Kernicterus on the Spectrum.

Kernicterus is the potential toxic sequela of extreme neonatal hyperbilirubinemia resulting from the passage of excess free, unconjugated bilirubin across the blood-brain barrier, irreversibly and selectively damaging vulnerable target brain cells including the basal ganglia, the cerebellum, and the auditory system. Kernicterus continues to plague the modern world. Not only does it continue to be uncontrolled in developing countries with underdeveloped medical systems, and health organizations rendered ineffective by the ravages of war, but it also remains prevalent in industrialized countries. In this review, we attempt to clarify the different and overlapping nomenclature used in the past to describe this entity and aim to offer a uniform approach to defining kernicterus spectrum disorder. We also discuss the different spectrum subtypes including motor-predominant kernicterus, auditory neural sensory dysfunction, subtle kernicterus, and kernicterus plus. In addition to reviewing several genetic factors that increase the risk of developing kernicterus, we also present some exciting potential therapeutic approaches.

Platelet Indices: Universally Available Clinical Adjunct for Diagnosing Necrotizing Enterocolitis.

OBJECTIVE: Platelet function parameters can be predictive of several adult diseases and their severity. However, few studies report on the association between platelet indices and neonatal diseases, specifically necrotizing enterocolitis (NEC). The objective of this study is to investigate whether platelet indices are associated with NEC diagnosis and NEC-related mortality. STUDY DESIGN: We retrospectively examined records from infants admitted to the neonatal intensive care unit with a diagnosis of NEC, verified by the presence of pneumatosis on X-ray or pathology at surgery. We compared them with an age-matched group of prematures without NEC. We investigated platelet count, mean platelet volume (MPV), platelet distribution width and red cell distribution width to platelet ratio (RPR) and delta platelets from birth to the time of NEC diagnosis or day of life 14 in the control group. RESULTS: Sixty-nine infants with NEC and 78 control infants were studied. Basic sociodemographic data were similar in both groups. All platelet parameters measured-except for MPV-were significantly associated with NEC diagnosis. Although MPV was not associated with the diagnosis of NEC (p = 0.800), it was significantly associated with NEC-related mortality (p < 0.001). Only total platelet count and RPR were significantly associated with both NEC diagnosis (p < 0.0001) and mortality (p = 0.04 and 0.01, respectively). On multivariable analysis only the change in platelet count from birth to time of diagnosis remained significant. CONCLUSION: While not definitive, this study demonstrates that these routinely available, inexpensive, and easily calculated platelet indices can provide a clinical adjunct in the often-elusive attempts to definitively diagnose NEC in preterm neonates. KEY POINTS: · Platelet indices were associated with NEC diagnosis.. · MPV was predictive of NEC-related mortality.. · Delta platelet count from birth was significantly related to NEC diagnosis..

Mildly Elevated Bilirubin Levels are Associated with Increased Magnetic Resonance Imaging Signal Intensity in the Basal Ganglia of Preterm Neonates.

OBJECTIVE: This study aimed to test whether mildly elevated bilirubin levels in preterm infants are associated with increased signal intensity (SI) on magnetic resonance imaging (MRI) of the basal ganglia (BG). STUDY DESIGN: MRI was performed at term equivalent age in 55 postpreterm infants using a neonatal MRI 1-T scanner. SI of the BG was correlated with mild hyperbilirubinemia. RESULTS: BG MRI SI was significantly increased in infants with mild hyperbilirubinemia on T1-weighted image (T1; p = 0.0393) and T2-weighted image (T2; p = 0.0309). We found no effect of gestational age or sepsis on BG MRI intensity; however, there was a significant effect of acidosis on T1 (p = 0.0223) but not on T2 (p = 0.2316). Infants with combined hyperbilirubinemia and acidosis had the most significant increase in SI on both T1 and T2 respectively (p = 0.0072 and 0.0195, respectively). CONCLUSION: We found a positive association between increased BG MRI SI and mildly elevated bilirubin levels. The effect was greatly strengthened when hyperbilirubinemia was associated with acidosis. KEY POINTS: · Excessive bilirubin is neurotoxic to the neonatal brain. It is deposited in the BG.. · BG MRI SI is increased with bilirubin deposition.. · The premature brain is more vulnerable to bilirubin associated MRI changes..

Detection of Global Brain Injury Using Point-of-Care Neonatal MRI Scanner.

