Clinical characteristics and long-term neurodevelopmental outcomes of leukomalacia in preterm infants and term infants: a cohort study.

BACKGROUND: Leukomalacia is a serious form of neonatal brain injury that often leads to neurodevelopmental impairment, and studies on neonatal leukomalacia and its long-term outcomes are lacking. The aim of this study was to analyze the clinical manifestations, imaging features, and long-term neurodevelopmental outcomes in preterm infants and term infants with leukomalacia. METHODS: Newborns diagnosed with leukomalacia by head magnetic resonance imaging (MRI) and who were admitted to intensive care units from January 2015 to June 2020 were enrolled. All infants were followed up to June 2022 (2-7 years old), and their neurodevelopmental outcomes were evaluated. The clinical data and long- term outcomes of preterm infants and term infants was analyzed by Chi-square tests. RESULTS: A total of 218 surviving infants with leukomalacia including 114 preterm infants and 104 term infants completed the follow-up. The major typesof leukomalacia on MRI were periventricular leukomalacia in the preterm group and subcortical cystic leukomalacia in the term group, respectively (χ2 = 55.166; p < 0.001). When followed up to 2-7 years old, the incidence of neurodevelopmental impairment in the preterm group and term group was not significantly different (χ2 = 0.917; p = 0.338). However, the incidence of cerebral palsy (CP) in the preterm group was significantly higher (χ2 = 4.896; p = 0.027), while the incidence of intellectual disability (ID) (χ2 = 9.445; p = 0.002), epilepsy (EP) (χ2 = 23.049; p < 0.001), and CP combined with ID andEP (χ2 = 4.122; p = 0.042) was significantly lower than that in the term group. CONCLUSIONS: Periventricular leukomalacia mainly occurred in preterm infants while subcortical cystic leukomalacia was commonly seen in term infants. Although the long-term neurodevelopmental outcomes of leukomalacia were both poor, preterm infants were more prone to CP, while term infants were more prone to ID, EP, and the combination of CP with ID and EP.

The Impact of Intraventricular Hemorrhage and Periventricular Leukomalacia on Mortality and Neurodevelopmental Outcome in Very Preterm and Very Low Birthweight Infants: A Prospective Population-based Cohort Study.

OBJECTIVE: To survey the incidence of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) by gestational age and to report the impact on mortality and neurodevelopmental outcome in very preterm/very low birthweight infants. STUDY DESIGN: This was a population-based cohort study of 1927 very preterm/very low birthweight infants born in 2014-2016 and admitted to Flemish neonatal intensive care units. Infants underwent standard follow-up assessment until 2 years corrected age with the Bayley Scales of Infant and Toddler Development and neurological assessments. RESULTS: No brain lesion was present in 31% of infants born at <26 weeks of gestation and 75.8% in infants born at 29-32 weeks of gestation. The prevalence of low-grade IVH/PVL (grades I and II) was 16.8% and 12.7%, respectively. Low-grade IVH/PVL was not related significantly to an increased likelihood of mortality, motor delay, or cognitive delay, except for PVL grade II, which was associated with a 4-fold increase in developing cerebral palsy (OR, 4.1; 95% CI, 1.2-14.6). High-grade lesions (III-IV) were present in 22.0% of the infants born at <26 weeks of gestational and 3.1% at 29-32 weeks of gestation, and the odds of death were ≥14.0 (IVH: OR, 14.0; 95% CI, 9.0-21.9; PVL: OR, 14.1; 95% CI, 6.6-29.9). PVL grades III-IV showed an increased odds of 17.2 for motor delay and 12.3 for cerebral palsy, but were not found to be associated significantly with cognitive delay (OR, 2.9; 95% CI, 0.5-17.5; P = .24). CONCLUSIONS: Both the prevalence and severity of IVH/PVL decreased significantly with advancing gestational age. More than 75% of all infants with low grades of IVH/PVL showed normal motor and cognitive outcome at 2 years corrected age. High-grade PVL/IVH has become less common and is associated with adverse outcomes.

