Posterior subependymal germinal matrix hemorrhage as a mild form of hemorrhage in extremely preterm infants: neurodevelopmental outcomes at corrected ages of 18-24 months
Article information
Abstract
Purpose
This study aimed to explore the effects of both the presence and size of posterior subependymal germinal matrix hemorrhage (PS-GMH), considered a mild form of hemorrhage, on the neurodevelopmental outcomes of extremely preterm infants.
Methods
A retrospective analysis was conducted on 221 extremely preterm infants, assessing their initial and term-equivalent age (TEA) cranial ultrasound (cUS) examinations from 2016 to 2021. Infants were classified based on the presence and size (small/large) of PS-GMH. Neurodevelopmental outcomes at corrected ages of 18-24 months were analyzed in 135 infants.
Results
PS-GMH was identified in 86.9% (192/221) of the infants, with 13.5% (26/192) exhibiting large PS-GMH. Among the 135 infants who were followed up, those with PS-GMH were found to have younger gestational ages (P<0.001) and a higher incidence of maternal chorioamnionitis (P=0.016) than those without PS-GMH. Significant differences were observed in the incidence of grade II intraventricular hemorrhage (IVH) on initial cUS (P=0.003) and ventriculomegaly at TEA cUS (P=0.026) across the groups with no PS-GMH, small PS-GMH, and large PS-GMH. The large PS-GMH group exhibited a higher occurrence of grade II IVH than the small PS-GMH group (P=0.006). However, ventriculomegaly incidence did not significantly vary with PS-GMH status. Neurodevelopmental outcomes were also not significantly different across PS-GMH statuses. The adjusted odds ratios for any neurodevelopmental impairment, compared to the no PS-GMH group, were 1.70 (95% confidence interval [CI], 0.40 to 7.26; P=0.471) for all PS-GMH, 1.61 (95% CI, 0.37 to 6.93; P=0.526) for small PS-GMH, and 3.84 (95% CI, 0.62 to 24.00; P=0.150) for large PS-GMH.
Conclusion
PS-GMH was frequently observed in extremely preterm infants; however, it did not independently predict adverse neurodevelopmental outcomes.
Introduction
Germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH) is a significant cause of neonatal brain injury, particularly in preterm infants, and is a major concern in neonatal radiology [1]. The incidence of GMH-IVH is inversely related to both gestational age and birth weight [2,3]. The germinal matrix is particularly vulnerable due to its fragile basal lamina, immature vasculature, and low levels of glial fibrillary acidic protein expression. This vulnerability is exacerbated by structural anomalies in the subependymal vein, hypoxia, and a lack of adaptability, all of which increase the risk of vascular rupture [4]. Such conditions often lead to hemorrhage in the small vessels of the germinal matrix, which can disrupt the ependymal lining and extend into the lateral ventricle [3,4]. GMH-IVH is typically classified into grades I-IV based on the severity, according to the classification system developed by Papile et al. [3].
The germinal matrix, which is located below the floor of the lateral ventricles, undergoes extensive cellular proliferation during early fetal life. It reaches its peak volume between 20 and 26 weeks of gestation before gradually regressing in a site-specific manner [5,6]. This reduction in volume is especially pronounced in the dorsal portion, whereas the ventral portion remains within the anterior caudothalamic groove until it fully involutes by 34 to 36 weeks of gestation [5-7].
Given the dynamic nature of the germinal matrix throughout gestation, it is understood that GMH presentations may vary between extremely preterm and late preterm infants, reflecting developmental differences [7]. In extremely preterm infants, hemorrhage can occur in the remaining posterior germinal matrix, termed posterior subependymal GMH (PS-GMH), located behind the typical grade I GMH-IVH found in the caudothalamic groove [7,8]. However, large PS-GMH has sometimes been misidentified as high-grade GMH-IVH, choroid plexus hemorrhage, or parenchymal injury due to an incomplete understanding of the germinal matrix [7].
