|Year : 2020 | Volume
| Issue : 4 | Page : 286-291
The neurobehavioral outcomes of very low birth weight infants with intraventricular hemorrhage at corrected age of 24–36 months
Khalid A Altirkawi, Badr Sobaih, Abdulrahman Altuwaym, Alhanouf Almuhanna, Rasha Bassas, Rozina Banoo, Amull Fariss
Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia
|Date of Submission||30-May-2020|
|Date of Decision||18-Jun-2020|
|Date of Acceptance||20-Jun-2020|
|Date of Web Publication||25-Aug-2020|
Khalid A Altirkawi
Department of Pediatrics, # 39, King Khalid University Hospital, Post Box 7805, Riyadh 11472
Source of Support: None, Conflict of Interest: None
Objectives: A proper neurobehavioral development is important for acquiring the skills of a healthy and productive life. Determining intraventricular hemorrhage (IVH) impact on different aspects of development may help in mitigation, and probably, prevention of the developmental delays. Materials and Methods: We evaluated the developmental quotients (DQ) of very low birth weight (VLBW) infants, who experienced IVH during neonatal period, at 24–36 months of their corrected age, using Gesell schedules of child development. Furthermore, we assessed the relationship between the severity, extent and sidedness of IVH, and total DQ, its subdomains, and common neurological and non-neurological comorbidities. Results: The study included 54 patients (36 males and 18 females). Bilateral IVH was more common in females, who exhibited also a trend toward left-sided IVH. Patient's sex, birth-weight, and gestational age, however, have not shown significant associations with the total DQ, or its subdomains. Severe IVH was significantly associated with both cerebral palsy, and reduction in total DQ, but not in its personal-social subdomain. Left-sided IVH was associated with a significant reduction in total DQ, but right-sidedness showed no such association. Periventricular leukomalacia was significantly associated with reduction in total DQ and in its personal-social subdomain. No significant associations were detected in patients with the non-neurological comorbidities. Conclusions: VLBW infants with left-sided, bilateral or severe IVH are at higher risk of worse neurobehavioral outcomes at 24–36 months of age. Non-neurological comorbidities seem to have little impact on the DQ and its subdomains assessed at this age.
Keywords: Intraventricular hemorrhage, neurobehavioral development, outcomes, very low birthweight infant
|How to cite this article:|
Altirkawi KA, Sobaih B, Altuwaym A, Almuhanna A, Bassas R, Banoo R, Fariss A. The neurobehavioral outcomes of very low birth weight infants with intraventricular hemorrhage at corrected age of 24–36 months. J Nat Sci Med 2020;3:286-91
|How to cite this URL:|
Altirkawi KA, Sobaih B, Altuwaym A, Almuhanna A, Bassas R, Banoo R, Fariss A. The neurobehavioral outcomes of very low birth weight infants with intraventricular hemorrhage at corrected age of 24–36 months. J Nat Sci Med [serial online] 2020 [cited 2021 Oct 16];3:286-91. Available from: https://www.jnsmonline.org/text.asp?2020/3/4/286/294057
| Introduction|| |
Among the many risks faced by the premature infants, intraventricular hemorrhage (IVH) stands out as one of the most common and debilitating morbidities. Typically, IVH takes place in the fragile blood vessels of the preterm brain germinal matrix. Small IVH remains confined to this site, but larger ones may spread into the ventricles and even the cerebral parenchyma; and leading at times, to periventricular white matter injury, post-hemorrhagic hydrocephalus and cerebral palsy (CP). Although most IVH incidents occur within the first 72 h of life, some still occur at a later time, thus, timed scanning for IVH is usually recommended in these infants.
In the USA, it is estimated that almost 12,000 premature infants develop IVH annually, and almost 45% of extremely premature infants weighing 500 –750 g would be affected by this condition.,, Locally, Haque et al. reported that the incidence of any grade of periventricular hemorrhage/IVH (PVH/IVH) in inborn infants delivered at or before 35 weeks of gestation was 20.9%. A more recent study reported that 13.9% of the very low birth weight (VLBW) infants had IVH, and about 7.8% were affected by its severe form (Grades 3 and 4).