BACKGROUND: Conventional magnetic resonance imaging (MRI) neuroimaging of infants is complicated by the need to transport infants outside the neonatal intensive care unit (NICU), often to distant areas of the hospital. PRIMARY OBJECTIVE: The main aim of this study was to evaluate and compare scoring of images from a novel 1T MRI, which enables neuroimaging within the NICU, with those from a conventional MRI. SECONDARY OBJECTIVE: The second aim of this study was to document improved expediency, and thereby greater patient safety, as reflected by decreased transport time. MATERIALS AND METHODS: Thirty premature infants (mean gestational age: 28.8 ± 2.1 weeks) were scanned consecutively on the novel 1T and 1.5T conventional scanners at term-equivalent age. Orthogonal T1- and T2-weighted images were acquired and reviewed. A global brain abnormality score (Kidokoro) was assigned independently to all images by two radiologists. Interrater agreement was evaluated using the kappa statistic and interscanner agreement was evaluated by Bland-Altman analysis. Transport time to and from both scanners was monitored and compared. RESULTS: Weighted kappas were 0.77 (standard error of measurement [SEM] 0.08; confidence interval [CI]: 0.62-0.92) and 0.86 (SEM: 0.07; CI: 0.73-1), for the 1T and 1.5T scanners, respectively, reflecting substantial interrater agreement. Bland-Altman analysis showed excellent agreement between the two scanners.Transport time was 8 ± 6 minutes for the 1T MRI versus 46 ± 21 minutes for the conventional MRI (p < 0.00001). No adverse events were recorded during transport. Standard transport times will vary from institution to institution. CONCLUSION: Kidokoro scores are similar when comparing images obtained from a 1T MRI with those of a conventional 1.5T MRI, reflecting comparable image quality. Transport time was significantly decreased using the 1T neonatal MRI.

Mitral valve Doppler for cardiac output assessment in preterm neonates.

INTRODUCTION: Cardiac output (CO) assessment in neonates is commonly done by echocardiography. It is unclear which is the best site to measure the left ventricular (LV) outflow tract for CO assessment (the aortic valve [AV] aortic sinus [AS] or the sinotubular junction [STJ]). In the normal heart, the blood flow entering the LV equals the blood ejected from it. Therefore, measuring the blood flow into the LV through the mitral valve (MV) is an alternative way to measure CO. METHODS: In stable preterm infants the MV CO was compared with the right ventricular (RV) CO and the three ways to measure LV CO, in 30 stable preterm neonates. Interobserver variability for MV CO was established. RESULTS: In the 30 neonates studied, MV CO was best correlated and had a minimal bias to the RV CO and LV CO measured at the STJ. Left ventricular CO measured at the AV and AS had significant bias relative to RV CO and MV CO. MV CO inter-observer variability was similar to other echocardiographic CO assessment methods. CONCLUSION: MV CO may be used as an alternative way to assess CO. The STJ may be the optimal site to measure LV outflow tract.

Dual Therapy vs. Monotherapy for the Patent Ductus Arteriosus: A Systematic Review.

To evaluate the efficacy of dual patent ductus arteriosus (PDA) pharmacotherapy compared to monotherapy we searched Medline, Embase, Cochrane Library, and references of relevant articles through October 20, 2021 for randomized clinical trials (RCTs) and cohort studies comparing dual PDA treatment vs. monotherapy. Data were analyzed using a fixed effects model. The fixed effects model assumes that all studies included in a meta-analysis are estimating a single true underlying effect, that of ductal closure. Primary outcome was ductal closure; secondary outcome was surgical ligation. Of 170 articles retrieved, three cohort studies and two RCTs were included, totaling 470 patients: 384 babies received monotherapy and 86 dual therapy. Because of the small numbers, RCTs and cohort studies were pooled for analysis. Ductus closed in 67% of those who received combination compared with 58% those with monotherapy. Overall fixed effect shows an OR of 1.97 [1.10; 3.53; p = 0.023] favoring dual therapy. Dual pharmacologic treatment appears more effective than monotherapy. Future well-powered, high-quality, prospective RCTs are needed to further investigate this potential approach.

A simple noninvasive biomarker can reflect both the acute and chronic pulmonary impact of patent ductus arteriosus shunting.

