Magnetic resonance spectroscopy and auditory brain-stem response audiometry as predictors of bilirubin-induced neurologic dysfunction in full-term jaundiced neonates.

The purpose of this research was to define the functions of MRS and ABR as predictors of bilirubin-induced neurologic dysfunction (BIND) in full-term neonates who required intervention (phototherapy and/or exchange transfusion). This prospective cohort study was done at the NICU of Tanta University Hospitals over a 2-year duration. Fifty-six full-term neonates with pathological unconjugated hyperbilirubinemia were divided according to MRS and ABR findings into 2 groups: group (1) included 26 cases with mild acute bilirubin encephalopathy (BIND-M score 1-4). Group (2) included 30 cases with neonatal hyperbilirubinemia only. In addition, 20 healthy neonates with similar ages were employed as the controls. When compared to group 2 and the control group, group 1's peak-area ratios of NAA/Cr and NAA/Cho were found to be significantly reduced (P < 0.05). As compared to group 2 and the control group, group 1's Lac/Cr ratio was significantly greater (P < 0.05), but the differences were not significant for group 2 when compared to the control group. Waves III and V peak latencies, I-III, and I-V interpeak intervals were significantly prolonged in group 1 in comparison to group 2 and controls (P < 0.05) with no significant difference between group 2 and control group.   Conclusion: When the symptoms of ABE are mild and MRI does not show any evident abnormalities, MRS and ABR are helpful in differentiating individuals with ABE from patients with neonatal hyperbilirubinemia.    Trial registration:  ClinicalTrials.gov , Identifier: NCT06018012. What is Known: • MRS can be used as a diagnostic and prognostic tool for the differential diagnosis of patients with acute bilirubin encephalopathy, from patients with neonatal hyperbilirubinemia What is New: • ABR is a useful diagnostic and prognostic tool in the care and management of neonates with significantly raised bilirubin. It can be used as early predictor of acute bilirubin encephalopathy in the earliest stage of auditory damage caused by bilirubin.

Validity of transcutaneous bilirubin measurements during and after phototherapy in term and late preterm infants.

The purpose of the study was to investigate correlation and concordance between total serum bilirubin (TSB) and transcutaneous bilirubin measured at covered (TcBC) and uncovered (TcBU) skin during and after discontinuation of phototherapy. A cross-sectional study included ≥ 34 weeks gestation infants requiring phototherapy for neonatal hyperbilirubinemia. In-house, photo-opaque patches were placed on infants' sternums before phototherapy initiation. Simultaneous blood sampling for TSB, TcBC, and TcBU measurements were performed. Among 103 infants included in the final analysis, 70% were full-term. Covering skin during phototherapy resulted in strong TcBC-TSB correlation (r = 0.91, 95% CI 0.87-0.94, P < 0.001) compared to TcBU (r = 0.53, 95% CI 0.37-0.65, P < 0.001), persisting post-phototherapy (r = 0.88, 95% CI 0.82-0.91, P < 0.001). Bland-Altman analysis showed a higher mean difference and wider 95% limits of agreement for TcBU-TSB during phototherapy (-6.3 mg/dL and -11.1 to -1.6) vs TcBC-TSB (0.9 mg/dL and -1.2 to 2.9). Passing-Bablok regression analysis confirmed good agreement between TcBC and TSB. CONCLUSIONS: The application of in-house, photo-opaque patches enhanced the correlation and agreement between TcBC and TSB during and after discontinuation of phototherapy. This may prove particularly useful in resource-limited settings where commercial devices are unavailable. WHAT IS KNOWN: • Transcutaneous bilirubin measurement has been widely used as a screening method for neonatal hyperbilirubinemia. • The accuracy of transcutaneous bilirubin measurements during and after phototherapy in infants with hyperbilirubinemia has been debated. WHAT IS NEW: • Our study demonstrated that utilizing carefully designed photo-opaque patches enhanced the accuracy of transcutaneous bilirubin measurement during and after phototherapy. • Effective in-house alternatives are crucial in resource-limited settings where commercial opaque patches are not always accessible or affordable.