Previous studies have demonstrated that abnormalities in the germinal matrix, identified via fetal imaging in the second trimester—including abnormal persistence, enlargement, and cavitation—are associated with significantly reduced fetal head size, underdevelopment of sulcation, and malformations in cortical development [9-11]. Additionally, experimental research has shown that germinal matrix hemorrhage in preterm infants (aged 18-34 weeks post-menstrual) correlates with decreased Ki67 immunoreactivity, suggesting a reduction in germinal cell proliferation [5]. This reduction may lead to impaired oligodendrocyte development near the germinal matrix, negatively impacting cerebral myelination. It could also disrupt the production of GABAergic interneurons for the neocortex and interfere with the generation of thalamic neurons, potentially resulting in adverse delayed effects [12,13]. However, the neurodevelopmental outcomes for preterm infants with PS-GMH identified through postnatal imaging remain uncertain.
This study aims to explore the effect of both the presence and size of PS-GMH, considered a mild form of hemorrhage, on the neurodevelopmental outcomes of extremely preterm infants.
Materials and Methods
Compliance with Ethical Standards
This study is a retrospective analysis carried out at a single tertiary academic center. This study was approved by the Institutional Review Board of Samsung Medical Center (IRB No. 2022-05-151-001) with a waiver of informed consent.
Study Population
This study examined data from 282 extremely preterm infants, defined as those born before 27 completed weeks of gestation, who were admitted to the neonatal intensive care unit (NICU) at the authors’ affiliated center between January 2016 and December 2021. According to the institution's protocol, all preterm infants underwent at least two cranial ultrasound (cUS) scans: the initial cUS within 1 week of birth and a second at term-equivalent age (TEA cUS). Additional cUS scans were scheduled based on findings from previous scans or changes in the infants' clinical condition, at the discretion of the on-duty neonatologists.
In total, 61 infants were excluded from this cohort due to (1) death before reaching a gestational age of 36 weeks (n=49), (2) a large infarction or high-grade (III-IV) IVH on initial or follow-up cUS (n=9), (3) congenital anomalies (n=2), or (4) congenital infection (n=1). This led to a study population of 221 infants who survived to TEA and had both initial and TEA cUS.
Out of the 221 infants, 135 underwent neurodevelopmental assessments at corrected ages of 18 to 24 months. The remaining 86 infants were not assessed; 77 were lost to follow-up, and nine had died. The infants were categorized based on the presence and size of PS-GMH observed in the initial cUS. The analysis focused on the 135 infants who had a complete dataset, which included both initial and TEA cUS scans, along with a neurodevelopmental examination at corrected ages of 18-24 months (Fig. 1). Additionally, the initial and TEA cUS data were evaluated for the entire cohort of 221 infants.
Flow diagram of the patient selection process used in the study.
cUS, cranial ultrasound; IVH, intraventricular hemorrhage.
Clinical Data Collection
The medical records of eligible infants were reviewed to collect information on demographics, clinical characteristics, and neurodevelopmental outcomes. Demographic data included gestational age at birth, sex, birth weight, and Apgar scores at 1 and 5 minutes. Comorbid conditions diagnosed during the infants' NICU stay were also recorded. These conditions included neonatal sepsis, necrotizing enterocolitis (NEC, modified Bell’s stage IIA-IIIA) [14], and acute kidney injury (AKI). In addition, relevant maternal clinical data were documented, covering pathologically confirmed chorioamnionitis, premature rupture of membranes, pregnancy-induced hypertension (PIH), and exposure to antenatal steroids. Neonatal sepsis was identified either through culture-proven sepsis or by clinical signs accompanied by a negative culture [15]. AKI was defined as either a reduction in urine output after the first 24 hours of life or an increase in serum creatinine levels above 1.5 mg/dL between 48 and 72 hours after birth [16].
The assessment of neurodevelopmental outcomes at corrected ages of 18 to 24 months included the use of Bayley Scales of Infant Development (BSID)-II (from 2017 to 2020, n=57) and BSID-III (from 2019 to 2022, n=78), along with evaluations for cerebral palsy. The assessment tools were organized into three categories: cognitive domain, motor domain, and cerebral palsy. Cognitive impairment was defined as a mental developmental index below 70 on the BSID-II or a cognitive scale below 70 on the BSID-III. Similarly, motor impairment was defined as a psychomotor developmental index below 70 on the BSID-II or a motor score below 70 on the BSID-III [17-19]. Cerebral palsy was characterized as a non-progressive neuromotor disorder marked by abnormal motor function in at least one extremity. This condition also involves disrupted control of movement and posture, which interferes with age-appropriate activities. It is diagnosed at corrected ages of 18 to 24 months by a pediatric rehabilitation physician [19]. Neurodevelopmental impairment was identified in participants who exhibited at least one developmental problem, including cognitive impairment, motor impairment, or cerebral palsy.
