Entropy Analysis of Neonatal Electrodermal Activity during the First Three Days after Birth.

The entropy-based parameters determined from the electrodermal activity (EDA) biosignal evaluate the complexity within the activity of the sympathetic cholinergic system. We focused on the evaluation of the complex sympathetic cholinergic regulation by assessing EDA using conventional indices (skin conductance level (SCL), non-specific skin conductance responses, spectral EDA indices), and entropy-based parameters (approximate, sample, fuzzy, permutation, Shannon, and symbolic information entropies) in newborns during the first three days of postnatal life. The studied group consisted of 50 healthy newborns (21 boys, average gestational age: 39.0 ± 0.2 weeks). EDA was recorded continuously from the feet at rest for three periods (the first day-2 h after birth, the second day-24 h after birth, and the third day-72 h after birth). Our results revealed higher SCL, spectral EDA index in a very-low frequency band, approximate, sample, fuzzy, and permutation entropy during the first compared to second and third days, while Shannon and symbolic information entropies were lower during the first day compared to other periods. In conclusion, EDA parameters seem to be sensitive in the detection of the sympathetic regulation changes in early postnatal life and which can represent an important step towards a non-invasive early diagnosis of the pathological states linked to autonomic dysmaturation in newborns.

Heart rate variability in healthy term newborns is related to delivery mode: a prospective observational study.

BACKGROUND: Early postnatal period is characterized by dramatic adaptation changes of cardiovascular and respiratory systems in newborns. There is still insufficient data regarding maturation of autonomic regulatory mechanisms in neonates early after delivery. Aim of this study was to analyze cardiac autonomic regulation in newborns within the first few postnatal days in relation to different modes of delivery using time and spectral heart rate variability analysis. METHODS: Eutrophic healthy term newborns (n = 46) were divided into three groups according to the delivery mode: vaginal delivery (VD group; n = 16), vaginal delivery with epidural analgesia (EDA group; n = 16), and caesarean section under general anesthesia (CS group; n = 14). Heart rate variability (HRV), blood pressure (BP), and blood oxygen saturation (SpO2) were measured within the first two hours after birth and on the third to fourth postnatal day. HRV parameters were evaluated in the time domain (RR intervals, mean square of successive differences - MSSD) and frequency domain (total spectral power - TP, absolute and relative low and high frequency powers). RESULTS: The HRV spectral analysis showed significantly higher relative power of the high-frequency band (HF%) in the VD group compared to the CS group early after delivery (p = 0.002). HRV parameters and BP significantly increased on the third to fourth postnatal day in all groups (p < 0.05). No significant differences in basic characteristics, BP and SpO2 were identified between groups during both measurements. CONCLUSIONS: HRV analysis revealed higher cardiovagal modulation in spontaneously born newborns without analgesia compared to neonates born by caesarean section. It could represent a potential pathomechanism that leads to discrete abnormal neurocardiac regulation associated with higher risk for worsened postnatal adaptation of cardiovascular system in surgically delivered neonates.

Neonatal Marfan syndrome: Report of two cases.

Marfan syndrome is rarely diagnosed in the neonatal period because of variable expression and age-dependent appearance of clinical signs. The prognosis is usually poor due to high probability of congestive heart failure, mitral and tricuspid regurgitations with suboptimal response to medical therapy and difficulties in surgical management. The authors have studied two cases of Marfan syndrome in the newborn period. Two cases of neonatal Marfan syndrome, one male and one female, were diagnosed by characteristic physical appearance. Both infants had significant cardiovascular abnormalities diagnosed by ultrasonography. Genetic DNA analysis in the second case confirmed the mutations in the fibrillin-1 gene located on chromosome 15q21 which is responsible for the development of Marfan syndrome. The boy died at six weeks of age with signs of rapidly progressive left ventricular failure associated with pneumonia. The second infant was having only mild signs of congestive heart failure and has been treated with beta blockers. At the age of 4 years her symptoms of congestive heart failure had worsened due to progression of mitral and tricuspid insufficiency and development of significant cardiomegaly. Mitral and tricuspid valvuloplasy had to be done at that time. Early diagnosis of Marfan syndrome in the newborn period can allow treatment in the early stages of cardiovascular abnormalities and may improve the prognosis. It also helps to explain to the family the serious health problem of their child.

