Publications by authors named "Janessa B Law"

6 Publications

  • Page 1 of 1

Diffusion Tensor Imaging Changes Do Not Affect Long-Term Neurodevelopment following Early Erythropoietin among Extremely Preterm Infants in the Preterm Erythropoietin Neuroprotection Trial.

Brain Sci 2021 Oct 16;11(10). Epub 2021 Oct 16.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24-25 weeks vs. 26-27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.
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http://dx.doi.org/10.3390/brainsci11101360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533828PMC
October 2021

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial.

EBioMedicine 2021 Oct 4;72:103605. Epub 2021 Oct 4.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA. Electronic address:

Background: In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks' gestation) infants.

Methods: Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III).

Findings: Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years.

Interpretation: Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice.

Funding: PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).
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http://dx.doi.org/10.1016/j.ebiom.2021.103605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498235PMC
October 2021

Evaluating Neuroprotective Effects of Uridine, Erythropoietin, and Therapeutic Hypothermia in a Ferret Model of Inflammation-Sensitized Hypoxic-Ischemic Encephalopathy.

Int J Mol Sci 2021 Sep 11;22(18). Epub 2021 Sep 11.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

Perinatal hypoxic-ischemic (HI) brain injury, often in conjunction with an inflammatory insult, is the most common cause of death or disability in neonates. Therapeutic hypothermia (TH) is the standard of care for HI encephalopathy in term and near-term infants. However, TH may not always be available or efficacious, creating a need for novel or adjunctive neurotherapeutics. Using a near-term model of inflammation-sensitized HI brain injury in postnatal day (P) 17 ferrets, animals were randomized to either the control group ( = 43) or the HI-exposed groups: saline vehicle (Veh; = 42), Ur (uridine monophosphate, = 23), Epo (erythropoietin, = 26), or TH ( = 24) to test their respective therapeutic effects. Motor development was assessed from P21 to P42 followed by analysis of cortical anatomy, ex vivo MRI, and neuropathology. HI animals took longer to complete the motor assessments compared to controls, which was exacerbated in the Ur group. Injury resulted in thinned white matter tracts and narrowed cortical sulci and gyri, which was mitigated in Epo-treated animals in addition to normalization of cortical neuropathology scores to control levels. TH and Epo treatment also resulted in region-specific improvements in diffusion parameters on ex vivo MRI; however, TH was not robustly neuroprotective in any behavioral or neuropathological outcome measures. Overall, Ur and TH did not provide meaningful neuroprotection after inflammation-sensitized HI brain injury in the ferret, and Ur appeared to worsen outcomes. By comparison, Epo appears to provide significant, though not complete, neuroprotection in this model.
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http://dx.doi.org/10.3390/ijms22189841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469346PMC
September 2021

Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines.

JAMA Netw Open 2021 Jul 1;4(7):e2115998. Epub 2021 Jul 1.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle.

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood.

Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age.

Design, Setting, And Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020.

Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay.

Main Outcomes And Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III).

Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure.

Conclusions And Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.15998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264640PMC
July 2021

Intracranial Hemorrhage and 2-Year Neurodevelopmental Outcomes in Infants Born Extremely Preterm.

J Pediatr 2021 Nov 2;238:124-134.e10. Epub 2021 Jul 2.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 24 to 27 weeks of gestational age and to characterize the association between ICH and death or neurodevelopmental impairment (NDI) at 2 years of corrected age.

Study Design: Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial had serial cranial ultrasound scans performed on day 1, day 7-9, and 36 weeks of postmenstrual age to evaluate ICH. Potential risk factors for development of ICH were examined. Outcomes included death or severe NDI as well as Bayley Scales of Infant and Toddler Development, 3rd Edition, at 2 years of corrected age.

Results: ICH was identified in 38% (n = 339) of 883 enrolled infants. Multiple gestation and cesarean delivery reduced the risk of any ICH on day 1. Risk factors for development of bilateral Grade 2, Grade 3, or Grade 4 ICH at day 7-9 included any ICH at day 1; 2 or more doses of prenatal steroids decreased risk. Bilateral Grade 2, Grade 3, or Grade 4 ICH at 36 weeks were associated with previous ICH at day 7-9. Bilateral Grade 2, any Grade 3, and any Grade 4 ICH at 7-9 days or 36 weeks of postmenstrual age were associated with increased risk of death or severe NDI and lower Bayley Scales of Infant and Toddler Development, 3rd Edition, scores.

Conclusions: Risk factors for ICH varied by timing of bleed. Bilateral and increasing grade of ICH were associated with death or NDI in infants born extremely preterm.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551011PMC
November 2021

Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin.

J Cereb Blood Flow Metab 2021 08 7;41(8):2054-2066. Epub 2021 Feb 7.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h-6h, and significantly lower MCP-4 and MDC at 24 h-72h, respectively. IL-12p40 was lower at 24 h-72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.
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http://dx.doi.org/10.1177/0271678X21991439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327104PMC
August 2021
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