Publications by authors named "Ernest M Graham"

45 Publications

Perinatal blood biomarkers for the identification of brain injury in very low birth weight growth-restricted infants.

J Perinatol 2021 Jun 3. Epub 2021 Jun 3.

Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: To determine if blood biomarkers measured at delivery and shortly after birth can identify growth-restricted infants at risk for developing severe brain injury.

Study Design: In a cohort of very low birth weight neonates, fetal growth restricted (FGR) (birth weight <10%) were compared to non-FGR neonates, and within the FGR group those with brain injury were compared to those without. Biomarkers were measured in cord blood at delivery, and daily for the 1st 5 days of life.

Result: FGR was associated with significantly higher levels of interleukin (IL)-6, IL-8, IL-10, and lower levels of vascular endothelial growth factor (VEGF). FGR and brain injury were associated with significantly higher levels of IL-6, IL-8, IL-10, and glial fibrillary acidic protein (GFAP).

Conclusion: Interleukins may be involved in a common pathway contributing to both the development of growth restriction and brain injury, and GFAP may help identify brain injury within this growth-restricted group.
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http://dx.doi.org/10.1038/s41372-021-01112-8DOI Listing
June 2021

Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples.

Biopreserv Biobank 2021 Apr 21;19(2):106-110. Epub 2021 Jan 21.

Johns Hopkins All Children's Maternal, Fetal, and Neonatal Institute, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, USA.

Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury.
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http://dx.doi.org/10.1089/bio.2020.0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080915PMC
April 2021

Blood biomarkers for neonatal hypoxic-ischemic encephalopathy in the presence and absence of sentinel events.

J Perinatol 2021 Jun 6;41(6):1322-1330. Epub 2020 Oct 6.

Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

Objective: To determine if neonatal serum biomarkers representing different pathways of injury differ for cases of HIE of unknown cause to gain insight into timing and mechanism of injury.

Study Design: In this cohort of all neonates with HIE admitted to our NICU, newborns with sentinel events were compared to those without during the 1st 3 days of life. Discard neonatal blood during the 1st 3 days of life was used for analysis.

Results: Of 277 babies with HIE treated with whole-body hypothermia, 190 (68.6%) had blood available for biomarker analysis. In total, 71 (37.4%) were born within our system, and 119 (62.6%) were transferred in from outside hospitals. Of these babies, 77 (40.5%) had a sentinel event and 113 (59.6%) had no sentinel event. Although the degree of metabolic acidosis was similar, repeated measures analysis showed that during the initial 3 days of life neonates born with HIE in the absence of sentinel events had 41.4% decreased VEGF (p = 0.027) and 62.5% increased IL-10 serum concentrations (p = 0.005).

Conclusion: These changes indicate that neonatal HIE in the absence of sentinel events is not related to an unrecognized acute intrapartum event and is possibly related to chronic hypoxia of lower severity or recovery from a remote event.
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http://dx.doi.org/10.1038/s41372-020-00850-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021592PMC
June 2021

Placental malperfusion in response to intrauterine inflammation and its connection to fetal sequelae.

PLoS One 2019 3;14(4):e0214951. Epub 2019 Apr 3.

Integrated Research Center for Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University, School of Medicine, Baltimore, MD, United States of America.

Exposure to intrauterine inflammation (IUI) is associated with short- and long-term adverse perinatal outcomes. However, little data exist on utilizing placenta to prognosticate fetal injury in this scenario. Our study aimed to utilize imaging modalities to evaluate mechanisms contributing to placental injury following IUI exposure and correlated it to concomitant fetal brain injury. CD1 pregnant dams underwent laparotomies and received intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS). In utero ultrasound Doppler velocimetry of uterine and umbilical arteries and magnetic resonance imaging (MRI) of placental volumes with confirmatory immunohistochemical (vimentin) and histochemistry (fibrin) analyses were performed. ELISA for thrombosis markers, fibrinogen and fibrin was performed to analyze thrombi in placenta. Fetal brain immunohistochemistry was performed to detect microglial activation (ionized calcium-binding adaptor molecule 1, Iba1). On ultrasound, LPS group demonstrated elevated resistance indices, pulsatility indices and a greater occurrence of absent end-diastolic flow in the umbilical and uterine arteries. In the fetus, there was an increased cardiac Tei indices in the LPS group. MRI revealed decreased volume of placenta in the LPS group associated with placental thinning and placental endothelial damage on immunohistochemistry. Decreased fibrinogen content and more thrombi staining in placenta exposed to maternal LPS indicated the hypercoagulability. Furthermore, the expression of Iba1was significantly associated with placental thickness (r = -0.7890, Pearson correlation coefficient). Our data indicate that IUI can trigger events leading to maternal placental malperfusion and fetal vessel resistance, as well as predispose the developing fetus to cardiac dysfunction and brain damage. Furthermore, our data suggest that prenatal ultrasound can be a real-time clinical tool for assessing fetal risk for adverse neurologic outcomes following the potential IUI exposure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214951PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447225PMC
December 2019

17α-Hydroxyprogesterone Caproate and the Risk of Glucose Intolerance in Pregnancy: A Systematic Review and Meta-analysis.

Obstet Gynecol 2019 03;133(3):468-475

Division of Maternal Fetal Medicine and Clinical Pharmacology, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine; and Doctoral (PhD) Program in Clinical Investigation, Graduate Training Program in Clinical Investigation (GTPCI), Johns Hopkins University School of Public Health, Baltimore, Maryland.

Objective: To evaluate whether 17α-hydroxyprogesterone caproate use in preventing preterm birth increases the risk of gestational diabetes mellitus (GDM).

Data Sources: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, Scielo and the Cochrane Central Register of Controlled Trials) were searched for studies published before October 2018. Keywords included "gestational diabetes," "preterm birth," "pregnancy," and "17-hydroxyprogesterone caproate."

Methods Of Study Selection: Studies comparing 17α-hydroxyprogesterone caproate with unexposed control groups in women with singleton gestation and a history of a prior spontaneous preterm birth were included. The primary outcome was the development of GDM. Secondary outcomes included abnormal 1-hour, 50-g glucose screen results and mean venous blood glucose levels. Summary estimates were reported as mean differences and 95% CI for continuous variables or relative risk (RR) with 95% CI for dichotomous outcomes. Meta-analysis was performed using the random effects model of DerSimonian and Laird.

