Association of a Delayed Cord-Clamping Protocol With Hyperbilirubinemia in Term Neonates.

OBJECTIVE: To evaluate the implementation of a delayed cord-clamping protocol at an academic medical center, and its short-term associations on term neonates. METHODS: This was a retrospective cohort study of women aged 18 years or older delivering a term neonate at an academic medical center before and 5-7 months after implementation of a universal delayed cord-clamping protocol (October-December 2015 and October-December 2016, respectively). The primary outcome measure was the mean peak neonatal transcutaneous bilirubin level, with secondary outcome measures including mean initial transcutaneous bilirubin levels, mean serum bilirubin levels, number of serum bilirubin levels drawn, incidence of clinical jaundice, and phototherapy. RESULTS: Protocol adherence was 87.8%. Data are presented on 424 neonates. The mean peak neonatal transcutaneous bilirubin levels were significantly higher among neonates in the postprotocol group (10.0±3.4 mg/dL vs 8.4±2.7 mg/dL, P<.01). More neonates in the postprotocol group were diagnosed with jaundice (27.2% vs 16.6%; odds ratio [OR] 1.88; 95% CI 1.17-3.01) and required serum blood draws (43.7% vs 29.4%; OR 1.86; 95% CI 1.25-2.78). However, there were no differences in mean peak serum bilirubin levels between groups (9.7±3.0 mg/dL vs 9.1±3.1 mg/dL, P=.17) or need for phototherapy (5.2% vs 6.6%, OR 1.28; 95% CI 0.57-2.89). CONCLUSION: Implementation of a delayed cord-clamping protocol for term neonates was associated with significantly higher mean transcutaneous bilirubin levels, an increased number of serum blood draws, and more clinical diagnoses of jaundice, although there was no increase in the incidence of phototherapy.

Effect of metoclopramide administration to mothers on neonatal bilirubin and maternal prolactin: a randomized, controlled, clinical trial.

BACKGROUND: Jaundice is a common neonatal problem. This study was conducted to determine the effect of metoclopramide on neonatal bilirubin and maternal prolactin (primary outcomes) and milk volume (secondary outcome). METHODS: This triple-blind, randomized, controlled, clinical trial was conducted on 112 mothers. The participants were assigned to the intervention (metoclopramide) and control groups (placebo) using block randomization. Ten-mg metoclopramide and placebo tablets were taken by the participants three times a day. The intervention began in the first 2-10 hours after childbirth and continued until the fifth day. The mothers' prolactin level was measured on the first morning after the intervention and on the sixth day (1 day after the intervention was over). Neonatal total bilirubin was also measured before the intervention and on the sixth day. RESULTS: After the intervention, the two groups did not differ significantly in terms of the mean neonatal indirect bilirubin (P = 0.565) and milk volume (P = 0.261), but the mean serum prolactin was significantly higher in the metoclopramide group compared to the placebo group (adjusted mean difference 37; 95% confidence interval 58.1-16.5; P = 0.001). CONCLUSIONS: Metoclopramide increased maternal serum prolactin but had no effects on neonatal jaundice. The insufficient numbers of studies on this subject mandate further research.

Paediatric fatty liver disease (PeFLD): All is not NAFLD - Pathophysiological insights and approach to management.

The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease, but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease has since become the most common chronic liver disease in adults owing to the global epidemic of obesity. However, in paediatrics, the term NAFLD seems incongruous: alcohol consumption is largely not a factor and inherited metabolic disorders can mimic or co-exist with a diagnosis of NAFLD. The term paediatric fatty liver disease may be more appropriate. In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. We offer this model as a means to provide pathophysiological insights and an approach to management of the ever more complex subject of fatty liver.

Management options for cholestatic liver disease in children.

INTRODUCTION: Due to a peculiar age-dependent increased susceptibility, neonatal cholestasis affects the liver of approximately 1 in every 2500 term infants. A high index of suspicion is the key to an early diagnosis, and to implement timely, often life-saving treatments. Even when specific treatment is not available or curative, prompt medical management and optimization of nutrition are of paramount importance to survival and avoidance of complications. Areas covered: The present article will prominently focus on a series of newer diagnostic and therapeutic options of cholestasis in neonates and infants blended with consolidated established paradigms. The overview of strategies for the management reported here is based on a systematic literature search published in English using accessible databases (PubMed, MEDLINE) with the keywords biliary atresia, choleretics and neonatal cholestasis. References lists from retrieved articles were also reviewed. Expert commentary: A large number of uncommon and rare hepatobiliary disorders may present with cholestasis during the neonatal and infantile period. Potentially life-saving disease-specific pharmacological and surgical therapeutic approaches are currently available. Advances in hepatobiliary transport mechanisms have started clarifying fundamental aspects of inherited and acquired cholestasis, laying the foundation for the development of possibly more effective specific therapies.