Placental fetal vascular malperfusion, neonatal neurologic morbidity, and infant neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the association of placental fetal vascular malperfusion lesions with neonatal brain injury and adverse infant neurodevelopmental outcomes. DATA SOURCES: PubMed and Medline, Scopus, and Cochrane databases were searched from inception to July 2022. STUDY ELIGIBILITY CRITERIA: We included cohort and case-control studies reporting the associations of fetal vascular malperfusion lesions with neonatal encephalopathy, perinatal stroke, intracranial hemorrhage, periventricular leukomalacia, and infant neurodevelopmental and cognitive outcomes. METHODS: Data were analyzed by including fetal vascular malperfusion lesions as an exposure variable and brain injuries or neurodevelopmental impairment as outcomes using random-effects models. The effect of moderators, such as gestational age or study type, was assessed by subgroup analysis. Study quality and risk of bias were assessed by applying the Observational Study Quality Evaluation method. RESULTS: Out of the 1115 identified articles, 26 were selected for quantitative analysis. The rates of neonatal central nervous system injury (neonatal encephalopathy or perinatal stroke) in term or near-term infants were more common among fetal vascular malperfusion cases (n=145) than among controls (n=1623) (odds ratio, 4.00; 95% confidence interval, 2.72-5.90). In premature deliveries, fetal vascular malperfusion lesions did not influence the risk of intracranial hemorrhage or periventricular leukomalacia (odds ratio, 1.40; 95% confidence interval, 0.90-2.18). Fetal vascular malperfusion-associated risk of abnormal infant neurodevelopmental outcome (314 fetal vascular malperfusion cases and 1329 controls) was modulated by gestational age being higher in term infants (odds ratio, 5.02; 95% confidence interval, 1.59-15.91) than in preterm infants (odds ratio, 1.70; 95% confidence interval, 1.13-2.56). Abnormal infant cognitive development and mental development were more common among fetal vascular malperfusion cases (n=241) than among controls (n=2477) (odds ratio, 2.14; 95% confidence interval, 1.40-3.27). The type of study (cohort vs case-control) did not influence the association between fetal vascular malperfusion and subsequent infant brain injury or abnormal neurodevelopmental outcome. CONCLUSION: The findings of cohort and case-control studies indicate a considerable association between fetal vascular malperfusion placental lesions and increased risk of brain injury in term neonates, and neurodevelopmental impairment in both term and preterm infants. A diagnosis of placental fetal vascular malperfusion should be taken into consideration by both pediatricians and neurologists during the follow-up of infants at risk of adverse neurodevelopmental outcomes.

The validity of hospital diagnostic and procedure codes reflecting morbidity in preterm neonates born <32 weeks gestation.

OBJECTIVE: To determine the validity of diagnostic hospital billing codes for complications of prematurity in neonates <32 weeks gestation. STUDY DESIGN: Retrospective cohort data from discharge summaries and clinical notes (n = 160) were reviewed by trained, blinded abstractors for the presence of intraventricular hemorrhage (IVH) grades 3 or 4, periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), stage 3 or higher, retinopathy of prematurity (ROP), and surgery for NEC or ROP. Data were compared to diagnostic billing codes from the neonatal electronic health record. RESULTS: IVH, PVL, ROP and ROP surgery had strong positive predictive values (PPV > 75%) and excellent negative predictive values (NPV > 95%). The PPVs for NEC (66.7%) and NEC surgery (37.1%) were low. CONCLUSION: Diagnostic hospital billing codes were observed to be a valid metric to evaluate preterm neonatal morbidities and surgeries except in the instance of more ambiguous diagnoses such as NEC and NEC surgery.

Factors associated with the development of epilepsy in very low birth weight infants.

