Umbilical Cord Milking Versus Delayed Cord Clamping in Infants 28 to 32 Weeks: A Randomized Trial.

OBJECTIVES: To determine whether rate of severe intraventricular hemorrhage (IVH) or death among preterm infants receiving placental transfusion with UCM is noninferior to delayed cord clamping (DCC). METHODS: Noninferiority randomized controlled trial comparing UCM versus DCC in preterm infants born 28 to 32 weeks recruited between June 2017 through September 2022 from 19 university and private medical centers in 4 countries. The primary outcome was Grade III/IV IVH or death evaluated at a 1% noninferiority margin. RESULTS: Among 1019 infants (UCM n = 511 and DCC n = 508), all completed the trial from birth through initial hospitalization (mean gestational age 31 weeks, 44% female). For the primary outcome, 7 of 511 (1.4%) infants randomized to UCM developed severe IVH or died compared to 7 of 508 (1.4%) infants randomized to DCC (rate difference 0.01%, 95% confidence interval: (-1.4% to 1.4%), P = .99). CONCLUSIONS: In this randomized controlled trial of UCM versus DCC among preterm infants born between 28 and 32 weeks' gestation, there was no difference in the rates of severe IVH or death. UCM may be a safe alternative to DCC in premature infants born at 28 to 32 weeks who require resuscitation.

Assessment of systemic circulation using ultrasound Doppler in late onset neonatal sepsis and its clinical correlation: an observational study.

OBJECTIVES: To measure the Doppler velocimetry parameters in the anterior cerebral artery (ACA), superior mesenteric artery (SMA), and main renal artery (RA) in neonates with late-onset sepsis and correlate it with associated clinical morbidities. METHODOLOGY: Prospective observational study carried out at a tertiary-level neonatal intensive care unit in India in 2022, enrolling 20 neonates with late-onset neonatal sepsis (LONS). Baseline characteristics and sepsis parameters obtained. Serial ultrasound performed on days 1, 3, and 7 from the day of clinical sepsis in the ACA, SMA, and RA and velocimetry measurements obtained. The findings were compared with 20 gestational age (GA) matched neonates in the control arm. RESULTS: The mean GA of neonates with LONS was 31.03 ± 2.79 weeks and their mean birthweight was 1474 ± 509.99 g. The peak systolic velocity, resistive and pulsatility indices were significantly higher in ACA, SMA, and RA and the end-diastolic velocity was significantly lower in ACA and RA (P < 0.05) in LONS. The incidences of intraventricular hemorrhage (IVH), necrotising enterocolitis (NEC), and acute kidney injury (AKI) in neonates with LONS were 45%, 50%, and 10% respectively. A subgroup analysis of the Doppler velocimetry parameters in the neonates with LONS and for neonates with and without clinical outcomes did not suggest a significant difference. CONCLUSION: LONS is associated with alterations in cerebral, splanchnic, and renal perfusion seen as abnormal blood flow velocimetry and vascular resistance which may predispose to IVH, NEC, and AKI.

Does Severity of Brain Injury on Magnetic Resonance Imaging Predict Short-Term Outcome in Neonates Who Received Therapeutic Hypothermia?