Effect of Early Skin-to-Skin Contact to Breast Milk Volume and Breastfeeding Jaundice at 48 Hours after Delivery.

Objective: To evaluate effect of maternal-infant skin-to-skin contact in the first hour postbirth to breast milk volume and breastfeeding jaundice at 48 hours after delivery. Material and Method: This was a prospective cohort study. The subjects were 133 postpartum women, who delivered without complications between October 2013 and July 2014 at MSMC and was allocated into early skin-to-skin contact (SSC) and control groups. In the SSC group, the newborns were placed prone on mothers' bare chest after finishing routine newborn care for at least 30 minutes. The breast milk volume were collected at 16-24 hours, 40-48 hours postpartum and before discharge. The infants' microbilirubins were measured at 48 hours postbirth. Demographic data including age, parity, GA at delivery, birth weight and gender of the newborns were collected. Data were analyzed using descriptive statistics, Chi-square test and t-test. Results: The mean breast milk volume in the SSC group were 5.68+5.46, 16.98+11.09, and 31.44+20.06 milliliters at 16-24 hours, 40-48 hours postpartum and before discharge, respectively, while the mean breast milk volume in the control group were 6.19+5.77, 13.99+13.07 and 25.81+20.26 milliliters, respectively in the same period of time, and no statistically difference of the breast milk volume was found between the two groups. The percentage of mothers who had the onset of lactation within 24 hours postpartum in the SSC group (95.51%, 85/89) was significantly higher than the control group (77.27%, 34/44, p<0.01). The percentages of breastfeeding jaundice cases were 16.85 in the SSC group and 27.27 in the control group, and had no significant difference. Conclusion: Early skin-to-skin contact had no direct effect to breast milk volume and incidence of breastfeeding jaundice at 48 hours after delivery but related to the onset of lactation within 24 hours postpartum.

Visuocortical function in infants with a history of neonatal jaundice.

PURPOSE: High concentrations of unconjugated bilirubin are neurotoxic and cause brain damage in newborn infants. However, the exact level of bilirubin that may be neurotoxic in a given infant is unknown. The aim of this study was to use a quantitative measure of neural activity, the swept parameter visual evoked potential (sVEP) to determine the relationship between neonatal bilirubin levels and visual responsivity several months later. METHODS: We compared sVEP response functions over a wide range of contrast, spatial frequency, and Vernier offset sizes in 16 full-term infants with high bilirubin levels (>10 mg/dL) and 18 age-matched infants with no visible neonatal jaundice, all enrolled at 14 to 22 weeks of age. The group means of sVEP thresholds and suprathreshold response amplitudes were compared. The correlation between individual sVEP thresholds and bilirubin levels in jaundiced infants was studied. RESULTS: Infants who had a history of neonatal jaundice showed lower response amplitudes (P < 0.05) and worse or immeasurable sVEP thresholds compared with control infants for all three measures (P < 0.05). Swept parameter visual evoked potential thresholds for Vernier offset were correlated with bilirubin level (P < 0.05), but spatial acuity and contrast sensitivity measures in the infants with neonatal jaundice were not (P > 0.05). CONCLUSIONS: These results indicate that elevated neonatal bilirubin levels affect measures of visual function in infancy up to at least 14 to 22 weeks of postnatal age.

Age-dependent pattern of cerebellar susceptibility to bilirubin neurotoxicity in vivo in mice.