Arteriovenous malformation of vein of Galen as a rare non-hypoxic cause of changes in fetal heart rate pattern during labor.

The aim of this case report is to describe a rare non-hypoxic cause of pathological changes in fetal heart rate pattern during labor, and to determine management, including a description of important prenatal aspects when pathologic cardiotocographic recording is performed during labor. A fetus with rare arteriovenous malformation of the vein of Galen, which represents less than 1% of all intracranial arteriovenous malformations, was monitored by intrapartum external cardiotocography in the 37 + 5 gestational week. The baby was born by cesarean section because of signs of imminent intrauterine hypoxia on cardiotocography. However, metabolic acidosis was not confirmed in umbilical cord blood sampling. Despite intensive neonatal care management, the newborn died 31 h after delivery because of progressive cardiac decompensation, hypotension and multi-organ failure. Precise diagnosis of the abovementioned pathology, a pre-labor plan for delivery and postnatal prognosis assessment can significantly contribute to the avoidance of a misdiagnosis of fetal hypoxia and unnecessary operative delivery with marked medico-legal consequences.

Changes of cardiovascular regulation during rewarming in newborns undergoing whole-body hypothermia.

OBJECTIVES: The aim of the study was to determine changes of oxygenation and cardiovascular parameters during body temperature recovery in newborns undergoing therapeutic hypothermia. DESIGN AND SETTINGS: Three full-term newborns treated by whole-body hypothermia according to TOBY trial were included in the study. They were cooled to body temperature of 33.5 °C for 72 hours, thereafter gradual rewarming was initiated. During rewarming period following parameters were measured: heart rate and heart rate variability, blood pressure, core body temperature, blood oxygen saturation, cerebral and splanchnic tissue oxygenation. In one of the infants Doppler sonography examination of truncus coeliacus and arteria mesenterica superior was performed to assess blood flow in these arteries. RESULTS: During rewarming period the heart rate increased, whereas blood pressure tended to decrease. It was observed ascending trend in parameters of heart rate variability (MSSD and total spectral power) due to increasing spectral activity in LF and also HF bands. Blood oxygen saturation and cerebral tissue oxygenation remained stable, but significant decrease of splanchnic tissue oxygenation was noticed. This finding corresponded to Doppler sonography parameters in arteria mesenterica superior. THE MAIN FINDING: Therapeutic hypothermia and subsequent rewarming in newborns influenced cardiovascular regulation (blood pressure, heart rate, heart rate variability). Body temperature recovery was accompanied by reduction in splanchnic oxygenation and blood flow in superior mesenteric artery. CONCLUSIONS: Body temperature recovery in neonates led to changes in autonomic cardiovascular regulation resulting in redistribution of blood flow to vital organs. Reduction of blood flow to splanchnic organs during heating is a finding that has not been described yet. Further studies are needed to confirm these findings.

Prenatal diagnosis of cardiac rhabdomyoma associated with tuberous sclerosis: report of 3 cases.

Cardiac rhabdomyoma is the most common cardiac tumor in fetal life, accounting for 60-86% of primary fetal cardiac tumors. It is primarily benign, originating form myocardial muscles and consisting of immature myocytes. About 50-60% of these tumors are associated with tuberous sclerosis. In this report, we present the clinical course and discuss the importance of prenatal diagnosis of cardiac tumors and their follow-up after birth.

Very early postnatal changes in splanchnic circulation in term infants.

BACKGROUND: Reversed blood flow has been reported in the superior mesenteric artery (SMA) in 92% of healthy term newborns at 2 h of age. By 24 h after birth the end-diastolic velocity became positive in all of the infants. OBJECTIVE: To characterize hemodynamic changes in the coeliac artery and superior mesenteric artery in healthy term newborns during the first 6 h after birth and to specify the time interval when the negative values of end-diastolic velocity in the superior mesenteric artery become positive. MATERIALS AND METHODS: Our study included 30 healthy term newborns. The blood flow velocity was assessed by Doppler ultrasonography at 2 h, 4 h and 6 h after birth. RESULTS: The end-diastolic velocity in the superior mesenteric artery changed from negative values at the age of 2 h (-0.9 cm/s, range -13.2 to 0.0) to positive (7.08 cm/s, range 6.3 to 13.5, P < 0.001) at 6 h after birth. In the coeliac artery, the end-diastolic velocity increased during this period, but negative values were not observed (11.8 cm/s, range 9.3 to 13.9 at 2 h and 18.03 cm/s, range 14.2 to 27.6 at 6 h). CONCLUSION: Important changes occur in splanchnic circulation during the first 6 h after birth. The rise in end-diastolic velocity in the superior mesenteric artery from negative to positive values in 83% of healthy term newborns is the most important change.

