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1.  Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status 
Reproduction (Cambridge, England)  2014;148(3):295-302.
LDL receptor-related protein 1 (LRP 1) is a transmembrane receptor highly expressed in human placenta. It was recently found to be the receptor for heme and its plasma binding protein hemopexin and is integral to systemic heme clearance. Little is known about systemic concentrations of hemopexin during pregnancy and whether maternal hemopexin and placental LRP1 contributes to fetal iron homeostasis during pregnancy. We hypothesized that placental LRP1 would be up-regulated in maternal/neonatal iron insufficiency and would be related to maternal circulating hemopexin. Placental LRP1 expression was assessed in 57 pregnant adolescents (14–18 y) in relation to maternal and cord blood iron status indicators [hemoglobin, serum ferritin, transferrin receptor], the iron regulatory hormone hepcidin and serum hemopexin. Hemopexin at mid-gestation correlated positively with hemoglobin at mid-gestation (r = 0.35, P = 0.02) and hemopexin at delivery correlated positively with cord hepcidin (r = 0.37, P = 0.005). Placental LRP1 protein expression was significantly higher in women who exhibited greater decreases in serum hemopexin from mid-gestation to term (r = 0.28, P = 0.04). Significant associations were also found between placental LRP1 protein with cord hepcidin (r = − 0.29, P = 0.03) and placental heme exporter FLVCR1 (r = 0.34, P = 0.03). Our data are consistent with a role for placental heme iron utilization in supporting fetal iron demands.
PMCID: PMC4196258  PMID: 24947444
2.  Intraoperative EEG Predicts Postoperative Seizures in Infants with Congenital Heart Disease 
Pediatric neurology  2013;50(4):313-317.
During the surgical repair of infants with congenital cardiac defects, there can be periods of decreased cerebral blood flow, particularly during deep hypothermic circulatory arrest (DHCA). As a result, these infants are at increased risk for seizures and long-term neuro-developmental difficulties.
Thirty-two infants with congenital heart disease had continuous video-EEG monitoring pre-, intra-, and post-operatively for 48 hours following surgery.
RESULTS: For patients requiring DHCA (n=17)
the EEG pattern for all patients became suppressed and eventually isoelectric below 25°C. Two of the 32 infants had electrical seizures within the 48 hour monitoring window. Both required DHCA and the burst pattern during recovery had rhythmic, sharp components that were high amplitude and often asynchronous between the hemispheres. The interval between the onset of seizure activity, and initiation of the sharp burst pattern during surgery, was 29 and 40 hours. This pattern was not observed during isoelectric recovery from infants who did not develop post-operative seizures.
The EEG in infants during DHCA displayed predictable changes. We identified an EEG pattern following the isoelectric period that may be predictive of seizure development in the subsequent 48 hours.
PMCID: PMC4203305  PMID: 24507699
Congenital heart disease; Postoperative seizures; Deep hypothermic circulatory arrest; Intraoperative EEG monitoring
3.  Auditory Neural Maturation After Exposure to Multiple Courses of Antenatal Betamethasone in Premature Infants as Evaluated by Auditory Brainstem Response 
Pediatrics  2007;119(3):502-508.
Our goal was to determine if multiple courses of antenatal betamethasone affect auditory neural maturation in 28 to 32 weeks’ gestational age infants.
A retrospective cohort study was performed to compare auditory neural maturation between premature infants exposed to 1 course of betamethasone and infants exposed to ≥2 courses of betamethasone. Inclusion criteria included all 28 to 32 weeks’ gestational age infants delivered between July 1996 and December 1998 who had auditory brainstem response testing performed (80-dB click stimuli at a repetition rate of 39.9/second) within 24 hours of postnatal life as part of bilirubin-auditory studies. Infants with toxoplasmosis, rubella, cytomegalovirus, herpes infections, chromosomal disorders, unstable conditions, exposure to antenatal dexamethasone, and exposure to <1 complete course of betamethasone were excluded. Auditory waveforms were categorized into response types on response replicability and peak identification as types 1 through 4 (type 1 indicating most mature). Absolute and interpeak wave latencies were measured when applicable. Categorical and continuous variables were analyzed by using the χ2 test and Student’s t test, respectively.
