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1.  Inhaled Nitric Oxide Usage in Preterm Infants in the NICHD Neonatal Research Network: Inter-site Variation and Propensity Evaluation 
Background
The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, an NIH consensus development conference cautioned against use of iNO in preterm infants.
Objective
1) To determine prevalence and variability in use of iNO in the NICHD Neonatal Research Network (NRN) before and after the consensus conference and 2) separately, to examine associations between iNO use and severe BPD or death.
Design/Methods
The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008–2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.
Results
A total of 4,885 infants were assessed between 2008–2011; 128 (2.6%) received iNO before Day 7, 140 (2.9%) between Day 7 and 28 and 47 (1.0%) at >28 days. Center-specific iNO use during 2008–2010 ranged from 21.9% to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6% to 1.6% (p<0.001) in 2011. Use of iNO started between Day 7 and Day 14 was more prevalent among younger infants with more severe courses in Week 1 and associated with increased risk of severe BPD or death (OR 2.24;95% CI 1.23–4.07).
Conclusions
The variability and total use of iNO decreased in 2011 compared to 2008–2010. iNO administration started at ≥Day 7 was associated with more severe outcomes compared to infants without iNO exposure.
doi:10.1038/jp.2014.105
PMCID: PMC4323079  PMID: 24901452
Inhaled nitric oxide; bronchopulmonary dysplasia; extremely premature infant
2.  Early Feeding Factors Associated with Exclusive versus Partial Human Milk Feeding in Neonates Receiving Intensive Care 
Objective
To evaluate early feeding factors associated with exclusive human milk (EHM) feeding at discharge in a cohort of human milk fed infants admitted to the neonatal intensive care unit (NICU).
Study Design
Retrospective cohort of consecutively discharged infants from two NICUs over a 12 month period who received any human milk during the 24 hours prior to hospital discharge. We used logistic regression to evaluate early feeding factors associated with EHM feeding at discharge.
Results
We evaluated a total of 264 infants. EHM-fed infants were twice as likely to receive human milk at the first feeding compared to partial human milk fed infants (65% vs. 32%; P<0.01). In multivariable analysis, including adjustment for race and type of maternal insurance, infants receiving human milk as the initial feeding, compared to formula, had a greater odds of EHM feeding at hospital discharge (adjusted OR 3.41; 95% CI 1.82–6.39; P<0.001).
Conclusion
Among infants admitted to the NICU whose mothers provide human milk, those receiving human milk as the first feeding were more likely to receive EHM feeding at discharge.
doi:10.1038/jp.2014.63
PMCID: PMC4117706  PMID: 24743134
breast milk; breast feeding; preterm infants; quality improvement; nutrition
3.  Neurodevelopmental Outcomes after Hypothermia Therapy in the Era of Bayley-III 
Background
Bayley-III scales are currently used to evaluate outcomes of term infants following hypothermia therapy, while all prior reported outcomes in this population have used Bayley-II.
Objective
To determine the incidence of abnormal neurodevelopmental outcomes using Bayley III and the predictive value of MRI in infants who received systemic hypothermia.
Methods
We conducted a prospective cohort study of inborn infants who underwent hypothermia for moderate/severe neonatal encephalopathy from 10/2005–11/2011.
Results
80 newborns underwent hypothermia (incidence of 1/1000). Of the survivors, 89% had Bayley-III performed around 24 months of age. An abnormal outcome using Bayley-III <85 occurred in 50%, while Bayley III <70 occurred in 13%. MRI predicted Bayley III < 85 with sensitivity of 73%, specificity of 84%, PPV of 84%, NPV of 74%.
Conclusions
A Bayley-III 85 cut off identifies a disability rate of 50%, and MRI was predictive of abnormal outcomes. Findings can be useful for counseling of families and planning of future studies using Bayley III.
doi:10.1038/jp.2014.67
PMCID: PMC4117736  PMID: 24743133
Neonatal encephalopathy; hypothermia; magnetic resonance imaging; Bayley-scores; neurodevelopmental outcomes
4.  Obstructive Sleep Apnea in Pregnancy: Reliability of Prevalence and Prediction Estimates 
Objective
We sought to ascertain the validity of two screening scales for obstructive sleep apnea (OSA) in pregnancy and to establish the prevalence of OSA in pregnancy.
