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Determination of Predictors of Brain Injury in Very Preterm Infants – A Retrospective Cohort Study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.355129
Keywords: Cranial ultrasound, magnetic resonance imaging, odds ratio, periventricular leukomalacia, preterm brain injury, risk factors
Prematurity associated brain injury is a major cause of cerebral palsy in children.[1] Though periventricular leukomalacia (PVL) is the most common neuropathology in preterm infants, injury to other regions of the brain such as cerebral cortex, cerebellum, basal ganglia, and thalamus are known components of preterm brain injury.[2] Neuroimaging at term equivalent age (TEA) is used to assess the extent of brain injury and prognosticate neurodevelopmental outcomes in preterm infants.[3] Preterm brain injury results from multiple antenatal and postnatal insults causing hypoxia-ischemia and infection-inflammation mediated injury to the developing brain.[2],[3] Many factors such as chorioamnionitis, perinatal asphyxia, hypocarbia, and intraventricular hemorrhage (IVH) have been shown to increase the risk of PVL and preterm brain injury.[4],[5] However, there is a wide disparity in the description of risk factors across the studies, which suggests that the available evidence is inadequate. In this study, we aimed to assess the various risk factors for preterm brain injury and to identify the strength of association between these factors and brain injury in preterm infants at TEA.
This retrospective cohort study was conducted in a level IIIb neonatal intensive care unit (NICU) from January 2015 to December 2019. Approval was obtained from the Institutional Ethics Committee. The study protocol was registered in Clinical Trial Registry of India (CTRI/2021/01/040553) before the commencement of data collection. We included preterm infants born at <32 weeks' gestation who had either a cranial ultrasound (CUS) scan or magnetic resonance imaging (MRI) performed at TEA. The choice of neuroimaging (CUS or MRI) was decided based on the clinical course of the neonate and logistic reasons. The MRI and CUS images from picture archiving and communication system (PACS) were reviewed by the radiologist (SN). MRI scans were evaluated as per the Kidokoro scoring system,[6] and global brain abnormality scores were calculated as the sum of white and gray matter injury scores. CUS images were used to diagnose cystic PVL alone, which was identified by the presence of one or more echolucent areas (≥3 mm size) in bilateral periventricular regions. Significant brain injury was diagnosed based on a Kidokoro score of ≥4 in MRI or the presence of cystic PVL on CUS. Demographic, clinical, and laboratory data of the infants were collected from online case records. Definition of risk factors Gestational age was calculated based on first trimester ultrasound or the last menstrual period. Small for gestational age (SGA) was defined as birth weight less than tenth percentile in Fenton's growth charts.[7] Abnormal antenatal Doppler included various grades of abnormalities of blood flow in fetal vessels ranging from high resistance flow in umbilical arteries to abnormal blood flow in ductus venosus. Chorioamnionitis was diagnosed based on placental histopathology with or without maternal and fetal clinical features. Prolonged ventilation was defined as requirement of invasive ventilation for more than 7 days. Bronchopulmonary dysplasia was diagnosed based on the requirement of oxygen and/or pressure support until postnatal day 28. Necrotising enterocolitis (NEC) was diagnosed if it was stage 2 or 3 according to modified Bell's staging.[8] Meningitis was diagnosed based on a positive culture or abnormal cytology and biochemistry of the cerebrospinal fluid. Hyponatremia was defined as serum sodium concentration less than 130 meq/L, along with requirement of sodium supplementation. IVH was diagnosed by two CUS scans on postnatal days 1–3 and 7–10, and graded as per Volpe's classification.[9] Retinopathy of prematurity (ROP) was diagnosed based on international classification for ROP criteria, and laser therapy was performed for pre-threshold disease.[10] Statistical analysis Data were expressed as mean and standard deviation (SD) or number and percentage as appropriate. Univariate analysis was performed using Chi-square or Fisher's exact test, and odds ratio (OR) was calculated for each risk factor. Multiple logistic regression was used to calculate adjusted OR. All statistical analyses were performed using SPSS 23.0. A P value of < 0.05 was taken as statistically significant.
Among the 856 very preterm infants admitted to the NICU during the study period, 698 infants had a neuroimaging performed at TEA [Figure 1]. A total of 48 infants had significant brain injury in neuroimaging and were considered as cases. The remaining 650 infants were taken as controls. The mean (SD) gestational age was 29.5 (1.7) and 29.4 (1.5) weeks, and birth weight was 1232 (327) and 1137 (309) g in cases and controls, respectively.