Tabulation, Integration And Results: Six studies, four of which were cohort studies, met inclusion criteria and were included in the final meta-analysis. Of the 5,053 women, 1,538 (30.4%) received 17α-hydroxyprogesterone caproate and 3,515 (69.6%) were in unexposed control groups. The overall rate of GDM in women exposed to 17α-hydroxyprogesterone caproate was 10.9% vs 6.1% in women who were not exposed (RR 1.77, 95% CI 1.22-2.55). After exclusion of the cohort studies, the summary estimate of effect was nonsignificant among women who had been randomly allocated to 17α-hydroxyprogesterone caproate (RR 1.21, 95% CI 0.63-2.36).

Conclusion: Women with singleton gestations receiving weekly 17α-hydroxyprogesterone caproate for recurrent preterm birth prevention had a significantly higher incidence of abnormal glucose test results and GDM compared with those in unexposed control groups, a finding that did not hold among women who had been randomly allocated to 17α-hydroxyprogesterone caproate.

Systematic Review Registration: PROSPERO, CRD42016041694.
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http://dx.doi.org/10.1097/AOG.0000000000003115DOI Listing
March 2019

Obstetric management, tests, and technologies that impact childhood development.

Dev Med Child Neurol 2019 09 28;61(9):1002-1007. Epub 2019 Jan 28.

Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Childhood brain development begins before birth, and obstetric management, tests, and technologies designed to diagnose and treat fetal conditions can have an impact on development. Preconception counseling for maternal diabetes and hypertension affect the risk of fetal congenital anomalies and growth restriction. Patients with risk factors for pre-existing maternal diabetes are offered early diabetic screening because earlier diagnosis and treatment can decrease the risk of fetal and neonatal complications. Screening for chromosomal abnormalities in the first or second trimester is offered to all females regardless of age. Cell-free fetal DNA screening can be used to test for fetal genetic abnormalities as early as 9 weeks of gestation with results available in 10 days. Ultrasound performed around 20 weeks' gestation can identify the 3% of fetuses that have a major congenital malformation. Fetal magnetic resonance imaging can be used to better assess fetal central nervous system abnormalities when neurosonography is inconclusive. Doppler ultrasound can be used to assess blood flow in the umbilical artery and fetal middle cerebral artery to aid in the management of the growth-restricted fetus. In summary, diagnosis and treatment of maternal and fetal conditions from the preconception period throughout pregnancy are important for optimizing fetal health and provide the best opportunity for optimal child development. WHAT THIS PAPER ADDS: Cell-free fetal DNA screening can identify fetal genetic abnormalities as early as 9 weeks' gestation. Ultrasound performed around 20 weeks' gestation can detect major fetal congenital malformations. Fetal magnetic resonance imaging can aid neurosonography in the assessment of fetal central nervous system abnormalities. Doppler ultrasound to assess fetal blood flow is used to successfully manage the growth-restricted fetus.
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http://dx.doi.org/10.1111/dmcn.14160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661226PMC
September 2019

Adjuvant 17-hydroxyprogesterone caproate in women withultrasound-indicated cerclage: a systematic review and meta-analysis.

J Matern Fetal Neonatal Med 2020 Sep 24;33(18):3177-3184. Epub 2019 Jan 24.

Department of Gynecology and Obstetrics, Division of Maternal Fetal Medicine and Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

To assess the additional benefits of 17-hydroxyprogesterone caproate (17-OHPC) therapy in preventing recurrent spontaneous preterm birth in women with an ultrasound-indicated cerclage. Electronic databases (Medline, Scopus, ClinicalTrials.gov, PROSPERO, Embase, Scielo, and the Cochrane Central Register of Controlled Trials) were searched for studies published before September 2018. Keywords included "preterm birth", "ultrasound-indicated cerclage", "pregnancy" and "17-hydroxyprogesterone caproate". Studies comparing ultrasound-indicated cerclage alone to cerclage plus 17-OHPC were included. The primary outcome measure was preterm birth at <35 weeks of gestation. Secondary outcome measures include preterm birth <24 weeks, <28 weeks, <32 weeks and <37 weeks of gestation, necrotizing enterocolitis (NEC), fetal birth weight, and intraventricular hemorrhage (grades III and IV). Meta-analysis was performed using the random effects model of DerSimonian and Laird. Risk of bias and quality assessment was performed using the risk of bias in nonrandomized studies of interventions (ROBINS-I). Four studies met inclusion criteria and were included in the final analysis. Of the 396 women who received ultrasound-indicated cerclage, 142 (35.9%) received adjuvant 17-OHPC. The primary outcome, preterm birth <35 weeks of gestation, was present in three studies and 332/396 singleton pregnancies. Though there was a trend towards a reduced risk of preterm birth, the summary estimate of effect was not statistically significant when comparing cerclage alone to cerclage plus 17-OHPC at <35 weeks (relative risk (RR) 0.95, 95% CI 0.77-1.17). Similarly, we found no differences in preterm birth at <24 weeks (RR 0.30, 95% CI 0.06-1.60), <28 weeks (RR 0.57, 95% CI 0.13-2.53), and <32 weeks (RR 0.99, 95% CI 0.44-2.27) when comparing cerclage alone to cerclage plus 17-OHPC. There were no differences in fetal birth weight, intraventricular hemorrhage and necrotizing enterocolitis comparing cerclage alone to cerclage plus 17-OHPC. Intramuscular 17-OHPC in combination with ultrasound-indicated cerclage in women with prior preterm birth had no additional effect in reducing spontaneous recurrent preterm birth or improving perinatal outcomes.
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http://dx.doi.org/10.1080/14767058.2019.1568406DOI Listing
September 2020

Adjuvant 17-hydroxyprogesterone caproate in women with history-indicated cerclage: A systematic review and meta-analysis.

Acta Obstet Gynecol Scand 2019 02 18;98(2):139-153. Epub 2018 Nov 18.

Division of Maternal Fetal Medicine & Clinical Pharmacology, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: The purpose of this study was to evaluate whether there are additional benefits of 17-hydroxyprogesterone caproate (17-OHPC) supplementation in preventing recurrent spontaneous preterm birth in women with a prophylactic cerclage.