Study Design
In this prospective observational study, two screening scales were administered. Screen positive subjects were referred for diagnostic polysomnography (PSG); if admitted for antepartum care, screen positive subjects underwent a modified study with a type 3 device (T3D).
Result
1509 subjects underwent OSA screening; 58 completed diagnostic testing. Neither measure was a reliable diagnostic tool for OSA as determined by T3D or PSG (detection rates of 10.3% and 18.0%, respectively). Among screen positive subjects undergoing PSG or T3D testing, 15.5% ultimately met ‘gold standard’ OSA diagnostic criteria for an estimated point prevalence of 4.9%.
Conclusion
In this prospective trial, screening positive on the BQ or ESS was poorly predictive of OSA among gravidae and was associated with a high false referral rate.
doi:10.1038/jp.2014.48
PMCID: PMC4117820  PMID: 24674980
Obesity; Sleep-Disordered Breathing; Screening
5.  Unbound bilirubin predicts abnormal automated auditory brainstem response in a diverse newborn population 
Objective
The objective of this study was to determine if plasma unbound or ‘free’ bilirubin concentration (Bf) measured during the first 30 days of life is associated with subsequent abnormal hearing screening testing by automated auditory brainstem response (AABR) in a diverse population of newborns.
Study Design
An observational study of newborns receiving AABR, plasma total bilirubin concentration (TBC) and Bf measurements and without underlying conditions known to affect hearing was conducted. Logistic regression was used to determine associations between abnormal AABR and Bf or TBC. The impacts of a variety of clinical factors on the regression model were also assessed.
Result
A total of 191 patients with birth weights and gestations ranging from 406 to 4727 g and 24 to 42 weeks, respectively, were studied. Among them, 175 (92%) had normal (bilateral PASS) AABR and 16 had abnormal AABR (6 had unilateral REFER AABR, and 10 had bilateral REFER AABR). Mean TBC was not significantly different in babies with normal or abnormal AABR, but mean Bf was greater in the latter group (1.76 versus 0.93 µg per 100 ml, respectively, P = 0.012). Bf, but not TBC, was associated with an abnormal AABR (Bf adjusted odds ratio 3.3, 95% CI 1.8 to 6.1). Comparing receiver-operating characteristics curves, the Bf/TBC ratio was a better predictor of an abnormal AABR than Bf alone. Intraventricular hemorrhage was the only confounding clinical variable.
Conclusion
An abnormal AABR is associated with an elevated Bf or Bf/TBC ratio, but not the TBC alone. The prevalence of bilirubin neurotoxicity as a cause of audiological dysfunction may be underestimated if the TBC alone is used to assess the severity of newborn jaundice.
doi:10.1038/jp.2008.199
PMCID: PMC4285409  PMID: 19242487
hyperbilirubinemia; unbound bilirubin; automated auditory brainstem response
6.  Acute Drop in Blood Monocyte Count Differentiates NEC from Other Causes of Feeding Intolerance 
Objective
Necrotizing enterocolitis (NEC) is characterized by macrophage infiltration into affected tissues. Because intestinal macrophages are derived from recruitment and in situ differentiation of blood monocytes in the gut mucosa, we hypothesized that increased recruitment of monocytes to the intestine during NEC reduces the blood monocyte concentration, and that this fall in blood monocytes can be a useful biomarker for NEC.
Patients and methods
We reviewed medical records of very low birth weight (VLBW) infants treated for NEC, and compared them with a matched control group comprised of infants with feeding intolerance but no signs of NEC. Clinical characteristics and absolute monocyte counts (AMC) were recorded. Diagnostic accuracy of AMC values was tested using receiver-operator characteristics (ROC).
Results
We compared 69 cases and 257 controls (median 27 weeks, range 26–29 in both groups). In stage II NEC, AMC decreased from median 1.7 × 109/L (interquartile range (IQR) 0.98–2.4) to 0.8 (IQR 0.62–2.1); p <0.05. In stage III NEC, monocyte counts decreased from median 2.1 × 109/L (IQR 0.1.5–3.2) to 0.8 (IQR 0.6–1.9); p <0.05. There was no change in AMC in control infants. ROC of AMC values showed a diagnostic accuracy (area under the curve) of 0.76. In a given infant with feeding intolerance, a drop in AMC of >20% indicated NEC with sensitivity of 0.70 (95% CI 0.57–0.81) and specificity of 0.71 (95% CI 0.64–0.77).