US Examinations
All infants underwent cUS examinations performed by one of four pediatric radiologists, each with over 10 years of experience, or by two pediatric radiology fellows under supervision.
The US system utilized was the LOGIQ E9 (GE Healthcare, Milwaukee, WI, USA), which featured a 9 MHz linear-array transducer. The protocol comprised six standard coronal and five parasagittal views obtained through the anterior fontanelle, serving as the sonographic window. This procedure did not require fasting or sedation. Two radiologists, each with 21 and 13 years of experience in pediatric imaging interpretation, independently reviewed all images in a blind process and resolved any discrepancies by consensus. Both initial and subsequent ultrasound images were evaluated at intervals exceeding 1 week. Following the analysis, the inter-observer agreement on cUS findings was determined.
The US parameters encompassed the presence and size of PS-GMH, grade II IVH, and white matter hyper-echogenicity on the initial cUS, as well as ventriculomegaly and periventricular leukomalacia on TEA cUS.
PS-GMH was defined as hemorrhage located along the lateral ependymal surface of the lateral ventricles, paralleling the caudate nucleus, in areas where the germinal matrix is present in extremely preterm infants. It is not situated above the ventricles in the periventricular white matter region or the caudothalamic groove [7].
PS-GMH typically presents as linear echogenicity under 1 mm. In this study, PS-GMH thickness was classified based on the initial parasagittal cUS scan: less than 3 mm was considered small, and 3 mm or more was considered large (Fig. 2). Grade II IVH was classified according to the system developed by Papile et al. [3]. White matter hyper-echogenicity was defined as either increased echogenicity in the periventricular white matter, appearing equal to or greater than that of the choroid plexus, or as inhomogeneous echogenicity [20]. A ventricular index greater than 13 mm at the foramen of Monro was defined as ventriculomegaly [21]. Periventricular leukomalacia was diagnosed in cases showing either apparent cystic lesions within the white matter surrounding the lateral ventricles or white matter hyper-echogenicity accompanied by bumpy, irregular, or square-bordered ventricles [20,22].
Representative examples of small and large posterior subependymal germinal matrix hemorrhage (PS-GMH).
A, B. Small PS-GMH: coronal (A) and right parasagittal (B) ultrasound (US) images on day of life 3 depict a small hyperechoic hemorrhage (1.3 mm thickness; less than 3 mm on parasagittal scan, arrow) along the right posterior germinal matrix in an extremely preterm male infant (born at a gestational age of 25 weeks and 6 days). C, D. Large PS-GMH: coronal (C) and right parasagittal (D) US images on day of life 4 illustrate a large hyperechoic hemorrhage (6.4 mm thickness; more than 3 mm on parasagittal scan, arrow) along the right posterior germinal matrix in an extremely preterm male infant (born at a gestational age of 25 weeks and 4 days).
Statistical Analysis
Statistical analyses were conducted using SAS version 9.4 (SAS Institution Inc., Cary, NC, USA) and R Software Statistics version 20 (IBM SPSS Statistics, IBM Corp., Armonk, NY, USA). Unadjusted comparisons were compared for neonatal factors, maternal factors, cUS findings, and neurodevelopmental outcomes between the no PS-GMH group and all PS-GMH groups, as well as among the no PS-GMH, small PS-GMH, and large PS-GMH groups. These comparisons utilized the chi-square or Fisher exact test for categorical data and the Wilcoxon rank sum or Kruskal-Wallis tests for continuous data. To mitigate the risk of type 1 error from multiple comparisons, a Bonferroni correction was applied. Multivariable logistic regression models, adjusted for potential confounders such as gestational age, gender, birth weight, an Apgar score <5 at 1 minute, an Apgar score <7 at 5 minutes, neonatal sepsis, NEC, AKI, maternal chorioamnionitis, and PIH, were employed to explore the associations between the study groups (no PS-GMH, all PS-GMH, small PS-GMH, and large PS-GMH) and neurodevelopmental outcomes. The no PS-GMH group was used as a control for subsequent pairwise comparisons. Results are presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Inter-observer agreement was assessed using kappa (κ) statistics, which were interpreted as follows: poor reliability (<0.4), fair to good reliability (0.20-0.75), and excellent reliability (0.76-1). All P-values were two-sided, and a significance threshold was set at 0.05.