AIM: The SFR (SpO2 /FiO2 ratio) offers a continuous, noninvasive reflection of pulmonary function regardless of whether the baby is ventilated or breathing spontaneously. We hypothesized that significant patent ductus arteriosus (PDA) shunting would impair pulmonary oxygen diffusion, reflected by decreased SFR; and that early PDA related decreases in SFR predict subsequent chronic lung disease (CLD). METHODS: We retrospectively examined records from preterm neonates ≤30 weeks gestational age. Ductal shunting was graded for severity by first week echocardiogram. SFR was calculated as SpO2 /FiO2 and recorded on Day 7 of life and 36 weeks postmenstrual age (PMA). RESULTS: We studied 104 infants: 65 with closed duct, 17 with hemodynamically insignificant PDA, and 22 with hemodynamically significant (hsPDAs). CLD developed in 9 (14%) of those with closed ducts; 6 (35%) of those with hisPDA; and in 12 (55%) of those with hsPDA (p = 0.005). SFR values at 1 week postnatally were decreased in those with hsPDA and with hisPDA as compared with those with closed ducts (closed ducts 452 [448-457] vs. hisPDA 396 [294-442] vs. hsPDA 327 [235-369]; p = 0.00001). However, at 36 weeks only SFRs of babies with hsPDA remained significantly lower (467 [461-467] vs. 467 [413-471] vs. 369 [262-436] for closed vs. hisPDA vs. hsPDA respectively; p = 0.000148). Using ROC curve analysis, Week 1 SFR was strongly associated with hsPDA (area under curve [AUC] = 0.770; p < 0.0001) and highly predictive (AUC = 0.801; p < 0.0001) of CLD at 36 weeks PMA. CONCLUSION: Early decreases in SFR reflect both the acute and chronic pulmonary impact of PDA shunting, possibly providing the missing link supporting an association between hemodynamically significant PDA and subsequent CLD.

Hypercapnia: An Added Culprit in Gray Matter Injury in Preterm Neonates.

Over the last decade, there has been increased recognition of diverse forms of primary gray matter injury (GMI) in postpreterm neonates. In this study, we aimed to assess whether early neonatal hypercapnia in the preterm infant was associated with GMI on magnetic resonance imaging (MRI) at term equivalent age (TEA). All blood gases taken during the first 2 weeks of life were analyzed for hypercapnia. MRI was performed at TEA postpreterm infants using a unique neonatal MRI 1T scanner. The neonatal MRI scans were assessed using a standardized scoring system, the Kidokoro scoring system, a method used to assess abnormal brain metrics and the presence and severity of brain abnormalities. Subscores are assigned for different regions of the brain. Twenty-nine infants were studied, about half of whom had evidence of some gray matter abnormality. Fifteen of the infants were hypercapnic. The hypercapnic infants had significantly higher deep gray matter abnormality readings as compared with the nonhypercapnic infants (12 [11; 12] vs. 10 [8; 11], respectively; p = 0.0106). Correlations were observed between peak pCO2 over the first 2 weeks of life and the overall gray matter abnormality score (GMAS) at TEA, and between the percentage of hypercapnic blood gases during the first 2 weeks of life and the GMAS. All of the infants in our population who had severe GMI at TEA were hypercapnic in the first 2 weeks of life. In conclusion, our data show a correlation between early hypercapnia in preterm neonates and GMI at TEA.

Does Early Neonatal Thrombocytopenia Affect Ductal Therapeutic Response to Acetaminophen in Preterm Neonates?

OBJECTIVE: Perinatal thrombocytopenia has been shown to affect responsiveness to therapeutic ductal closure with cyclooxygenase (COX) inhibitors. This has not been studied in responsiveness to acetaminophen, which has less effect on platelet function. The objective of this study was to evaluate whether thrombocytopenia affects ductal responsiveness to acetaminophen. STUDY DESIGN: This study was a retrospective review of preterm neonates <1,500 g. Echocardiograms were performed within the first week of life; if ductal status was found to be hemodynamically significant, infants were treated with acetaminophen. RESULTS: We studied 254 infants. Fifty-seven of these (22%) had a hemodynamically significant patent ductus arteriosus (hsPDA) and were treated with acetaminophen. Forty (70%) of those treated responded with ductal closure after one to two courses of acetaminophen. Seventeen infants were considered nonresponsive, requiring the addition of ibuprofen and/or surgical ligation. Sixty seven of the 254 infants (26%) developed moderate thrombocytopenia (platelets <100,000) within the first 10 days of life, more within the hsPDA group (54 vs. 18% p < 0.001); however, no differences in platelet-related parameters were observed between those who did and did not respond to acetaminophen treatment when comparing infants with hsPDA. Twenty-six of the 67 thrombocytopenic infants were already thrombocytopenic prior to acetaminophen treatment, and 19 of these 26 (73%) with pretreatment thrombocytopenia responded to acetaminophen treatment-with the overall response rate of 70%. CONCLUSIONS: This study is the first to document that, in contrast to the COX inhibitors, there is no association between early neonatal thrombocytopenia and ductal therapeutic responsiveness to acetaminophen. KEY POINTS: · Perinatal thrombocytopenia affects ductal closure with COX inhibitors.. · In contrast to the COX inhibitors, acetaminophen responsiveness is not affected by thrombocytopenia.. · Acetaminophen can be recommended to close hsPDA in the presence of thrombocytopenia..