Conclusions
We have identified a fall in blood monocyte concentration as a novel biomarker for NEC in VLBW infants.
doi:10.1038/jp.2014.52
PMCID: PMC4074443  PMID: 24674979
Absolute monocyte counts; feeding intolerance; diagnostic test; monocytopenia; diagnosis; neonate
7.  Neonatal Iron Status is Impaired by Maternal Obesity and Excessive Weight Gain during Pregnancy 
Objective
Maternal iron needs increase 6-fold during pregnancy, but obesity interferes with iron absorption. We hypothesized that maternal obesity impairs fetal iron status.
Study Design
316 newborns with risk factors for infantile iron deficiency anemia (IDA) were studied to examine obesity during pregnancy and neonatal iron status. Erythrocyte iron was assessed by cord blood hemoglobin (Hb), zinc protoporphyrin/heme (ZnPP/H) and reticulocyte-ZnPP/H and storage iron by serum ferritin.
Results
Women with body mass index ≥30 kg/m2, as compared with non-obese women, delivered larger offspring with higher reticulocyte-ZnPP/H, and lower serum ferritin concentrations (p<0.05 for both). With increasing BMI, estimated body iron was relatively lower (mg/kg) and the ratio of total Hb-bound iron (mg)/total body iron (mg) increased. Maternal diabetes compromised infant iron status, but multivariate analysis demonstrated that obesity was an independent predictor.
Conclusions
Obesity during pregnancy and excessive weight gain are independent risk factors for iron deficiency in the newborn.
doi:10.1038/jp.2014.42
PMCID: PMC4074453  PMID: 24651737
body mass index; weight gain; zinc protoporphyrin/heme; ferritin; iron transport; placenta; pregnancy; inflammation; iron deficiency; newborn
8.  A Premature Infant with Fetal Myocardial and Abdominal Calcifications and Factor V Leiden Homozygosity 
We present a premature male neonate with confirmed Factor V Leiden deficiency diagnosed prenatally with cardiac and abdominal calcifications. Our patient’s findings suggest that clinicians consider thromboembolic conditions when multiple fetal calcifications are visualized.
doi:10.1038/jp.2009.62
PMCID: PMC4241858  PMID: 19861970
factor V Leiden; thromboembolic disorders; hypercoagulation disorder; abdominal calcifications; cardiac calcifications; fetal calcifications
9.  Coverage and determinants of newborn feeding practices in rural Burkina Faso 
Objectives
Newborn feeding practices are important to neonatal health and survival, but understudied in sub-Saharan Africa. We assessed the prevalence and determinants of newborn feeding practices in Burkina Faso.
Study design
An 18 000 household survey was conducted in rural Burkina Faso in 2010–2011. Women of reproductive age were asked about antenatal, delivery, and newborn care practices for their most recent live birth. Coverage of newborn feeding practices was estimated and multivariate regression was used to assess determinants of these practices.
Results
Seventy-six percent of live births were breastfed within 24 hours of birth, 84% were given colostrum, and 21% received prelacteals. Facility delivery and antenatal care attendance were associated with positive feeding practices.
Conclusions
Positive newborn feeding practices were common in rural Burkina Faso, relative to other low-income settings. Interventions are needed to improve feeding practices among home-born babies, and to encourage earlier initiation of breastfeeding among facility-born newborns.
doi:10.1038/jp.2014.13
PMCID: PMC4006288  PMID: 24526006
Neonatal; breastfeeding; colostrum; prelacteal; household survey
10.  High oleic/stearic fatty acid desaturation index in cord plasma from infants of mothers with gestational diabetes 
Objective
Enhanced fatty acid desaturation by stearoyl-CoA desaturase enzyme-1 (SCD1) is associated with obesity. This study determined desaturation in cord plasma of newborns of mothers with and without gestational diabetes (GDM).
Study design
Newborns of mothers with GDM (n=21) and without (Control, n=22) were recruited. Cord plasma fatty acid desaturation indices (palmitoleic/palmitic, oleic/stearic ratios) were compared, and correlated with anthropometrics and biochemical measures. A subset of VLDL desaturation indices were determined to approximate liver SCD1 activity.
Results
The total oleic/stearic index was higher in GDM, despite adjustment for cord glucose concentrations. Among GDM and Controls, the oleic/stearic index correlated with cord glucose concentrations (rs=0.36, p=0.02). Both palmitoleic/palmitic and oleic/stearic indices correlated with waist circumference (r=0.47, p=0.001; r=0.37, p=0.01). The VLDL oleic/stearic index was higher in GDM.