BACKGROUND: The survival rate of very low birth weight (VLBW) infants has recently improved. However, the occurrence of and factors associated with epilepsy in VLBW infants remain unknown. This study aimed to clarify the incidence, characteristics, and factors associated with epilepsy development in VLBW infants. METHODS: All VLBW infants admitted to our hospital between 2012 and 2017 were included in this study. VLBW infants with a follow-up period of <1 year were excluded. Chromosomal abnormalities, brain anomalies, severe intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), and hypoxic ischemic encephalopathy (HIE) were considered to be risk factors. RESULTS: Epilepsy occurred in 21/526 (4.0%) VLBW infants. Chromosomal abnormalities, brain anomalies, severe IVH, cystic PVL, HIE, neonatal seizures, advanced maternal age, maternal diabetes mellitus, no administration of antenatal corticosteroids, and low Apgar scores at 1 and 5 min were associated with a risk of epilepsy. The median time to epilepsy onset was 8 months (range: 0-59 months), and the onset occurred within 2 years in 15/21 patients (71.4%) and within 4 years in 18/21 patients (85.7%). VLBW infants with risk factors developed epilepsy earlier and at a significantly higher rate than those without risk factors. Among infants who had risk factors and who developed epilepsy, 86.7% did so within 2 years of age, compared to 33.3% of those who developed epilepsy but did not have risk factors. CONCLUSION: These findings regarding factors associated with a risk of development of epilepsy and temporal feature of epilepsy may contribute to the development of monitoring and treatment protocols for epilepsy in VLBW infants.

Association of Cystic Periventricular Leukomalacia and Postnatal Epilepsy in Very Preterm Infants.

INTRODUCTION: Cystic periventricular leukomalacia (PVL) is the most common white matter injury and a common cause of cerebral palsy in preterm infants. Postnatal epilepsy may occur after cystic PVL, but their causal relationship remains uncertain. Our aim was to validate the contribution of cystic PVL to postnatal epilepsy in very preterm infants and demonstrate their seizure characteristics. METHODS: This prospective cohort study enrolled 1,342 preterm infants (birth weight <1,500 g and gestational age <32 weeks) from 2003 to 2015. Cystic PVL was diagnosed by serial cerebral ultrasound, and other comorbidities were recorded during hospitalization. Neurological developments and consequences, including epilepsy, were serially accessed until the age of 5. RESULTS: A total of 976 preterm infants completed a 5-year neurological follow-up; 47 (4.8%) had cystic PVL. Preterm infants with cystic PVL were commonly associated with other comorbidities, including necrotizing enterocolitis stage III, neonatal seizures, and intraventricular hemorrhage during hospitalization. At age 5, 14 of the 47 (29.8%) preterm infants with cystic PVL had postnatal epilepsy. After adjusting for gender, gestational age, and three common comorbidities, cystic PVL was an independent risk factor for postnatal epilepsy (adjust OR: 16.2; 95% CI: 6.8-38.4; p < 0.001). Postnatal epilepsy after cystic PVL was commonly the generalized type (13 of 14, 92.9%), not intractable and most occurred after 1 year of age. DISCUSSION/CONCLUSION: Cystic PVL would independently lead to postnatal epilepsy. Preterm infants with cystic PVL are at risk of postnatal epilepsy after age 1 in addition to cerebral palsy.

Late-onset sepsis in very preterm infants in Norway in 2009-2018: a population-based study.

OBJECTIVE: To evaluate epidemiology and outcomes among very preterm infants (<32 weeks' gestation) with culture-positive and culture-negative late-onset sepsis (LOS). DESIGN: Cohort study using a nationwide, population-based registry. SETTING: 21 neonatal units in Norway. PARTICIPANTS: All very preterm infants born 1 January 2009-31 December 2018 and admitted to a neonatal unit. MAIN OUTCOME MEASURES: Incidences, pathogen distribution, LOS-attributable mortality and associated morbidity at discharge. RESULTS: Among 5296 very preterm infants, we identified 582 culture-positive LOS episodes in 493 infants (incidence 9.3%) and 282 culture-negative LOS episodes in 282 infants (incidence 5.3%). Extremely preterm infants (<28 weeks' gestation) had highest incidences of culture-positive (21.6%) and culture-negative (11.1%) LOS. The major causative pathogens were coagulase-negative staphylococci (49%), Staphylococcus aureus (15%), group B streptococci (10%) and Escherichia coli (8%). We observed increased odds of severe bronchopulmonary dysplasia (BPD) associated with both culture-positive (adjusted OR (aOR) 1.7; 95% CI 1.3 to 2.2) and culture-negative (aOR 1.6; 95% CI 1.3 to 2.6) LOS. Only culture-positive LOS was associated with increased odds of cystic periventricular leukomalacia (cPVL) (aOR 2.2; 95% CI 1.4 to 3.4) and severe retinopathy of prematurity (ROP) (aOR 1.8; 95% CI 1.2 to 2.8). Culture-positive LOS-attributable mortality was 6.3%, higher in Gram-negative (15.8%) compared with Gram-positive (4.1%) LOS, p=0.009. Among extremely preterm infants, survival rates increased from 75.2% in 2009-2013 to 81.0% in 2014-2018, p=0.005. In the same period culture-positive LOS rates increased from 17.1% to 25.6%, p<0.001. CONCLUSIONS: LOS contributes to a significant burden of disease in very preterm infants and is associated with increased odds of severe BPD, cPVL and severe ROP.