Early breast expression for very low birth infants admitted to neonatal intensive care unit: the challenges of cesarean deliveries.

AIM OF THE STUDY: In preterm infants, the use of human milk is associated with unique benefits. However, successful breast feeding rates and prolonged breastfeeding duration is often reduced in preterm infants. Nevertheless, early initiation of breast expression after birth is believed to be one of the major variables that should improve the odds of successful breastfeeding. Hence, we aimed to assess correlation between timing of milk expression initiation and volume produced in regards to mode-of-delivery. MATERIALS AND METHODS: Prospective, observational study. Mothers delivering infants weighing < 1500 g measured 24-h milk volumes on days 1-7, 14, and 21. RESULTS: Mothers delivering vaginally (N = 11) expressed milk sooner (3.82 ± 5.03 h) than mothers in the cesarean group (N = 42; 11.5 ± 9.1 h). There were no significant differences in daily number of expressions (i.e. day 1 3.6 ± 1.6 versus 2.5 ± 2.1, p = .125) or daily volume (i.e. day 1 - 7.5 ± 6.1 ml versus 11.6 ± 22.9 ml, p = .563), until day 6 from which, both were lower in the cesarean group (i.e. day 21 - number - 6.0 ± 1.3 versus 4.6 ± 1.7, p = .029; volume - 796 ± 465ml versus 435 ± 368ml, p = .018). Expressed volume initially did not correlate with earlier expression, however, latter expressed volume inversely correlated with earlier expression. In multivariate-analysis, mode of delivery, gestational age, and daily number of expressions were correlated with volumes on day 21 (p = .001). CONCLUSIONS: Earlier human-milk expression is related to volumes on the second and the third week of lactation. This is overwhelmed by delivery mode, and by frequent milk expression from day 2. When early milk expression is not possible, more frequent milk expression might help increasing volumes.

Hyperbilirubinemia in the Term Infant: Re-evaluating What We Think We Know.

This article attempts to highlight contemporary issues relating to term neonatal hyperbilirubinemia and to focus attention on controversial issues and concepts with the potential to effect change in clinical approach. On the one hand, the focus is bilirubin neurotoxicity, which is now known to encompass a wide, diverse spectrum of features. The various aspects of this spectrum are outlined and defined. On the other hand, bilirubin also possesses antioxidant properties. As such, mild hyperbilirubinemia is suggested as actually offering the neonate some protective advantage.

Infant delivery and maternal stress during the COVID-19 pandemic: a comparison of the well-baby versus neonatal intensive care environments.

OBJECTIVE: To describe impact of COVID-19 pandemic on stress and mood of new mothers, in particular in neonatal intensive care unit (NICU); a secondary objective was to assess whether customary social gender distancing practiced by ultra-religious Jews and Muslims offers built-in anti-stress protection. METHODS: Cross-sectional, observational survey of mothers of 52 normal newborn nursery (NNB) and 52 NICU infants. In all, 86 filled all the 6 questionnaires (Demographics, COVID-19 virus experience, Mental Health Inventory, Neonatal Satisfaction Survey, Parental Stressor Scale, and Questionnaire of Coping Strategies). RESULTS: Most mothers stated that COVID-19 pandemic had hurt social and family relationships, maternal role, and expressed stress and loneliness. Mothers of NICU infants had higher degree of helplessness. Religious social distancing was not protective. Background tendency to coping poorly with stress and depression most highly predicted stress. CONCLUSION: COVID-19 pandemic harms psychosocial well-being of most mothers. Detection of high-risk individuals is necessary to provide appropriate support.

The Saga of Pulse Oximetry Screening for Critical Congenital Heart Disease in Israel: A Historical Perspective.

BACKGROUND: Many countries have adopted a mandatory routine pulse oximetry screening of newborn infants to identify babies with otherwise asymptomatic critical congenital heart disease (CCHD). OBJECTIVES: To describe the current status of pulse oximetry CCHD screening in Israel, with a special emphasis on the experience of the Shaare Zedek Medical Center. METHODS: We review the difficulties of the Israeli Medical system with adopting the SaO2 screening, and the preliminary results of the screening at the Shaare Zedek Medical Center, both in terms of protocol compliance and CCHD detection. RESULTS: Large scale protocol cannot be implemented in one day, and regular quality assessment programs must take place in order to improve protocol compliance and identify the reasons for protocol failures. CONCLUSIONS: Quality control reviews should be conducted soon after implementation of the screening to allow for prompt diagnosis and quick resolution.