Neonatal phototherapy and risk of epilepsy-A Danish population based study.

To evaluate the risk of epilepsy in children who received neonatal phototherapy. A cohort of live singletons born at a Danish hospital (2002-2016) with a gestational age ≥ 35 weeks. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy in children treated with neonatal phototherapy compared to children not treated with neonatal phototherapy in the general population, and in a subpopulation of children who had serum bilirubin measurement. Adjusted HRs (aHR) were computed using multivariable and propensity score matching models to take maternal and neonatal factors into consideration. Children were followed from day 29 after birth to diagnosis of epilepsy, death, emigration, or December 31, 2016. Among 65,365 children, 958 (1.5%) received neonatal phototherapy. Seven children (incidence rates (IRs): 10.8 /10,000 person-years) who received neonatal phototherapy and 354 children (IR: 7.7) who did not receive neonatal phototherapy were diagnosed with epilepsy. Neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 0.95, 95% CI: 0.43-2.09) and propensity score matched (aHR 0.94, 95% CI: 0.39-2.28) models. In the subpopulation of 9,378 children with bilirubin measurement, 928 (9.9%) received neonatal phototherapy. In the analysis of the subpopulation in which bilirubin level and age at the time of bilirubin measurement were further taking into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy using the multivariable (aHR 1.26, 95% CI: 0.54-2.97) and propensity score matched (aHR 1.24, 95% CI: 0.47-3.25) models,Conclusions: Neonatal phototherapy was not associated with an increased risk of epilepsy after taking maternal and neonatal factors into consideration. What is known: • A few studies have suggested that neonatal phototherapy for hyperbilirubinemia may increase the risk of childhood epilepsy. • Whether the observed associations contribute to hyperbilirubinemia, phototherapy, or underlying factors requires further investigation. What is new: • This study revealed no increased risk of epilepsy in children treated with neonatal phototherapy compared to children not treated with phototherapy after taking maternal and neonatal factors into consideration. • After further taking bilirubin level and age at the time of bilirubin measurement into consideration, neonatal phototherapy was not associated with an increased risk of epilepsy.

The correlation between serum total bile acid and alanine aminotransferase of pregnant women and the disorders of neonatal hyperbilirubinemia-related amino acid metabolism.

BACKGROUND: To explore the association between liver metabolism-related indicators in maternal serum and neonatal hyperbilirubinemia (NHB), and further investigate the predictive value of these indicators in NHB-related amino acid metabolism disorders. METHODS: 51 NHB and 182 No-NHB newborns and their mothers who treated in the Fourth Hospital of Shijiazhuang from 2018 to 2022 were participated in the study. The differences in clinical data were compared by the Mann-Whitney U test and Chi-square test. Multivariate logistic regression was used to analyze the relationship between maternal serum indicators and the occurrence of NHB. The correlation analysis and risk factor assessment of maternal serum indicators with NHB-related amino acid metabolic disorders were performed using Spearman correlation analysis and multivariate logistic regression. RESULTS: Compared to the non NHB group, the NHB group had higher maternal serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, and total bile acid (TBA), while lower levels of serum albumin (ALB), total cholesterol (TC) and high-density lipoprotein (HDL). The levels of alanine (ALA), valine (VAL), ornithine (ORN), and proline (PRO) in the newborns were reduced in NHB group, while arginine (ARG) showed a tendency to be elevated. Multiple logistic regression analysis showed that maternal ALT, AST, ALT/AST, and TBA levels were all at higher risk with the development of NHB, whereas ALB, TC, and HDL levels were negatively associated with NHB development. Increasing maternal TBA level was associated with lower ALA (r=-0.167, p = 0.011), VAL (r=-0.214, p = 0.001), ORN (r=-0.196, p = 0.003), and PRO in the newborns (r=-0.131, p = 0.045). Maternal ALT level was negatively associated with ALA (r=-0.135, p = 0.039), VAL (r=-0.177, p = 0.007), ORN (r=-0.257, p < 0.001), while ALT/AST was positively correlated with ARG (r = 0.133, p = 0.013). After adjustment for confounding factors, maternal serum TBA and ALT were the independent risk factor for neonatal ORN metabolic disorders [(adjusted odds ratio (AOR) = 0.379, 95%CI = 0.188-0.762, p = 0.006), (AOR = 0.441, 95%CI = 0.211-0.922, p = 0.030)]. Maternal ALT level was an independent risk factor for neonatal VAL metabolic disorders (AOR = 0.454, 95%CI = 0.218-0.949, p = 0.036). CONCLUSIONS: The levels of high TBA, ALT, AST, and low HDL, TC of maternal were associated with the risk of NHB. Maternal TBA and ALT levels were independent risk factors for NHB-related amino acid disturbances which have value as predictive makers.