Intracranial ultrasound abnormalities and mortality in preterm infants with and without fetal growth restriction stratified by fetal Doppler study results.

OBJECTIVE: To evaluate whether fetal growth restriction (FGR) with or without abnormal Dopplers is associated with intracranial abnormalities and death in premature infants. STUDY DESIGN: Premature infants with and without FGR born between 2016 and 2019 were included. Primary outcome was death, severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Groups were compared using standard bivariate testing and multivariable regression. RESULTS: Among 168 FGR and 560 non-FGR infants, FGR infants with abnormal Dopplers had an increased incidence of death, severe IVH or PVL compared to non-FGR infants (13% (16/123) vs. 7% (41/560); p = 0.03) while FGR infants with normal Dopplers had a nonsignificant decrease. In a logistic regression model, FGR with abnormal Dopplers was associated with more than three times higher odds of death, severe IVH or PVL (OR 3.2, 95% CI 1.54,6.49; p < 0.001). CONCLUSIONS: Growth-restricted infants with abnormal Dopplers had an increased risk of death, intracranial abnormalities, and prematurity-related morbidities.

Dystonia in individuals with spastic cerebral palsy and isolated periventricular leukomalacia.

AIM: To determine the prevalence of dystonia in individuals with periventricular leukomalacia (PVL) and spastic cerebral palsy (CP), but without basal ganglia and thalamic injury (BGTI) on brain magnetic resonance imaging (MRI). METHOD: This was a retrospective study of individuals with spastic CP and PVL on MRI evaluated between 2005 and 2018 in a CP center. Individuals with non-PVL brain lesions on MRI, including BGTI, were excluded. Dystonia was assessed via blinded review of neurological exam videos by pediatric movement disorders specialists. RESULTS: Eighty-five participants (45 males, 40 females; mean age at videotaping 12 years [standard deviation 5 years 6 months], range 4-26 years) met inclusion and exclusion criteria. Of these participants, 50 (59%) displayed dystonia in their exam videos. The most common locations of dystonia were the fingers and hip adductors. The prevalence of dystonia was unaffected by the gestational age or severity of PVL, and was affected by Gross Motor Function Classification System level. INTERPRETATION: Dystonia is common in individuals with spastic CP and PVL, even without BGTI on MRI. Our findings suggest vigilance for dystonia in individuals with spastic CP should remain high, even without MRI evidence of BGTI. WHAT THIS PAPER ADDS: Individuals with spastic cerebral palsy and isolated periventricular leukomalacia on magnetic resonance imaging commonly display dystonia. Common sites of dystonia are in the fingers and hip adductors.

Difference in Mortality and Morbidity Between Extremely and Very Low Birth Weight Neonates.

