Bilirubin In Infants Research Articles

Awareness, referral and age at Kasai surgery for biliary atresia in Europe: A survey of the Quality-of-Care Task Force of ESPGHAN.

To identify infants with biliary atresia (BA), European Society of Paediatric Gastroenteroloy and Nutrition (ESPGHAN)/North American Society of Pediatric Gastroenteroloy and Nutrition (NASPGHAN) guidelines recommend measurement of conjugated/direct bilirubin in infants with prolonged jaundice and using a stool colour card (SCC). The 'Quality of Care'Task Force of ESPGHAN performed two surveys to assess current case finding for BA and age at Kasai portoenterostomy (KPE). The first survey approached 26 European hepatology centres to report age at referral and age at KPE of all infants diagnosed with BA from 2015 to 2019. The second survey targeted paediatricians in France to assess awareness and compliance with the recently introduced SCC. Data from 785 patients with BA from 18 centres in 15 countries revealed a mean age at referral to tertiary centre of 55 days (median 53, IQR 48-60) (n = 636). The mean age at KPE was 61 days (median 60; IQR 54-67) (n = 772). For 6% of patients, cirrhosis was too advanced for surgery. Of 392 paediatricians answering the second survey, 53% felt familiar with the target diseases, 80% correctly identified cholestasisand 59% always inquired about the infant's stool colour. If abnormal, 93% would order blood tests and 85% call for advice. The SCC screening was considered helpful for case finding and improving knowledge of cholestatic diseases by 62% and 45% paediatricians, respectively. Referral of infants for KPE remains late, indicating low adherence to search for cholestasis in icteric infants by age 2-3 weeks. Knowledge and structures need improvement to allow earlier guideline conform case finding, diagnosis and therapy.

LITERATUR REVIEW: PENGARUH FOTOTERAPI TERHADAP NEONATUS DENGAN HIPERBILURUBIN

Hyperbilirubin is an excessive level of bilirubin in the blood with an amount of more than 10 mg% in the first week which causes jaundice or yellow color in infants to be clearly visible on the skin, sclera, mucosa, urine, and several others. organs, while the normal level of total bilirubin in infants is normal. infants, namely 5 mg% (Sembiring, 2019). Hyperbilirubinemia is the term used for neonatal jaundice after laboratory results show an increase in bilirubin levels. This hyperbilirubinemia can be caused by physiological and pathological processes (Sukadi; 2012 cited by Saptanto; 2016). Objective: To present a review and also a summary of phototherapy therapy in neonates with hyperbilirubinemia and provide an explanation of the therapies that can be performed in neonates with hyperbilirubinemia based on current evidence. Method: database search includes Google Scholar, Science Direct and Proquest with keywords phototherapy and hyperbilirubin Results: An analysis of 10 journals, 8 national journals and 2 international journals as well as 5 books showed that phototherapy was effective in reducing bilirubin levels in hyperbilirubin newborns. Conclusion: All interventions from this literature review were phototherapy efficacy in neonates with hyperbilirubinemia.

A-388 Evaluation of Performance of the nBili Assay on the RAPIDPoint®500e Analyzer Compared to the Total Bilirubin Assay for the Dimension EXL200 and Atellica CH Analyzers in Neonates Blood Samples

Abstract Background Neonatal hyperbilirubinemia is very common, with 60% of term newborns (NB) and 80% of premature neonates developing this condition. If not diagnosed and treated, can lead to severe complications, with bilirubin encephalopathy (BAE) being one of the most feared outcomes. Analysis of whole blood samples measured by the RapidPoint®500 Blood Gas Analyzer (RP500) is a technology option that provides rapid bilirubin results with a small sample volume and can also measure other important analytes. However, it is still unclear whether the blood gas analyzer can be used for biochemical dosage of bilirubin in newborns. Objective This study aimed to evaluate the clinical and analytical reliability of the method for detecting bilirubin in infants in comparison with classic biochemical analyzers such as Atellica® CH 930 and Dimension® EXL200. Methods A comparative clinical study was performed to evaluate the acceptable analytical agreement of total bilirubin results from 41 samples from neonatal patients between Atellica® CH 930, Dimension® EXL200 and RapidPoint®500 analyzers. Data were analyzed using Vericheck® software. Results Forty-one whole blood samples from newborn patients were analyzed for total bilirubin measurement. The range of analyzed results was from 2.7 to 20.8 mg/dL. Were considered for the analysis of clinical data: gestational age, weight, age, visual assessment of the newborn, criteria for hospitalization, whether phototherapy was performed and how long it took. In the regression analysis, it was possible to obtain a Pearson regression coefficient of 0.9806 between the Atellica® CH 930 and RP500 analyzer. The average of the values obtained with the RP500 was 10.8 and for the Atellica® CH930 it was 11.10, obtaining a percentage difference of means of 2.70%. In comparison with the Dimension®EXL200 analyzer, it was possible to obtain a Pearson correlation coefficient of 0.9814. The average of the values obtained with the RP500 was 10.8 and for the Dimension it was 9.32, resulting in a percentage difference of mean of 15.83%. Conclusion The study showed good results for analytical comparability between analyzers. There was no change in the clinical management according to the criteria analyzed in conjunction with the laboratory analyses, making it possible to guarantee the safety of using the RP500 platform in the diagnosis and follow-up of newborns with suspected hyperbilirubinemia.