Acceptability and operational feasibility of community health worker-led home phototherapy treatment for neonatal hyperbilirubinemia in rural Bangladesh.

There is an unmet need for phototherapy treatment in low- and middle-income countries (LMICs) to prevent disability and death of newborns with neonatal hyperbilirubinemia. Home phototherapy deployed by community health workers (CHWs) in LMICs may help increase access to essential newborn postnatal care in a more acceptable way for families and lead to an increase in indicated treatment rates for newborns with hyperbilirubinemia. We aimed to investigate the operational feasibility and acceptability of a CHW-led home phototherapy intervention in a rural sub-district of Bangladesh for families and CHWs where home delivery was common and a treatment facility for neonatal hyperbilirubinemia was often more than two hours from households. We enrolled 23 newborns who were ≥ 2 kg in weight and ≥ 35 weeks gestational age, without clinical danger signs, and met the American Academy of Pediatric treatment criteria for phototherapy for hyperbilirubinemia. We employed a mixed-method investigation to evaluate the feasibility and acceptability of home phototherapy through surveys, in-depth interviews and focus group discussions with CHWs, mothers, and grandparents. Mothers and family members found home phototherapy worked well, saved them money, and was convenient and easy to operate. CHWs found it feasible to deploy home phototherapy and identified hands-on training, mHealth job aids, a manageable workload, and prenatal education as facilitating factors for implementation. Feasibility and acceptability concerns were limited amongst parents and included: a lack of confidence in CHWs' skills, fear of putting newborn infants in a phototherapy device, and unreliable home power supply. CHW-led home phototherapy was acceptable to families and CHWs in rural Bangladesh. Further investigation should be done to determine the impact of home phototherapy on treatment rates and on preventing morbidity associated with neonatal hyperbilirubinemia. Clinical Trial (CT) registration ID: NCT03933423, full protocol can be accessed at https://doi.org/10.1186/s13102-024-00824-6 . Name of the trial registry: clinicaltrials.gov. Clinical Trial (CT) registration Date: 01/05/2019.

Associations between UGT1A1, SLCO1B1, SLCO1B3, BLVRA and HMOX1 polymorphisms and susceptibility to neonatal severe hyperbilirubinemia in Chinese Han population.

BACKGROUND: Severe neonatal hyperbilirubinemia could lead to kernicterus and neonatal death. This study aimed to analyze the association between single nucleotide polymorphisms in genes involved in bilirubin metabolism and the incidence of severe hyperbilirubinemia. METHODS: A total of 144 neonates with severe hyperbilirubinemia and 50 neonates without or mild hyperbilirubinemia were enrolled in 3 institutions between 2019 and 2020. Twelve polymorphisms of 5 genes (UGT1A1, SLCO1B1, SLCO1B3, BLVRA, and HMOX1) were analyzed by PCR amplification of genomic DNA. Genotyping was performed using an improved multiplex ligation detection reaction technique based on ligase detection reaction. RESULTS: The frequencies of the A allele in UGT1A1-rs4148323 and the C allele in SLCO1B3-rs2417940 in the severe hyperbilirubinemia group (30.2% and 90.6%, respectively) were significantly higher than those in the controls (30.2% vs.13.0%, 90.6% vs. 78.0%, respectively, both p < 0.05). Haplotype analysis showed the ACG haplotype of UGT1A1 were associated with an increased hyperbilirubinemia risk (OR 3.122, p = 0.001), whereas the GCG haplotype was related to a reduced risk (OR 0.523, p = 0.018). CONCLUSION: The frequencies of the A allele in rs4148323 and the C allele in rs2417940 are highly associated with the incidence of severe hyperbilirubinemia in Chinese Han neonates. TRIAL REGISTRATION: Trial registration number:ChiCTR1800020424; Date of registration:2018-12-29.