Results
The study included 221 infants, of which 192 (86.9%) were diagnosed with PS-GMH. This group consisted of 166 (86.4%) cases of small PS-GMH and 26 (13.5%) cases of large PS-GMH. Among these, 84 (43.8%) had bilateral PS-GMH, while 108 (56.3%) had unilateral PS-GMH. On the initial cUS, 21 of the 192 infants with PS-GMH (10.9%) also presented with typical anterior GMH (Fig. 3). Additionally, 76 infants (39.6%) did not exhibit typical anterior GMH initially but developed it on delayed follow-up cUS. The median interval between the initial and follow-up cUS was 36 days (interquartile range, 29 to 60 days). There were no instances of delayed PS-GMH at follow-up cUS. Neurodevelopmental outcomes were evaluated in 135 infants at corrected ages of 18-24 months. Comparisons between infants with and without neurodevelopmental outcomes revealed no significant differences in neonatal and maternal factors, or in cUS findings (Table 1).
Large anterior and posterior subependymal hemorrhage simulating grade III intraventricular hemorrhage (IVH) in an extremely preterm infant (born at a gestational age of 26 weeks and 5 days), performed on day 6 of life.
A. Coronal ultrasonography (US) shows hyperechoic hemorrhage at the right caudothalamic groove (black arrow). B. More posteriorly angled US shows large hemorrhage along the lateral wall of the posterior right lateral ventricle, at the posterior caudothalamic groove (white arrow), simulating grade III IVH. C. Right parasagittal US shows the subependymal hemorrhage at both the caudothalamic groove (black arrow) and posterior to the caudothalamic grooves (white arrow).
Comparisons of infants with neurodevelopmental outcomes and those without neurodevelopmental outcomes (n=221)
The median timing for cUS examinations was 3 days (interquartile range, 2 to 5 days) after the initial assessment and 84 days (interquartile range, 74 to 93 days) for the term-equivalent assessment.
Clinical characteristics, cUS findings, and neurodevelopmental outcomes based on the presence and size of PS-GMH are presented in Table 2. Infants with PS-GMH were born at a significantly younger gestational age than those without PS-GMH (P<0.001). When comparing the groups with no PS-GMH, small PS-GMH, and large PS-GMH, there were significant differences in gestational age (P<0.001). However, post-hoc tests indicated no significant difference in gestational age between the small and large PS-GMH groups (P>0.99) (Fig. 4). Maternal chorioamnionitis occurred more frequently in infants with PS-GMH (P=0.016); however, this difference was not statistically significant when analyzed by the size of PS-GMH (P=0.053). No significant differences were observed in other neonatal and maternal factors with respect to the presence and size of PS-GMH.
Comparisons of clinical characteristics, cUS findings, and neurodevelopmental outcomes according to PS-GMH status in 135 extremely preterm infants
Boxplots visualizing significant results of post-hoc pairwise comparisons among the no posterior subependymal germinal matrix hemorrhage (PS-GMH), small PS-GMH, and large PS-GMH groups.
A. Significant differences in gestational age are observed in post-hoc pairwise comparisons among the three groups (using the Wilcoxon rank sum test): no PS-GMH vs. small PS-GMH (P<0.001), no PS-GMH vs. large PS-GMH (P=0.005), small PS-GMH vs. large PS-GMH (P>0.99). B. Significant differences in grade II IVH are found only in post-hoc pairwise comparisons between small PS-GMH and large PS-GMH groups (using the Fisher exact test): no PS-GMH vs. small PS-GMH (P>0.99), no PS-GMH vs. large PS-GMH (P=0.130), small PS-GMH vs. large PS-GMH (P=0.006). C. No statistically significant differences are found in ventriculomegaly in post-hoc pairwise comparisons among the three groups (using the Fisher exact test): no PS-GMH vs. small PS-GMH (P=0.400), no PS-GMH vs. large PS-GMH (P>0.99), small PS-GMH vs. large PS-GMH (P=0.094). cUS, cranial ultrasound; TEA, term-equivalent age.
