Postnatal Growth Trajectories and Neurodevelopmental Outcomes Following Bevacizumab Treatment for Retinopathy of Prematurity.

Purpose: To investigate the postnatal growth and neurodevelopment of infants with retinopathy of prematurity (ROP) treated with intravitreal bevacizumab (IVB). Patients and Methods: This was a retrospective comparative study. A total of 262 infants were divided among three study groups: 22 treated with intravitreal bevacizumab, 55 treated with laser, and 185 with ROP that resolved without treatment. Infants with nonviable course or hydrocephalus, a source of non-physiologic weight gain, were excluded. Neurodevelopment was assessed with Bayley III scores at 17-28 months if available and presence of hearing loss or cerebral palsy. Weekly weight, height, and head circumference from birth through 50 weeks postmenstrual age (PMA) were modeled to determine differences in growth trajectories following treatment. Results: Comparison of postnatal growth curves from the time of treatment to 50 weeks PMA showed no significant differences in growth trajectories between groups after adjusting for the corresponding growth parameters at birth. Comparison of Bayley scores in patients with available data (n = 120) showed no significant differences. There was an increased risk of cerebral palsy in the IVB group after logistic regression adjusting for baseline confounders, but this did not retain statistical significance after applying the false discovery rate correction for multiple testing. Conclusion: To our knowledge, this is the first large retrospective study to examine longitudinal growth in infants treated with IVB compared to controls. There were no significant differences in postnatal growth or neurodevelopmental outcomes between groups, which overall continue to support the safety of bevacizumab treatment for ROP.

Differential Gene Expression in Cord Blood of Infants Diagnosed with Cerebral Palsy: A Pilot Analysis of the Beneficial Effects of Antenatal Magnesium Cohort.

The Beneficial Effects of Antenatal Magnesium clinical trial was conducted between 1997 and 2007, and demonstrated a significant reduction in cerebral palsy (CP) in preterm infants who were exposed to peripartum magnesium sulfate (MgSO4). However, the mechanism by which MgSO4 confers neuroprotection remains incompletely understood. Cord blood samples from this study were interrogated during an era when next-generation sequencing was not widely accessible and few gene expression differences or biomarkers were identified between treatment groups. Our goal was to use bulk RNA deep sequencing to identify differentially expressed genes comparing the following four groups: newborns who ultimately developed CP treated with MgSO4 or placebo, and controls (newborns who ultimately did not develop CP) treated with MgSO4 or placebo. Those who died after birth were excluded. We found that MgSO4 upregulated expression of SCN5A only in the control group, with no change in gene expression in cord blood of newborns who ultimately developed CP. Regardless of MgSO4 exposure, expression of NPBWR1 and FTO was upregulated in cord blood of newborns who ultimately developed CP compared with controls. These data support that MgSO4 may not exert its neuroprotective effect through changes in gene expression. Moreover, NPBWR1 and FTO may be useful as biomarkers and may suggest new mechanistic pathways to pursue in understanding the pathogenesis of CP. The small number of cases ultimately available for this secondary analysis, with male predominance and mild CP phenotype, is a limitation of the study. In addition, differentially expressed genes were not validated by qRT-PCR.

Ventriculomegaly thresholds for prediction of symptomatic post-hemorrhagic ventricular dilatation in preterm infants.

BACKGROUND: Benefits from early surgical intervention in preterm infants with intraventricular hemorrhage (IVH) prior to symptomatic ventriculomegaly must be weighed against risks of surgery. We calculated thresholds of common ventriculomegaly indices at a late-intervention institution to predict subsequent symptomatic ventriculomegaly requiring neurosurgery. METHODS: We retrospectively reviewed neuroimaging and neurosurgical outcomes in preterm infants with grade III/IV IVH between 2007 and 2020. Frontal-occipital horn ratio (FOHR), frontal-temporal horn ratio (FTHR), anterior horn width (AHW), and ventricular index (VI) were measured. Area under the receiver operating curve (AUC) for predicting intervention (initiated after progressive symptomatic ventriculomegaly) was calculated for diagnostic scan, scans during weeks 1-4, and maximum measurement prior to intervention. Threshold values that optimized sensitivity and specificity were derived. RESULTS: A total of 1254 scans in 132 patients were measured. In all, 37 patients had a neurosurgical intervention. All indices differed between those with and without intervention from the first diagnostic scan (p < 0.001). AUC of maximum measurement was 97.1% (95% CI 94.6-99.7) for FOHR, 97.7% (95% CI 95.6-99.8) for FTHR, 96.6% (95% CI 93.9-99.4) for AHW, and 96.8% (95% CI 94.0-99.5) for VI. Calculated thresholds were FOHR 0.66, FTHR 0.62, AHW 15.5 mm, and VI 8.4 mm > p97 (sensitivities >86.8%, specificities >90.1%). CONCLUSION: Ventriculomegaly indices were greater for patients who developed progressive persistent ventriculomegaly from the first diagnostic scan and predicted neurosurgical intervention. IMPACT: We derived thresholds of common ventriculomegaly indices (ventricular index, anterior frontal horn width, fronto-occipital horn and fronto-temporal horn index) to best predict the development of progressive symptomatic post-hemorrhage hydrocephalus in preterm infants with intraventricular hemorrhage. While current thresholds were established by a priori expert consensus, we report the first data-driven derivation of ventriculomegaly thresholds across all indices for the prediction of symptomatic hydrocephalus. Data-derived thresholds will more precisely weigh the risks and benefits of early intervention.