Investigation of EEG changes before and after phototherapy in infants with severe hyperbilirubinemia.

Despite the known effect of hyperbilirubinemia in neonates, the effect of phototherapy on electroencephalography (EEG) remains unknown. Therefore, we aimed to determine the alteration of electroencephalography in infants with hyperbilirubinemia before and after phototherapy. This cross-sectional study was performed on infants of≥35 weeks of gestation with hyperbilirubinemia. Information including age, sex, birth weight, hemoglobin levels, and treatment measures was recorded. In all studied infants, an EEG was performed before (in the first eight hours of hospitalization) and after treatment (after phototherapy or blood transfusion). The required duration of phototherapy, hospitalization and adverse effects were assessed then EEG of the neonates was compared before and after treatment. A total of 52 infants (44% female and 56% male) were included in this study. Mean gestational age, weight, and bilirubin were 38.6±1.53 weeks, 3150±625 g, and 23.87±4.36 mg/dl, respectively. The most common findings before phototherapy were Frontal Theta (21 patients, 40.4 percent) and Delta Brush (14 patients, 26.9%), while the most common findings after phototherapy were Frontal Theta (20 patients, 38.5%) and Delta Brush (19 patients, 36.5%). Mean±SD of bilirubin in infants with and without Delta Brush was 21.30±1.67 mg/dl and 19.95±0.94 mg/dl, respectively. Hyperbilirubinemia in newborns may be linked to altered EEG findings. After phototherapy, the Frontal theta was reduced, but the Delta brush was intensified. Bilirubin levels were higher in infants with Delta Brush in their EEG compared to infants without this finding.

Differential effects of delayed cord clamping on bilirubin levels in normal and diabetic pregnancies

Delayed cord clamping increased the risk of jaundice in newborns born to diabetic mothers, but had no effect in newborns from mothers with normal pregnancies. DCC may be a risk factor for increased bilirubin in infants of diabetic mothers. ClinicalTrials.gov: NCT04369313; date of registration: April 27, 2020 (retrospectively registered). • Delayed cord clamping had significant benefits for newborns by increasing neonatal hemoglobin levels and reducing the risk of neonatal anemia, etc. • Delayed cord clamping may lead to neonatal hyperemia, erythrocytosis, and hyperbilirubinemia, which increases the risk of neonatal jaundice. • Our trial focused on the differential effects of delayed cord clamping on jaundice in full-term newborns between diabetic pregnancies and normal pregnancies. And newborns of diabetic mothers who received delayed cord clamping had a significantly increased risk of jaundice compared to newborns with normal pregnancy. • Delayed cord clamping may be a risk factor for increased bilirubin levels in neonates of diabetic mothers.

The Effect of Field Massage on Bilirubin Levels in Neonates with Hyperbilirubinemia

Hyperbilirubinemia is one of the most common clinical phenomena. It is found in 80% of premature infants and 60% of term infants in the first week of life. Most hyperbilirubinemia does not require special therapy, but because of the potential toxic effects, all neonates should be monitored to detect the possibility of severe hyperbilirubinemia. Based on data from the Directorate of Family Health, in 2019, out of 29,322 under-5 deaths, 69% of deaths occurred in the neonatal period. One of the causes of mortality in neonates is bilirubin encephalopathy/kernicterus. Bilirubin encephalopathy is the most severe complication of neonatal jaundice. In addition to encephalopathy, other risks include sequelae in the form of cerebral palsy, high-pitched deafness, paralysis and dental dysplasia, which greatly affect the quality of life. Several studies have been conducted to find alternative supporting therapies that can be used to effectively reduce bilirubin levels in addition to providing phototherapy, one of which is the provision of field massages. Field massage is thought to increase the excretion of bilirubin in infants during phototherapy. The purpose of this literature review was to determine the effect of field massage on reducing bilirubin levels in neonates with hyperbilirubinemia. This was a traditional narrative literature review which grouped similar extracted data according to the results measured to answer the objectives. According to the results, giving field massages two times a day for three days for 15 minutes each time was able to significantly reduce bilirubin levels.
 Keywords: field massage, hyperbilirubinemia, neonates

Changes in bilirubin in infants with hypoxic-ischemic encephalopathy.