Material And Methods: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, Scielo and the Cochrane Central Register of Controlled Trials) were searched for studies published before June 2018. Keywords included "preterm birth", "prophylactic cerclage", "history-indicated cerclage", "pregnancy" and "17-hydroxyprogesterone caproate". Studies comparing history-indicated cerclage alone with cerclage+17-OHPC were included. The primary outcome measure was preterm birth at <24 weeks of gestation. Secondary outcome measures include preterm birth at <28 weeks, <32 weeks and <37 weeks of gestation, respiratory distress syndrome, necrotizing enterocolitis, fetal birthweight, neonatal intensive care unit stay, mean gestational age at delivery, fetal/neonatal death, neurological morbidity (intraventricular hemorrhage plus periventricular leukomalacia), neonatal sepsis and a composite of severe neonatal morbidity. Severe neonatal morbidity was defined as a composite measure of periventricular leukomalacia, intraventricular hemorrhage (grades III and IV), necrotizing enterocolitis or respiratory distress syndrome. Meta-analysis was performed using the random-effects model of DerSimonian and Laird. Risk of bias and quality assessment were performed using the ROBINS-I and GRADE tools, respectively. PROSPERO Registration Number: CRD42018094559.

Results: Five studies met the inclusion criteria and were included in the final analysis. Of the 546 women, 357 (75%) received history-indicated cerclage alone and 189 (35%) received adjuvant 17-OHPC. The composite endpoint, severe neonatal morbidity, was present in 84 of 1515 neonates. Though there was a trend toward a reduced risk of preterm birth, the summary estimate of effect was not statistically significant when comparing cerclage alone with cerclage+17-OHPC at <24 weeks (relative risk [RR] .86, 95% confidence interval [CI] .45-1.65). Similarly, we found no differences in preterm birth at <37 weeks (RR .90, 95% CI .70-1.17) and <28 weeks (RR .85, 95% CI .54-1.32) when comparing cerclage alone with cerclage+17-OHPC. There were no differences in fetal birthweight, respiratory distress syndrome or necrotizing enterocolitis comparing cerclage alone with cerclage+17-OHPC.

Conclusions: Intramuscular 17-OHPC in combination with prophylactic cerclage in women with prior preterm birth had no synergistic effect in reducing spontaneous recurrent preterm birth or improving perinatal outcomes.
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http://dx.doi.org/10.1111/aogs.13488DOI Listing
February 2019

Validation of noninvasive photoacoustic measurements of sagittal sinus oxyhemoglobin saturation in hypoxic neonatal piglets.

J Appl Physiol (1985) 2018 10 21;125(4):983-989. Epub 2018 Jun 21.

Division of Maternal-Fetal Medicine, Department of Gynecology-Obstetrics, Johns Hopkins University School of Medicine , Baltimore, Maryland.

We hypothesize that noninvasive photoacoustic imaging can accurately measure cerebral venous oxyhemoglobin saturation (So) in a neonatal model of hypoxia-ischemia. In neonatal piglets, which have a skull thickness comparable to that of human neonates, we compared the photoacoustic measurement of sagittal sinus So against that measured directly by blood sampling over a wide range of conditions. Systemic hypoxia was produced by decreasing inspired oxygen stepwise (i.e., 100, 21, 19, 17, 15, 14, 13, 12, 11, and 10%) with and without unilateral or bilateral ligation of the common carotid arteries to enhance hypoxia-ischemia. Transcranial photoacoustic sensing enabled us to detect changes in sagittal sinus O saturation throughout the tested range of 5-80% without physiologically relevant bias. Despite lower cortical perfusion and higher oxygen extraction in groups with carotid occlusion at equivalent inspired oxygen, photoacoustic measurements successfully provided a robust linear correlation that approached the line of identity with direct blood sample measurements. Receiver-operating characteristic analysis for discriminating So <30% showed an area under the curve of 0.84 for the pooled group data, and 0.87, 0.91, and 0.92 for hypoxia alone, hypoxia plus unilateral occlusion, and hypoxia plus bilateral occlusion subgroups, respectively. The detection precision in this critical range was confirmed with sensitivity (87.0%), specificity (86.5%), accuracy (86.8%), positive predictive value (90.5%), and negative predictive value (81.8%) in the combined dataset. These results validate the capability of photoacoustic sensing technology to accurately monitor sagittal sinus So noninvasively over a wide range and support its use for early detection of neonatal hypoxia-ischemia. NEW & NOTEWORTHY We present data to validate the noninvasive photoacoustic measurement of sagittal sinus oxyhemoglobin saturation. In particular, this paper demonstrates the robustness of this methodology during a wide range of hemodynamic and physiological changes induced by the stepwise decrease of fractional inspired oxygen to produce hypoxia and by unilateral and bilateral ligation of the common carotid arteries preceding hypoxia to produce hypoxia-ischemia. This technique may be useful for diagnosing risk of neonatal hypoxic-ischemic encephalopathy.
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http://dx.doi.org/10.1152/japplphysiol.00184.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335091PMC
October 2018

Risk Factors for Neonatal Hypoxic-Ischemic Encephalopathy in the Absence of Sentinel Events.

Am J Perinatol 2019 01 26;36(1):27-33. Epub 2018 Mar 26.

Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: Hypoxic-ischemic encephalopathy (HIE) may be associated with intrapartum sentinel events or may be unexplained. We sought to identify risk factors for unexplained HIE cases and compare their morbidity and mortality to cases associated with sentinel events.

Study Design: Retrospective cohort study of all neonates admitted with suspected HIE treated with whole-body hypothermia from January 2007 through July 2017. Cases of unexplained HIE were compared with those with a sentinel event.

Results: A total of 223 neonates met the inclusion criteria, of which 86 (38.6%) experienced a sentinel event and 137 (61.4%) did not. Placental histopathology was performed for 28/31 (90.3%) and 48/53 (90.6%) inborn neonates with and without sentinel events, respectively. Placentas from unexplained HIE cases more often exhibited histologic chorioamnionitis (43.8% vs. 17.9%,  = 0.02) and funisitis (25% vs. 3.6%,  = 0.02). Neonatal morbidity and mortality were similar. On multivariable regression, nulliparity (odds ratio [OR], 4.11, 95% confidence interval [CI]: 1.24-13.62) and histologic funisitis (OR, 20.33, 95% CI: 1.11-373.4) remained significant.

Conclusion: Other than nulliparity and infection which could be identified on umbilical cord examination following delivery but not on clinical assessment prior to delivery, there are no other identifiable risk factors for HIE in the absence of a sentinel event, and morbidity and mortality are similar between groups.
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http://dx.doi.org/10.1055/s-0038-1639356DOI Listing
January 2019

Blood biomarkers for evaluation of perinatal encephalopathy: state of the art.