During both initial and TEA cUS assessments, no significant differences were observed in the presence of grade II IVH, white matter hyper-echogenicity, ventriculomegaly, and periventricular leukomalacia between infants with and without PS-GMH. However, when comparing groups with no PS-GMH, small PS-GMH, and large PS-GMH, statistically significant differences were noted in the incidence of grade II IVH at the initial cUS (P=0.003) and ventriculomegaly at TEA cUS (P=0.026). Specifically, the large PS-GMH group exhibited a higher prevalence of grade II IVH during the initial cUS than the small PS-GMH group (P=0.006) (Figs. 5, 6). Nevertheless, there were no statistically significant differences in ventriculomegaly at TEA cUS based on PS-GMH status (Figs. 5, 6).
Large posterior subependymal germinal matrix hemorrhage (PS-GMH) simulating grade III intervertebral hemorrhage (IVH) in an extremely preterm female infant (born at gestational age of 25 weeks and 4 days), performed on day 5 of life.
A, B. Coronal ultrasonography (A) shows a hyperechoic hemorrhage along the lateral walls of the bilateral lateral ventricle (arrows), simulating grade III IVH. A left parasagittal image (B) shows the hemorrhage posterior to the caudothalamic groove along the subependymal surface of the lateral ventricle (arrow), congruent with the posterior location of germinal matrix. Normal periventricular white matter is separated by a cerebrospinal fluid cleft from the subependymal hemorrhage. Intraventricular blood is also observed in the bilateral occipital horn (arrowheads). C, D. The evolution of hemorrhage in the same infant at 4 weeks of age is shown in coronal (C) and left parasagittal (D) images, which show decreased size of bilateral large PS-GMH with cystic evolution (arrows) E, F. The evolution of hemorrhage in the same infant at term-equivalent age (corrected gestational age of 39 weeks and 4 days) is shown in coronal (E) and left parasagittal (F) images, which show nearly resolved large PS-GMH (arrows), with no evidence of ventriculomegaly and periventricular leukomalacia. This girl revealed no neurodevelopmental impairment diagnosed at a corrected age of 18 to 24 months.
Large posterior subependymal germinal matrix hemorrhage (PS-GMH) simulating periventricular white matter hemorrhage in an extremely preterm male infant (born at a gestational age of 26 weeks and 6 days), performed on day 4 of life.
A-C. Coronal (A) and more posteriorly angled coronal (B) images show a hemorrhagic focus at the right anterior and PS-GMH in the anterior caudothalamic groove and along the posterior lateral walls of the right lateral ventricle (arrow), mimicking periventricular white matter hemorrhage. Right parasagittal image (C) shows anterior and posterior large subependymal hemorrhage (arrow). Normal periventricular white matter is separated by a cerebrospinal fluid cleft from the subependymal hemorrhage. D-F. The evolution of hemorrhage in the same infant at 4 weeks of age is shown in coronal (D, E) and right parasagittal (F) images, which show decreased size of right anterior and PS-GMH with cystic evolution (arrow). G-I. The evolution of hemorrhage in the same infant at term-equivalent age (corrected gestational age of 38 weeks and 1 day) is shown in coronal (G, H) and right parasagittal (I) images, which show nearly resolved right PS-GMH (arrow), with no evidence of ventriculomegaly and periventricular leukomalacia. This boy exhibited no neurodevelopmental impairment diagnosed at a corrected age of 18 to 24 months.
At corrected ages of 18-24 months, 47 infants (34.8%) were found to have at least one neurodevelopmental impairment. There was no significant difference in the proportion of neurodevelopmental impairments across different PS-GMH statuses (no PS-GMH, all PS-GMH, small PS-GMH, large PS-GMH), with rates of 31.3% (5/16), 35.3% (42/119), 33.0% (34/103), and 50.5% (8/16), respectively.
In comparison to the no PS-GMH group, the adjusted ORs for any neurodevelopmental impairment were 1.70 (95% CI, 0.40 to 7.26; P=0.471) in all infants with PS-GMH, 1.61 (95% CI, 0.37 to 6.93; P=0.526) in the small PS-GMH group, and 3.84 (95% CI, 0.62 to 24.00; P=0.150) in the large PS-GMH group (Table 3).