OBJECTIVE: The National Institute of Child Health and Human Development (NICHD) magnetic resonance imaging (MRI) pattern of brain injury is a known biomarker of childhood outcome following therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). However, usefulness of this classification has not been evaluated to predict short-term outcomes. The study aimed to test the hypothesis that infants with NICHD MRI pattern of severe hypoxic-ischemic brain injury will be sicker with more severe asphyxia-induced multiorgan dysfunction resulting in prolonged length of stay (LOS) following therapeutic hypothermia. We also evaluated the role of other risk factors which may prolong LOS. STUDY DESIGN: We retrospectively reviewed the medical records of 71 consecutively cooled neonates to examine the ability of MRI patterns of brain injury to predict the LOS. A neuroradiologist masked to outcomes classified the patterns of brain injury on MRI as per NICHD. Pattern 2A (basal ganglia thalamic, internal capsule, or watershed infarction), 2B (2A with cerebral lesions), and 3 (hemispheric devastation) of brain injury was deemed "severe injury." RESULTS: Out of 71 infants, 59 surviving infants had both MRI and LOS data. LOS was higher for infants who had Apgar's score of ≤5 at 10 minutes, severe HIE, seizures, coagulopathy, or needed vasopressors or inhaled nitric oxide, or had persistent feeding difficulty, or remained intubated following cooling. However, median LOS did not differ between the infants with and without MRI pattern of severe injury (15 days, interquartile range [IQR]: 9-28 vs. 12 days, IQR: 10-20; p = 0.4294). On multivariate linear regression analysis, only persistent feeding difficulty (ß coefficient = 11, p = 0.001; or LOS = 11 days longer if had feeding difficulty) and ventilator days (ß coefficient 1.7, p < 0.001; or LOS increased 1.7 times for each day of ventilator support) but not the severity of brain injury predicted LOS. CONCLUSION: Unlike neurodevelopmental outcome, LOS is not related to severity of brain injury as defined by the NICHD. KEY POINTS: · The NICHD pattern of brain injury on MRI predicts neurodevelopmental outcome following hypothermia treatment for neonatal HIE.. · LOS did not differ between the infants with and without MRI patterns of severe injury.. · The severity of brain injury as defined by the NICHD was not predictive of the LOS following therapeutic hypothermia..

Higher daily doses of caffeine lowered the incidence of moderate to severe neurodevelopmental disabilities in very low birth weight infants.

AIM: We determined the influence of cumulative dosing of caffeine citrate on the neurodevelopmental outcomes of low birth weight (VLBW) infants at 18-22 months of postmenstrual age. METHODS: This retrospective chart analysis was conducted at Detroit Medical Center, Michigan, USA. The 181 infants we included were born between January 2006 and December 2016, were less than 32 weeks of gestational age and weighed less than 1500 grams. Data on their perinatal and postnatal characteristics were retrieved from their medical records and they were assessed using the Bayley Scales of Infant Development - Third Edition. RESULTS: The 64 infants with no neurodevelopmental disability or a mild disability received a significantly higher average daily dose (mg/kg/day) of caffeine citrate with a median of 7.58 (range 2.7-12.2) mg/kg/day, than the 79 infants with a moderate to severe disability, who received a median of 6.47 (range 3.1-12.5, p = 0.01). The total cumulative dose had no effect on bronchopulmonary dysplasia or neurodevelopmental outcomes. CONCLUSION: A higher average daily dose of caffeine citrate was associated with better neurodevelopmental outcomes of VLBW infants. However, the cumulative dose did not have an impact on their short-term or long-term outcomes. Further research is needed to confirm our findings.

Can Functional Polymorphisms in VEGF and MMP Predict Intraventricular Hemorrhage in Extremely Preterm Newborns?

BACKGROUND: The pathophysiology of intraventricular hemorrhage (IVH) is multifactorial. This study attempts to identify genetic and clinical factors contributing to IVH in newborns with a focus on those born ≤28 weeks of gestation. METHODS: This was a prospective study of 382 consecutive newborns admitted to the neonatal intensive care unit. DNA purification was conducted using standard methods. TaqMan SNP assays were conducted for functional polymorphisms in VEGF (RS699947, RS2010963, RS3025039, and RS1570360) and MMP2 (RS243685 and RS2285053) genes. An RFLP assay was done for a polymorphism in MMP9 (RS3918242). RESULTS: The GG genotype in VEGF RS1570360 (p = 0.013) and the CC genotype in VEGF RS699947 (p = 0.036) were associated with a lower incidence of IVH amongst newborns ≤28 weeks of gestation. Chorioamnionitis, Caucasian race, and patent ductus arteriosus were associated with a higher incidence of IVH. A binary logistic regression analysis of clinical and SNP data that was significant from bivariate analysis demonstrated that VEGF RS1570360 was significantly associated with IVH (p = 0.017). CONCLUSION: This study demonstrated that the GA/AA genotype in VEGF RS1570360 and the AA/AC genotype in VEGF RS699947 were associated with higher incidence rates of IVH in newborns ≤28 weeks of gestation. A future study is warranted to comprehensively examine VEGF polymorphisms in association with IVH.