Purpose: The aim of the present study was to evaluate the mortality and morbidity of extremely low (ELBW < 1,000 g) and very low birth weight neonates (VLBW: 1,000-1,500 g) hospitalized in a referral NICU of a Children's hospital. Design: A retrospective study was conducted in records of the Neonatal Unit of a tertiary care Children's hospital in Greece from January 2009 to March 2019. Sample: All neonates with birth weight ≤1,500 grams, who were all outborn, were reviewed. Main Outcome Variable: Mortality and morbidity, including respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, early onset sepsis, late onset sepsis, retinopathy of prematurity (ROP), ROP treated with laser and neurological findings were investigated. Results: A total of 444 neonates (52 percent males) were analyzed. Among them, 187 (42 percent) were ELBW and 257 (58 percent) were VLBW. The mean gestational age was lower in ELBW neonates compared to VLBW (26.3 ± 2.3 vs. 29.7 ± 2.4 weeks, respectively; p < .001). Mortality was significantly higher in ELBW compared to VLBW neonates (26.7 percent vs. 7.0 percent, p < .001). Morbidity was significantly higher in ELBW compared to VLBW for respiratory distress syndrome (p < .001), bronchopulmonary dysplasia (p < .001), intraventricular hemorrhage (p < .001), periventricular leukomalacia (p < .001), necrotizing enterocolitis (p = .05), early onset sepsis (p < .001) and late onset sepsis (p = 0.001). Similarly, the incidence of ROP and ROP treated with laser was higher in ELBW compared to VLBW neonates (p < .001). Severe neurological findings during follow-up were more prevalent in ELBW compared to VLBW neonates. Finally, the incidence of eye disorders was higher in ELBW compared to VLBW (p = .05). Conclusion: Our results confirmed that ELBW have higher mortality and morbidity than VLBW neonates. Efforts should be made in order to ameliorate perinatal and neonatal care to reduce the burden of prematurity.

Prevention of severe brain injury in very preterm neonates: A quality improvement initiative.

OBJECTIVE: To determine the impact of neuroprotection interventions bundle on the incidence of severe brain injury or early death (intraventricular hemorrhage grade 3/4 or death by 7 days or ventriculomegaly or cystic periventricular leukomalacia on 1-month head ultrasound, primary composite outcome) in very preterm (270/7 to ≤ 296/7 weeks gestational age) infants. STUDY DESIGN: Prospective quality improvement initiative, from April 2017-September 2019, with neuroprotection interventions bundle including cerebral NIRS, TcCO2, and HeRO monitoring-based management algorithm, indomethacin prophylaxis, protocolized bicarbonate and inotropes use, noise reduction, and neutral positioning. RESULT: There was a decrease in the incidence of the primary composite outcome in the intervention period on unadjusted (N = 11/99, pre-intervention to N = 0/127, intervention period, p < 0.001) and adjusted analysis (adjusted for birthweight and Apgar score <5 at 5 min, aOR = 0.042, 95% CI = 0.003-0.670, p = 0.024). CONCLUSIONS: Neuroprotection interventions bundle was associated with significant decrease in severe brain injury or early death in very preterm infants.

Prevalence of the Infantile Strabismus Complex in Premature Children With and Without Periventricular Leukomalacia.

PURPOSE: To determine whether rates of strabismus and associated visuomotor deficits differed among children with different severities of periventricular leukomalacia (PVL). DESIGN: Retrospective, case-control study. METHODS: Brain magnetic resonance images (MRI) obtained from 98 children aged ≥2 years were analyzed using a standardized scoring system: 67 of 98 had PVL (mean GA 31 weeks) and 31 of 98 did not have PVL (mean GA 29 weeks). Severity of PVL was scored as degree of damage to the posterior optic radiations and the splenium of the corpus callosum on MRI. Ophthalmologic examination data were collated to assess the prevalence of visuomotor deficits and the relationship to PVL severity (grades 1-3, mild to severe). RESULTS: Infantile strabismus was documented in 61% of children with mild, 74% with moderate, and 88% with severe PVL (esotropia: exotropia ratio 3.5:1). Associated ocular motor deficits also increased systematically with PVL severity: latent ("fusion maldevelopment") nystagmus (20%, 47%, and 40%, respectively), dissociated vertical deviation (13%, 28%, and 30%), and nasotemporal pursuit/optokinetic nystagmus asymmetry (23%, 38%, and 54%). Additionally, the prevalence of retrograde optic neuropathy increased with PVL severity (5%, 26%, and 38%). The prevalence of each of these signs was substantially lower in children who had no PVL. CONCLUSIONS: Children who suffer PVL are likely to develop the deficits of the infantile strabismus complex. The deficits tend to increase systematically as a function of PVL severity. These findings provide evidence that infantile strabismus is linked to perinatal damage to cerebral vergence and gaze pathways.