Neonatal hyperbilirubinemia and repercussions on neurodevelopment: A systematic review.

BACKGROUND: Accumulation of bilirubin above normal levels is considered a neurological risk factor for both premature and full-term newborns. This systematic review aimed to determine the effect of neonatal hyperbilirubinemia on neurodevelopment in preterm and full-term newborns. METHODS: PubMed, EMBASE, Cochrane Library, CINAHL, PsycINFO, Scopus and Lilacs databases were searched for articles published until 1 June 2022. The quality of cohort and case-control studies was assessed with the Newcastle-Ottawa Scale, and the MINCir scale was used to evaluate the methodological quality of therapy studies or the therapeutic procedures. Premature neonates without neurological conditions and those born at term with hyperbilirubinemia as the sole risk factor were included. Studies reporting one or more neurodevelopmental outcomes were included with an inter-group comparison of a hyperbilirubinemia group versus a non-hyperbilirubinemia or non-pathological hyperbilirubinemia group. The main outcomes were auditory function, visual function, cognitive function, motor function, behavior, global development and neurological risk. RESULTS: The search identified 951 studies, 19 of which (n = 2210 newborns) were finally included. Fifteen of the cohort and case-control studies presented low risk of bias, and six studies showed high methodological quality. Within the preterm population, hyperbilirubinemia as the sole risk factor was not shown to affect neurodevelopment. Auditory, neurological and motor development alterations were found in the population of full-term newborns with hyperbilirubinemia, which were more evident during the first year of life. CONCLUSIONS: Elevated bilirubin levels may be a trigger for the onset of neurodevelopmental disorders in full-term infants during the first year of life. More studies are warranted in the preterm population with hyperbilirubinemia to draw conclusions about its impact on their neurodevelopment.

A Method for Compensating Hemoglobin Interference in Total Serum Bilirubin Measurement Using a Simple Two-Wavelength Reflectance Photometer.

Neonatal hyperbilirubinemia (NH) is a common condition in newborns, with elevated bilirubin levels potentially causing neurological damage or death. Accurate and timely measurements of total serum bilirubin are essential to prevent these outcomes. Direct spectrophotometry, a reliable method for measuring bilirubin, is particularly useful in constrained settings due to its potential for portable low-cost instrumentation. However, this method is susceptible to interference from hemoglobin, often present due to hemolysis. Typically, this interference is reduced using complex optical filters, reagents, multiple wavelengths, or combinations thereof, which increase costs and complexity while reducing usability. This study presents a hemoglobin compensation algorithm applied to a simple, portable, two-wavelength (465 and 590 nm) reflectance photometer designed to receive 30 µL of plasma or whole blood samples and perform the measurement without any reagents. Testing across five bilirubin and hemoglobin levels (4.96 to 28 mg/dL and 0.06 to 0.99 g/dL, respectively) demonstrated that the algorithm effectively reduces hemoglobin interference and overestimation errors. The overall root mean square error was reduced from 4.86 to 1.45 mg/dL, while the measurement bias decreased from -4.46 to -0.10 mg/dL. This substantial reduction in overestimation errors supports future clinical trials with neonatal blood samples.

Feasibility and acceptability of home-based neonatal hyperbilirubinemia screening by community health workers using transcutaneous bilimeters in Bangladesh.