A preliminary evaluation of glial cell line-derived neurotrophic factor (GDNF) levels in cerebrospinal fluid across various gestational ages and clinical conditions of the neonate.

BACKGROUND: This study aims to investigate glial cell derived neurotrophic factor (GDNF) levels in newborns' umbilical cord blood and cerebrospinal fluid across various perinatal growth parameters and clinical conditions. METHODS: Cord blood from 20 newborns and 58 residual CSF samples (stored after completion of clinical testing) were collected. GDNF levels were determined using GDNF ELISA kits from R&D Systems in triplicates with appropriate controls to eliminate background. RESULTS: Cord blood GDNF levels were significantly higher (p=0.004) in preterm newborns (n=6) (115.05±57.17,pg/ml) when compared to term newborns (n=14) (19.67±10.67,pg/ml). GDNF levels in CSF trended (p=0.07) higher in term newborns (n=10) (19.56±9.11,pg/ml) when compared to preterm newborns at term or post term corrected gestational ages (n=5) (14.49±3.53,pg/ml). CONCLUSIONS: GDNF levels in preterm newborns were higher in cord blood and lower in CSF as compared to term newborns. It is important to further study circulating and CSF-GDNF levels in newborns at different gestational ages and clinical conditions.

Effects of maternal medication use on NGF and IL-6 levels in human breast milk.

BACKGROUND: The objective of this study was to evaluate the effect of maternal medications on nerve growth factor (NGF) and interleukin-6 (IL-6) levels in human breast milk (HBM). METHODS: A total of 30 samples of HBM were collected after consent from consecutively born term newborns. NGF and IL-6 concentrations were analyzed using ELISA assays from R&D Systems. The HBM samples were centrifuged, and the clear portion of the HBM after discarding the fat was analyzed and cytokine data were expressed as NGFC or IL-6C. Ten samples of HBM, which were not centrifuged, were also used in ELISA assays and cytokine data were expressed as NGFF or IL-6F. RESULTS: After exposure to NSAIDs (7636 ± 9610, mean ± SD, pg/mL), the NGFC levels in HBM were significantly higher as compared to those who were exposed to narcotics (522 ± 1000) (p = 0.008). NGFC and IL-6C levels positively correlated with each other in HBM (R = 0.194 p < 0.0001). NGFC levels (360 ± 237) were significantly lower than NGFF levels (888 ± 751) (p < 0.0001). IL-6F was higher than IL-6C levels without statistical significance. CONCLUSION: Further studies are warranted to elucidate effect of maternal medications on cytokine changes in HBM and effect of these cytokine changes on newborn gastrointestinal milieu.

Clinical utility of transcutaneous bilirubinometer (TcB) in very low birth weight (VLBW) infants.

OBJECTIVE: This is a comprehensive study designed to evaluate the clinical usefulness of transcutaneous bilirubinometry (TcB) in very low birth weight (VLBW) newborns of African American (AA) descent. METHODS: TcB was conducted at the anterior superior iliac spine (ASIS), temporal region and sternum within 2 h of total serum bilirubin (TSB) measurements in newborns born at ≤32 weeks' gestation prospectively. Average (AVG) TcB levels were also calculated. The relationships between TSB and TcB levels were analyzed using non-parametric Spearman bivariate correlations, a Bland-Altman plot procedure and a decision tree (DT) analysis. RESULTS: One hundred newborns and 555 TSB data points were available. Eighty-nine percent of the newborns were AA. A significant correlation (P<0.0001) was observed between TSB and TcB values obtained at the ASIS (r=0.73), sternum (0.73), temporal region (0.61) and AVG (0.77). The Bland-Altman plot revealed a good agreement between AVG TcB values and TSB values. A DT analysis indicated that AVG TcB was also found to be the most significant predictor of TSB values in both the no phototherapy (PT) and biliblanket subgroups. CONCLUSION: TcB can be used reliably in VLBW AA newborns in the absence of overhead PT. The use of TcB in monitoring jaundice in VLBW newborns would help decrease the number of blood draws and cost of care.