Antioxidant properties of bilirubin have been reported in many studies. We hypothesized that bilirubin might be involved in neuroprotection mechanisms against oxidative stress in infants with hypoxic-ischemic encephalopathy (HIE) and that total serum bilirubin (TSB) might increase in these patients. We retrospectively studied infants with gestational age ≥ 35weeks and birth weight ≥ 1800g who were admitted to the neonatal intensive care unit (NICU) with a diagnosis of moderate-to-severe HIE and received or did not receive therapeutic hypothermia. We evaluated peak TSB and changes of mean TSB in these patients in comparison with a control group of infants admitted to the NICU with diagnoses other than HIE. Peak and mean TSB values were lower in the no hypothermia and hypothermia groups in comparison with the control group, while differences were not noted between infants who received hypothermia or did not. Regression analysis showed that HIE and hypothermia significantly reduced the risk of developing TSB values higher than median value (> 8.4mg/dL) in our population.Conclusion: Peak and mean TSB values were lower in infants with moderate-to-severe HIE than in control infants. HIE and hypothermia independently decreased TSB. These results exclude a TSB increase as a neuroprotective mechanism in infants with HIE. We speculated that low TSB values in infants with HIE could be due to hypoxic repression of HO expression and represent a defensive strategy for limiting brain injuries in these patients. What is Known: • The role of oxidative stress in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) has been elucidated in many studies, and other studies have demonstrated the antioxidant properties of bilirubin. • The potential neuroprotective role of bilirubin as antioxidant agent has never been evaluated in infants with HIE. What is New: • Mean total serum bilirubin (TSB) values are lower in infants with moderate-to-severe HIE than in control infants, since HIE and hypothermia independently decreased TSB. • An increase in bilirubin was not a neuroprotective mechanism in infants with HIE possibly because of hypoxic repression of HO expression as defensive strategy for limiting brain injuries.

Cord blood bilirubin used as an early predictor of hyperbilirubinemia

Background: Neonatal hyperbilirubinemia is among the commonest symptoms found in neonates. The information about risk of high bilirubin in infants allows simpler methods for reduction of bilirubin to be implemented before hyperbilirubinemia becomes significant and could help to take a decision for early discharge from Hospital. Thus, the authors were aimed at the assessment of the usefulness of the cord blood bilirubin as an early predictor of neonatal hyperbilirubinemia and the usefulness of 1st day bilirubin in predicting the neonatal hyperbilirubinemia.Methods: The present study was planned to conduct in Department of Pediatrics, Government Thiruvarur Medical College and Hospital, Thiruvarur among neonates delivered from 1st August 2011 to 1st December 2013. These neonates were followed from birth to 2nd postnatal day. Cord blood was collected at birth and bilirubin estimation was done within 12 hours of collection of the blood.Results: Cord blood bilirubin level of ≥2.15 mg/dl has a sensitivity of 73.08% and specificity of 59.49%, positive predictive value 14.6% and negative predictive value of 95.88% in predicting the risk of neonatal hyperbilirubinemia. 1st day bilirubin level of ≥5 mg/dl has a sensitivity of 92.3% and specificity of 71.16% and positive predictive value of 23.3% and negative predictive value of 98.9% in predicting the risk of neonatal hyperbilirubinemia.Conclusions: The use of the critical cord bilirubin level of 2 mg/dl in all healthy term newborns will predict significant hyperbilirubinemia.