The use of transcutaneous bilirubin nomograms for the prevention of bilirubin neurotoxicity in the neonates.

Purpose: Although neonatal jaundice is a ubiquitous and predominantly benign phenomenon, the risk of neurotoxicity exists in a number of infants with unconjugated hyperbilirubinemia. Plotting bilirubin values on nomograms enables clinicians to employ an anticipatory and individualized approach with the goal of avoiding excessive hyperbilirubinemia and preventing acute bilirubin encephalopathy and its progression to kernicterus. We aimed to construct nomograms for White term infants based on transcutaneous bilirubin (TcB) measurements using a JM-105 device. Methods: TcB measurements were taken in infants at ages ranging from 0 to 96 postnatal hours. We then constructed hour-specific TcB nomograms from forehead and sternum measurements in infants who did not require subsequent phototherapy. Results: We included 2,981 TcB measurements taken on the forehead and 2,977 measurements taken on the sternum in 301 White term newborn infants. We assessed the predictive abilities of the nomograms at six postnatal time intervals using receiver operating characteristic curves. The areas under the curves indicated reasonable prediction of hyperbilirubinemia requiring phototherapy, except for the forehead measurement taken within the first 12 h of life. Sensitivity tended to rise as postnatal age increased. Conclusion: The nomograms illustrate dermal bilirubin dynamics in White term neonates during the first 4 days of life. They may be useful tools to predict individualized risk of hyperbilirubinemia requiring treatment, and to plan optimal follow-up of infants at risk of bilirubin neurotoxicity.

The Common Haplotype GATGACA in Surfactant-Protein B Gene Is Protective for Respiratory Distress Syndrome in Preterm Neonates.

Background: Respiratory distress syndrome (RDS), a disorder of primary surfactant deficiency resulting in pulmonary insufficiency, remains a significant problem for preterm neonates. Associations between genetic variants of surfactant proteins and RDS have been reported, but haplotypes of the surfactant protein B gene (SFTPB) have not been studied. The aim of the study was to prove the hypothesis that certain haplotypes of SFTPB may be protective or risk factors for RDS. Methods: The study was performed with 149 preterm infants, born <34 weeks of gestation, with 86 infants with mild RDS or without RDS (control group) and 63 infants with severe RDS (patient group). RDS was considered severe if multiple doses of exogenous surfactant and/or mechanical ventilation within the first 72 h of life were needed. The venous blood sample was used for the analysis of gene polymorphisms associated with RDS, genotyping, and haplotype estimation. Multivariate logistic regression analysis and the odds ratio were calculated to detect the contribution of the studied variables to the development of RDS. Results: A new association of the common single nucleotide polymorphism (SNP) rs2304566 with RDS in premature infants was detected. Analysis of rs2304566 polymorphisms using a logistic regression model showed that there are two significant predictors inversely related to the occurrence of RDS (Apgar score of 5 min, CT and TT genotype in rs2304566 polymorphism). Gestational age, birth weight, and sex have border significance. Moreover, in the patient group, the frequency of the GATGACA haplotype in the SFTPB gene was lower (p = 0.037), and the GATGGCA haplotype was higher (p = 0.059) in comparison with the control group. Conclusion: The common haplotype GATGACA of the SFTPB gene can be protective against RDS in preterm infants. The trend of a higher frequency of GATGGCA in the SFTPB gene in infants with severe RDS suggests that this haplotype may be a risk factor for RDS susceptibility.

Blood Pressure Variability and Baroreflex Sensitivity in Premature Newborns-An Effect of Postconceptional and Gestational Age.