Neonatal jaundice is caused by high levels of unconjugated bilirubin. It is usually a temporary condition caused by delayed induction of UGT1A1, which conjugates bilirubin in the liver. To reduce bilirubin levels, affected babies are exposed to phototherapy (PT), which converts toxic bilirubin into water-soluble photoisomers that are readily excreted out. However, in some cases uncontrolled hyperbilirubinemia leads to neurotoxicity. To study the mechanisms of bilirubin-induced neurological damage (BIND) in vivo, we generated a mouse model lacking the Ugt1a1 protein and, consequently, mutant mice developed jaundice as early as 36 hours after birth. The mutation was transferred into two genetic backgrounds (C57BL/6 and FVB/NJ). We exposed mutant mice to PT for different periods and analyzed the resulting phenotypes from the molecular, histological and behavioral points of view. Severity of BIND was associated with genetic background, with 50% survival of C57BL/6­Ugt1(-/-) mutant mice at postnatal day 5 (P5), and of FVB/NJ-Ugt1(-/-) mice at P11. Life-long exposure to PT prevented cerebellar architecture alterations and rescued neuronal damage in FVB/NJ-Ugt1(-/-) but not in C57BL/6-Ugt1(-/-) mice. Survival of FVB/NJ-Ugt1(-/-) mice was directly related to the extent of PT treatment. PT treatment of FVB/NJ-Ugt1(-/-) mice from P0 to P8 did not prevent bilirubin-induced reduction in dendritic arborization and spine density of Purkinje cells. Moreover, PT treatment from P8 to P20 did not rescue BIND accumulated up to P8. However, PT treatment administered in the time-window P0-P15 was sufficient to obtain full rescue of cerebellar damage and motor impairment in FVB/NJ-Ugt1(-/-) mice. The possibility to modulate the severity of the phenotype by PT makes FVB/NJ-Ugt1(-/-) mice an excellent and versatile model to study bilirubin neurotoxicity, the role of modifier genes, alternative therapies and cerebellar development during high bilirubin conditions.

Bodyweight loss in predicting neonatal hyperbilirubinemia 72 hours after birth in term newborn infants.

BACKGROUND: Severe dehydration is generally believed to be a cause of significant hyperbilirubinemia in newborn babies. This study aimed to analyze the weight loss of healthy term newborn infants at 24, 48 and 72 hours after birth to predict significant hyperbilirubinemia at 72 hours. METHODS: From January 2007 to December 2008, we conducted this retrospective chart review by measuring total bilirubin (transcutaneous and serum) in 343 healthy, term newborns with a birth body weight of more than 2500 g. We then analyzed the association between body weight loss (BWL) and significant hyperbilirubinemia (total bilirubin more than 15 mg/dL) 72 hours after birth. Receiver operating characteristic curves were used to evaluate the appropriate cutoff BWL percentages on the first three days after birth for the prediction of neonatal hyperbilirubinemia 72 hours after birth. RESULTS: A total of 115 (33.5%) neonates presented with significant hyperbilirubinemia 72 hours after birth, and the percentages of BWL on the first three days were all higher than those in the non-significant hyperbilirubinemia group (all p < 0.05). Breastfeeding was not statistically correlated with significant hyperbilirubinemia (p=0.86). To predict significant hyperbilirubinemia 72 hours after birth, receiver operating characteristic curve analysis showed that the optimum cutoff BWL percentages were 4.48% on the first day of life (sensitivity: 43%, specificity: 70%, positive likelihood ratio [LR+]: 1.43, and negative likelihood ratio [LR-]: 0.82), 7.60% on day 2 (sensitivity: 47%, specificity: 74%, LR+: 1.81, LR-: 0.72), and 8.15% on day 3 (sensitivity: 57%, specificity: 70%, LR+: 1.92, LR-: 0.61) (all p < 0.05). CONCLUSIONS: BWL on the first three days after birth may be a predisposing factor for neonatal hyperbilirubinemia, and may also serve as a helpful clinical factor to prevent significant hyperbilirubinemia 72 hours after birth. The optimal BWL cutoff percentages on the first three days after birth presented in this study may predict hyperbilirubinemia and indicate the need for supplementary feeding.

Clinical update: understanding jaundice in the breastfed infant.

Breastfed infants are more likely to be jaundiced than infants who are formula fed. Community practitioners need to understand the physiology of jaundice and the issues associated with breastfeeding so that they can support parents. Visible jaundice is a result of hyperbilirubinaemia and, in most cases, is harmless and caused by normal physiological processes. It does, however, require detection monitoring and sometimes treatment to prevent rare but serious health complications. Although some debate remains over the association between breastfeeding and jaundice, the literature suggests that in the breastfed infant, early onset jaundice may be a result of insufficient intake of breast milk and prolonged jaundice may be related to a constituent of breast milk itself (breast milk jaundice). Early breastfeeding support to promote good positioning, attachment and baby-led feeding may help prevent early onset jaundice. Management of jaundice in the breastfed infant involves referral to local services to determine bilirubin levels and exclude pathologies.