INVESTIGATING THE PHOTOTHERAPY THRESHOLDS IN PRETERM INFANTS

Abstract BACKGROUND Currently there are limited guidelines for the management of hyperbilirubinemia in preterm infants. Current guidelines are limited to individual sites and are consensus-based opinions. The current decrease in chronic bilirubin encephalopathy in preterm infants is a result of liberal use of phototherapy that are not based on evidence from a large dataset of preterm infants. The pattern of bilirubin levels in preterm is unclear and currently based on clinical judgement. Nomograms in term infants has been proven to be beneficial and effective in reducing unnecessary treatment of hyperbilirubinemia. A nomogram designed for preterm infants would allow health professionals to quantify risk based on evidence based methods and reduce the number of test done on preterm infants. OBJECTIVES The objectives of this study are 1) To determine photherapy thresholds in preterm infants and 2) To determine the normative pattern of bilirubin values in preterm infants. DESIGN/METHODS A multi-site retrospective chart review of preterm infants ≤ 35 weeks gestation born between January 2012- November 2017 was conducted. The following data was collected; all TSB, postnatal hours of age, duration of phototherapy, infant characteristics (gestational age, birth weight, outcomes) and maternal history (inter and anter partum medication). TSB samples prior to the initiation of phototherapy were analyzed per hour and stratified by gestational age groups. RESULTS A total of 330 preterm infants were included in the retrospective review (50 24-28 weeks gestation, 100 29-32 weeks gestation, and 180 33–35 weeks gestation). The mean peak bilirubin in infants 33-35 week gestation was 198 umol/L at 4 days. These infants were started on phototherapy at a mean age of 89 hours. At 24 hours of age these infants’ bilirubin was 104 umol/L (72-189umol/L). The mean peak bilirubin in infants 29–32 weeks gestation was 181umol/L at 5 days. At 24 hours of age the mean bilirubin was 109 umol/L. Finally in infants 24–28 weeks gestation the mean peak bilirubin was 127 umol/L at 4 days. These infants were started on phototherapy at 44 hours of age. CONCLUSION Bilirubin values in preterm infants is hetergenous across gestional ages. Phototherapy treatment thresholds are lower in preterm infants between 24–28 weeks gestation. A nomogram for preterm infants maybe possible in infants between 29–35 weeks. Further research is required to determine hour specific bilirubin levels in preterm infants.

Maternal socio-demographic and psychological predictors for risk of developmental delays among young children in Mongolia

BackgroundFactors influencing child development are not well studied in developing settings, and especially in Mongolia. This cohort study examined the relationship between maternal socio-demographic and psychological conditions on risk of young child developmental delay.MethodsA total of 150 children aged between 13 ~ 24 months old participated in this study. The participants were randomly selected from a pre-existing cohort of 1297 children who were involved in a study on infant bilirubin nomogram development conducted at a tertiary health facility in Mongolia between 2012 and 2013. Child development was evaluated using the Mongolian Rapid Baby Scale (MORBAS), a validated scale for child development. The potential factors for child developmental delay were assessed using a pre-tested questionnaire comprising of 52 questions. Fisher’s exact test and multivariable logistic regression analysis were conducted.ResultsSeventeen (11%) out of the 150 children that participated in the study were at risk of developmental delay. There was a negative association between the risk of child developmental delay and higher maternal education (AOR 0.15, 95% CI: 0.03–0.66). Increasing maternal age (AOR 1.12, 95%CI: 0.98–1.27), maternal depression symptoms (AOR 4.93, 95%CI: 0.93–26.10), child gender being female (AOR 0.25, 95%CI: 0.06–1.00) and being from single mother household (AOR 0.14, 95%CI: 0.01–1.11) were also predictors for risk of developmental delay – although the association was marginal.ConclusionsOur findings suggest that being of underprivileged social status, and poor psychological condition of mothers in Mongolia possibly increases the risk of child developmental delays. Interventions targeting these modifiable predictors are needed to develop prevention strategies for child developmental delay.

The lowering of bilirubin levels in patients with neonatal jaundice using massage therapy: A randomized, double-blind clinical trial

ObjectiveDue to the effects of massage on various laboratory parameters (including those related to jaundice) in infants and the expansion of existing studies to achieve effective and safe therapy in the treatment of neonatal jaundice, this study aimed to investigate the effect of massage on bilirubin levels in cases of neonatal jaundice. MethodsIn this study, 134 patients were randomly assigned to either an intervention group (massage combined with phototherapy, n=67) or a control group (phototherapy only, n=67). In both groups, serum total bilirubin level and frequency of daily bowel movements were measured and compared during each of the first four days of treatment. ResultsBaseline levels of bilirubin were similar between the two groups (P>0.05). During the measurements obtained post-intervention, significant differences surfaces between the two groups in bilirubin levels and frequency of daily bowel movements (P<0.05 for both). No significant relationship was observed during days 1 and 2 of massage therapy between daily frequency of bowel movements and serum bilirubin level (P>0.05); this relationship became significant during the third and fourth days (P<0.05). ConclusionMassage therapy combined with phototherapy is an effective method for reducing serum total bilirubin in infants with neonatal jaundice.