Insulin-Like Growth Factor-1 Levels in Term Newborns with Hypoxic-Ischemic Encephalopathy.

Objective This study aims to evaluate the correlation of changes in serum insulin-like growth factor-1 (IGF-1) levels with the clinical staging of hypoxic-ischemic encephalopathy (HIE) in term newborns. Study Design A prospective study of 29 newborns with HIE (stage I = 15, stage II + III = 14) and 28 healthy term newborns as the control group was performed in the neonatal intensive care unit. IGF-1 levels were obtained within 6 hours after birth from HIE and control groups and again on day 3 from HIE group. HIE was classified using the Sarnat staging I to III. Results IGF-1 levels were significantly lower in the HIE group than in the control group (p = 0.024). It was lower in the HIE stage II to III group compared with HIE stage I group at birth (p < 0.0001) and on day 3 (p = 0.009). The mean IGF-1 levels were significantly higher on day 3 than on day 1 among stage II to III HIE (p = 0.006) and it was inversely correlated with staging (R = - 0.475, p = 0.009). There was a significant correlation between IGF-1 levels and Apgar score at 5 (R = 0.39, p = 0.042) and 10 minutes (R = 0.38, p = 0.035). Conclusions IGF-1 was lower in HIE and inversely correlated with clinical staging. It was increased with clinical improvement in the subsequent days.

SNAPPE II Score As a Predictor of Survival in Neonates with Congenital Diaphragmatic Hernia: A Single Center Experience.

Introduction Prediction of mortality and morbidity in newborns with congenital diaphragmatic hernia (CDH) is too complex for practical use and may not be accurate. The main objective of this study was to evaluate the usefulness of the CDH Study Group equation and Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE) II score to predict short-term outcomes of newborns with CDH. Materials and Methods Fifty-two neonates were admitted with CDH at Children's Hospital of Michigan from November 2001 to July 2009. Retrospective chart analysis was performed. Predicted survival rates were calculated using the equation published by the CDH Study Group in 2001. SNAPPE II scores were also obtained within 12 hours of admission. Statistical analysis was performed using SPSS statistical package. Results Thirty out of 52 (58%) neonates survived to discharge. SNAPPE II score was significantly lower (p < 0.0001) in survivors (20 ± 15) versus nonsurvivors (41 ± 16). When neonates were stratified according to the CDH Study Group, low-risk patients had a survival rate of 68% (predicted 84%), moderate-risk patients had a survival rate of 43% (predicted 57%), and high-risk patients had a survival rate of 33% (predicted 36%). A total of 83% of the newborns who survived were operated within 48 hours of life, while only 17% of the nonsurvivors were operated within 48 hours of life. Conclusion SNAPPE II scores were better predictors of mortality than the CDH Study Group equation published in 2001. Further exploration is warranted to evaluate validity of survival advantage for those who were operated within 48 hours of life. A future study of combination of prenatal and postnatal factors may help in improved outcomes of the newborns with CDH.

Effect of early caffeine on neurodevelopmental outcome of very low-birth weight newborns.

