.1136/fn.82.2.fl28. [5] C.-L. Hsu, et al., Cranial ultrasonographic findings in healthy full-term neonates: a retrospective review, J. Chin. Med. Assoc. 75 (2012) 389e395, https://doi.org/10. 1016/j.jcma.2012.06.007. [6] L.W. Wang, C.C. Huang, T.F. Yeh, Major brain lesions detected on sonographic
[20]
[21]
[22]
6
screening of apparently normal term neonates, Neuroradiology 46 (5) (2004) 368–373, https://doi.org/10.1007/s00234-003-1160-4. E. Ballardini, et al., Universal head ultrasound screening in full-term neonates: a retrospective analysis of 6771 infants, Pediatr. Neurol. 71 (2017) 14–17, https:// doi.org/10.1016/j.pediatrneurol.2017.03.012. C.F. Hagmann, N.J. Robertson, D. Acolet, et al., Cranial ultrasound findings in well newborn Ugandan infants, Arch. Dis. Child. Fetal Neonatal Ed. 95 (5) (2010) F338–F344, https://doi.org/10.1136/adc.2009.174607. E. Bertino, E. Spada, L. Occhi, et al., Neonatal anthropometric charts: the Italian neonatal study compared with other European studies, J. Pediatr. Gastroenterol. Nutr. 51 (3) (2010) 353–361, https://doi.org/10.1097/MPG.0b013e3181da213e. L.M.S. Dubowitz, V. Dubowitz, E. Mercuri, The Neurological Assessment of the Preterm and Full-term Newborn Infant Clinics in Developmental Medicine, 148 Mac Keith Press, London, 1999. M.J. Brouwer, L.S. de Vries, F. Groenendaal, et al., New reference values for the neonatal cerebral ventricles, Radiology 262 (2012) 224–233, https://doi.org/10. 1148/radiol.11110334. L. Goodwin, R.G. Quisling, The neonatal cisterna magna: ultrasonic evaluation, Radiology 149 (1983) 691–695, https://doi.org/10.1148/radiology.149.3. 6647845. P. Govaert, L.S. de Vries, An Atlas of Neonatal Brain Sonography Clinics in Developmental Medicine, Mac Keith Press, London, 2010, pp. 182–183. A. Yikilmaz, G.A. Taylor, Cranial sonography in term and near-term infants, Pediatr. Radiol. (6) (2008) 605–616, https://doi.org/10.1007/s00247-007-0692-x. A. Gagnon, R.D. Wilson, V.M. Allen, F. Audibert, C. Blight, J.A. Brock, V.A. Désilets, J.A. Johnson, S. Langlois, L. Murphy-Kaulbeck, P. Wyatt, Society of Obstetricians and Gynaecologists of Canada, Evaluation of prenatally diagnosed structural congenital anomalies, J. Obstet. Gynaecol. Can. 31 (9) (2009) 875–881 Sep. 882-9. G.M. Senapati, D. Levine, C. Smith, J.A. Estroff, C.E. Barnewolt, R.L. Robertson, T.Y. Poussaint, T.S. Mehta, X.Q. Werdich, D. Pier, H.A. Feldman, C.D. Robson, Frequency and cause of disagreements in imaging diagnosis in children with ventriculomegaly diagnosed prenatally, Ultrasound Obstet. Gynecol. 36 (5) (2010) 582–595 Nov. A.A. Zuppa, F. Gallini, D. De Luca, R. Luciano, S. Frezza, P.L. de Turris, G. Tortorolo, Cerebral ultrasound findings in neonatal lupus syndrome, Biol. Neonate 86 (2004) 230–234, https://doi.org/10.1159/000079820. M. Motta, C. Zambelloni, C. Rodriguez-Perez, A. Angeli, A. Lojacono, A. Tincani, G. Chirico, Cerebral ultrasound abnormalities in infants born to mothers with autoimmune disease, Arch. Dis. Child. Fetal Neonatal Ed. 96 (5) (2011) F355–F358, https://doi.org/10.1136/adc.2010.195099 Sep. Mazzucchelli, et al., Maternal and neonatal outcomes in pregnant women with autoimmune diseases in Pavia, Italy, BMC Pediatr. 15 (2015) 217, https://doi.org/ 10.1186/s12887-015-0532-3. T. Arcangeli, B. Thilaganathan, R. Hooper, K.S. Khan, A. Bhide, Neurodevelopmental delay in small babies at term: a systematic review, Ultrasound Obstet. Gynecol. 40 (2012) 267–275, https://doi.org/10.1002/uog.11112. R. Luciano, G. Baranello, L. Masini, D. Ricci, F. Gallini, S. Ciotti, D. Leone, F. Serrao, M. De Santis, E. Zecca, A. Zuppa, C. Romagnoli, C. Di Rocco, F. Guzzetta, E. Mercuri, Antenatal post-hemorrhagic ventriculomegaly: a prospective follow-up study, Neuropediatrics 38 (3) (2007) 137–142, https://doi.org/10.1055/s-2007985366 Jun. D. Ricci, R. Luciano, G. Baranello, C. Veredice, L. Cesarini, F. Bianco, M. Pane, F. Gallini, G. Vasco, I. Savarese, A. Zuppa, L. Masini, C. Di Rocco, C. Romagnoli, F. Guzzetta, E. Mercuri, Visual development in prenatal post-haemorrhagic ventricular dilatation, Arch. Dis. Child. Fetal Neonatal Ed. 92 (4) (2007) F255–F258, https://doi.org/10.1136/adc.2006.101485 Jul.