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.

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.

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.

An emergency medicine approach to neonatal hyperbilirubinemia.

Jaundice (also known as hyperbilirubinemia) is a yellowish-greenish pigmentation of the sclera and skin caused by an increase in bilirubin production or a defect in bilirubin elimination. Management of hyperbilirubinemia is one of the most common reasons for readmission of a newborn. Prolonged unconjugated hyperbilirubinemia can result in acute bilirubin encephalopathy and eventually develop into chronic bilirubin encephalopathy (kernicterus). Kernicterus, the feared complication of hyperbilirubinemia, was considered almost extinct but has recently re-emerged despite virtual elimination of Rh disease. This review provides a systematic approach to the presentation, evaluation, and management of the jaundiced newborn.

Randomized, controlled trial of early intravenous nutrition for prevention of neonatal jaundice in term and near-term neonates.

BACKGROUND: This study was undertaken to investigate the effects of early parenteral nutrition on prevention of neonatal jaundice in term and near-term neonates who could not be enterally fed. PATIENTS AND METHODS: Seventy-two infants were randomized into 2 groups: the early parenteral nutrition group (group 1) received 1.0 g/kg/d amino acids beginning within the first day and 1.0 g/kg/d lipid added the next day. The conventional nutrition group (group 2) started on a solution containing 10% glucose and electrolytes in the first 72 hours of life, followed by 0.5 g/kg/d amino acids and lipid. Amino acids and lipid were each increased by 0.5 g/kg/d to a maximum of 3.0 g/kg/d in both groups. Main outcome measures were energy intake; serum bilirubin levels at 24, 48, and 72 hours; need for phototherapy; and duration of phototherapy. RESULTS: Higher energy intake was achieved after the first day in group 1. Daily serum bilirubin levels did not significantly differ between groups. Nine patients in each group required phototherapy. The initiation times of phototherapy were 92.9 hours +/- 25.5 in group 1 and 83.1 hours +/- 28.5 in group 2. Durations of phototherapy were 37.3 hours +/- 11.1 in group 1 and 52.0 hours +/- 20.7 in group 2. There were no significant differences in the requirement, initiation time, and duration of phototherapy. CONCLUSIONS: Early parenteral nutrition has no proven benefit in terms of therapy requirement or severity and duration of neonatal jaundice compared with conventional parenteral nutrition in term and near-term infants who could not be enterally fed.

Jaundice in the full-term newborn.

Jaundice is a common problem affecting over half of all full-term and most preterm infants. Jaundice describes the yellow orange hue of the skin caused by excessive circulating levels of bilirubin that accumulate in the skin. In most healthy full-term newborns, jaundice is noticed during the first week of life. Shortened hospital stays and inconsistent follow up, especially for first-time breastfeeding mothers, prompted the American Academy of Pediatrics (AAP) to update management guidelines. Health care providers need to be familiar with the diagnosis and management of jaundice to prevent brain, vision, and hearing damage. Treatment of choice for jaundice remains close observation and frequent feeding followed by phototherapy, and finally exchange transfusion for severe or refractory cases.

Fundamentals of phototherapy for neonatal jaundice.

Phototherapy is the use of visible light for the treatment of hyperbilirubinemia in the newborn. This relatively common therapy lowers the serum bilirubin level by transforming bilirubin into water-soluble isomers that can be eliminated without conjugation in the liver. The dose of phototherapy largely determines how quickly it works; the dose, in turn, is determined by the wavelength of the light, the intensity of the light (irradiance), the distance between the light and the infant, and the body surface area exposed to the light. Commercially available phototherapy systems include those that deliver light via fluorescent bulbs, halogen quartz lamps, light-emitting diodes, and fiberoptic mattresses. Proper nursing care enhances the effectiveness of phototherapy and minimizes complications. Caregiver responsibilities include ensuring effective irradiance delivery, maximizing skin exposure, providing eye protection and eye care, carefully monitoring thermoregulation, maintaining adequate hydration, promoting elimination, and supporting parent-infant interaction.

Diagnosis and management of G6PD deficiency.