Development of muscle tone impairments in high-risk infants: Associations with cerebral palsy and cystic periventricular leukomalacia.

AIM: To assess the prevalence and development of muscle tone impairments in infants at high risk of developmental disorders, and their associations with cerebral palsy (CP) and cystic periventricular leukomalacia (cPVL). METHOD: Longitudinal exploration of muscle tone in 39 infants at high risk of CP (LEARN2MOVE 0-2 project) mostly due to an early lesion of the brain. Muscle tone was assessed ≥4 times between 0 and 21 months corrected age (CA) with the Touwen Infant Neurological Examination. Diagnosis of CP was determined at 21 months CA. Neonatal neuro-imaging was available. Developmental trajectories were calculated using generalized linear mixed effect models. RESULTS: Infants showed atypical muscle tone in three or four body parts in 93% (172/185) of the assessments. The most prevalent muscle tone pattern was hypotonia of neck and trunk with hypertonia of the limbs (28%). From 7 months CA onwards hypertonia of the arms was associated with CP. Asymmetric arm tone during infancy was associated with unilateral CP. At 18-21 months CA ankle hypertonia was associated with CP at 21 months; leg hypertonia in infancy was not associated with CP. Leg hypertonia was associated with cPVL, regardless of age. INTERPRETATION: High-risk infants due to an early lesion of the brain often present with muscle tone impairment. In these infants, hypertonia and asymmetric muscle tone of the arms were from 7 months onwards associated with the diagnosis of CP at 21 months; hypertonia of the legs was not.

Ocular signs, visual and general developmental outcome in Indian children with radiologically proven periventricular leukomalacia.

PURPOSE: Owing to the paucity of literature on Indian children with periventricular leukomalacia (PVL), this retrospective study aimed to describe the visual and associated developmental abnormalities in a series of affected children attending a tertiary level eye care facility. METHODS: Children with radiologically confirmed PVL who attended the Pediatric Department of a tertiary eye hospital were included and underwent a detailed ocular and general developmental assessment. RESULTS: Of the 75 children, the mean age was 2.3 years, the mean follow-up was 3.1 years, 68% were males and 43% were born preterm. Grade I PVL was identified in 13 children (17%), Grade 2 PVL in 39 (52%), and Grade 3 PVL in 23 (31%). Premies with ≤2 kg (72.5%) and term babies with >2 kg (75%) had a greater association of PVL occurrence with a preponderance to severe PVL; 46% of the children were visually impaired which was significantly higher in the children with Grade 3 PVL (74%) than those with Grade 2 PVL (15%). Strabismus was common (80%) with a change in deviation over time. Seventy-one percent of the children had a refractive error, frequently myopic astigmatism. All the children except two had a delay in one or more general developmental milestones. CONCLUSION: PVL occurrence is observed both in the babies born at term and premies, resulting in significant ocular and systemic morbidities. We recommend a system in place for early identification and referral to initiate an early intervention program which goes a long way toward improving the quality of life in these children.

Reevaluating 30-day head ultrasound screening for preterm infants in the era of decreasing periventricular leukomalacia.