Of 174 infants studied, 123 received antenatal steroids. Of these, 50 received 1 course and 29 received ≥2 courses of betamethasone. There were no significant differences in perinatal demographics between the 2 groups. After controlling for confounding variables, there was no significant difference in mean absolute wave latencies, mean interpeak latencies, or distribution of response type between the 2 groups. There also was no significant difference in any auditory brainstem response parameters between infants exposed to 1 course of betamethasone (n = 50) and infants exposed to >2 courses of betamethasone (n = 17).
Compared with a single recommended course of antenatal steroids, multiple courses of antenatal betamethasone are not associated with a deleterious effect on auditory neural maturation in 28 to 32 weeks’ gestational age infants.
PMCID: PMC4285434  PMID: 17332203
antenatal betamethasone; auditory neural; maturation; auditory brainstem evoked; response; premature infants
4.  Apolipoprotein E (APOE) Genotype and Outcome in Infants with Hypoxic-Ischemic Encephalopathy (HIE) 
Pediatric research  2013;75(3):424-430.
Adults with the apolipoprotein E gene (APOE) alleles e4 and e2 are at high risk of poor neurologic outcome after brain injury. The e4 allele has been associated with cerebral palsy and the e2 allele has been associated with worse neurologic outcome with congenital heart disease. This study was done to test the hypothesis that APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).
We conducted a cohort study of infants who survived HIE and had 18 – 22 month standardized neurodevelopmental evaluations to assess associations between disability and APOE genotypes e3/e3, e4/-, and e2/-
139 survivors were genotyped. 86 (62%) were e3/e3, 41 (29%) were e4/-, and 14 (10%) were e2/-. 129 infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30% and 19% among those with and without e3/e3 genotype, 25% and 26% among those with and without the e2 allele, and 18% and 29% among those with and without the e4 allele. None of the differences were statistically significant. Cerebral palsy prevalence was also similar among genotype groups.
Disability was not associated with APOE genotype in this cohort of HIE survivors.
PMCID: PMC4095992  PMID: 24322171
5.  Elevated Temperature and 6-7 Year Outcome of Neonatal Encephalopathy 
Annals of neurology  2013;73(4):520-528.
Determine if higher temperature after hypoxia-ischemia is associated with death or IQ < 70 at 6-7 yr among infants treated with intensive care without hypothermia.
Control infants (non-cooled, n=106) of the NICHD Neonatal Research Network hypothermia trial had serial esophageal and skin temperatures over 72hrs. Each infant's temperature was ranked to derive an average of the upper and lower quartile, and median of each site. Temperatures were used in logistic regressions to determine adjusted associations with death or IQ < 70 at 6-7yrs. Secondary outcomes were death, IQ < 70, and moderate/severe CP. IQ and motor function were assessed with Wechsler Scales for Children and Gross Motor Function Classification System. Results are odds ratio (OR, per °C increment within the quartile or median) and 95% confidence interval (CI).
Primary outcome was available for 89 infants. At 6-7yrs death or IQ < 70 occurred in 54 infants (37 deaths, 17 survivors with IQ < 70) and moderate/severe CP in 15 infants. Death or IQ < 70 was associated with the upper quartile average of esophageal (OR 7.3, 95% CI 2.0-26.3) and skin temperature (OR 3.5, 95% 1.2-10.4). CP was associated with the upper quartile average of esophageal (OR 12.5, 95% CI 1.02-155) and skin temperature (OR 10.3, 95% 1.3-80.2).
Among non-cooled infants of a randomized trial, elevated temperatures during the first post-natal days are associated with increase odds of a worse outcome at 6-7yrs.
PMCID: PMC3720800  PMID: 23595408
encephalopathy; hypoxia-ischemia; hyperthermia; cerebral palsy
6.  Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy 
The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic–ischaemic encephalopathy treated with hypothermia.
Design and patients
Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18–22 months of age.
Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability.
Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18–22 months following hypothermia for neonatal encephalopathy.