Introduction: Cardiovascular system is the vitally important system in the dynamical adaptation process of the newborns to the extrauterine environment. To reliably detect immaturity in the given organ system, it is crucial to study the development of the organ functions in relation to maturation process. Objectives: The objective was to determine the changes in the spontaneous short-term blood pressure variability (BPV) and baroreflex sensitivity (BRS) reflecting various aspects of cardiovascular control during the process of maturation in preterm babies and to separate effects of gestational age and postnatal age. Methods: Thirty-three prematurely born infants without any signs of cardio-respiratory disorders (gestational age: 31.8, range: 27-36 weeks; birth weight: 1,704, range: 820-2,730 grams) were enrolled. Continuous peripheral blood pressure signal was obtained by non-invasive volume-clamp photoplethysmography method during supine rest. The recordings of 250 continuous beat-to-beat blood pressure values were processed by spectral analysis of BPV (assessed measures: total power, low frequency and high frequency powers of systolic BPV) and BRS calculation. For each infant we also assessed systolic, diastolic and mean blood pressures, heart rate and respiratory rate. Results: With the postconceptional age, BPV measures decreased (for total power: Spearman correlation coefficient rs = -0.345, P = 0.049; for low frequency power: rs = -0.365, P = 0.037; for high frequency power rs = -0.349; P = 0.046); and BRS increased significantly (rs = 0.448, P = 0.009). The further analysis demonstrated that these effects were more attributable to gestational age than to postnatal age. BRS correlated negatively with BPV magnitude (rs = -0.479 to -0.592, P = 0.001-0.005). Mean blood pressure and diastolic blood pressure increased during maturation (rs = 0.517 and 0.537, P = 0.002 and 0.001, respectively) while heart rate and respiratory rate decreased (rs = -0.366 and -0.516, P = 0.036 and 0.002, respectively). Conclusion: We conclude that maturation process is accompanied by an increased involvement of baroreflex buffering of spontaneous short-term blood pressure oscillations. Gestational age plays a dominant role not only in BPV changes but also in BRS, mean blood pressure, diastolic blood pressure and heart rate changes.

Accuracy of enhanced transcutaneous bilirubinometry according to various measurement sites.

OBJECTIVE: The goal of the study was to provide missing data on the accuracy of enhanced transcutaneous bilirubinometry in a monoracial population of term neonates, considering three different measurement sites. MATERIAL AND METHODS: Transcutaneous bilirubin was measured using the JM-105 device on the forehead, chest, and abdomen. Blood sampling for total serum bilirubin concentration has been performed within 10 minutes of transcutaneous measurements. Paired transcutaneous bilirubin and total serum bilirubin measurements were statistically analyzed. RESULTS: The study group consisted of 102 healthy term Slovak infants. The correlation between total serum bilirubin and transcutaneous bilirubin was significant (coefficient of determination R2: 0.9045 forehead, 0.8808 sternum, 0.8467 abdomen). Transcutaneous measurements underestimated serum bilirubin levels significantly when total serum bilirubin values were higher than 15 mg/dL, irrespective of the site of transcutaneous measurements. The lowest mean difference between total serum bilirubin and transcutaneous bilirubin was identified on the sternum (median: -1.1 mg/dL). The area under the curve was >0.97 and >0.93 for detecting total serum bilirubin levels >10 mg/dL and >13 mg/dL, respectively, for all measurement sites. Transcutaneous measurements on the forehead and sternum provided very high sensitivity, with the best performance at the forehead. CONCLUSION: Transcutaneous bilirubinometry using an enhanced device is an accurate, sensitive, and convenient screening method in term Caucasian neonates. Transcutaneous bilirubin measurements on the forehead, sternum, and abdomen are reliable, with the best performance on the forehead. It is necessary to confirm higher transcutaneous bilirubin values with a total serum bilirubin measurement.

Clinical considerations when treating neonatal aspiration syndromes.

INTRODUCTION: In physiological conditions, neonatal airways are well-protected against aspiration of fluid or particulate material into the lungs, with laryngeal chemoreflex (LCR) being the most powerful mechanism. Failure of this protection allows substances to enter the lower airways, which starts a series of pathophysiological events initiated by inflammation and surfactant inactivation. The condition is defined as neonatal acute respiratory distress syndrome (ARDS), and its symptoms can range from mild respiratory distress to respiratory failure, often accompanied by persistent pulmonary hypertension (PPHN), in turn even leading to death. The management, therefore, may be very challenging. Areas covered: This review covers protection mechanisms of the neonatal lower airways, the etiology, and pathophysiology of neonatal aspiration syndrome (NAS), its definition in view of current literature, possible treatment options, and future trends. Expert commentary: Inflammation and secondary surfactant deficiency stand in the foreground of neonatal aspiration. Management focuses mainly on appropriate oxygenation, ventilation, improvement in PPHN, and maintenance of systemic circulation, which is largely symptomatic and supportive. Future research is required to evaluate the justification of using exogenous surfactants, antibiotics, anti-inflammatory and antioxidative drugs, or their combinations.