BACKGROUND: Universal screening for neonatal hyperbilirubinemia risk assessment is recommended by the American Academy of Pediatrics to reduce related morbidity. In Bangladesh and in many low- and middle-income countries, there is no screening for neonatal hyperbilirubinemia. Furthermore, neonatal hyperbilirubinemia may not be recognized as a medically significant condition by caregivers and community members. We aimed to evaluate the acceptability and operational feasibility of community health worker (CHW)-led, home-based, non-invasive neonatal hyperbilirubinemia screening using a transcutaneous bilimeter in Shakhipur, a rural subdistrict in Bangladesh. METHODS: We employed a two-step process. In the formative phase, we conducted eight focus group discussions with parents and grandparents of infants and eight key informant interviews with public and private healthcare providers and managers to explore their current knowledge, perceptions, practices, and challenges regarding identification and management of neonatal hyperbilirubinemia. Next, we piloted a prenatal sensitization intervention and home-based screening by CHWs using transcutaneous bilimeters and evaluated the acceptability and operational feasibility of this approach through focus group discussions and key informant interviews with parents, grandparents and CHWs. RESULTS: Formative findings identified misconceptions regarding neonatal hyperbilirubinemia causes and health risks among caregivers in rural Bangladesh. CHWs were comfortable with adoption, maintenance and use of the device in routine home visits. Transcutaneous bilimeter-based screening was also widely accepted by caregivers and family members due to its noninvasive technique and immediate display of findings at home. Prenatal sensitization of caregivers and family members helped to create a supportive environment in the family and empowered mothers as primary caregivers. CONCLUSION: Adopting household neonatal hyperbilirubinemia screening in the postnatal period by CHWs using a transcutaneous bilimeter is an acceptable approach by both CHWs and families and may increase rates of screening to prevent morbidity and mortality.

Vitamin D metabolic pathway genes polymorphisms and vitamin D levels in association with neonatal hyperbilirubinemia in China: a single-center retrospective cohort study.

BACKGROUND: Neonatal hyperbilirubinemia (NH) is a major cause of hospitalization after birth. Previous studies indicated that vitamin D deficiency might play an important role in NH susceptibility, but the results were controversial. Meanwhile, there has been limited description of the association between vitamin D related genes single nucleotide polymorphisms (SNP) and NH susceptibility. We aimed to investigate the vitamin D metabolic pathway genes polymorphisms and vitamin D levels with NH susceptibility. METHODS: We retrospectively analyzed the clinical data, vitamin D levels and its metabolic pathway gene polymorphisms of 187 NH neonates and 149 controls at Tianjin Children's Hospital/Tianjin University Children's Hospital between April 2019 and August 2022. Vitamin D levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and the genetic polymorphism of NADSYN1/DHCR7, GC, CYP2R1, CYP24A1 and CYP27B1 was detected by high resolution melting (HRM) analysis. RESULTS: The frequency of vitamin D deficiency (25(OH)D < 15 ng/mL) was significantly increased in the NH group compared to controls. TT genotype of rs12785878 and GT genotype of rs10877012 were protective factors of vitamin D deficiency and NH, and GT genotype and dominant model carriers of rs12785878 had a higher risk of severe NH than the GG genotype carriers (GT genotype: OR: 2.43; 95% CI: 1.22-4.86; P = 0.012, dominant model: OR: 1.97; 95% CI: 1.04-3.73; P = 0.037). GC gene haplotype was associated with vitamin D deficiency. No significant SNP-SNP and SNP-vitamin D levels interaction combinations were found. CONCLUSIONS: There were associations among NH, vitamin D deficiency and NADSYN1/DHCR7 and CYP27B1 polymorphisms, TT genotype of rs12785878 and GT genotype of rs10877012 could reduce the risk of vitamin D deficiency and NH. Furthermore, rs12785878 was significantly associated with severe NH.

Do Gene Polymorphisms Play a Role in Newborn Hyperbilirubinemia?