Developmental physiology of late and moderate prematurity.

This is a brief review of the developmental physiology of selected organ and functional systems in moderate and late preterm infants. This outline provides a discussion of the physiological underpinnings for some of the clinical conditions seen in this group of infants, including hypothermia, hypoglycemia, respiratory distress syndrome, transient tachypnea, severe respiratory failure, apnea, feeding difficulties, jaundice, and increased susceptibility to infections.

Prevention of neurodevelopmental sequelae of jaundice in the newborn.

Although its cause, jaundice in the newborn, is extremely common, the disabling neurological disorder kernicterus is very rare. Kernicterus may be prevented by selecting those infants who are at risk of extreme jaundice or who may be particularly vulnerable to bilirubin neurotoxicity. Because the tools for achieving that goal are inadequate, a secondary strategy is needed. This involves a plan for emergency treatment of severely jaundiced infants, in particular those who present with neurological symptoms. In this paper I review the strategies for preventing extreme jaundice, and for reversing neurotoxicity in those infants for whom the principal strategies fail. Briefly, the tools for prevention include measurement of bilirubin while the infant is staying in the maternity unit, plotting the value on an hour-specific chart, assessing other risk factors for jaundice, and educating the parents. Emergency treatment should include immediate, high-irradiance phototherapy, consideration of intravenous immune globulin, and preparation for an exchange transfusion.

Hearing status in neonatal hyperbilirubinemia by auditory brain stem evoked response and transient evoked otoacoustic emission.

Hyperbilirubinemia at neonatal period is one of the major deteriorating factors of the auditory system. If left untreated, it may cause certain cerebral damage. This study aims to evaluate the impact of hyperbilirubinemia on the hearing of neonate. This study was conducted on 35 newborn babies with jaundice (bilirubin more than 20 mg/dL). Auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) tests were performed, after treatment and one year after. ABR test results indicated that 26 children (74.3%) had normal hearing but 9 (25.7%) suffered from an impairment. As for TEOAE test, 30 children (85.7%) passed whereas the remaining (14.3%) seemed to be failures. The comparative results of the two tests pointed to autonomic neuropathy /autonomic dysreflexia symptoms in 5 babies. Due to the high incidence of autonomic neuropathy/autonomic dysreflexia among hyperbilirubinemic babies, screening in this regard seems reasonable. Our result emphasizes the necessity of more experiments on the afflicted areas.

Understanding neonatal jaundice: a perspective on causation.

Neonatal jaundice can be best understood as a balance between the production and elimination of bilirubin, with a multitude of factors and conditions affecting each of these processes. When an imbalance results because of an increase in circulating bilirubin (or the bilirubin load) to significantly high levels (severe hyperbilirubinemia), it may cause permanent neurologic sequelae (kernicterus). In most infants, an increase in bilirubin production (e.g., due to hemolysis) is the primary cause of severe hyperbilirubinemia, and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and/or polymorphism. Combining information about bilirubin production and genetic information about bilirubin elimination with the tracking of bilirubin levels means that a relative assessment of jaundice risk might be feasible. Information on the level of bilirubin production and its rate of elimination may help to guide the clinical management of neonatal jaundice.

The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects.

Class III multidrug resistance P-glycoproteins, Mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an ABCB4 gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation. Several ABCB4 mutations have been identified in children with PFIC3 and are associated with low level of phospholipids in bile leading to a high biliary cholesterol saturation index. ABCB4 mutations are associated with loss of canalicular MDR3 protein and /or loss of protein function. There is evidence that a biallelic or monoallelic ABCB4 defect causes or predisposes to several human liver diseases (PFIC3, low phospholipid associated cholelithiasis syndrome, intrahepatic cholestasis of pregnancy, drug-induced liver injury, transient neonatal cholestasis, adult biliary fibrosis, or cirrhosis). Most patients with MDR3 deficiency have a favorable outcome with ursodeoxycholic acid (UDCA) therapy, but some PFIC3 patients who do not respond to UDCA treatment still require liver transplantation. The latter should be good candidates for a targeted pharmacologic approach and/or to cell therapy in the future.