Adjusted odds ratios for neurodevelopmental impairment by PS-GMH status among 135 extremely preterm infants
The inter-observer agreement for cUS findings in 221 patients showed substantial to almost perfect reliability (κ=0.67-0.97), with specific follows as possible: PS-GMH presence (κ=0.92), PS-GMH size (κ=0.94), grade II IVH (κ=0.97), white matter hyper-echogenicity (κ=0.67), ventriculomegaly (κ=0.77), and periventricular leukomalacia (κ=0.87).
Discussion
The present study revealed that 87% of extremely preterm infants exhibited PS-GMH, with 86% having small PS-GMH and 14% having large PS-GMH. Additionally, 44% of these infants had bilateral PS-GMH, while 56% had unilateral PS-GMH. Infants with PS-GMH were born at earlier gestational ages and had a higher prevalence of maternal chorioamnionitis compared to those without PS-GMH. Significant differences were observed in the incidence of grade II IVH and ventriculomegaly among groups with no PS-GMH, small PS-GMH, and large PS-GMH. Specifically, the large PS-GMH group showed a higher prevalence of grade II IVH during initial cUS compared to the small PS-GMH group. This study is the first to assess neurodevelopmental outcomes in extremely preterm infants with PS-GMH. Regardless of size, PS-GMH did not predict adverse neurodevelopmental outcomes based on BSID and assessment of cerebral palsy at corrected ages of 18-24 months.
Despite advancements in neonatal care, the prevalence of GMH-IVH among preterm infants has remained unchanged, partly due to the higher survival rates of extremely preterm infants [23]. There is a significant correlation between the severity of GMH-IVH and earlier gestational ages, which frequently results in major neurological impairments such as cerebral palsy and post-hemorrhagic hydrocephalus [1,23,24]. Imaging studies conducted after GMH-IVH have shown considerable abnormal development in brain volume [25]. However, early detection and neuroprotective interventions can improve outcomes for these infants [26].
The GMH-IVH classification, which is based on the grading system developed by Papile et al. [3] over four decades ago, continues to be used primarily for the more mature preterm population. According to this system [3], grade I GMH-IVH is typically defined as a hemorrhage located in the subependymal region, particularly at the caudothalamic grooves. GMH-IVH may arise from any part of the residual germinal matrix, which has been found to extend to new, previously unrecognized locations in infants born as early as 28 weeks' gestational age. Recent studies by Snyder et al. [7] have shown that the survival of extremely preterm infants has led to the identification of a "posterior GMH," which reflects a fetal pattern of germinal matrix distribution not previously documented.
The germinal matrix, a transient embryonic structure in the fetal brain, is situated along the lateral wall of the frontal horns of the lateral ventricles and begins to form by the fifth week of gestation at the base of the telencephalon [27]. It is essential for the development of various brain structures, including the basal ganglia, thalamic and olfactory interneurons, and cortical GABAergic interneurons [27,28]. As gestation advances, the size of the germinal matrix shows an inverse correlation with the overall brain and cortical volumes, reaching its peak between weeks 20 and 26, and subsequently diminishing in a pattern that progresses from the dorsal to the ventral parts, completing its regression by weeks 34 to 36 [5,6]. In late preterm infants, GMH typically occurs in the ventral portion of the germinal matrix, near the caudothalamic groove. In contrast, in extremely preterm infants, particularly those born before 28 weeks of gestation, a significant portion of the germinal matrix persists in the dorsal area, where hemorrhage may present as hyper-echogenicity behind the caudothalamic groove [7,8]. This study highlights the importance of recognizing a new pattern of GMH-IVH in extremely preterm infants to avoid misdiagnosing other types of intracranial hemorrhage (Figs. 3, 5, 6), which could lead to unnecessary and invasive treatments. When the ventricles are distended with cerebrospinal fluid (CSF), observing a CSF cleft on parasagittal US images can help accurately differentiate PS-GMH from periventricular white matter, facilitating correct diagnosis and treatment planning [7,29] (Figs. 3, 5, 6).