Curr Opin Pediatr 2018 04;30(2):199-203

Neurosciences Intensive Care Nursery program.

Purpose Of Review: The rapid progress in biomarker science is on the threshold of significantly changing clinical care for infants in the neonatal ICU. Infants with neonatal brain injuries will likely be the first group whose management is dramatically altered with point-of-care, rapidly available brain biomarker analysis. Providing an interim update on progress in this area is the purpose of this review.

Recent Findings: Highlighted findings from the past 18 months of publications on biomarkers in neonatal brain injury include; Specific nonbrain markers of cardiac health and global asphyxia continue to provide information on brain injury after hypoxic-ischemic encephalopathy (HIE). Prediction of injury in the piglet hypoxia-ischemia model is improved with the use of a combination score of plasma metabolites. In a neonatal piglet model of perinatal hypoxia-ischemia, a systemic proinflammatory surge of cytokines has been identified after rewarming from therapeutic hypothermia. New biomarkers identified recently include osteopontin, activin A, neutrophil gelatinase-associated lipocalin, secretoneurin, Tau and neurofilament light protein. Brain-based biomarkers differ in their ability to predict short-term in-hospital outcomes and long-term neurologic deficits.

Summary: Neonatal brain biomarker research is currently in its very early development with major advances still to be made.
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http://dx.doi.org/10.1097/MOP.0000000000000591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884146PMC
April 2018

P2X7 receptor blockade prevents preterm birth and perinatal brain injury in a mouse model of intrauterine inflammation.

Biol Reprod 2017 Aug;97(2):230-239

Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The P2X7 is an adenosine triphosphate (ATP)-gated ion channel involved in several facets of immune activation and neuronal function through its importance in interleukin (IL)-1β secretion. We hypothesized that blockade of P2X7 would prevent perinatal brain injury associated with exposure to intrauterine (IU) inflammation. Dams received 45 mg/kg of Brilliant Blue G (BBG), a specific P2X7 receptor (P2X7R) antagonist, on gestation day 17 (E17) prior to administration of lipopolysaccharide (LPS) or phosphate-buffered saline (PBS). Furthermore, we utilized embryo transfer experiments to delineate whether the P2X7 was the key mediator of IU inflammation-associated brain injury on maternal or fetal sides. In these experiments, P2X7-/- dams were embryo-transferred wild type embryos and wild type dams were embryo-transferred P2X7-/- embryos. In the mouse model of intrauterine inflammation, pharmacologic blockade of P2X7R reduced preterm birth rate, improved offspring performance on neuromotor tests as well as the dendritic arborization and density of cortical neurons. Embryo transfer experiments demonstrated the importance of maternal P2X7R in IU inflammation-mediated effects on offspring. Both genetic and pharmacologic blockade of IL-1β signaling, by targeting maternal P2X7R, ameliorated perinatal brain injury following exposure to IU inflammation. Specific targeting of maternal P2X7R may provide a clinically useful tool to prevent both preterm birth and prematurity-associated perinatal brain injury, and further studies are urgently needed.
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http://dx.doi.org/10.1093/biolre/iox081DOI Listing
August 2017

Umbilical Cord Blood NOS1 as a Potential Biomarker of Neonatal Encephalopathy.

Front Pediatr 2017 22;5:112. Epub 2017 May 22.

Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: There are no definitive markers to aid in diagnosis of neonatal encephalopathy (NE). The purpose of our study was (1) to identify and evaluate the utility of neuronal nitric oxide synthase (NOS1) in umbilical cord blood as a NE biomarker and (2) to identify the source of NOS1 in umbilical cord blood.

Methods: This was a nested case-control study of neonates >35 weeks of gestation. ELISA for NOS1 in umbilical cord blood was performed. Sources of NOS1 in umbilical cord were investigated by immunohistochemistry, western blot, ELISA, and quantitative PCR. Furthermore, umbilical cords of full-term neonates were subjected to 1% hypoxia .

Results: NOS1 was present in umbilical cord blood and increased in NE cases compared with controls. NOS1 was expressed in endothelial cells of the umbilical cord vein, but not in artery or blood cells. In experiments, hypoxia was associated with increased levels of NOS1 in venous endothelial cells of the umbilical cord as well as in culture medium.

Conclusion: This is the first study to investigate an early marker of NE. NOS1 is elevated with hypoxia, and further studies are needed to investigate it as a valuable tool for early diagnosis of neonatal brain injury.
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http://dx.doi.org/10.3389/fped.2017.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466059PMC
May 2017

In Reply.

Obstet Gynecol 2017 02;129(2):389-390

Department of Gynecology & Obstetrics, Division of Maternal-Fetal Medicine, and the Neurosciences Intensive Care Nursery Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1097/AOG.0000000000001885DOI Listing
February 2017

Distinguishing Arterial Ischemic Stroke From Hypoxic-Ischemic Encephalopathy in the Neonate at Birth.

Obstet Gynecol 2016 10;128(4):704-712

Department of Gynecology & Obstetrics, Division of Maternal-Fetal Medicine, the Russell H. Morgan Department of Radiology and Radiological Science, Division of Pediatric Radiology, Section of Pediatric Neuroradiology, the Neurosciences Intensive Care Nursery Program, and the Department of Neurology, Division of Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland; and the Department of Pediatrics, Division of Pediatric Neurology, Duke University Medical Center, Durham, North Carolina.

Objective: To identify perinatal risk factors that can distinguish arterial ischemic stroke from hypoxic-ischemic encephalopathy at birth.

Methods: This is a cohort study of all neonates born at 35 weeks of gestation or greater admitted to our neonatal intensive care unit from January 1, 2010, to December 31, 2015, that compares neonates with stroke with those with hypoxic-ischemic encephalopathy undergoing whole-body hypothermia with abnormal brain magnetic resonance imaging.

Results: During this 6-year period, there were 22 neonates with stroke and 47 with hypoxic-ischemic encephalopathy undergoing whole-body hypothermia with abnormal magnetic resonance imaging. Three neonates triaged to hypothermia initially thought to have hypoxic-ischemic encephalopathy were later diagnosed with stroke. All neonates with stroke had a negative thrombophilia workup. Neonates with stroke had a significantly higher incidence of seizures and increased initial platelet counts on univariate analysis. A multivariable model of variables with P<.1 on univariate analysis present within 6 hours of birth found significant increases in nonreassuring fetal heart rate tracings, sentinel events, low Apgar score at 5 minutes, and metabolic acidosis at birth with hypoxic-ischemic encephalopathy. Stroke was associated with a significantly increased initial platelet count.