Degree of ventriculomegaly predicts school-aged functional outcomes in preterm infants with intraventricular hemorrhage.

BACKGROUND: Greater ventriculomegaly in preterm infants with intraventricular hemorrhage (IVH) has been associated with worse neurodevelopmental outcomes in infancy. We aim to explore the relationship between ventriculomegaly and school-age functional outcome. METHODS: Retrospective review of preterm infants with Grade III/IV IVH from 2006 to 2020. Frontal-occipital horn ratio (FOHR) was measured on imaging throughout hospitalization and last available follow-up scan. Pediatric Cerebral Performance Category (PCPC) scale was used to assess functional outcome at ≥4 years. Ordinal logistic regression was used to determine the relationship between functional outcome and FOHR at the time of Neurosurgery consult, neurosurgical intervention, and last follow-up scan while adjusting for confounders. RESULTS: One hundred and thirty-four infants had Grade III/IV IVH. FOHR at consult was 0.62 ± 0.12 and 0.75 ± 0.13 at first intervention (p < 0.001). On univariable analysis, maximum FOHR, FOHR at the last follow-up scan, and at Neurosurgery consult predicted worse functional outcome (p < 0.01). PVL, longer hospital admission, and gastrotomy/tracheostomy tube also predicted worse outcome (p < 0.05). PVL, maximum FOHR, and FOHR at consult remained significant on multivariable analysis (p < 0.05). Maximum FOHR of 0.61 is a fair predictor for moderate-severe impairment (AUC 75%, 95% CI: 62-87%). CONCLUSIONS: Greater ventricular dilatation and PVL were independently associated with worse functional outcome in Grade III/IV IVH regardless of neurosurgical intervention. IMPACT: Ventriculomegaly measured by frontal-occipital horn ratio (FOHR) and periventricular leukomalacia are independent correlates of school-age functional outcomes in preterm infants with intraventricular hemorrhage regardless of need for neurosurgical intervention. These findings extend the known association between ventriculomegaly and neurodevelopmental outcomes in infancy to functional outcomes at school age. FOHR is a fair predictor of school-age functional outcome, but there are likely other factors that influence functional status, which highlights the need for prospective studies to incorporate other clinical and demographic variables in predictive models.

Neonatal Mortality After Interhospital Transfer of Pregnant Women for Imminent Very Preterm Birth in Illinois.