Conclusion
The elevated total oleic/stearic index suggests increased lipogenesis in GDM newborns. Factors in addition to glucose supply may influence fetal SCD1 activity.
doi:10.1038/jp.2014.23
PMCID: PMC4022182  PMID: 24577432
fatty acid; desaturation; lipogenesis; obesity; fetal programming
11.  Anti-inflammatory Actions of Endogenous and Exogenous Interleukin-10 versus Glucocorticoids on Macrophage Functions of the Newly Born 
OBJECTIVE
To determine whether specific macrophage immune functions of the newly born are insensitive to the actions of therapeutic levels of dexamethasone (DEX), previously measured in infants with bronchopulmonary dysplasia (BPD), compared to betamethasone (BETA) and exogenous or endogenous interleukin-10 (IL-10).
STUDY DESIGN
Macrophages were differentiated from cord blood monocytes (N=18). A serial dose response (around 10−8M), in vitro study was used to examine the effect of DEX, BETA and IL-10, on pro-inflammatory (PI) cytokine release, phagocytosis and respiratory burst.
RESULTS
Exogenous IL-10 (10−8M) significantly (p<0.05) inhibited the endotoxin-stimulated release of IL-6, IL-8 and tumor necrosis factor by 63% to 82% with no significant effect by DEX and BETA. There was no inhibition by these 3 agents at 10−8M on phagocytosis and respiratory burst. Inhibition of endogenous IL-10 with a monoclonal antibody significantly raised endotoxin-stimulated cytokine release by at least 4 fold.
CONCLUSION
Macrophages were relatively insensitive to therapeutic levels of DEX and BETA with regard to PI cytokine release. This study provides rationale for translational, preclinical research using airway instillation of IL-10 for the treatment of BPD.
doi:10.1038/jp.2014.16
PMCID: PMC4211413  PMID: 24526008
dexamethasone; betamethasone; bronchopulmonary dysplasia; inflammation; cytokines; phagocytosis; respiratory burst
12.  Neonatal morbidity occurs despite pulmonary maturity prior to 39 weeks gestation 
Objective
To compare outcomes among late-preterm or early-term neonates according to fetal lung maturity status.
Study Design
We conducted a retrospective cohort study of 234 eligible singletons delivered after fetal lung maturity (FLM) testing prior to 39 weeks gestation at our center over a two year time period. A primary composite neonatal outcome included death and major morbidities.
Results
The overall rate of primary composite morbidity was 25/46 (52.2%) and 61/188 (32.4%) in the immature/transitional and mature groups, respectively. After adjustment for confounders including gestational age, the composite outcome was not significantly different; aOR 1.4 (CI 0.7-3.0). The rate of respiratory distress syndrome was significantly higher in the immature/transitional group; OR 3.4 (CI 1.1-10.3) as expected.
Conclusions
FLM status did not correlate with the spectrum of neonatal morbidities in late preterm and early term births. Neonatal complications remained common in both groups.
doi:10.1038/jp.2013.173
PMCID: PMC3969761  PMID: 24434777
fetal lung maturity; late preterm birth; amniocentesis; neonatal outcomes; prematurity
13.  Quality Indicators for Human Milk Use in Very Low Birthweight Infants: Are We Measuring What We Should be Measuring? 
Objective
The objective of this study was to compare the currently used human milk (HM) quality indicators that measure whether very low birthweight (VLBW; <1500 g birthweight) infants “ever” received HM and whether they were still receiving HM at discharge from the neonatal intensive care unit (NICU) to the actual amount and timing of HM received.
Study Design
This study used data from a large NIH-funded cohort study and calculated whether VLBW infants ever received HM (HM-Ever) and of these infants, the percentage who were still receiving HM at NICU discharge (HM-DC). Then, the HM-DC indicator (exclusive, partial and none) was compared with the amount and timing of HM feedings received by these same infants.
Results
Of the 291 VLBW infants who met inclusion criteria, 285 received some HM (HM-Ever = 98%). At NICU discharge (HM-DC), 24.2%, 15.1% and 60.7% were receiving exclusive, partial and no HM, respectively. Of the 60.7% infants with no HM-DC, some had received higher amounts of HM during the NICU hospitalization than infants categorized as exclusive and partial for HM-DC. Of the infants with no HM-DC, 76.8% and 59.7% had received exclusive HM during the Days 1–14 and Days 1–28 exposure periods, respectively.