Fate of Neural Progenitor Cells Transplanted into Jaundiced and Nonjaundiced Rat Brains

High levels of bilirubin in infants can cause kernicterus, which includes basal ganglia damage and dystonia. Stem cell transplantation may be an effective treatment for this disease. In this study, we transplanted human neural progenitor cells differentiated toward propriospinal interneurons into the striatum of 20-day-old spontaneously jaundiced (jj) Gunn rats and nonjaundiced (Nj) littermates. Using immunohistochemical methods, we found that grafted cells survived and grew fibers in jj and Nj brains 3 weeks after transplantation. Grafted cells had a higher survival rate in jj than in Nj brains, suggesting that slightly elevated bilirubin may protect graft survival due to its antioxidative and immunosuppressive effects. Despite their survival, only a small portion of grafted neurons expressed GAD-6 or ChAT, which mark GABAergic and cholinergic neurons, respectively, and are the cells that we are attempting to replace in kernicterus. Thus, NPCs containing large populations of GABAergic and cholinergic neurons should be used for further study in this field.

75: Effect of Phototherapy on the Reliability of Transcutaneous Devices in Infants &gt;35 Weeks of Gestational Age: A Systematic Review

American Academy of Pediatrics (AAP) recommends the use of TcB devices for the diagnosis of significant hyperbilirubinemia in infants >35 weeks of gestational age and for making decisions for initiation of phototherapy. However, the accuracy of TcB devices in infants receiving phototherapy is unclear. To conduct systematic review of diagnostic accuracy studies comparing TcB devices with total serum bilirubin (TSB) estimation in near-term and term neonates receiving phototherapy or post-phototherapy phase Search Strategy MEDLINE, EMBASE, Cochrane library, CINAHL, Scopus databases (all from the date of inception to August 2013) were searched. Additional citations were identified from the bibliography of selected articles and from abstracts of the conference proceedings. Study Selection and Data Extraction The studies were included if they compared TcB results with TSB in term and near-term infants during phototherapy or after discontinuation of phototherapy in neonatal period. Two reviewers independently assessed studies for inclusion and discrepancies were resolved with consensus. Data were extracted by one reviewer and checked for accuracy by the second reviewer. Quality assessment of included studies was performed using QUADAS-2 tool. Seventy-three studies were selected for full text review of which 12 were eligible for inclusion (seven studies awaiting decision). Studies varied in terms of site of TcB estimation (forehead [12], sternum [6], back [2]); TcB devices used (Bilicheck [2], Minolta air shields [4], JM101 [6]); method of estimation of TSB (Direct Spectrophotometry [5], Diazo method [8], both [2], not specified [1]). All studies provided results of comparison of TcB with TSB as co-relation coefficients (r=0.67 [95% CI 0.61 to 0.72]), with five studies providing data separately for TcB measurements from a covered area (r=0.71 [95% CI 0.65 to 0.77]) and two studies providing results for post phototherapy phase (r=0.75 [95% CI 0.66 to 0.82]) data One study provided data for Bland-Altman difference plots and showed TcB underestimated TSB by a mean difference of29.2 mmol/L. Our results show that TcB devices were not as reliable for estimation of serum bilirubin in infants receiving phototherapy as compared to pre-phototherapy phase. However, majority of studies were conducted using older TcB devices that are currently not in practice. Also, there is insufficient data for recommending the use of TcB devices in post phototherapy phase.

Prospective Validation of a Novel Strategy for Assessing Risk of Significant Hyperbilirubinemia

Our aim was to validate a strategy for assessing the risk of significant hyperbilirubinemia in newborns with gestational ages of ≥35 weeks by combining predischarge bilirubin percentile data with gestational age data, for a European, predominantly white population. We conducted a prospective cohort study with 463 newborns with gestational ages of ≥35 weeks who were admitted to the well-infant nursery. Total bilirubin levels were measured daily until discharge and once after discharge, between the third and eighth days of life, by using a Bilicheck device (Respironics, Murrysville, PA). The values obtained (<52 hours) were plotted on an hour-specific bilirubin nomogram to determine the infant's bilirubin percentile, expressed as a risk zone. Patients were assigned to 1 of 3 risk groups (very low, low, or high) on the basis of a combination of risk zone and gestational age data and were monitored prospectively for the development of significant hyperbilirubinemia. The 95% confidence interval (CI) for the prevalence of significant hyperbilirubinemia was estimated with the binomial distribution method. Forty-four infants (11%) developed significant neonatal hyperbilirubinemia. The risks of developing significant hyperbilirubinemia were 1.3% (95% CI: 0.2%-3.7%) for the very low risk group (n = 230 [58.1%]), 3.4% (95% CI: 0.7%-9.8%) for the low risk group (n = 86 [21.7%]), and 47.50% (95% CI: 36.2%-59.0%) for the high risk group (n = 80 [20.20%]). The proposed strategy, based on predischarge bilirubin level and gestational age data, was a valid method for significant hyperbilirubinemia risk assessment in our population.