OBJECTIVE: Neonatal brain injury is a potentially devastating cause of neurodevelopmental impairment. There is no consensus, however, on the appropriate timing and frequency of routine head ultrasound (HUS) screening for such injuries. We evaluated the diagnostic utility of routine HUS screening at 30 days of life ("late HUS") for detecting severe intraventricular hemorrhage (IVH) or cystic periventricular leukomalacia (c-PVL) in preterm infants with a negative HUS before 14 days of life ("early HUS"). METHODS: Single-center retrospective cohort analysis of infants born at ≤ 32 weeks gestational age (GA) admitted to the University of Nebraska Medical Center NICU from 2011-2018. Demographics, HUS and MRI diagnoses were abstracted from clinical records. Fisher's exact test and t-test assessed associations between categorical and continuous variable, respectively. RESULTS: 205 infants were included-120 very preterm (28-32 weeks GA) and 85 extremely preterm (<28 weeks GA). Negative predictive value of early HUS for predicting any clinically significant anomalies (severe IVH or c-PVL) on late HUS was 100% for extremely and 99.2% for very preterm infants. Term-equivalent MRI detected previously undiagnosed c-PVL in 16.7% of the 24 patients that received MRI; all infants with new c-PVL on MRI had severe IVH on early HUS. CONCLUSION: Following negative early HUS, late HUS detected significant new abnormalities in one infant. These data suggest that in a unit with low prevalence of c-PVL, 30-day HUS may have limited clinical utility following negative screening. In infants with abnormal early HUS, clinicians should consider obtaining term-equivalent MRI screening to detect c-PVL.

Risk Factors for Periventricular Leukomalacia in Preterm Infants: A Systematic Review, Meta-analysis, and GRADE-Based Assessment of Certainty of Evidence.

BACKGROUND: We analyzed the certainty of evidence (CoE) for risk factors of periventricular leukomalacia (PVL) in preterm neonates, a common morbidity of prematurity. METHODS: Medline, CENTRAL, Embase, and CINAHL were searched. Cohort and case-control studies and randomised randomized controlled trials were included. Data extraction was performed in duplicate. A random random-effects meta-analysis was utilizedused. CoE was evaluated as per Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. RESULTS: One hundred eighty-six studies evaluating 95 risk factors for PVL were included. Of the 2,509,507 neonates assessed, 16,569 were diagnosed with PVL. Intraventricular hemorrhage [adjusted odds ratio: 3.22 (2.52-4.12)] had moderate CoE for its association with PVL. Other factors such as hypocarbia, chorioamnionitis, PPROM >48 hour, multifetal pregnancy reduction, antenatal indomethacin, lack of antenatal steroids, perinatal asphyxia, ventilation, shock/hypotension, patent ductus arteriosus requiring surgical ligation, late-onset circulatory collapse, sepsis, necrotizing enterocolitis, and neonatal surgery showed significant association with PVL after adjustment for confounders (CoE: very low to low). Amongst the risk factors associated with mother placental fetal (MPF) triad, there was paucity of literature related to genetic predisposition and defective placentation. Sensitivity analysis revealed that the strength of association between invasive ventilation and PVL decreased over time (P < 0.01), suggesting progress in ventilation strategies. Limited studies had evaluated diffuse PVL. CONCLUSION: Despite decades of research, our findings indicate that the CoE is low to very low for most of the commonly attributed risk factors of PVL. Future studies should evaluate genetic predisposition and defective placentation in the MPF triad contributing to PVL. Studies evaluating exclusively diffuse PVL are warranted.

Mode of delivery and adverse short- and long-term outcomes in vertex-presenting very preterm born infants: a European population-based prospective cohort study.

OBJECTIVES: To compare mortality, morbidity and neurodevelopment by mode of delivery (MOD) for very preterm births with low prelabour risk of caesarean section (CS). METHODS: The study was a population-based prospective cohort study in 19 regions in 11 European countries. Multivariable mixed effects models and weighted propensity score models were used to estimate adjusted odds ratios (aOR) by observed MOD and the unit's policy regarding MOD. Population: Singleton vertex-presenting live births at 24 + 0 to 31 + 6 weeks of gestation without serious congenital anomalies, preeclampsia, HELLP or eclampsia, antenatal detection of growth restriction and prelabour CS for fetal or maternal indications. RESULTS: Main outcome measures: A composite of in-hospital mortality and intraventricular haemorrhage (grade III/IV) or periventricular leukomalacia. Secondary outcomes were components of the primary outcome, 5 min Apgar score <7 and moderate to severe neurodevelopmental impairment at two years of corrected age. The rate of CS was 29.6% but varied greatly between countries (8.0-52.6%). MOD was not associated with the primary outcome (aOR for CS 0.99; 95% confidence interval [CI] 0.65-1.50) when comparing units with a systematic policy of CS or no policy of MOD to units with a policy of vaginal delivery (aOR 0.88; 95% CI 0.59-1.32). No association was observed for two-year neurodevelopment impairment for CS (aOR 1.15; 95% CI 0.66-2.01) or unit policies (aOR 1.04; 95% CI 0.63-1.70). CONCLUSIONS: Among singleton vertex-presenting live births without medical complications requiring a CS at 24 + 0 to 31 + 6 weeks of gestation, CS was not associated with improved neonatal or long-term outcomes.