The early postnatal blood flow characteristics in the superior mesenteric and coeliac arteries in late preterm neonates.

OBJECTIVES: The objective of this study is to evaluate intestinal blood flow changes within the first 72 h in the late preterm infants in comparison with the healthy term neonates. METHODS: In this prospective study, we analyzed Doppler flow velocity waveforms of superior mesenteric artery (SMA) and coeliac trunc (TC) in 20 late preterm and 20 term infants at the age of 2, 24, and 72 h. RESULTS: Significant end-diastolic velocity (end-diastolic velocity (EDV)SMA) rise up to 24 h was documented in all patients (late preterm: -9.32 ± 9.48 to 17.01 ± 6.94; p < .05; term: -8 ± 5.74 to 12.39 ± 3.33; p < .001), associated with a conversion from negative values to positive ones. Reversed blood flow was documented in SMA at 2 h in 75% late preterm neonates. Preterm infants showed significantly higher mean peak systolic velocities (peak systolic velocity (PSV)SMA), end-diastolic velocities (EDVSMA) at 24 h and PSVTC at 72 h than term infants (p < .05). The resistance and pulsatility indices (PI) decreased within 24 h in both groups and inversely reflected the postnatal changes in EDVSMA. Mean PIAMS at 2 h was significantly higher in term neonates. CONCLUSION: Late preterm neonates show similar progressive postnatal increase in blood flow velocities accompanied with a decrease in vascular resistance in SMA and TC then term neonates.

Genetic association of single nucleotide polymorphisms of FZD4 and BDNF genes with retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a multifactorial disease occurring in preterm neonates, caused by incorrect development of retinal blood vessels. It has been suggested that, in addition to gestational age, weight, and oxygen supplementation, genetic factors can play a role in the pathogenesis of ROP. METHODS: In the present prospective study, 97 neonates were enrolled based on the gestational age and weight, and genomic DNA from patients diagnosed with ROP and premature newborns without ROP was collected. The DNA sequence of protein coding and 5´and 3´ untranslated regions (UTRs) of the frizzled-4 (FZD4) gene and the genotype of the locus rs7934165:G˃A (NM_170731.4: c.3 + 10976 C˃T) within the brain-derived neurotrophic factor gene (BDNF) were determined. RESULTS: We detected a significant association between rs61749246:C˃A (NM_012193.3: c.*2G˃T) and ROP in a general genetic model as well as in a multiplicative model and by the Cochran-Armitage test for trend. Moreover, rs61749246 was strongly associated with ROP, requiring surgical intervention. CONCLUSION: We suggest that rs61749246:C˃A of the FZD4 gene is likely associated with the development of ROP. It is necessary to confirm this suggestion in larger studies.

Early postnatal changes in superior mesenteric artery blood flow velocity in healthy term infants.

OBJECTIVES: After birth, the newborn intestinal circulation undergoes physiological changes. The purpose of this work was to characterize the changes in mesenteric blood flow velocity occuring during the first three days of life in healthy term infants. METHODS: 30 healthy term newborns were studied repeatedly at the age of 2, 24 and 70 hours. Blood flow velocity in superior mesenteric artery (SMA) was measured by Doppler ultrasound, peak systolic velocity (PSV), end-diastolic velocity (EDV) and time-averaged mean velocity (TAV) were recorded at each time point. Resistance index (RI) and pulsatility index (PI) were calculated. RESULTS: SMA EDV increased from 2 h [-5.2+/-6.8 cm/s (mean +/- SD)] to 24 h (12.9+/-3.8 cm/s, p<0.001) with further insignificant increase to 70 h (14.9+/-4.7 cm/s). At 2 h of age the mean EDV was negative in 23 of 30 cases (76.7%). PSV did not change between 2 h (58.0+/-21.8 cm/s) and 24 h (58.5+/-15.0 cm/s) but it increased to 70 h (79.6+/-17.7 cm/s). TAV showed a significant increase with time. RI decreased from 2 h (1.09+/-0.11) to 24 h (0.78+/-0.06, p<0.001) with further insignificant increase to 70 h (0.81+/-0.06). CONCLUSIONS: The blood flow velocity in SMA increases during the early neonatal period in term infants. The most remarkable changes occur within the first 24 hours of life. At 2 h of age a reversed blood flow is present in majority of infants.