Glucose-6-phosphate dehydrogenase deficiency, the most common enzyme deficiency worldwide, causes a spectrum of disease including neonatal hyperbilirubinemia, acute hemolysis, and chronic hemolysis. Persons with this condition also may be asymptomatic. This X-linked inherited disorder most commonly affects persons of African, Asian, Mediterranean, or Middle-Eastern descent. Approximately 400 million people are affected worldwide. Homozygotes and heterozygotes can be symptomatic, although the disease typically is more severe in persons who are homozygous for the deficiency. The conversion of nicotinamide adenine dinucleotide phosphate to its reduced form in erythrocytes is the basis of diagnostic testing for the deficiency. This usually is done by fluorescent spot test. Different gene mutations cause different levels of enzyme deficiency, with classes assigned to various degrees of deficiency and disease manifestation. Because acute hemolysis is caused by exposure to an oxidative stressor in the form of an infection, oxidative drug, or fava beans, treatment is geared toward avoidance of these and other stressors. Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a blood transfusion. Neonatal hyperbilirubinemia may require treatment with phototherapy or exchange transfusion to prevent kernicterus. The variant that causes chronic hemolysis is uncommon because it is related to sporadic gene mutation rather than the more common inherited gene mutation.

An evidence-based review of important issues concerning neonatal hyperbilirubinemia.

This article is adapted from a published evidence report concerning neonatal hyperbilirubinemia with an added section on the risk of blood exchange transfusion (BET). Based on a summary of multiple case reports that spanned more than 30 years, we conclude that kernicterus, although infrequent, has at least 10% mortality and at least 70% long-term morbidity. It is evident that the preponderance of kernicterus cases occurred in infants with a bilirubin level higher than 20 mg/dL. Given the diversity of conclusions on the relationship between peak bilirubin levels and behavioral and neurodevelopmental outcomes, it is apparent that the use of a single total serum bilirubin level to predict long-term outcomes is inadequate and will lead to conflicting results. Evidence for efficacy of treatments for neonatal hyperbilirubinemia was limited. Overall, the 4 qualifying studies showed that phototherapy had an absolute risk-reduction rate of 10% to 17% for prevention of serum bilirubin levels higher than 20 mg/dL in healthy infants with jaundice. There is no evidence to suggest that phototherapy for neonatal hyperbilirubinemia has any long-term adverse neurodevelopmental effects. Transcutaneous measurements of bilirubin have a linear correlation to total serum bilirubin and may be useful as screening devices to detect clinically significant jaundice and decrease the need for serum bilirubin determinations. Based on our review of the risks associated with BETs from 15 studies consisting mainly of infants born before 1970, we conclude that the mortality within 6 hours of BET ranged from 3 per 1000 to 4 per 1000 exchanged infants who were term and without serious hemolytic diseases. Regardless of the definitions and rates of BET-associated morbidity and the various pre-exchange clinical states of the exchanged infants, in many cases the morbidity was minor (eg, postexchange anemia). Based on the results from the most recent study to report BET morbidity, the overall risk of permanent sequelae in 25 sick infants who survived BET was from 5% to 10%.

Neonatal jaundice: physiologic variation or pathologic process.

Neonatal hyperbilirubinemia and jaundice affect approximately 60% of the 4 million newborns in the United States each year. Jaundice results from bilirubin deposition in the skin and mucous membranes, becoming clinically visible at a serum bilirubin level of 5 to 7 mg/dL. At a higher but undefined level, bilirubin may deposit in the brain where it can cause transient dysfunction or permanent neurologic impairment.

Reevaluation of recent criteria for blood exchange transfusion in term infants with hyperbilirubinemia.

For hyperbilirubinemic infants treated according to the higher criterion for a blood exchange transfusion (BET), auditory brainstem response (ABR) was performed to evaluate whether the treatment was adequate. Twenty hyperbilirubinemic infants were collected as the study group. They were divided into 2 groups; group A consisted of 17 infants receiving intensive phototherapy only, while group B consisted of 3 infants receiving BET plus phototherapy. Fourteen healthy neonates were collected as the control group. Language development was evaluated with "language/communication development milestone: infancy through school-age" at the age of 5 months to 3 years old. Wave V at 30 dB HL was clearly identified in all infants in group A and in the control group. There was no significant difference in the latency between them (p > 0.05). In group A, peak bilirubin levels of 16 cases reached the former criteria for BET Their ABRs were normal. Language development was normal in 12 cases, while 4 cases were lost to follow-up. In group B, 2 cases had abnormal ABRs, while the third had normal ABR and language development. By analyzing the condition of these babies, we could conclude that in addition to peak bilirubin level and age, other factors such as anemia, the duration of hyperbilirubinemia, and the decline rate of bilirubin in response to intensive phototherapy should also be taken into consideration. For infants with borderline bilirubin levels for BET, we suggest performing BET if they have severe anemia or if intensive phototherapy fails to produce a proper decline in bilirubin.