PMCID: PMC3722585  PMID: 23080477
7.  Childhood Outcomes after Hypothermia for Neonatal Encephalopathy 
The New England journal of medicine  2012;366(22):2085-2092.
We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.
In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.
Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P = 0.06); death occurred in 27 (28%) and 41 (44%) (P = 0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P = 0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P = 0.87). Attention–executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P = 0.19), and visuospatial dysfunction occurred in 4% and 3% (P = 0.80).
The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; number, NCT00005772.)
PMCID: PMC3459579  PMID: 22646631
9.  Predictive Value of an Early Amplitude Integrated Electroencephalogram and Neurologic Examination 
Pediatrics  2011;128(1):e112-e120.
To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia.
Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.
There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n = 12) or discontinuous normal voltage (n = 12), or abnormal, with burst suppression (n = 22), continuous low voltage (n = 26), or flat tracing (n = 36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P = .19).
The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.
PMCID: PMC3124102  PMID: 21669899
neonatal hypoxic-ischemic encephalopathy; amplitude integrated EEG
10.  The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants 
Pediatric Research  2012;71(1):77-84.
This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g).
BAER latencies of 751–1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501–750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.
The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.
Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.
PMCID: PMC3326602  PMID: 22289854
11.  Clinical Seizures in Neonatal Hypoxic-Ischemic Encephalopathy Have No Independent Impact on Neurodevelopmental Outcome: Secondary Analyses of Data from the Neonatal Research Network Hypothermia Trial 
Journal of Child Neurology  2010;26(3):322-328.
It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.
PMCID: PMC3290332  PMID: 20921569
neonatal seizures; whole-body hypothermia; neurodevelopmental outcome; hypoxic-ischemic encephalopathy
12.  Impact of Postnatal Corticosteroid (PNS) Use on Neurodevelopment at 18-22 Months Adjusted Age: Effects of Dose, Timing and Risk of Bronchopulmonary Dysplasia in Extremely Low Birthweight Infants (ELBW) 
Pediatrics  2009;123(3):e430-e437.
Postnatal steroid use in bronchopulmonary dysplasia (BPD) decreases lung inflammation but increases impairment (NDI). We hypothesized that increased dose is associated with increased NDI, lower postmenstrual age (PMA) at exposure increases NDI and risk of BPD modifies the effect of PNS.
Steroid dose and timing of exposure beyond 7 days was assessed among 2358 ELBW nested in a prospective trial, with 1667 (84%) survivors examined at 18-22 months PMA. Logistic regression tested the relationship between NDI (Bayley MDI/PDI < 70, disabling cerebral palsy (CP) or sensory impairment), total dose (tertiles < 0.9, 0.9-1.9, ≥ 1.9 mg/kg) and PMA at first dose. Separate logistic regression tested effect modification by BPD severity (Romagnoli Risk > 0.5 as high risk, n=2336 (99%) for days of life 4-7).
366 neonates (16%) were steroid treated (94% dexamethasone). Treated neonates were smaller and less mature. 72% of those treated were high risk for BPD. PNS exposure was associated with NDI/death (61 vs. 44%, p < 0.001). NDI increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg was associated with a 2.0 point reduction in MDI and a 40% risk increase in disabling CP. (OR 1.4, 95% CI: 1.2-1.6). Older PMA did not mitigate the harm. Treatment after 33 weeks PMA was associated with greatest harm (NDI/death OR 2.5, 95% CI: 1.1-5.5) despite not receiving highest dose. The relationship of PNS to NDI was modified by BPD risk, (High risk OR 1.9, 95% CI: 1.4-2.6; Low risk OR 2.9, 95% CI: 1.8-4.8) with those at highest risk experiencing less harm.
Higher PNS dose was associated with increased NDI. There is no “safe” window for PNS use in ELBWs. Neonates with low BPD risk should not be exposed. A randomized trial of PNS for infants at highest risk is warranted.
PMCID: PMC2846831  PMID: 19204058
postnatal corticosteroids; neurodevelopmental impairment; extremely low birth weight infants
13.  Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight 
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).
We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.
Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)
PMCID: PMC2821221  PMID: 18971491

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