Contrary to the present findings, Indrakanti et al. [29] observed linear or mildly lobulated hyper-echogenicity at the floor of the frontal horns of the lateral ventricle, which they interpreted as normal variations of the residual germinal matrix rather than signs of disease. However, their study did not establish a correlation between radiology and pathology. In contrast, Contro et al. [11] described the germinal matrix in fetal US as an ovoid-shaped area with iso-echogenicity similar to the surrounding white matter, challenging the interpretation of hyper-echogenicity as a normal variation. This discrepancy suggests that linear or nodular hyper-echogenicity observed along the subependymal layer on US could indeed indicate hemorrhages within the fragile residual germinal matrix, rather than merely normal variations.
This retrospective study is constrained by potential selection bias and a relatively small sample size, comprising only 221 extremely preterm infants from a single center. A significant limitation is the absence of pathology or magnetic resonance imaging (MRI) correlation. At the authors’ institution, brain MRIs are not routinely performed shortly after birth but may be conducted at TEA for specific cases. Detecting small PS-GMH can be challenging when the CSF space in the lateral ventricle is obliterated. Furthermore, differentiating between large PS-GMH and intraventricular blood clots that adhere to the subependymal lining can present a diagnostic challenge, although follow-up imaging typically assists in this differentiation.
In extremely preterm infants, the germinal matrix is larger than in more mature preterm infants, which may lead to more voluminous GMH. The Papile classification categorizes subependymal hemorrhages as grade I, regardless of their size. This classification becomes problematic when trying to differentiate between grade I and grade III hemorrhages, especially in cases of large PS-GMH. Due to their larger size and earlier gestational age, these hemorrhages do not align well with the severity spectrum outlined by the Papile classification. Thus, Snyder et al. [7] suggested that describing these hemorrhages as PS-GMH, including details about their location and size, offers a more accurate classification than simply categorizing them as grade I.
Although the findings indicate that PS-GMH does not seem to negatively impact neurodevelopmental outcomes at corrected ages of 18-24 months, there is a noticeable trend toward higher neurodevelopmental impairment in cases with large PS-GMH. This observation underscores the need for further research into the potential effects at toddler or early school age. Specifically, the influence of PS-GMH on subtle disabilities, such as late-onset high-prevalence/low-severity disabilities like attention-deficit hyperactivity disorder, specific neuropsychological deficits, and behavioral issues, needs further clarification. Additionally, it is crucial to recognize the weak correlation between BSID scores at corrected ages of 18-24 months and later school year outcomes [30,31]. Despite these limitations, this study offers valuable insights into the prognostic implications of PS-GMH detected via cUS in extremely preterm infants, highlighting the necessity for more comprehensive, long-term studies.
This study on extremely preterm infants reveals that PS-GMH, despite its high prevalence, does not predict neurodevelopmental outcomes at corrected ages of 18-24 months. The findings indicate that the size of PS-GMH, whether small or large, does not negatively impact the neurodevelopmental trajectory. This information is vital for radiologists and clinicians, emphasizing the importance of distinguishing PS-GMH from other types of intracranial hemorrhages to guide clinical decisions and effectively counsel families. Although associated with factors such as younger gestational age and maternal chorioamnionitis, the identification of PS-GMH should provide reassurance to healthcare providers and families regarding its lack of correlation with adverse neurodevelopmental outcomes within the study’s timeframe. This highlights the need for further research to investigate the long-term effects of PS-GMH beyond early childhood.
Notes
Author Contributions
Conceptualization: Koo JM, Yoo SY, Kim JH, Jeon TY. Data acquisition: Koo JM, Yoo SY, Kim JH, Park JE, Jeon TY. Data analysis or interpretation: Koo JM, Baek SY, Jeon TY. Drafting of the manuscript: Koo JM, Jeon TY. Critical revision of the manuscript: Koo JM, Yoo SY, Kim JH, Park JE, Baek SY, Jeon TY. Approval of the final version of the manuscript: all authors.
No potential conflict of interest relevant to this article was reported.
References
Article information Continued
Notes
Key point
Posterior subependymal germinal matrix hemorrhage (PS-GMH) is common in extremely preterm infants, influencing initial cranial ultrasound findings. PS-GMH does not predict adverse neurodevelopmental outcomes in extremely preterm infants. Identifying PS-GMH is crucial for clinical decision-making; however, it does not independently predict poor outcomes.