Effect of Free Fatty Acids on Bilirubin–Albumin Binding Affinity and Unbound Bilirubin in Premature Infants

The author has previously shown that intravenous lipid intake may be associated with an increase in unbound bilirubin in infants < or =28 weeks gestational age. The objective of this study was to evaluate whether this increase in unbound bilirubin is mediated by free fatty acids and to examine the secondary effect of free fatty acids on bilirubin-albumin binding affinity. A prospective study was conducted to include 26 infants < or =32 weeks gestational age with indirect hyperbilirubinemia and receiving intravenous lipids during the first 10 postnatal days. Blood samples were collected for unbound bilirubin, binding affinity, and free fatty acid measurement at varying intravenous lipid intakes (1-3 g/kg/d). Regression analyses were performed to evaluate the roles of free fatty acids and binding affinity as mediators. Intravenous lipid intake was significantly associated with an increase in free fatty acids and unbound bilirubin in infants < or =28 weeks but not >28 weeks gestational age. In infants < or =28 weeks gestational age, each unit increase in free fatty acids was significantly associated with a decrease in binding affinity, which was significantly associated with an increase in unbound bilirubin. In infants < or =28 weeks gestational age, intravenous lipid intake may be associated with an increase in unbound bilirubin, and this is mediated by an increase in free fatty acids and a secondary decrease in binding affinity. In infants >28 weeks gestational age, higher intravenous lipid intake may be used because it is unassociated with increases in free fatty acids and unbound bilirubin.

Index Of Suspicion In The Nursery

A 2.9-kg female infant is born at 35 weeks' gestation to a 33-year-old G4P3 woman via cesarean section due to chronic hypertension complicated by superimposed preeclampsia. The mother's blood type is A-negative; the antibody screen is positive for anti-D, anti-C, and anti-G antibodies; she has no prior history of sensitization; and her serologies are negative. The Apgar scores are 7 and 9 at 1 and 5 minutes, respectively. At birth, the infant appears pale and exhibits tachycardia, moderate hepatosplenomegaly, tachypnea, and mild respiratory distress requiring supplemental oxygen. Complete blood count and blood cultures are obtained, and ampicillin and gentamicin are started. The admission hematocrit is 21% (0.21), with a reticulocyte count of 64%. An umbilical venous catheter is placed for intravenous (IV) access. The infant receives a transfusion of packed red blood cells for significant anemia associated with tachycardia. Prophylactic phototherapy is started because of Rh sensitization. The cord blood bilirubin measures 11.4 mg/dL (195 mcmol/L). The infant's blood type is A-negative, and the antibody screen is positive for anti-D and anti-C antibodies, with a positive direct Coombs test. The red blood cell phenotype reveals the presence of “C” antigen. This is a very uncommon antigen in an Rh-negative infant, but the antigen had stimulated the anti-C antibodies that traversed the placenta and caused severe hemolysis of the newborn. At 7 hours of age, the infant's bilirubin is 16 mg/dL (273.6 mcmol/L). She is given two doses of intravenous immune globulin, and phototherapy is intensified. After 24 hours of intensive phototherapy, the infant develops a large reddish-purple discoloration on her abdomen that resembles a severe burn (Fig. 1). The well-demarcated, erythematous, purpuric rash is present over the areas closely exposed to the phototherapy lights and does not blanch with diascopy. No vesiculobullous eruptions, edema, or tenderness is noted. The unexposed …

Abuse of Casein Hydrolysate Formulas for Treating Infants With Severe Hyperbilirubinemia: In Reply