Postnatal penicillin prophylaxis of early-onset group B streptococcal infection in term newborns. A preliminary study.

BACKGROUND: Early-onset group B Streptococcal disease (EOGBSD) is a serious but preventable neonatal infection. Maternal intrapartum antibiotic prophylaxis (IAP) does not prevent all cases of the disease. Management of asymptomatic neonates of GBS colonized mothers is problematic. AIMS: The objective of this prospective study was to determine whether administration of intramuscular penicillin at birth to a strictly defined group of term newborns of GBS colonized mothers is an effective and safe method to prevent EOGBSD. METHODS: A protocol for management of full-term infants born to GBS colonized mothers was created. Either an abnormality of blood count or presence of more than one obstetric risk factor were chosen as the indication criteria for administering postnatal antibiotic prophylaxis (PAP). RESULTS: The study sample consists of 250 newborns (11.5% of all term infants). PAP was administered in 39 cases. Indication criteria included leucocytosis in 37 cases, leucopenia in 1 case and obstetric risk factors in 1 case. There was no case of clinically manifest infection, and no case of sepsis either suspect or proven. CONCLUSIONS: The authors suggest that the strategy of selective PAP using penicillin, may be an effective and safe method in order to reduce morbidity and mortality from streptococcal infections. They recommend a combination of IAP and selective PAP.

Use of near-infrared spectroscopy (NIRS) in cerebral tissue oxygenation monitoring in neonates.

Near-infrared spectroscopy (NIRS) is a technology capable of non-invasive, continuous measuring of regional tissue oxygen saturation (StO2). StO2 represents a state of hemodynamic stability, which is influenced by many factors. Extensive research has been done in the field of measuring StO2 of various organs. The current clinical availability of several NIRS-based devices reflects an important development in prevention, detection and correction of discrepancy in oxygen delivery to the brain and vital organs. Managing cerebral ischemia remains a significant issue in the neonatal intensive care units (NICU). Cerebral tissue oxygenation (cStO2) and cerebral fractional tissue extraction (cFTOE) are reported in a large number of clinical studies. This review provides a summary of the concept of function, current variability of NIRS-based devices used in neonatology, clinical applications in continuous cStO2 monitoring, limitations, disadvantages, and the potential of current technology.

Hyperbilirubinemia and phototherapy in newborns: Effects on cardiac autonomic control.

BACKGROUND: Neonatal jaundice and its phototherapeutic treatment can lead to several side effects involving activation of autonomic control mechanisms. AIM: The aims of this study are to investigate the autonomic nervous system changes in icteric neonates using heart rate variability (HRV) and to assess the effect of phototherapy on short-term heart rate dynamics as an indicator of autonomic nervous control of cardiovascular system. METHODS: HRV recordings from 20 icteric full-term neonates before, during and after phototherapy and from 20 healthy controls were analyzed. In addition to traditional time and frequency domain measures, heart rate complexity parameters including normalized complexity index (NCI), normalized unpredictability index (NUPI), pattern classification indices (0V%, 1V%, 2LV%, 2UV%) and irreversibility index (P%) on four time scales were evaluated. All measures were derived from data segments of 1000 RR intervals. RESULTS: The analysis revealed higher values of 1V%, 2LV%, and lower P% in neonates with hyperbilirubinemia compared to controls. While HRV magnitude did not change, mean heart rate increased during and after the phototherapy. Nonlinear analysis showed a decrease of complexity, unpredictability and pattern classification measures 2LV% and 2UV%. In contrast, 0V% and irreversibility index P% were increased during and at least 30min after phototherapy. CONCLUSION: The results suggest a shifted autonomic balance in icteric neonates compared to the controls and its further alterations during phototherapy. As the nonlinear HRV parameters are independent of the linear methods, they can provide new information about the cardiac regulatory mechanisms and their changes in neonates.