A proper neurobehavioral development is of paramount importance, as it lays the basis for development of skills necessary for living a healthy, productive, and an independent life. The potentially detrimental effects of IVH on the neurobehavioral outcomes have been debated extensively. Vohr et al. suggested that moderate-to-severe IVH in premature infants is highly associated with major cognitive deficits and the need for special education. In contrast, Roze reported that preterm infants who had survived a PVH infarction actually had better functional outcomes than expected. Thus, determining the relationship between IVH and developmental outcome is an essential step. If established, it could help physicians anticipate, mitigate, and probably, prevent the developmental delay and its complications.
Currently, evaluating preterm infants at 2 years of age is considered a common benchmark in any comprehensive follow-up program. We aim in this study to determine the neurodevelopmental outcomes of VLBW infants with IVH at a corrected age of 24–36 months; to explore whether the subdomains of developmental quotients (DQ) (adaptive, gross motor, fine motor, language, and personal-social) are affected differently. A special consideration is given to the relation of personal-social subdomain to both risk factors (IVH) and other outcomes (total DQ).
| Materials and Methods|| |
This is a retrospective analysis of data collected on all in-born, VLBW infants with any grade of IVH, who were followed up in the local neonatal follow-up program, between December 1999 and June 2017. This program enrolls all high-risk infants born at King Khalid University Hospital, and graduated from its neonatal intensive care unit (NICU). The program provides the post-discharge assessment of these high-risk infants, track their progress; both physically and behaviorally, and function as an entry point of early intervention, if needed. These services are extended also to infants born at peripheral hospitals, which lack such a follow-up program. The clinic is staffed by a qualified pediatrician who is certified in behavioral assessment, using the Gesell schedules of child development (GSCD), in addition to official training in pediatrics and neonatal medicine.
We excluded outborn infants and those with syndromes associated with the developmental delay or neurological deficits. To ensure consistency, a single certified assessor conducted all developmental evaluations, using the GSCD. All other data, demographic and otherwise, were collected prospectively and stored in a standardized format.
The baseline data collected were birth-weight, gestational age, sex, and length of hospital stay. Complications of prematurity included in this analysis were the occurrence of culture proven sepsis/meningitis, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and periventricular leukomalacia (PVL). The neurosensory and neurobehavioral outcomes assessed were blindness, deafness, CP, and behavioral and cognitive functions (DQs) at the age of 24–36 months. The clinically diagnosed blindness and/or deafness were confirmed by brainstem evoked potentials testing. Of note, the used case definitions of all tested outcomes have not changed over the span of the study.
The diagnosis of IVH was based on cranial ultrasound screening performed, as per NICU protocol, during the first 28 days of life, and graded according to Papile's scoring system. When multiple studies were performed, the patient was assigned to the worst grade of IVH reported. PVL was diagnosed when the characteristic cystic changes were detected on cranial ultrasound scan performed at any time during the NICU stay.
We assessed the relationship of the total DQ and its subdomains with IVH severity (grades 1 and 2 were designated as mild to moderate, whereas grades 3 and 4 were designated as severe), extent (unilateral vs. bilateral) and sidedness (left vs. right). We also explored the relationships of total DQ and its subdomains with the neurological morbidities (PVL and CP) and non-neurological ones (BPD, NEC, ROP, and Sepsis/meningitis), assessed first individually then in combination (composite outcome).
In general, scores on GSCD of ≥ 85 are considered indicative of normal function, scores of 71–84 are considered indicative of mild-to-moderate delay, and those of ≤70 refer to severe dysfunction. In this analysis, we divided patients into two groups; normal outcome (score ≥85), and abnormal outcome (score <85).
The study is conducted in accordance with the applicable local and international ethical standards, and approved by the Institutional Review Board, at the College of Medicine, King Saud University. After collecting the needed data for analysis, patients' identifiers were removed from the data file, which was kept on a computer set accessible only to the authorized investigators.
In this study, we tested the hypothesis that children who had sonographic evidence of IVH, with or without white matter injury, during the neonatal period were at increased risk of having adverse neurobehavioral development on evaluation at 24–36 months.