In Reply.—We thank Dr Bhutani for the opportunity to provide additional information regarding our controlled, randomized, double-blind trial of prophylaxis against jaundice among 64 breastfed newborns.1 Our study demonstrated that breastfed infants who received minimal aliquots of L-aspartic acid or enzymatically hydrolyzed casein for β-glucuronidase inhibition had increased fecal bilirubin excretion and less jaundice, without disruption of the breastfeeding experience. Although 2 previous studies of ours demonstrated that infants who were exclusively fed a casein hydrolysate formula had significantly less jaundice than infants who were exclusively fed either a routine formula or breast milk,2,3 we agree with Dr Bhutani that additional research would better define the ability of specific casein hydrolysate formula ingredients to reduce bilirubin and prevent excessive hyperbilirubinemia without interrupting breastfeeding.Space consideration prevented us from providing additional information regarding the subgroup analysis of 17 newborn infants with serum bilirubin levels in the first 48 hours of life that were above the low-risk zone (ie, >40th percentile on the nomogram developed by Bhutani et al4 that was included in the 2004 American Academy of Pediatrics hyperbilirubinemia guidelines5). The decline times (in hours) from a risk zone above the low-risk zone within the first 48 hours to a low-risk zone after 48 hours were compared among these 17 subjects and found to be significantly shorter in the combined groups that received a β-glucuronidase inhibitor compared with those that did not receive a β-glucuronidase inhibitor. Additional characteristics of these 17 infants are presented below in Table 1. The single infant in the enzymatically hydrolyzed casein group is particularly interesting because he was the only infant in the highest risk zone. As can be seen from these data, this infant had 2 significant risk factors for hyperbilirubinemia: male gender and a significantly lower gestational age (36 weeks) than the other groups. This infant's bilirubin level of 8.6 mg/dL at 22.7 hours of age (>95th percentile, highest risk zone) decreased to 8.5 mg/dL at 46.3 hours of age (40–75th percentile, low-intermediate–risk zone) and 7.7 mg/dL at 74.9 hours of age (<40th percentile, low-risk zone) and remained in the low-risk zone thereafter. Despite inclusion of this more significantly jaundiced, lower-gestational-age infant along with those in the L-aspartic acid group to form the group receiving β-glucuronidase inhibition, this group had a significantly faster decline from a risk zone above the low-risk zone within the first 48 hours to a low-risk zone after 48 hours than the group receiving no β-glucuronidase inhibition.Although our small study is very encouraging, at this point in time we concur with Dr Bhutani that the use of a casein hydrolysate formula, L-aspartic acid, or enzymatically hydrolyzed casein is premature and that administration of these supplements to infants at risk for severe hyperbilirubinemia requires additional research. Future research regarding use of such nutritional supplements for breastfed infants would be of particular interest in infants with either hour-specific bilirubin levels associated with increased risk for the subsequent development of severe hyperbilirubinemia or in infants with clinical risk factors increasing their risk of severe hyperbilirubinemia. This research should be conducted in a manner to minimize any possible negative effects on breastfeeding and must include careful analysis to assess any possible negative effects on breastfeeding.

Conflict of Interest and Purpose in Bilirubin Screening: In Reply

In Reply .— I thank Dr Lavin for his comments. Perhaps my conclusion was a trifle hyperbolic, but I have no hesitation in standing by the statement that the ability to measure a transcutaneous bilirubin (TcB) level in the office should be very valuable for the practicing physician. When Dr Lavin sees a jaundiced newborn on day 3 or 4 in his office and decides to get a bilirubin level, would he prefer a completely noninvasive, instantaneous measurement of the bilirubin or would he rather perform a heel stick on the infant (or have it done elsewhere) and wait several hours for the results? More important, what does he think the mother (and the infant) would prefer? In our study, data from 40 infants were obtained from a private-practice group, and discussions with these physicians amply confirms that they have found this instrument to be very useful. We have been using TcB measurements in our own outpatient clinic for >6 months, and I can assure Dr Lavin that our residents and attending physicians find it equally useful. In addition to providing instantaneous and important information about the infant's bilirubin level, the use of TcB measurements in both the nursery …