Conclusion: Stroke is associated with increased initial platelet counts and is not associated with cesarean delivery for nonreassuring fetal heart rate tracings, sentinel events, or perinatal metabolic acidosis. Stroke is a form of neonatal brain injury not associated with perinatal risk factors that allow early identification.
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http://dx.doi.org/10.1097/AOG.0000000000001631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895085PMC
October 2016

Blood Biomarkers for Evaluation of Perinatal Encephalopathy.

Front Pharmacol 2016 13;7:196. Epub 2016 Jul 13.

Neuroscience Intensive Care Nursery Program, Johns Hopkins University School of MedicineBaltimore, MD, USA; Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of MedicineBaltimore, MD, USA.

Recent research in identification of brain injury after trauma shows many possible blood biomarkers that may help identify the fetus and neonate with encephalopathy. Traumatic brain injury shares many common features with perinatal hypoxic-ischemic encephalopathy. Trauma has a hypoxic component, and one of the 1st physiologic consequences of moderate-severe traumatic brain injury is apnea. Trauma and hypoxia-ischemia initiate an excitotoxic cascade and free radical injury followed by the inflammatory cascade, producing injury in neurons, glial cells and white matter. Increased excitatory amino acids, lipid peroxidation products, and alteration in microRNAs and inflammatory markers are common to both traumatic brain injury and perinatal encephalopathy. The blood-brain barrier is disrupted in both leading to egress of substances normally only found in the central nervous system. Brain exosomes may represent ideal biomarker containers, as RNA and protein transported within the vesicles are protected from enzymatic degradation. Evaluation of fetal or neonatal brain derived exosomes that cross the blood-brain barrier and circulate peripherally has been referred to as the "liquid brain biopsy." A multiplex of serum biomarkers could improve upon the current imprecise methods of identifying fetal and neonatal brain injury such as fetal heart rate abnormalities, meconium, cord gases at delivery, and Apgar scores. Quantitative biomarker measurements of perinatal brain injury and recovery could lead to operative delivery only in the presence of significant fetal risk, triage to appropriate therapy after birth and measure the effectiveness of treatment.
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http://dx.doi.org/10.3389/fphar.2016.00196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942457PMC
July 2016

Glial fibrillary acidic protein as a biomarker for brain injury in neonatal CHD.

Cardiol Young 2016 Oct 20;26(7):1282-9. Epub 2016 Jan 20.

2Department of Pediatrics,Division of Pediatric Cardiology,Johns Hopkins University School of Medicine,Baltimore,Maryland,United States of America.

Neonates with critical CHD have evidence, by imaging, of preoperative brain injury, although the timing is unknown. We used circulating postnatal serum glial fibrillary acidic protein as a measure of acute perinatal brain injury in neonates with CHD. Glial fibrillary acidic protein was measured on admission and daily for the first 4 days of life in case and control groups; we included two control groups in this study - non-brain-injured newborns and brain-injured newborns. Comparisons were performed using the Kruskal-Wallis test with Dunn's multiple comparisons, Student's t-test, and χ2 test of independence where appropriate. In aggregate, there were no significant differences in overall glial fibrillary acidic protein levels between CHD patients (n=56) and negative controls (n=23) at any time point. By day 4 of life, 7/56 (12.5%) CHD versus 0/23 (0%) normal controls had detectable glial fibrillary acidic protein levels. Although not statistically significant, the 5/10 (50%) left heart obstruction group versus 1/17 (6%) conoventricular, 0/13 (0%) right heart, and 1/6 (17%) septal defect patients trended towards elevated levels of glial fibrillary acidic protein at day 4 of life. Overall, glial fibrillary acidic protein reflected no evidence for significant peripartum brain injury in neonates with CHD, but there was a trend for elevation by postnatal day 4 in neonates with left heart obstruction. This pilot study suggests that methods such as monitoring glial fibrillary acidic protein levels may provide new tools to optimise preoperative care and neuroprotection in high-risk neonates with specific types of CHD.
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http://dx.doi.org/10.1017/S1047951115002346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956580PMC
October 2016

Risk factors for periventricular white matter injury in very low birthweight neonates.

Am J Obstet Gynecol 2016 Mar 19;214(3):380.e1-6. Epub 2015 Nov 19.

Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Neuroscience Intensive Care Nursery Program, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: The development of periventricular white matter injury (PWMI) in the preterm neonate is the most common insult portending neurologic impairment and is linked with the later development of cerebral palsy. The pathogenesis of PWMI targets premyelinating oligodendrocytes of the periventricular region secondary to free radicals, cytokine toxicity, and excitatory neurotransmitters. The primitive nature of the vasculature in the developing fetal cortex lends to its predilection to PWMI and cerebral ischemia with less arterial anastomoses at arterial border zones and failure to compensate for global hypotension, termed the "pressure-passive" circulation.

Objective: Our objective is to determine the relative risk (RR) of fetal metabolic acidosis and perinatal infection in the development of PWMI in very low birthweight (VLBW) (<1500 g) neonates.

Study Design: This is a cohort study of all VLBW neonates admitted to our neonatal intensive care unit from April 2009 through December 2014, comparing those who developed PWMI on neonatal head ultrasound at 6 weeks of life to those who did not. Neonates with chromosomal or major congenital abnormalities were excluded. Generalized linear modeling, adjusting for variables significantly different on bivariate analysis, was conducted.

Results: During this 5-year and 8-month period there were 374 VLBW neonates admitted; 35 (9.4%) had PWMI. VLBW neonates without PWMI were significantly more likely to have intrauterine growth restriction (2.9% PWMI, 21.5% no PWMI; P = .006), while those neonates with PWMI had a significantly lower gestational age (26.3 ± 2.2 vs 28.0 ± 2.5 weeks; P < .001) and birthweight (868 ± 237 vs 993 ± 276 g; P = .009). There was no significant difference in umbilical arterial pH (7.25 ± 0.15 vs 7.27 ± 0.09; P = .34), base deficit (4.6 ± 6.0 vs 3.4 ± 3.3 mmol/L; P = .11), or pH <7.0 or base deficit >12 mmol/L at birth (10.7% vs 3.2%; P = .09). On bivariate analysis neonates with PWMI had a significant increase in positive cerebrospinal fluid (CSF) cultures (22.9% vs 1.5%; P < .001). The initial lumbar puncture was performed at a similar day of life, and neonates with PWMI had significantly elevated CSF white blood cell counts (5%, 50%, and 95%; 16, 175, and 709/mm(3); 1, 3, and 27/mm(3); P = .008). Generalized linear modeling, adjusted for gestational age and the presence of intrauterine growth restriction, showed that fetal metabolic acidosis had RR 2.59 (95% confidence interval, 1.14-5.92; P = .02) and neonatal CSF infection had RR 4.94 (95% confidence interval, 2.4-10.3; P < .001) for association with PWMI.