Effects of clear topical ointment on transepidermal water loss in jaundiced pretermm infants receiving phototherapy.

Thirty jaundiced preterm infants, gestational age < or = 34 weeks and postnatal age < or = 7 days, receiving conventional phototherapy for hyperbilirubinemia of prematurity in incubators were included. 1.5 ml of clear topical ointment was applied on the right side of the trunk and extremities while the left side was used as control. Data collection included transepidermal water loss (TEWL), ambient temperature and ambient humidity, before and at 30 minutes, 4-6 hours after application of the ointment during phototherapy. The measurements were executed both the right and left side in 3 positions; upper arm, back, lower leg. TEWL was reduced by 29 per cent (P value < 0.002) and 26 per cent (P value < 0.011) at 30 minutes and 4-6 hours after the application of clear topical ointment, respectively. Ambient temperature and humidity were not significantly different (P value > 0.18). We concluded that application of clear topical ointment on the skin of jaundiced preterm infants receiving conventional phototherapy in incubators reduced TEWL significantly.

Double versus single phototherapy in term newborns with significant hyperbilirubinemia.

The efficacy of double phototherapy, in the form of conventional phototherapy with special blue light plus fiberoptic phototherapy, was compared with conventional phototherapy consisting of special blue lamps alone in a relatively larger series of term newborns with significant hyperbilirubinemia. During the study period the sum of the average spectral irradiances in the double phototherapy group was significantly higher than that of the single phototherapy group (p < 0.05). Phototherapy was effective in decreasing bilirubin levels in both groups, but the response was greater in the double phototherapy group; the duration of exposure to phototherapy was significantly shorter (31.2 +/- 8.5 vs. 38.98 +/- 14.7 h, p < 0.05), and the overall bilirubin decline rate as mumol/l/h and per cent/h was significantly greater in the double phototherapy group (4.1 +/- 1.37 vs. 3.3 +/- 0.86 mumol/l/h, and 1.29 +/- 0.38 vs. 1.02 +/- 0.44 per cent/h, p < 0.05). In phototherapy treatment of term newborns with significant hyperbilirubinemia, double phototherapy provided more rapid and effective bilirubin reduction than conventional phototherapy alone due to higher spectral irradiance and larger body surface area exposed to phototherapy. The value of double phototherapy in the treatment of newborns with hemolytic hyperbilirubinemia remains to be determined.

Changes in mesenteric blood flow response to feeding: conventional versus fiber-optic phototherapy.

OBJECTIVE: To evaluate whether fiberoptic phototherapy influences the postprandial increase in mesenteric blood flow velocity similarly to conventional phototherapy in preterm infants. PATIENTS AND METHODS: With the use of Doppler color ultrasonography, blood flow velocity in the superior mesenteric artery was measured both preprandially and postprandially in 19 preterm infants during and after conventional phototherapy, and in 20 preterm infants during and after fiber-optic phototherapy. The mean arterial blood pressure/mean flow velocity ratio was calculated as an estimate of relative vascular resistance of the superior mesenteric artery. RESULTS: The study shows that conventional phototherapy blunts the postprandial mesenteric blood flow response to feeding in preterm infants. Furthermore, it shows that the postprandial increase in intestinal blood flow is not attenuated when fiber-optic phototherapy is administered, and that such postprandial increase of blood flow is significantly greater than in infants receiving conventional phototherapy. During and after fiber-optic phototherapy, a significant reduction in postprandial relative vascular resistance was found; such reduction was significantly greater than during conventional phototherapy. CONCLUSIONS: Fiber-optic phototherapy is preferable to conventional phototherapy for the treatment of hyperbilirubinemia in preterm infants because it does not affect the physiologic postprandial redistribution of blood flow from the periphery to the gastrointestinal system as does conventional phototherapy.