The statistical analysis was performed using IBM SPSS statistics, version 22.0 (IBM inc., Armonk, NY, USA). Continuous variable results were reported as (means and 95% confidence intervals [CIs]), whereas, categorical variables were reported as frequencies and percentages. Different tests of significance were used as appropriate; Fisher's exact test or Chi-square test for categorical data, and t-test for continuous data. All P values were two-sided, and considered statistically significant at 0.05 or less.
| Results|| |
Fifty-four patients met the study inclusion criteria, of them, 36 were male and 18 were female [Table 1]. As data of neurobehavioral evaluation of 12 patients were incomplete, we included only 42 patients for the analysis of neurodevelopmental outcomes and their relationship with patients' risk factors and comorbidities.
|Table 1: Distribution of intraventricular hemorrhage and the major prematurity comorbidities in very low birthweight infants|
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As shown in [Table 2], sex of the patient has not shown any significant association with the total DQ (male, 81; female, 80; P = 0.87) nor with the personal-social subdomain (male 88.3; female 88.8; P = 0.95). However, the patient's sex showed significant association with the extent of IVH; male infants were less likely to experience a bilateral IVH compared with female ones (males 19/36, females 16/18; odds ratio [OR] 0.14; 95% CI 0.03–07; P = 0.014).
|Table 2: Relationship of total developmental quotients and the personal-social subdomain with patients' sex, birthweight, and gestational age|
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As opposed to infants whose birthweight exceeds 1,000 g, being an extremely low birthweight (<1000 g) infant was not significantly associated with reduction in the total DQ values (79.4 vs. 82.3, P = 0.74) nor in values of the personal-social subdomain (89.3 vs. 89.6, P = 0.97). The same was true for the earlier gestational age (<28 weeks) as opposed to later gestational age (28 weeks and beyond); whereby the values of total DQ were (79.3 vs. 82.4, P = 0.74) and for the personal-social subdomain were (89.6 vs. 89.1, P = 0.97). All evaluated infants, however, had better values of the personal-social subdomain (on average, 9 to10 points) compared to total DQ values across all comparisons. Notably, both variables, the total DQ and its personal-social subdomain, were well correlated in all patients of this cohort (R = 0.98. 95% CI, 0.82–1.1, P = 0.0001) [Table 2].
[Table 3] summarizes the effects of severity, extent and sidedness of IVH on total DQ and its subdomains. Severe IVH (compared with mild-to-moderate IVH) was associated with a significant reduction in total DQ (72 vs. 90, P = 0.02) but not in its personal-social subdomain (84 vs. 95, P = 0.17). Despite this reduction, however, the values of estimated total DQ remained within 2 standard deviations from the mean, indication of mild to moderate delay. The same is true for the personal-social subdomain values; as they fell within one standard deviation of the mean, an indication of normal functioning.
|Table 3: Relationship of total developmental quotient and the personal-social subdomain with intraventricular hemorrhage characteristics|
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The extent of IVH (unilateral vs. bilateral) was not associated with a major difference in total DQ (bilateral, 81; unilateral, 79; P = 0.8) or its personal-social subdomain (bilateral, 88; unilateral 90; P = 0.8). Nonetheless, when IVH affected the left side of the brain, a significant association between the presence of IVH and total DQ was detected (71 vs. 88, P = 0.04), but association with personal-social subdomain was not significant (82 vs. 94, P = 0.13). When the right side was affected, however, such association was less pronounced on both of the total DQ (72 vs. 87; P = 0.08) and its personal-social subdomain (82 vs. 94; P = 0.24).
[Table 4] delineates the relationship between the presence of PVL and the total DQ and its subdomains. It was significantly associated with a reduction in both total DQ (37 vs. 88, P < 0.0001) and in its personal-social subdomain (49 vs. 96, P < 0.0001). On the contrary, such significant association was not detected in patients with the composite of nonneurological comorbidities; (total DQ, 79 vs. 93, P = 0.11; personal-social subdomain, 87 vs. 103, P = 0.1). Interestingly, there was no significant association between any one of the tested comorbidities taken individually and the IVH characteristics of severity and/or extent, except for CP which has a strong association with severe IVH; it was encountered only in patients with severe IVH, but not in those with the mild grades [Table 5].
|Table 4: Relationship of total developmental quotients and the personal-social subdomain with neurological and composite non-neurological comorbidities|
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|Table 5: Relationship of intraventricular hemorrhage characteristics with major prematurity comorbidities|
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| Discussion|| |
In general, our study has reaffirmed what is suggested previously by other investigators; that infants with IVH, with or without white matter injury, have an increased risk of adverse neurobehavioral outcomes identifiable during infancy. A closer look, however, provides some additional insights.