Conclusion: The RR of neonatal CSF infection being associated with PWMI was 2-fold greater than metabolic acidosis at the time of birth. Decreasing the incidence of CSF infections would have a greater impact on preventing PWMI, a precursor of cerebral palsy.
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http://dx.doi.org/10.1016/j.ajog.2015.09.108DOI Listing
March 2016

Prenatal cerebellar hemorrhage: fetal and postnatal neuroimaging findings and postnatal outcome.

Pediatr Neurol 2015 May 29;52(5):529-34. Epub 2015 Jan 29.

Division of Neonatology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Neuro Intensive Care Nursery Group, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background: Despite significant progress in fetal neuroimaging techniques, only a few well-documented examples of prenatal cerebellar hemorrhages are available in the literature. In the majority of these individuals, the diagnosis of prenatal cerebellar hemorrhages led to termination of pregnancy or death occurred in utero; data about postnatal outcome of children with prenatal diagnosis of cerebellar hemorrhages are scant. We describe fetal and postnatal neuroimaging findings and the neurodevelopmental outcome of a child with a large cerebellar hemorrhage that occurred at approximately 27 weeks' gestation.

Method: Data about neurological features and neurodevelopmental outcome were collected from the clinical history and follow-up examination. All pre- and postnatal MRI data were qualitatively evaluated for infra- and supratentorial abnormalities.

Results: Fetal MRI at 27 weeks' gestation showed a T1-hyperintense and T2-hypointense lesion within the cerebellum suggestive of bilateral cerebellar hemorrhages with extension into the adjacent subarachnoid, subdural, and intraventricular spaces. The prenatal cerebellar hemorrhage was possibly related to maternal sepsis. Postnatal MRI showed encephalomalacic changes involving the vermis and both cerebellar hemispheres. Neurodevelopmental follow-up at 15 months of age was concerning for global developmental delay and significant right esotropia.

Conclusion: This child illustrates (1) the role of prenatal neuroimaging in the diagnosis of fetal cerebellar hemorrhages, (2) the significance of cerebellar involvement for neurodevelopment, and (3) the importance of the collection of postnatal outcome data in children with prenatal diagnosis of cerebellar hemorrhage.
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http://dx.doi.org/10.1016/j.pediatrneurol.2015.01.011DOI Listing
May 2015

Diagnostic accuracy of fetal heart rate monitoring in the identification of neonatal encephalopathy.

Obstet Gynecol 2014 Sep;124(3):507-513

Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, the Neuroscience Intensive Care Nursery Program, the Department of Epidemiology, Bloomberg School of Public Health, the Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, the Department of Neurology, and the Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: To estimate the diagnostic accuracy of electronic fetal heart rate abnormalities in the identification of neonates with encephalopathy treated with whole-body hypothermia.

Methods: Between January 1, 2007, and July 1, 2013, there were 39 neonates born at two hospitals within our system treated with whole-body hypothermia within 6 hours of birth. Neurologically normal control neonates were matched to each case by gestational age and mode of delivery in a two-to-one fashion. The last hour of electronic fetal heart rate monitoring before delivery was evaluated by three obstetricians blinded to outcome.

Results: The differences in tracing category were not significantly different (neonates in the case group 10.3% I, 76.9% II, 12.8% III; neonates in the control group 9.0% I, 89.7% II, 1.3% III; P=.18). Bivariate analysis showed neonates in the case group had significantly increased late decelerations, total deceleration area 30 (debt 30) and 60 minutes (debt 60) before delivery and were more likely to be nonreactive. Multivariable logistic regression showed neonates in the case group had a significant decrease in early decelerations (P=.03) and a significant increase in debt 30 (.01) and debt 60 (P=.005). The area under the receiver operating characteristic curve, sensitivity, and specificity were 0.72, 23.1%, and 94.9% for early decelerations; 0.66, 33.3%, and 87.2% for debt 30, and 0.68, 35.9%, and 89.7% for debt 60, respectively.

Conclusion: Abnormalities during the last hour of fetal heart rate monitoring before delivery are poorly predictive of neonatal hypoxic-ischemic encephalopathy qualifying for whole-body hypothermia treatment within 6 hours of birth. LEVEL OF EVIEDENCE: II.
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http://dx.doi.org/10.1097/AOG.0000000000000424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147668PMC
September 2014

Perinatal risk factors for severe injury in neonates treated with whole-body hypothermia for encephalopathy.

Am J Obstet Gynecol 2014 Jul 18;211(1):41.e1-8. Epub 2014 Mar 18.

Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD; Neurosciences Intensive Care Nursery, Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: Our objective was to identify perinatal risk factors that are available within 1 hour of birth that are associated with severe brain injury after hypothermia treatment for suspected hypoxic-ischemic encephalopathy.

Study Design: One hundred nine neonates at ≥35 weeks' gestation who were admitted from January 2007 to September 2012 with suspected hypoxic-ischemic encephalopathy were treated with whole-body hypothermia; 98 of them (90%) underwent brain magnetic resonance imaging (MRI) at 7-10 days of life. Eight neonates died before brain imaging. Neonates who had severe brain injury, which was defined as death or abnormal MRI results (cases), were compared with surviving neonates with normal MRI (control subjects). Logistic regression models were used to identify risk factors that were predictive of severe injury.

Results: Cases and control subjects did not differ with regard to gestational age, birthweight, mode of delivery, or diagnosis of nonreassuring fetal heart rate before delivery. Cases were significantly (P < .05) more likely to have had an abruption, a cord and neonatal arterial gas level that showed metabolic acidosis, lower platelet counts, lower glucose level, longer time to spontaneous respirations, intubation, chest compressions in the delivery room, and seizures. In multivariable logistic regression, lower initial neonatal arterial pH (P = .004), spontaneous respiration at >30 minutes of life (P = .002), and absence of exposure to oxytocin (P = .033) were associated independently with severe injury with 74.3% sensitivity and 74.4% specificity.