The use of intramuscular glucagon to prevent IV glucose infusion in early neonatal hypoglycemia.

OBJECTIVE: To investigate the success rate of intramuscular (IM) glucagon in preventing need for IV glucose and describe its glycemic effect. METHODS: Retrospective study of 158 consecutive term neonates with feeding-resistant hypoglycemia treated with glucagon. RESULTS: After glucagon, blood glucose (BG) increased in all but 1 infant by 25.9 ± 17.1, 42.1 ± 21.1, and 39.2 ± 28.3 mg/dL (1.4 ± 0.9, 2.3 ± 1.2, 2.2 ± 1.6 mmol/L) at 30, 60 and 120 mins respectively. In multivariable logistic regression, glucagon success was dependent upon gender (increased male risk) (P = 0.021), meeting American Academy of Pediatrics (AAP) criteria for immediate IV glucose (P = 0.004), birth weight, (P = 0.018) and delta glucose concentration at 60 min (P = 0.013). After IM glucagon, 24 out of 49 infants that met AAP criteria for immediate IV glucose (49%) ended up not requiring any additional intervention. CONCLUSIONS: Glucagon increases BG nearly universally in hypoglycemic infants and allowed reducing the number of infants that needed immediate IV glucose infusion therapy by ≈half.

Neonatal Polycythemia and Hypoglycemia in Newborns: Are They Related?

OBJECTIVE: This study aimed to test whether neonatal hypoglycemia (NH) is more common in infants with neonatal polycythemia (NP). STUDY DESIGN: This is a retrospective study based on universal screening of NH and targeted screening for NP. Polycythemia was defined as venous hematocrit ≥ 65%. NH was defined as whole blood glucose (BG) concentration < 48 mg/dL (measured using a "point-of-care" analyzer [Accu-Chek]). RESULTS: The study population consisted of 119 consecutive term polycythemic infants and 117 controls. There were no significant differences between the two groups in perinatal characteristics, minimal BG concentration, and rate of hypoglycemia. In a stepwise backward multiple regression where NH was the dependent variable, only maternal gestational diabetes mellitus (p = 0.032) and toxemia (p = 0.001) remained significant, whereas NP was insignificant. CONCLUSION: NH is not more common in NP infants than in non-NP infants. We suggest that the occurrence of NH in infants with NP might be related to the common risk factors of the two morbidities.

Head Circumference Growth Is Enhanced by SMOFlipid in Preterm Neonates.

BACKGROUND: Suboptimal fat intake during the early postnatal weeks significantly affects brain growth and maturation. Studies to date have focused on the quantity rather than the quality of fat intake. OBJECTIVE: We hypothesized that early nutrition of premature neonates should also include optimization of the type of fat intake, and thus those receiving SMOFlipid, a balanced multicomponent lipid emulsion, would have improved head growth as measured by head circumference (HC) at discharge. STUDY DESIGN: We retrospectively reviewed HC in infants weighing <1,500 g who were hospitalized for two or more weeks during a 20-month period, in which all preterm infants received fat as Lipofundin, and the following 20-month period, in which all such infants received SMOFlipid.Lipids were dosed up to 3 g/kg/day and reduced as enteral nutrition progressed. Parenteral fish oil (Omegaven) was permitted as rescue therapy during both periods. RESULTS: Period 2 infants had better head growth (0.79 [0.69,0.90] vs. 0.75 [0.64,0.86] cm/week; p = 0.0158). More infants reached discharge with an HC of ≥50 percentile (51 vs. 31%; p = 0.0007), and fewer infants had an HC of ≤3 percentile (11 vs. 14%; p = 0.023). Median length of stay was reduced by more than 1 week.A multivariable regression was performed using the weekly increase in HC as the dependent variable, and the time epoch, birth weight, gestational age, hospitalization days, and gender as independent variables. Only the time epoch and days of hospitalization were significant (both p < 0.0001). CONCLUSION: Our data offer preliminary evidence of improved brain growth in those receiving a balanced lipid emulsion as compared with a soybean oil emulsion.

Elevated Nucleated Red Blood Cells in Neonates with Down Syndrome and Pulmonary Hypertension.

We report an association between higher absolute nucleated red blood cells and mean corpuscular volume and idiopathic persistent pulmonary hypertension of the newborn in neonates with Down syndrome. Elevation of these blood indicies should prompt echocardiographic studies to monitor pulmonary arterial pressures.