Preterm White Matter Injury: A Prospective Cohort Study.

OBJECTIVE: To determine the incidence and risk factors of preterm white matter injury [WMI; periventricular-intraventricular hemorrhage (PIVH) and/or periventricular leukomalacia (PVL)]. DESIGN: Prospective cohort study. SETTING: Level-3 neonatal intensive care unit. PATIENTS: Inborn preterm neonates (n=140) delivered at <32 weeks gestation or birthweight <1500 g. METHODS: Serial cranial ultrasounds were performed at postnatal ages of 3 days (±12 hour), 7 (±1) days, 21 (±3) days and 40 (±1) weeks postmenstrual age (PMA). PIVH and PVL were graded as per Volpe and De-Vries criteria, respectively. Univariate followed by multivariate analysis was done to evaluate risk factors for PIVH and PVL. OUTCOME MEASURES: The primary outcome was the incidence of preterm WMI. The secondary outcomes were evaluation of risk factors and natural course of WMI. RESULTS: The mean (range) gestation and birth weight of enrolled neonates were 29.7 (24-36) weeks and 1143 (440-1887) g, respectively. PIVH occurred in 25 (17.8%) neonates. PVL occurred in 34 (24.3%) neonates. None of them were grade III or IV PVL. Preterm WMI (any grade PIVH and/or PVL) occurred in 52 (37.1%) neonates. Severe PIVH (grade III) and cystic PVL occurred in 7 (5%) and 5 (3.6%) neonates, respectively. On multivariate analysis, none of the presumed risk factors were associated with PIVH. However, hemodynamically significant patent ductus arteriosus, and apnea of prematurity were significantly associated with increased risk of PVL. CONCLUSIONS: Significant WMI occurred only in one-third of the cohort, which is comparable to that described in literature from the developed countries.

Care practices and outcomes of extremely preterm neonates born at 22-24 weeks - A single centre experience.

BACKGROUND: Wide variation in the care practices and survival rates of neonates born at peri-viable gestational ages of 22+0 - 24+6 weeks. This study elucidates the postnatal risk factors for morbidity/mortality, contrasts the care practices and short-term outcomes of this vulnerable group of preterm neonates from a single center with others. METHODS: Retrospective study of neonates born at 22+0 -24+6 weeks in a level 3 neonatal intensive care unit in UK, over a period of 4 years (2016-2019). RESULTS: 94 neonates given active care were studied. Survival until discharge was 51.1%(22-23 wks -44%, 24 wks -59.1%) and survival with no major brain injury (MBI) [grade III/IV IVH, cystic periventricular leukomalacia] was 38.3%(22-23 wks -32%, 24 wks -45.4%). Of those who survived until discharge, 75%had no MBI (22-23 wks -72.7%, 24 wks -76.9%). Neonates requiring significant respiratory support within first 72 hours as well as needing rescue high frequency ventilation had significantly high risk of mortality or MBI [aOR -7.17 (2.24-25.79), p = 0.00; 4.76 (1.43-20.00), p = 0.01]. CONCLUSIONS: Survival rate differed from other centres. MBI was low amongst survivors. Severe respiratory disease in the initial days was associated with a higher risk of death or MBI.

Severe Brain Damage in a Moderate Preterm Infant as Complication of Post-COVID-19 Response during Pregnancy.

Current evidence from the COVID-19 pandemic suggests that neonatal SARS-coronavirus-2 infections usually have a mild course. Data on how maternal infection during pregnancy affects fetal development are scarce. We present the unique case of a moderate preterm infant with intracranial bleeding and periventricular leukomalacia as a potential consequence of post-COVID-19 hyperinflammation during pregnancy.