Conclusion: Worsening metabolic acidosis at birth, longer time to spontaneous respirations, and lack of exposure to oxytocin correlated with severe brain injury in neonates who were treated with whole-body hypothermia. These risk factors may help quickly identify neonatal candidates for time-sensitive investigational therapies for brain neuroprotection.
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http://dx.doi.org/10.1016/j.ajog.2014.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809753PMC
July 2014

Glial fibrillary acidic protein as a biomarker for periventricular white matter injury.

Am J Obstet Gynecol 2013 Jul 1;209(1):27.e1-7. Epub 2013 Mar 1.

Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University, Baltimore, MD.

Objective: Periventricular white matter injury (PWMI), a precursor of cerebral palsy, traditionally is not diagnosed until 6 weeks of life by head ultrasound scanning. We sought to determine whether early neonatal glial fibrillary acidic protein (GFAP) levels could identify PWMI in low birthweight (<2500 g) infants.

Study Design: Each case with PWMI on head ultrasound scanning at 6 weeks of life from April 2009 to April 2011 was matched by gestational age and mode of delivery to 2 subsequent neonates with a normal head ultrasound scan. GFAP was measured in cord blood at birth, at neonatal intensive care unit admission, and on days 1-4 of life.

Results: During this 2-year period, 21 cases with PWMI with gestational age 27.4 ± 3.3 weeks were compared with 42 control infants. The incidence of cesarean delivery was 61.9% in both groups. GFAP was not significantly different in cord blood or at neonatal intensive care unit admission but was significantly elevated on day 1 (median, 5-95%; 0, 0-0.98 ng/mL cases; 0, 0-0.06 ng/mL control infants; P = .03), day 2 (0, 0-1.21 ng/mL; 0, 0-0.05 ng/mL, respectively; P = .02), day 3 (0.05, 0-0.33 ng/mL; 0, 0-0.04 ng/mL, respectively; P = .004), and day 4 (0.02, 0-1.03 ng/mL; 0, 0-0.05 ng/mL, respectively; P < .001). The odds of the development of PWMI significantly increased with increasing levels of GFAP from day 1-4 of life when adjustment was made for preeclampsia, antenatal steroid administration, and neonatal chronic lung disease.

Conclusion: The ability to predict PWMI with a blood test for GFAP shortly after birth opens the possibility for rapid identification of infants for early intervention and provides a benchmark for the qualification of new therapies to improve neurodevelopmental outcomes.
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http://dx.doi.org/10.1016/j.ajog.2013.02.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708978PMC
July 2013

Detection of neurologic injury using vascular reactivity monitoring and glial fibrillary acidic protein.

Pediatrics 2013 Mar 18;131(3):e950-4. Epub 2013 Feb 18.

Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.

New noninvasive methods for monitoring cerebrovascular pressure reactivity coupled with a blood-based assay for brain-specific injury in preterm infants could allow early diagnosis of brain injury and set the stage for improved timing and effectiveness of interventions. Using an adaptation of near-infrared spectroscopy, we report a case of a very low birth weight infant undergoing hemoglobin volume index monitoring as a measure of cerebrovascular pressure reactivity. During the monitoring period, this infant demonstrated significant disturbances in cerebrovascular pressure reactivity that coincided with elevation of serum glial fibrillary acidic protein and new findings of brain injury on head ultrasound. This case report demonstrates the potential of emerging noninvasive monitoring methods to assist in both detection and therapeutic management to improve neurologic outcomes of the very low birth weight neonate.
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http://dx.doi.org/10.1542/peds.2012-1702DOI Listing
March 2013

Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling.

Am J Obstet Gynecol 2011 Sep 15;205(3):251.e1-7. Epub 2011 Jun 15.

Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: Glial fibrillary acidic protein (GFAP) is specific to astrocytes in the central nervous system. We hypothesized that serum GFAP would be increased in neonates with hypoxic-ischemic encephalopathy (HIE) treated with whole-body cooling.

Study Design: We measured GFAP at birth and daily for up to 7 days for neonates in the intensive care unit. We compared neonates with HIE treated with whole-body cooling to gestational age-matched controls without neurological injury and neonates with HIE by brain abnormalities on magnetic resonance imaging (MRI).

Results: Neonates with HIE had increased GFAP levels compared with controls. Neonates with HIE and abnormal brain imaging had elevated GFAP levels compared with neonates with HIE and normal imaging.

Conclusion: Serum GFAP levels during the first week of life were increased in neonates with HIE and were predictive of brain injury on MRI. Biomarkers such as GFAP could help triage neonates with HIE to treatment, measure treatment efficacy, and provide prognostic information.
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http://dx.doi.org/10.1016/j.ajog.2011.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011017PMC
September 2011

Pre- and postnatal imaging of a congenital hepatoblastoma.

Fetal Diagn Ther 2011 27;30(2):157-9. Epub 2011 May 27.

Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, Md., USA.

Prenatal ultrasound, magnetic resonance imaging and matching postnatal computer tomography imaging findings are presented in a neonate with histologically proven congenital hepatoblastoma. Familiarity with the prenatal imaging findings of a hepatoblastoma are essential to make a reliable, specific diagnosis facilitating decision-making about the pre-, peri- and postnatal management.
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http://dx.doi.org/10.1159/000327580DOI Listing
February 2012

Necrostatin decreases oxidative damage, inflammation, and injury after neonatal HI.

J Cereb Blood Flow Metab 2011 Jan 23;31(1):178-89. Epub 2010 Jun 23.