The finding that VLBW infants of this cohort with severe IVH are at higher risk of worse neurobehavioral outcomes at 24–36 months of age, is also consistent with many published reports suggesting a strong association of IVH with long-term neurodevelopmental impairments. Nonetheless, the absence of significant differences between infants of varying degrees of IVH on some comparisons, concurs with other studies remained unclear about the impact of milder grades of IVH (Grades 1 and 2) on neurodevelopmental outcomes.,, This ambiguity is probably due to the limitations of currently used screening tools; cranial ultrasonography, which fails to discern the subtle radiological defects in the less severe cases. Such lesions, however, would be more readily identified by magnetic resonance imaging performed closer to term.,
Furthermore, the strong association of PVL and the reduction observed in the values of total DQ and its subdomains resonates with the current literature, which suggests that “IVH is associated with no more than a modest increase in the risk of adverse developmental outcome during infancy, unless it is accompanied with white matter damage.” And that “most of the association between IVH and developmental limitations appears to be mediated through white matter damage.”
Despite its questionable significance, the higher rates of bilateral and left-sided IVH (but not the severe form) observed in female infants of this cohort constitute a novel observation. Notably, no discernable intervention in our practice lends an explanation to this finding. Furthermore, the differing strength of the association observed between the total DQ and IVH sidedness (right vs. left) is another less reported finding. Apparently, there is no plausible anatomical or physiological anomaly that can readily explain this observation. It deserves, however, a closer look in a larger cohort. Interestingly, none of the published studies so far linked the cognitive deficits to injuries in any specific brain region.
The observation that values of the personal-social subdomain were consistently better than their corresponding total DQ values, may indicate a lesser role of the areas affected with IVH in executing these social functions, or it may be an indication of a larger role played by the social modifiers, such as maternal education, on the functions tested.
Finally, when it comes to the nonneurological comorbidities, they seem to have a little or no impact on the total DQ and its subdomains assessed in infants of this cohort at this age. Such finding suggests that these comorbidities, despite their overall detriment to the infants' health, are more of an innocent bystander in the process of neurobehavioral development rather than an integral player. Nonetheless, literature suggests that some neurobehavioral deficits may be recognized at a later age, even during the adulthood years, thus, longer follow-up schemes for these preterm infants are recommended.
Using the GSCD as the sole screening tool, in assessments performed by a single certified examiner, and the prospective nature of data collection, have enabled us to perform consistent comparisons across data collected over the extended study span. In addition, excluding the out-born infants and limiting the patients' cohort to a single birthing center helped in maintaining consistency of care provided to these infants, and the evaluation process that followed. Finally, the timing of assessment at 24–36 months of corrected age ensured detecting most of the long-term outcomes of interest in this cohort.
On the other hand, restricting the study population to those who attended our neonatal high-risk clinic makes some of the findings not applicable to the spectrum of the preterm infant population at large. In addition, the relatively small number of infants with CP may have decreased the precision of OR to predict this outcome following an incidence of IVH. Moreover, having small number of blindness and hearing loss cases (one case each) made it impossible to render precise conclusions about associations of IVH to these outcomes.
Furthermore, in confirming the presence of white matter damage, we relied mostly on cranial ultrasonography, an approach deemed by some investigators as inadequate. Despite its noninvasive nature and cost-effectiveness, cranial ultrasonography fails to detect some of these lesions in the preterm infants, this may have impacted the strength of some associations described earlier.
Finally, measuring neurobehavioral impairment using GSCD may lack some of the rigor of other screening tools. A recent study, however, supported continued usefulness of this instrument in determining child's development levels. Notably, utilizing another widely used tool, Bayley scales of infant development, in other studies was found to be only moderately predictive of cognitive impairment at school age.,
| Conclusions|| |
The impact of IVH on neurobehavioral development of VLBW infants is an established finding. However, the extent and strength of this impact is still debatable. Physicians caring for such infants need to deliver balanced prognostic statements upon counseling their families, due to the increased risk for neurobehavioral deficits in late childhood. Consequently, a long-term follow-up plans seem very much in need as deficits may emerge at a later age.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]