2 Neuro-Developmental Outcomes at 18 Months Corrected Age in Infants Weighing

The “safe” level of serum bilirubin in infants <1500 grams is controversial, but recent retrospective reviews show direct correlation between peak bilirubin level and adverse neuro-developmental outcome. Our recent randomized study showed that infants <1000 grams who received conservative phototherapy had higher peak bilirubin levels and that infants <1500 grams who received conservative phototherapy reached peak bilirubin levels earlier than those treated with aggressive phototherapy. The purpose of this study was to examine the 18 month neuro-developmental outcomes in infants <1500 grams who had been enrolled in our randomized trial of aggressive versus conservative phototherapy. This follow-up phase of an unmasked, randomized study included infants with birth weight <1500 grams who had no evidence of major anomaly or iso-immunization and for whom parental consent was obtained. Aggressive phototherapy was started by 12 hours of post-natal age, while conservative phototherapy was started when the serum bilirubin level exceeded 8.8 mg/dL (150 μmol/L). All surviving infants were enrolled in a comprehensive neuro-developmental follow-up program at 4, 8, 12, 18, 14 and 36-months corrected age. At each visit, a full neuro-developmental assessment was performed and information on growth, hospital readmission, interval health and medication use was collected. All children had hearing screens at the 12-month visit, regular vision screening, and Bayley Scales of Infant Development (BSID-III) at the 18 and 36 month visits, if cooperative. Of 95 patients enrolled in the original study, 87 (92%) survived until hospital discharge, of whom 82 (94% of survivors) attended for comprehensive neuro-developmental assessment until 12 months corrected age and 75 (86% of survivors) attended until 18 months corrected age. The incidence of cerebral palsy was higher in the conservative phototherapy group 7/41 (17%) vs 2/41 (5%), p=0.15, OR 4.01 [0.69, 41.50]. The combined outcome of CP/death was also higher in the conservative group at 12/46 (26%) vs 5/44 (11%), p=0.04, OR 3.44 [0.92, 15.82]. Two-thirds of the infants with CP were in the <1000 grams subgroup. An MDI <84 on 18-month corrected age BSID-III testing did not differ between the two groups being 6/38 (16%) in the conservative group and 8/37 (22%) in the aggressive group, p=0.52, OR 0.68 [0.17, 2.56]. Although the numbers in this study are too small to draw definitive conclusions, there is a worrisome trend for poor neuro-developmental outcome for infants receiving conservative phototherapy, particularly in the <1000 grams group. Further studies with long-term neuro-developmental outcome as the primary outcome are urgently required.

Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate- glucuronosyltransferase gene.

Breast milk jaundice is a common problem in nursing infants. It has been ascribed to various breast milk substances, but the component or combination of components that is responsible remains unknown. During our study of defects of the bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) in patients with hereditary unconjugated hyperbilirubinemia (Crigler-Najjar syndrome and Gilbert's syndrome) and neonatal hyperbilirubinemia, we encountered a prolonged case associated with breastfeeding; after cessation of breastfeeding, the infant's bilirubin level became normal. Genetic analysis revealed a missense mutation identical to that found in patients with Gilbert's syndrome, which usually causes jaundice after puberty. We analyzed the bilirubin UGT1A1 of infants with prolonged unconjugated hyperbilirubinemia associated with breast milk to ascertain whether genetic factors are involved. We analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (total serum bilirubin concentrations above 171 micromol/L [10 mg/dL]) 3 weeks to 1 month after their birth. Except for jaundice, the infants were healthy and did not show evidence of hemolytic anemia, liver dysfunction, or hypothyroidism. After cessation of breastfeeding, the serum bilirubin concentration began to decrease in all cases. When breastfeeding was resumed, serum bilirubin concentration again became elevated in some infants, but the concentration fell to within normal by 4 months of age. We analyzed the polymerase chain reaction-amplified exon, promoter, and enhancer regions of UGT1A1 by direct sequencing. Sixteen infants had at least one mutation of the UGT1A1. Seven were homozygous for 211G-->A (G71R), which is the most common mutation detected in the East Asian population, and the mutant enzyme had one third of the normal activity. G71R is the most common missense mutation we found in our analyses in Japanese patients with Gilbert's syndrome, and it corresponds to a UGT1A1 polymorphism in the Japanese population (the allele frequency is.16). One was heterozygous for 1456T-->G (Y486D) and homozygous for 211G-->A. Six were heterozygous for 211G-->A. One was heterozygous for both 211G-->A and a TATA box mutation (A(TA)7TAA). One had a heterozygous mutation in an enhancer region (C-->A at -1353). We did not detect a homozygous A(TA)7TAA mutation, which was the most common cause of Gilbert's syndrome in European population, in this study of Japanese infants with prolonged hyperbilirubinemia triggered by breast milk. The results indicate that defects of UGT1A1 are an underlying cause of the prolonged unconjugated hyperbilirubinemia associated with breast milk. One or more components in the milk may trigger the jaundice in infants who have such mutations. The mutations we found were identical to those detected in patients with Gilbert's syndrome, a risk factor of neonatal nonphysiologic hyperbilirubinemia and a genetic factor in fasting hyperbilirubinemia.