Conclusion
The average daily dose (HM-DD; in mL/kg/d) and cumulative percentage (HM-PCT; as % of cumulative enteral intake) of HM feedings were sufficient to significantly reduce the risk of multiple morbidities, including late onset sepsis, necrotizing enterocolitis, neurocognitive delay and rehospitalization, in the majority of the VLBW infants who were discharged with no HM-DC. Quality indicators that focus on the amount and timing of HM feedings in the NICU should be added to the HM-Ever and HM-DC measures.
doi:10.1038/jp.2014.5
PMCID: PMC3969767  PMID: 24526005
VLBW infants; NICU; human milk; quality indicators; prematurity-related morbidities
14.  Evaluating Retinopathy of Prematurity Screening Guidelines for 24-27 Week Gestational Age Infants 
Objective
To determine if current retinopathy of prematurity screening guidelines1 adequately identify treatable ROP in a contemporary cohort of extremely low gestation infants.
Study Design
Data from the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial were used. Inborn infants 24 0/7 to 27 6/7 weeks gestational age with consent prior to delivery were enrolled in 2005-2009. Severe retinopathy of prematurity (Type 1 retinopathy of prematurity or treatment with laser, cryotherapy, or bevacizumab) or death was the primary outcome for the randomized trial. Examinations followed then current American Academy of Pediatrics (AAP) screening recommendations, beginning by 31-33 weeks postmenstrual age.2,3
Results
1316 infants were enrolled in the trial. 997 of the 1121 who survived to first eye exam had final retinopathy of prematurity outcome determined. 137 (14% of 997) met criteria for severe retinopathy of prematurity and 128 (93%) of those had sufficient data (without missing or delayed exams) to determine age of onset of severe retinopathy of prematurity. Postmenstrual age at onset was 32.1 to 53.1 wks. In this referral center cohort, 1.4% (14/997) developed severe retinopathy of prematurity after discharge.
Conclusion
Our contemporary data support the 2013 AAP screening guidelines for ROP for infants 24 0/7 to 27 6/7 weeks gestational age.1 Some infants do not meet treatment criteria until after discharge home. Post-discharge follow-up of infants who are still at risk for severe ROP is crucial for timely detection and treatment.
doi:10.1038/jp.2014.12
PMCID: PMC3969774  PMID: 24503911
extremely premature infant
15.  Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects 
Objective
Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in premature infants. We sought to identify the frequency of NEC in very-low-birth-weight infants with isolated ventricular septal defects (VSD) or atrial septal defects (ASD) using a large multicenter database.
Methods
We identified a cohort of infants with birth weight <1500 g cared for in 312 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. We examined the association between presence of an ASD or a VSD with development of NEC using logistic regression to control for small-for-gestational-age status, antenatal steroid use, antenatal antibiotic use, gestational age, sex, race, Apgar score at 5 minutes, and method of delivery.
Results
Of the 98,523 infants who met inclusion criteria, 1,904 (1.9%) had an ASD, 1943 (2.0%) had a VSD, and 146 (0.1%) had both. The incidence of NEC was 6.2% in infants without septal defects, 9.3% in those with an ASD, 7.8% in those with a VSD, and 10.3% in infants with both an ASD and a VSD. Compared to infants without septal defects, the adjusted odds ratios for developing NEC for each group—ASD alone, VSD alone, and ASD with VSD—were 1.26 (95% confidence interval 1.06–1.49), 1.27 (1.08–1.52), and 1.80 (1.03–3.12), respectively.
Conclusion
The presence of an ASD or a VSD was associated with NEC in this cohort of premature infants.
doi:10.1038/jp.2013.174
PMCID: PMC3969778  PMID: 24434778
necrotizing enterocolitis; atrial septal defect; ventricular septal defect
16.  Evolving blood pressure dynamics for extremely preterm infants 
Objective
To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants.
Study Design
Prospective observational study of infants 230/7 – 266/7 weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 hours.
Results
A cohort of 367 infants had 18,709 ABP measurements recorded. ABP decreased for the first three hours, reached a nadir at 4 – 5 hours, then increased at an average rate of 0.2 mmHg / hour. The rise in ABP from hour 4 – 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135), or dopamine (n=92). GA specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA.