Importance: Reducing neonatal mortality is a national health care priority. Understanding the association between neonatal mortality and antenatal transfer of pregnant women to a level III perinatal hospital for delivery of infants who are very preterm (VPT) may help identify opportunities for improvement. Objective: To assess whether antenatal transfer to a level III hospital is associated with neonatal mortality in infants who are VPT. Design, Setting, and Participants: This population-based cross-sectional study included infants who were born VPT to Illinois residents in Illinois perinatal-network hospitals between January 1, 2015, and December 31, 2016, and followed up for 28 days after birth. Data analysis was conducted from June 2017 to September 2018. Exposures: Delivery of an infant who was VPT at a (1) level III hospital after maternal presentation at that hospital (reference group), (2) a level III hospital after antenatal (in utero) transfer from another hospital, or (3) a non-level III hospital. Main Outcomes and Measures: Neonatal mortality. Results: The study included 4817 infants who were VPT (gestational age, 22-31 completed weeks) and were born to Illinois residents in 2015 and 2016. Of those, 3302 infants (68.5%) were born at a level III hospital after maternal presentation at that hospital, 677 (14.1%) were born at a level III hospital after antenatal transfer, and 838 (17.4%) were born at a non-level III hospital. Neonatal mortality for all infants who were VPT included in this study was 573 of 4817 infants (11.9%). The neonatal mortality was 10.7% for the reference group (362 of 3302 infants), 9.8% for the antenatal transfer group (66 of 677 infants), and 17.3% for the non-level III birth group (145 of 838 infants). When adjusted for significant social and medical characteristics, infants born VPT at a level III hospital after antenatal transfer from another facility had a similar risk of neonatal mortality as infants born at a level III hospital (odds ratio, 0.79 [95% CI, 0.56-1.13]) after maternal presentation at the same hospital. Infants born at a non-level III hospital had an increased risk of neonatal mortality compared with infants born at a level III hospital after maternal presentation to the same hospital (odds ratio, 1.52 [95% CI, 1.14-2.02]). Conclusions and Relevance: The risk of neonatal mortality was similar for infants who were VPT, whether women initially presented at a level III hospital or were transferred to a level III hospital before delivery. This suggests that the increased risk of mortality associated with delivery at a non-level III hospital may be mitigated by optimizing opportunities for early maternal transfer to a level III hospital.

Transcranial Doppler Identification of Neurologic Injury during Pediatric Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND: We used transcranial Doppler to examine changes in cerebral blood flow velocity in children treated with extracorporeal membrane oxygenation. We examined the association between those changes and radiologic, electroencephalographic, and clinical evidence of neurologic injury. METHODS: This was a retrospective review and prospective observational study of patients 18 years old and younger at a single university children's hospital. Transcranial Doppler studies were obtained every other day during the first 7 days of extracorporeal membrane oxygenation, and 1 additional study following decannulation, in conjunction with serial neurologic examinations, brain imaging, and 6- to 12-month follow-up. RESULTS: The study included 27 patients, the majority (26) receiving veno-arterial extracorporeal membrane oxygenation. Transcranial Doppler velocities during extracorporeal membrane oxygenation were significantly lower than published values for age-matched healthy and critically ill children across different cerebral arteries. Neonates younger than 10 days had higher velocities than expected. Blood flow velocity increased after extracorporeal membrane oxygenation decannulation and was comparable with age-matched critically ill children. There was no significant association between velocity measurements of individual arteries and acute neurologic injury as defined by either abnormal neurologic examination, seizures during admission, or poor pediatric cerebral performance category. However, case analysis identified several patients with regional and global increases in velocities that corresponded to neurologic injury including stroke and seizures. CONCLUSIONS: Cerebral blood flow velocities during extracorporeal membrane oxygenation deviate from age-specific normal values in all major cerebral vessels and across different age groups. Global or regional elevations and asymmetries in flow velocity may suggest impending neurologic injury.

Growth and Development in Extremely Low Birth Weight Infants After the Introduction of Exclusive Human Milk Feedings.

Objective To estimate associations of exclusive human milk (EHM) feedings with growth and neurodevelopment through 18 months corrected age (CA) in extremely low birth weight (ELBW) infants. Study Design ELBW infants admitted from July 2011 to June 2013 who survived were reviewed. Infants managed from July 2011 to June 2012 were fed with bovine milk-based fortifiers and formula (BOV). Beginning in July 2012, initial feedings used a human milk-based fortifier to provide EHM feedings. Infants were grouped on the basis of feeding regimen. Primary outcomes were the Bayley-III cognitive scores at 6, 12, and 18 months and growth. Results Infants (n = 85; 46% received EHM) were born at 26 ± 1.9 weeks (p = 0.92 between groups) weighing 776 ± 139 g (p = 0.67 between groups). Cognitive domain scores were similar at 6 months (BOV: 96 ± 7; EHM: 95 ± 14; p = 0.70), 12 months (BOV: 97 ± 10; EHM: 98 ± 9; p = 0.86), and 18 months (BOV: 97 ± 16; EHM: 98 ± 14; p = 0.71) CA. Growth velocity prior to discharge (BOV: 12.1 ± 5.2 g/kg/day; EHM: 13.1 ± 4.0 g/kg/day; p = 0.33) and subsequent growth was similar between groups. Conclusion EHM feedings appear to support similar growth and neurodevelopment in ELBW infants as compared with feedings containing primarily bovine milk-based products.

Periviable birth: Interim update.

Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values.

#3: Periviable birth.