OBJECTIVES: The objective of this study is to evaluate the effect of early caffeine therapy started within the first 48 h of life on neurodevelopmental outcome in very low birth weight (VLBW) newborns. STUDY DESIGN: VLBW newborns received either caffeine therapy within first 48 h of life (Early group), after 3rd day of life (Late group) or no caffeine during first month of life as per clinical team. A cohort of these newborns (n = 160) who survived were evaluated using Bayley Scale of Infant Development III (BSID III) developmental testing between 18 and 22 months of corrected age. RESULTS: VLBW newborns in the "Early group" had significantly better composite, cognitive, language and motor BSID III scores as compared to those in "Late group" and no caffeine group. Composite BSID III scores were unchanged in the presence or absence of chorioamnionitis for "Early group", while the BSID III scores were significantly lower in the presence of acute chorioamnionitis in "Late group" and no caffeine group. CONCLUSIONS: Early caffeine therapy was associated with better BSID III scores in a cohort of VLBW newborns. Newborns with acute chorioamnionitis benefited from early caffeine therapy.

Hyperglycemia is associated with poor outcome in newborn infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

BACKGROUND: Therapeutic hypothermia (TH) improves survival and neurodevelopmental outcome in neonatal hypoxic ischemic encephalopathy (HIE). Both, hypoglycemia and hyperglycemia are common in infants with HIE. The relationship between hypoglycemia and hyperglycemia, and immediate outcome has not been well described. METHODS: A retrospective analysis of newborn infants with HIE (N = 56) was conducted. Blood glucose concentrations recorded during the first 96 hours were noted. Glucose levels of infants who underwent TH (TH group, N = 20) were compared with those that did not undergo TH (No-TH group, N = 36). The relationship between blood glucose and mortality and/or moderate/severe disability was determined. RESULTS: Mean ± SD blood glucose concentration during the first 24 hours of age was significantly higher in the TH group (148 ± 65 mg/dl), compared with the No-TH group (113 ± 50 mg/dl; p = 0.02), despite a lower glucose infusion rate in the former (4.05 ± 1.77 mg/kg/hr vs. 5.36 ± 2.51 mg/kg/hr; p = 0.04). One hundred percent of infants (n = 9) in the TH group with blood glucose levels >200 mg/dl during the first 24 hours of age died or had moderate/severe disability, compared with 54.5% of those with blood glucose <200 mg/dl in this group (p = 0.03). A similar effect was not present in the No-TH group. CONCLUSION: Hyperglycemia on the first day portends poor outcome in newborn infants undergoing TH for HIE.

Use of Raman spectroscopy to decrease time for identifying the species of Candida growth in cultures.

BACKGROUND: The objective of this study is to establish Raman signatures from pure cultures of different Candida species using Raman Spectroscopy (RS) and use these signatures for rapid identification of unknown Candida species. METHODS: Pure cultures of five Candida species were evaluated using RS to build a limited signature library. 'Raman Processing' (RP) software was used for Principal Component Analysis (PCA) and Differential Functional Analysis (DFA). RESULTS: Eleven principal components described at least 95% variance in the spectra. Raman signatures from these known Candida species were able to identify the species of unknown Candida cultures with 100% accuracy. CONCLUSION: Raman spectroscopy can improve early identification of Candida species and may facilitate early optimal antifungal therapy.

A comprehensive study of clinical biomarkers, use of inotropic medications and fluid resuscitation in newborns with persistent pulmonary hypertension.

Persistent pulmonary hypertension of the newborn (PPHN) is associated with high morbidity and mortality. This study evaluated clinical outcomes in PPHN in relation to echocardiographic (EC) markers, score of neonatal acute physiology, perinatal extension, version II (SNAPPE II) scores, inotropic agent use, and the amount of fluid received as boluses. In this retrospective chart analysis of 98 neonates with PPHN born at >34 weeks' gestation, we compared two cohorts of newborns: those who received inhaled nitric oxide and mechanical ventilation only, and who survived to discharge (Group 1); and those who required extracorporeal membrane oxygenation (ECMO) or who died (Group 2). Of 21 EC parameters assessed, seven were significantly different between Group 1 and Group 2. Eleven (24.4%) newborns in Group 2 had decreased left ventricular (LV) function, compared with three (5.1%) in Group 1 (p = 0.011). Median SNAPPE II scores were significantly higher in Group 2 than in Group 1 (p < 0.001). Newborns in Group 2 also received a significantly higher amount of fluid as boluses during the first 7 days of hospitalization compared with Group 1 (p = 0.018). Following logistic regression analysis, only the difference in total SNAPPE II score retained statistical significance (p < 0.001); however, the total amount of fluid administered as boluses trended higher (p = 0.087) for newborns in Group 2. Our findings show that SNAPPE II scores may help guide counseling for parents of newborns with PPHN regarding the likelihood of death or the need for ECMO. Limiting fluid boluses may improve outcomes in newborns with high SNAPPE II scores and decreased LV function.