Conclusion
Arterial blood pressure increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.
doi:10.1038/jp.2014.6
PMCID: PMC3982788  PMID: 24503912
Antihypotensive therapy; fluid bolus; dopamine
17.  DISCORDANCE IN NEONATAL RISK FACTORS AND EARLY CHILDHOOD OUTCOMES OF VERY LOW BIRTH WEIGHT (<1.5KG) TWINS 
Objective
To examine rates of discordance in neonatal risk factors and neurodevelopmental outcomes within very low birth weight twin pairs and factors associated with discordant outcomes.
Study Design
Rates of neonatal risk factors and neurodevelopmental outcomes and discordance in outcomes were examined for 88 very low birth weight twin pairs born 1990–2005 and followed through 20 months corrected age.
Results
Discordance rates ranged from 17–42% for neonatal risk factors and 18–31% for neurodevelopmental outcomes. In regression analysis, affected co-twins were significantly more likely to have had an abnormal cerebral ultrasound than their unaffected co-twins in pairs discordant for cerebral palsy (OR: 13.00, 95% CI: 2.22–76.03) and in pairs discordant for neurodevelopmental impairment (OR: 4.00, 95% CI: 1.13–14.18). Outcomes and discordance in outcomes were similar for monochorionic and dichorionic pairs.
Conclusion
Despite shared genetics and risk factors, twins may have discordant outcomes. Information on discordant neonatal and neurodevelopmental outcomes is important for counseling families of twins.
doi:10.1038/jp.2012.121
PMCID: PMC4174277  PMID: 23047425
neonatal morbidity; neurodevelopmental impairment; chorionicity
18.  Effect of mode of birth on purine and malondialdehyde in umbilical arterial plasma in normal term newborns 
Objective
To examine the effect of mode of birth on plasma purine and malondialdehyde levels in normal term infants.
Study Design
Umbilical arterial cord blood was obtained immediately after birth from a convenience sample of 119 normal term newborns born by vaginal delivery, with or without oxytocin augmentation or by elective cesarean delivery. Plasma was analyzed for purine and/or malondialdehyde levels. Numeric data were analyzed utilizing independent samples t-test and ordinal data were analyzed using Mann–Whitney test. Correlation coefficients were obtained using Spearman’s ρ.
Result
Uric acid levels were significantly elevated (P<0.001) in neonates undergoing vaginal birth, compared to neonates born by elective cesarean delivery. When the effect of oxytocin and length of labor was analyzed, neonates born to mothers on oxytocin had lower hypoxanthine, significantly lower xanthine (P = 0.05) and higher uric acid levels. In addition, malondialdehyde levels were significantly higher (P<0.006) in neonates born to mothers who received oxytocin compared to neonates born to mothers without oxytocin augmentation. We also found significant correlations between malondialdehyde (MDA) and hypoxanthine (r = −0.465, P< 0.039) and between MDA and xanthine (r = −0.753, P = 0.003) in neonates born via oxytocin-augmented birth. Mode of birth had no statistically significant effect on clinical outcomes, although infants born by elective cesarean had higher incidence of acute respiratory distress and transient tachypnea of the newborn compared to those born vaginally.
Conclusion
Neonates born by elective cesarean had the lowest purine levels in cord blood compared to neonates born vaginally. Oxytocin augmentation is associated with some degree of uterine hyperstimulation which may enhance the ATP degradation pathway resulting in the rapid conversion of hypoxanthine to xanthine and xanthine to uric acid. Significantly higher MDA levels in neonates whose mothers received oxytocin as well as significant correlation between MDA and the purines hypoxanthine and xanthine, suggest free-radical production, most likely due to xanthine oxidase activation. However, despite differences in plasma purine and malondialdehyde levels, no significant differences were seen in neonatal outcome. Further studies are required to fully characterize the effect of mode of birth on purine metabolism and free-radical production.
doi:10.1038/jp.2008.29
PMCID: PMC4158434  PMID: 18368062
mode of birth; purines; MDA
19.  Great Expectorations: The Potential of Salivary “Omic” Approaches in Neonatal Intensive Care 
Among those that require critical care, preterm neonates have the greatest limitations on available blood or body fluids for clinical or research-based assessments. Recent technological advancements have improved our ability to detect genetic, proteomic and microbial material at the nanoscale level, making analyte and biomarker assessment from even the smallest quantities possible. Saliva is a unique body fluid that not only may be noninvasively and repeatedly obtained, but also contains multiple serum components making it promising for noninvasive assessment of the newborn. The integration of high-throughput or ‘omic’ approaches on neonatal saliva holds great potential to improve diagnostic and prognostic accuracy for a wide range of developmental and pathological conditions affecting the vulnerable preterm neonatal population. Herein, we review the clinical applications and technical considerations regarding the integration of salivary ‘omic’ technology into the neonatal intensive care unit (NICU).