In univariate analysis, SGA, abnormal fetal Doppler, requirement of delivery room continuous positive airway pressure (CPAP), requirement of ventilation, requirement of inotropic support, IVH, NEC stage 2 or 3, culture-positive sepsis, meningitis, any surgery and packed red blood cells (PRBC) transfusion were associated with increased risk of preterm brain injury [Table 1].
In multiple logistic regression including the factors that were significant in univariate analysis, SGA [2.645 (1.181-5.924], prolonged ventilation [3.688 (1.087-12.510)], culture-positive sepsis [4.162 (1.729-10.021)], and IVH grade 3-4 [92.892 (19.495-442.619)] were associated with greater risk of brain injury [Figure 2]. The proportional contribution of each factor was calculated using the formula P = 1/1 + e-logit (P). IVH (74.8%) had the greatest contribution to the risk of brain injury followed by culture-positive sepsis (10.3%), prolonged ventilation (8.9%), and SGA (5.6%).
The study showed four factors namely severe IVH, culture-positive sepsis, prolonged ventilation, and SGA as significant predictors of preterm brain injury in adjusted analysis. Severe IVH was the strongest predictor of brain injury in preterm neonates. Kusters et al.[11] showed a dose-response gradient between IVH and preterm brain injury, with increasing grades of IVH increasing the incidence and severity of brain injury. Some authors have suggested that PVL associated with IVH and that not associated with IVH could be two different entities with different pathophysiological mechanisms.[12] IVH causes brain injury by generating free radicals from the iron content in the blood.[5] The association is also due to common antecedents of both the morbidities such as perinatal asphyxia, mechanical ventilation, and shock/hypotension.[11] Inflammation induces microglial activation resulting in oligodendroglial injury, myelin loss, and PVL.[13] Conditions that cause systemic inflammation in the fetus or the neonate such as chorioamnionitis, neonatal sepsis, and NEC are strong risk factors for preterm brain injury.[5],[12],[14] However, only culture-positive sepsis had a significant association with preterm brain injury in the adjusted analysis in our study. The association between prolonged ventilation and brain injury is probably mediated by altered cerebral hemodynamics during positive pressure ventilation, hypocarbia, and other factors associated with increased baseline sickness in these infants. Hypocarbia, defined variably as PCO2 <25–30 mm Hg, is a strong risk factor for PVL.[15] Hypocarbia-induced white matter injury is probably mediated by its vasoconstrictive effects and cerebral ischemia.[2] Periventricular white matter, being the watershed region in preterm neonates, is the most commonly affected region in conditions that cause hypoxic-ischemia-mediated brain damage.[2] SGA was found to increase the risk of preterm brain injury. This is in contrast to most of the previous studies.[16] Since three-fourths of preterm infants are born in low- and middle- income countries where the risk of SGA is greater, this finding is relevant. The association is probably mediated by ischemic injury during antenatal period due to altered cerebral blood flow in growth-restricted fetuses and by increased post-natal morbidities in SGA infants. Other controversial risk factors such as male gender, vaginal delivery, and PDA did not have a significant association with preterm brain injury in our study. A recent meta-analysis showed that antenatal corticosteroids reduced the risk of cystic PVL.[17] However, though magnesium sulfate did not reduce the risk of PVL, it improved the overall neurodevelopmental outcomes.[18] We did not find a reduction in the risk of preterm brain injury with either of these standard antenatal interventions. The available data on the impact of gestational age on preterm brain injury is intriguing. Though a few studies found a significant association, most of them showed that the risk of brain injury does not increase with decreasing gestational age.[19] Likewise, we did not find a significant association between gestational age or birth weight and preterm brain injury. This suggests that the perinatal morbidities and the stormy NICU course of the infant have a greater impact on the risk of brain injury than the degree of prematurity. The major limitations of the study are the retrospective nature, single-center data and small sample size. We did not have data on other potential risk factors such as tocolysis, hypocarbia, and postnatal acidosis.
Severe IVH, culture-positive sepsis, prolonged ventilation, and SGA were associated with greater risk of brain injury in preterm infants at TEA, with severe IVH being the most significant contributing factor. Given the inadequate and wavering evidence, we suggest a large multicentric prospective study with robust methodology to elucidate the risk factors for brain injury in preterm infants. Acknowledgments This retrospective cohort study was conducted as part of a preclinical study funded by Department of Biotechnology (DBT), Government of India. The funding agency had no role in the conduct of this retrospective study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1]
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