Neonatal Research Laboratory, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Necrostatin-1 inhibits receptor-interacting protein (RIP)-1 kinase and programmed necrosis and is neuroprotective in adult rodent models. Owing to the prominence of necrosis and continuum cell death in neonatal hypoxia-ischemia (HI), we tested whether necrostatin was neuroprotective in the developing brain. Postnatal day (P)7 mice were exposed to HI and injected intracerebroventricularly with 0.1 μL of 80 μmol necrostatin, Nec-1, 5-(1H-Indol-3-ylmethyl)-(2-thio-3-methyl) hydantoin, or vehicle. Necrostatin significantly decreased injury in the forebrain and thalamus at P11 and P28. There was specific neuroprotection in necrostatin-treated males. Necrostatin treatment decreased necrotic cell death and increased apoptotic cell death. Hypoxia-ischemia enforced RIP1-RIP3 complex formation and inhibited RIP3-FADD (Fas-associated protein with death domain) interaction, and these effects were blocked by necrostatin. Necrostatin also decreased HI-induced oxidative damage to proteins and attenuated markers of inflammation coincidental with decreased nuclear factor-κB and caspase 1 activation, and FLIP ((Fas-associated death-domain-like IL-1β-converting enzyme)-inhibitory protein) gene and protein expression. In this model of severe neonatal brain injury, we find that cellular necrosis can be managed therapeutically by a single dose of necrostatin, administered after HI, possibly by interrupting RIP1-RIP3-driven oxidative injury and inflammation. The effects of necrostatin treatment after HI reflect the importance of necrosis in the delayed phases of neonatal brain injury and represent a new direction for therapy of neonatal HI.
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http://dx.doi.org/10.1038/jcbfm.2010.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049482PMC
January 2011

Congenital giant cervical teratoma: pre- and postnatal imaging.

Fetal Diagn Ther 2010 2;27(4):231-2. Epub 2010 Mar 2.

Division of Pediatric Radiology, Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD 21287-0842, USA.

Pre- and postnatal imaging findings are presented in a fetus/neonate with congenital cervical teratoma (CCT). Prenatal fetal MRI proved to be essential in the exact localization and characterization of the CCT while excluding potentially life-threatening prenatal complications. The provided information improved outcome by guiding decisions concerning delivery and postnatal care.
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http://dx.doi.org/10.1159/000291488DOI Listing
December 2010

Periventricular leukomalacia and placental histopathologic abnormalities.

Obstet Gynecol 2009 Nov;114(5):1115-1120

From the Department of Pathology and Department of Gynecology & Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: To estimate whether there are placental histopathologic abnormalities associated with neonatal periventricular leukomalacia (PVL), a major precursor of cerebral palsy.

Methods: This is a case-control study of 167 neonates born between 23 and 34 weeks of gestation diagnosed with PVL by head ultrasonography within 6 weeks of birth, and 167 control neonates without neurologic morbidity matched by gestational age. Placentas for both case neonates and control neonates were reviewed by two perinatal pathologists who were blinded to neonatal course.

Results: Neonates with PVL were significantly more likely to have positive neonatal blood (28.7%, 16.8%, P=.001) and cerebrospinal fluid (14.4%, 4.8%, P=.007) cultures. The ratio of placental weight to birth weight did not differ between groups, but neonates with PVL had significantly more chronic diffuse capsular deciduitis (20.4%, 10.8%, P=.02) and capsular decidual plasma cells (8.4%, 2.4%, P=.02). Conditional logistic regression adjusting for birth weight and the presence of multiple gestation in the identification of PVL showed a significant increase for diffuse capsular deciduitis (P=.02) and capsular decidual plasma cells (P=.03).

Conclusion: Periventricular leukomalacia has a significant but weak association with chronic diffuse capsular deciduitis and the presence of capsular decidual plasma cells, evidence of chronic infection but not histologic acute chorioamnionitis.

Level Of Evidence: II.
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http://dx.doi.org/10.1097/AOG.0b013e3181bdcfc4DOI Listing
November 2009

Neonatal brain imaging and the identification of metabolic acidemia and hypoxic-ischemic encephalopathy.

J Matern Fetal Neonatal Med 2009 Oct;22(10):823-8

Division of Maternal-Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-1228, USA.

Objective: To determine the precision with which intrapartum metabolic acidemia and hypoxic-ischemic encephalopathy (HIE) in term and near-term infants can be identified by neonatal brain imaging.

Study Design: This is a case-control study whose inclusion criteria were neonates born at > or =34 weeks gestation with a cord gas at delivery, suspected neurological abnormalities, and computed tomography (CT) or magnetic resonance (MR) imaging of the brain. Neonates with chromosomal and major congenital malformations were excluded. Brain imaging for neonates with and without metabolic acidemia (pH < 7.0 and base deficit > 12 mM) at birth and HIE were retrospectively reviewed by a neuroradiologist blinded to their clinical course and compared.

Results: There were 54 neonates admitted to the NICU at a single university hospital between 1992 and 2006 that met these inclusion criteria of which 27 had metabolic acidemia at birth. There were 16 diagnosed clinically as having HIE at the time of neonatal discharge, 13 from the acidemic group and 3 from the nonacidemic group. Radiological signs of basal ganglia injury were significantly more common in neonates with metabolic acidemia (29.6%, 3.7%, p = 0.02) and HIE (37.5%, 7.9%, p = 0.01). Logistic regression corrected for gestational age showed that radiological signs of basal ganglia injury could identify the presence of HIE with area under the ROC curve of 0.71, sensitivity 37.5%, specificity 92.1%, positive predictive value 66.7%, and negative predictive value of 77.8%.

Conclusion: Radiological signs of basal ganglia injury on early neonatal imaging are associated with metabolic acidemia and HIE, but is not precise enough to serve as a gold standard in the identification of these conditions.
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http://dx.doi.org/10.1080/14767050902769990DOI Listing
October 2009

A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy.

Am J Obstet Gynecol 2008 Dec;199(6):587-95

Division of Maternal-Fetal Medicine, Department of Gynecology-Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The object of this review was to determine the incidence, morbidity, and mortality of an umbilical arterial pH < 7.0; the incidence of hypoxic-ischemic encephalopathy; and the proportion of cerebral palsy associated with intrapartum hypoxia-ischemia in nonanomalous term infants. A systematic review of the English language literature on the association between intrapartum hypoxia-ischemia and neonatal encephalopathy was conducted by using Pubmed and Embase. For nonanomalous term infants, the incidence of an umbilical arterial pH < 7.0 at birth is 3.7 of 1000, of which 51 of 297 (17.2%) survived with neonatal neurologic morbidity, 45 of 276 (16.3%) had seizures, and 24 of 407 (5.9%) died during the neonatal period. The incidence of neonatal neurologic morbidity and mortality for term infants born with cord pH < 7.0 was 23.1%. The incidence of hypoxic-ischemic encephalopathy is 2.5 of 1000 live births. The proportion of cerebral palsy associated with intrapartum hypoxia-ischemia is 14.5%. The vast majority of cases of cerebral palsy in nonanomalous term infants are not associated with intrapartum hypoxia-ischemia.
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http://dx.doi.org/10.1016/j.ajog.2008.06.094DOI Listing
December 2008
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