doi:10.1038/jp.2013.170
PMCID: PMC3962691  PMID: 24406743
Saliva; proteome; microbiome; genome; transcriptome; neonate
20.  Amplitude-Integrated EEG and Range-EEG Modulation Associated with Pneumatic Orocutaneous Stimulation in Preterm Infants 
Background
Controlled somatosensory stimulation strategies have demonstrated merit in developing oral feeding skills in premature infants who lack a functional suck, however, the effects of orosensory entrainment stimulation on electrocortical dynamics is unknown.
Objective
To determine the effects of servo-controlled pneumatic orocutaneous stimulation presented during gavage feedings on the modulation of aEEG and rEEG activity.
Methods
Two-channel EEG recordings were collected during 180 sessions that included orocutaneous stimulation and non-stimulation epochs among 22 preterm infants (mean gestational age = 28.56 weeks) who were randomized to treatment and control ‘sham’ conditions. The study was initiated at around 32 weeks post-menstrual age (PMA). The raw EEG was transformed into amplitude-integrated EEG (aEEG) margins, and range-EEG (rEEG) amplitude bands measured at 1-minute intervals and subjected to a mixed models statistical analysis.
Results
Multiple significant effects were observed in the processed EEG during and immediately following 3-minute periods of orocutaneous stimulation, including modulation of the upper and lower margins of the aEEG, and a reorganization of rEEG with an apparent shift from amplitude bands D and E to band C throughout the 23-minute recording period that followed the first stimulus block when compared to the sham condition. Cortical asymmetry also was apparent in both EEG measures.
Conclusions
Orocutaneous stimulation represents a salient trigeminal input which has both short- and long-term effects in modulating electrocortical activity, and thus, is hypothesized to represent a form of neural adaptation or plasticity that may benefit the preterm infant during this critical period of brain maturation.
doi:10.1038/jp.2013.150
PMCID: PMC3943746  PMID: 24310443
somatosensory; orofacial; brain; prematurity; electroencephalography; experience-dependent
21.  Telemedicine for genetic and neurologic evaluation in the Neonatal Intensive Care Unit 
Objectives
Evaluate whether telemedicine can be used to perform dysmorphology and neurologic examinations in the neonatal intensive care unit (NICU) by determining the examination accuracy, limitations, and optimized procedures.
Study design
Prospective evaluation of NICU patients referred for subspecialty consultation for dysmorphic features (n=10) or encephalopathy (n=10). A physician at bedside (bedside clinician) performed an in-person examination which was viewed in real-time by a remote physician (remote consultant). Standardized examinations were recorded and compared. Subsequently, a qualitative approach established technique adjustments and optimization procedures necessary to improve visualization.
Results
Telemedicine examinations identified 81 of 87 (93%) dysmorphology examination abnormalities and 37 of 39 (92%) neurologic examination abnormalities. Optimization of remote consultant visualization required an active bedside clinician assisting in camera and patient adjustments.
Conclusions
Telemedicine can be used to accurately perform many components of the dysmorphology or neurologic examinations in NICU patients, but physicians must be mindful of specific limitations.
doi:10.1038/jp.2013.159
PMCID: PMC3943754  PMID: 24406740
22.  Outcomes of extremely preterm infants following severe intracranial hemorrhage 
Objective
Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH.
Study design
Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: i) unilateral vs. bilateral ICH; and ii) presence vs. absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI).
Results
Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI.