Approximately 0.5% of all births occur before the third trimester of pregnancy, and these very early deliveries result in the majority of neonatal deaths and more than 40% of infant deaths. A recent executive summary of proceedings from a joint workshop defined periviable birth as delivery occurring from 20 0/7 weeks to 25 6/7 weeks of gestation. When delivery is anticipated near the limit of viability, families and health care teams are faced with complex and ethically challenging decisions. Multiple factors have been found to be associated with short-term and long-term outcomes of periviable births in addition to gestational age at birth. These include, but are not limited to, nonmodifiable factors (eg, fetal sex, weight, plurality), potentially modifiable antepartum and intrapartum factors (eg, location of delivery, intent to intervene by cesarean delivery or induction for delivery, administration of antenatal corticosteroids and magnesium sulfate), and postnatal management (eg, starting or withholding and continuing or withdrawing intensive care after birth). Antepartum and intrapartum management options vary depending upon the specific circumstances but may include short-term tocolytic therapy for preterm labor to allow time for administration of antenatal steroids, antibiotics to prolong latency after preterm premature rupture of membranes or for intrapartum group B streptococci prophylaxis, and delivery, including cesarean delivery, for concern regarding fetal well-being or fetal malpresentation. Whenever possible, periviable births for which maternal or neonatal intervention is planned should occur in centers that offer expertise in maternal and neonatal care and the needed infrastructure, including intensive care units, to support such services. This document describes newborn outcomes after periviable birth, provides current evidence and recommendations regarding interventions in this setting, and provides an outline for family counseling with the goal of incorporating informed patient preferences. Its intent is to provide support and guidance regarding decisions, including declining and accepting interventions and therapies, based on individual circumstances and patient values.

Neonatal extracorporeal life support: impact of new therapies on survival.

OBJECTIVE: To evaluate the effects of pre-extracorporeal life support (ECLS) management with nitric oxide (NO), high frequency ventilation (HFV), and surfactant on mortality among neonates supported with ECLS. STUDY DESIGN: Extracorporeal Life Support Organization (ELSO) data on 7017 neonates cannulated for respiratory reasons between 1996 and 2003 were analyzed using chi2, analysis of variance, and logistic regression. RESULTS: The use of ECLS declined by 26.6% over the study period with no significant change in mortality. Unadjusted ECLS mortality for NO-treated patients was lower than for infants not treated with NO (25.1% vs 28.6%, P = .0012) and for infants treated with surfactant than for infants not treated with surfactant (18.7% vs 30.3%, p <.0001.) Unadjusted mortality for HFV-treated patients was no different than for non-HFV-treated patients (26.0% vs 26.6%, P = .56). After adjusting for confounders (primary diagnosis, age at cannulation, ECMO year 1996-1999 vs 2000-2003), surfactant use was associated with decreased mortality. NO-treated neonates were less likely to have a pre-ECLS cardiopulmonary arrest than infants not treated with NO. NO, HFV, and surfactant were not associated with prolongation of ECLS or mechanical ventilation. CONCLUSIONS: NO, HFV, and surfactant were not associated with increased mortality in neonates who require ECLS for hypoxic respiratory failure.

Altered pathways for auditory discrimination and recognition memory in preterm infants.

Preterm infants are at increased risk for cognitive disorders, including impairments in recognition memory. This study evaluated the effects of extreme prematurity on the neural pathway for auditory recognition memory using event-related potentials (ERPs), a neurophysiological technique widely used in cognitive neuroscience. ERPs were recorded at term postmenstrual age in 35 preterm infants born at less than 32 weeks' gestation (22 males, 13 females; mean birthweight ([BW] 1154g, SD 374g) with normal brain ultrasounds, compared with 40 healthy, term newborns (1 to 3 days of age; 20 males, 20 females; BW 3672g, SD 420g). Because infants must be able to detect and discriminate sounds before recognizing them, two paradigms were used to assess these functions. The first evaluated the detection and discrimination of speech sounds. The second tested recognition of the mother's voice compared with a stranger's. Results showed significantly different patterns of speech sound discrimination in preterm infants compared with term infants. No evidence of maternal voice recognition was elicited from the preterm infants. No specific patterns of auditory detection or discrimination were associated with patterns of recognition memory, suggesting that the function of multiple neural pathways may have been altered in this group of preterm infants. These results provide a functional corroboration of magnetic resonance imaging studies showing effects of prematurity on early brain development, even among preterm infants with normal cranial ultrasonography.