Neonatal thyrotoxicosis presenting as persistent pulmonary hypertension.

Neonatal hyperthyroidism is a rare condition caused either by transplacental passage of thyroid-stimulating immunoglobulins from a mother with Graves' disease or by activating mutations of the thyrotropin receptors and α-subunit of G-protein. The clinical features may vary. We report a case of neonatal thyrotoxicosis in an infant born to a mother with Graves' disease, who presented with cardiorespiratory failure and persistent pulmonary hypertension (PPHN). PPHN resolved with specific antithyroid treatment and extracorporeal membrane oxygenation was not required.

Effect of preeclampsia and intrauterine growth restriction on endothelial progenitor cells in human umbilical cord blood.

OBJECTIVES: Endothelial progenitor cells (EPCs) might play important roles in vascular homeostasis. This study evaluated the influence of prematurity, preeclampsia (PE) and intrauterine growth restriction (IUGR) on the EPC population in human umbilical cord blood (CB). METHODS: CB was obtained from 19 preterm and 27 term deliveries. Mononuclear cells were isolated by gradient centrifugation and subjected to flow cytometry to obtain percentages of CD45(d) CD34+, CD45(d) CD133+, CD 45(d) CD34+ CD133+, and CD45(d) CD34+ CD133+ VEGFR-2+ cells. Clinical data were obtained using chart review. RESULTS: Percentages of EPCs were comparable between preterm and term cord blood. CD45(d) CD34+ CD133+ cells were significantly decreased in CB samples obtained from women with PE (n = 14) [0.01, (0.00-2.6), [median, (range)], as compared to those without PE (n = 32) [1.74 (0.00-3.1)] (p = 0.005). CD45(d) CD133+ CD34- cells were significantly increased in presence of PE [0.43, (0.06-1.38)], (p = 0.002). CD45(d) CD34+ CD133+ cells were significantly decreased in presence of IUGR, with no change in CD45(d) CD133+ CD34- cells. Differences in EPC types associated with PE and IUGR were present only in term CB. CONCLUSIONS: Exposure to PE and IUGR is associated with significant changes in EPC population. Future studies are needed to explore the clinical impact of observed changes.

Stable integration of recombinant adeno-associated virus vector genomes after transduction of murine hematopoietic stem cells.

We previously reported that among single-stranded adeno-associated virus (ssAAV) vectors, serotypes 1 through 5, ssAAV1 is the most efficient in transducing murine hematopoietic stem cells (HSCs), but viral second-strand DNA synthesis remains a rate-limiting step. Subsequently, using double-stranded, self-complementary AAV (scAAV) vectors, serotypes 7 through 10, we observed that scAAV7 vectors also transduce murine HSCs efficiently. In the present study, we used scAAV1 and scAAV7 shuttle vectors to transduce HSCs in a murine bone marrow serial transplant model in vivo, which allowed examination of the AAV proviral integration pattern in the mouse genome, as well as recovery and nucleotide sequence analyses of AAV-HSC DNA junction fragments. The proviral genomes were stably integrated, and integration sites were localized to different mouse chromosomes. None of the integration sites was found to be in a transcribed gene, or near a cellular oncogene. None of the animals, monitored for up to 1 year, exhibited pathological abnormalities. Thus, AAV proviral integration-induced risk of oncogenesis was not found in our study, which provides functional confirmation of stable transduction of self-renewing multipotential HSCs by scAAV vectors as well as promise for the use of these vectors in the potential treatment of disorders of the hematopoietic system.