Conclusions
Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks.
doi:10.1038/jp.2013.162
PMCID: PMC4143234  PMID: 24370654
intraventricular hemorrhage; neurodevelopmental impairment; extremely low birth weight; cranial ultrasound
23.  Developmental and behavioral consequences of prenatal cocaine exposure: a review 
Substance use among pregnant women continues to be a major public health concern, posing potential risk to their drug-exposed children as well as burdens on society. This review is intended to discuss the most recent literature regarding the association between in utero cocaine exposure and developmental and behavioral outcomes from birth through adolescence across various domains of functioning (growth, neurobiology, intelligence, academic achievement, language, executive functioning, behavioral regulation and psychopathology). In addition, methodological limitations, associated biological, sociodemographic and environmental risk factors and future directions in this area of research are discussed. Given the large number of exposed children in the child welfare system and the increased need for medical, mental health and special education services within this population, more definitively documenting associations between prenatal cocaine exposure and later child outcomes is essential in order to be able to prospectively address the many significant public health, economic and public policy implications.
doi:10.1038/jp.2012.90
PMCID: PMC4143247  PMID: 22791278
behavior; cocaine; development; high-risk population; prenatal exposure
24.  Work of breathing indices in infants with respiratory insufficiency receiving high-flow nasal cannula and nasal continuous positive airway pressure 
OBJECTIVE
To compare work of breathing (WOB) indices between two nCPAP settings and two levels of HFNC in a crossover study.
STUDY DESIGN
Infants with a CGA 28–40 weeks, baseline of HFNC 3–5 lpm or nCPAP 5–6 cmH2O and fraction of inspired oxygen ≤40% were eligible. WOB was analyzed using respiratory inductive plethysmography (RIP) for each of the four modalities: HFNC 3 and 5 lpm, nCPAP 5 and 6 cmH2O. N = 20; Study weight 1516 g (±40 g).
RESULT
Approximately 12 000 breaths were analyzed indicating a high degree of asynchronous breathing and elevated WOB indices at all four levels of support. Phase angle values (means) (P<0.01): HFNC 3 lpm (114.7°), HFNC 5 lpm (96.7°), nCPAP 5 cmH2O (87.2°), nCPAP 6 cmH2O (80.5°). The mean phase relation of total breath (PhRTB) (means) (P<0.01): HFNC 3 lpm (63.2%), HFNC 5 lpm (55.3%), nCPAP 5 cmH2O (49.3%), nCPAP 6 cmH2O (48.0%). The relative labored breathing index (LBI) (means) (P≤0.001): HFNC 3 lpm (1.39), HFNC 5 lpm (1.31), nCPAP 5 cmH2O (1.29), nCPAP 6 cmH2O (1.26). Eighty-two percent of the study subjects—respiratory mode combinations displayed clustering, in which a proportion of breaths either occurred predominantly out-of-phase (relative asynchrony) or in-phase (relative synchrony).
CONCLUSION
In this study, WOB indices were statistically different, yet clinically similar in that they were elevated with respect to normal values. These infants with mild-to-moderate respiratory insufficiency demonstrate a meaningful elevation in WOB indices and continue to require non-invasive respiratory support. Patient variability exists with regard to biphasic clustered breathing patterns and the level of supplemental fraction of inspired oxygen ≤40% alone does not provide guidance to the optimal matching of WOB indices and non-invasive respiratory support.
doi:10.1038/jp.2013.120
PMCID: PMC4141486  PMID: 24071905
preterm; infant; respiratory inductive plethysmography
25.  Telemedicine Collaboration Improves Perinatal Regionalization and Lowers Statewide Infant Mortality 
OBJECTIVES
We assessed a telemedicine (TM) network's effects on decreasing deliveries of very low birth-weight (VLBW, <1500 grams) neonates in hospitals without Neonatal Intensive Care Units (NICUs) and statewide infant mortality.
STUDY DESIGN
This prospective study used obstetrical and neonatal interventions through TM consults, education, and census rounds with 9 hospitals from July 1, 2009 – March 31, 2010. Using a generalized linear model, Medicaid data compared VLBW birth sites, mortality, and morbidity before and after TM use. Arkansas Health Department data and chi square analysis were used to compare infant mortality.
RESULTS
Deliveries of VLBW neonates in targeted hospitals decreased from 13.1% to 7.0% (p=0.0099); deliveries of VLBW neonates in remaining hospitals was unchanged. Mortality decreased in targeted hospitals (13.0% before TM and 6.7% after TM). Statewide infant mortality decreased from 8.5 to 7.0 per 1000 deliveries (p=0.043).
CONCLUSIONS
TM decreased deliveries of VLBW neonates in hospitals without NICUs and was associated with decreased statewide infant mortality..
doi:10.1038/jp.2013.37
PMCID: PMC4138978  PMID: 23579490
Very Low Birth Weight; Premature; Neonates; Neonatal; Neonatal Intensive Care Unit

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