Objectives: Polymorphisms of the uridine-diphospho-glucuronosyltransferase 1A1 (UGT1A1) gene, hepatic solute carrier organic anion transporter 1B1/B3 (SLCO1B1/3) gene, and glutathione S-transferase (GST) gene have been associated with significant hyperbilirubinemia in some populations. This study aims to determine whether the variation of UGT1A1, SLCO1B1/3 and GST genes play an important role in neonatal hyperbilirubinemia in Turkish newborn infants. Methods: The study included 61 idiopathic hyperbilirubinemia cases, 28 prolonged jaundice cases, and 41 controls. Ten common polymorphisms in four genes involved in bilirubin metabolism were examined. Polymerase chain reaction-restriction fragment length polymorphism method was used to detect variants of those genes. Results: No association was found between the variants of UGT1A1 at nt 211, the SLCO1B1 gene at nt 388, 463, 521, 1463, the SLCO1B3 gene at nt 334, 727+118, 1865+19721, and the GST gene at nt 313, 341, and neonatal hyperbilirubinemia. There was no difference between the case and control groups in terms of allele frequencies of these genes (except SLCO1B3 at nt 334) (p>0.05 in all comparisons). The presence of the G allele of the SLCO1B3 at nt 334 variant gene seemed to protect from jaundice in infants with idiopathic hyperbilirubinemia. Conclusion: These gene polymorphisms currently studied do not seem to modulate the risk of hyperbilirubinemia in Turkish newborn infants.

Evaluation of hematologic factors and bilirubin following exchange transfusion in neonatal hyperbilirubinemia.

INTRODUCTION: Exchange transfusion (ECT) is one of effective treatments for rapid reduction of the bilirubin serum levels. The main purpose of this study was to offer greater insights into the effects of ECT on the hematologic factors and bilirubin in neonatal hyperbilirubinemia. METHODS: This cross-sectional study was performed on 380 neonates over 35 gestational weeks, and 2-14 days old with a bilirubin of above 17 mg/dl who had undergone ECT at Ghaem Hospital of Mashhad in Iran from 2011 to 2021. Blood samples were examined before, immediately after, 6 h and 60 h after ECT for complete blood cell count (CBC), platelet count and bilirubin serum level analysis. RESULTS: In this study, the mean age of neonates was 5.21 ± 3.55 days with a mean birth weight of 2810 ± 710 gr. The mean platelet count (PLT), white blood cell (WBC) and the serum level of bilirubin were estimated at 260,000/mm2, 12,400/mm2, 23 mg/dl before ECT and 97,000/mm2, 7370//mm2 and 12.6 mg/dl immediately after ECT, respectively (P-value <0.001). CONCLUSION: The results indicated that the mean serum levels of bilirubin, platelets, and leukocytes dropped to 55%, 30%, and 60% of their baseline levels before ECT, respectively, but they all spiked after ECT.

Severe neonatal hyperbilirubinemia secondary to combined RhC hemolytic disease, congenital hypothyroidism and large adrenal hematoma: a case report.

BACKGROUND: ABO blood group incompatibility, neonatal sepsis, G-6-PD deficiency, thyroid dysfunction, and hereditary spherocytosis are all probable causes of neonatal hyperbilirubinemia. However, the etiology of some hyperbilirubinemia is extremely complicated, which may be caused by multiple factors, resulting in severe jaundice. We report a case of severe jaundice due to three causes, showing the significance for the investigation of the etiology of neonatal hyperbilirubinemia. CASE PRESENTATION: At 96 h of life, a full-term and vaginal delivery male infant with yellowish discoloration of body was transferred to our hospital. When he entered neonatal intensive care unit on the fourth day after birth, he developed jaundice and the transcutaneous bilirubin was 28 mg/dl. Total bilirubin was 540.2 µmol/L, while the indirect bilirubin was 516.7 µmol/L. Both parents and the baby's blood types were O Rh(D +), and direct coomb's test was negative. But mother's indirect coomb's test was positive. Investigating for minor blood group revealed that the father's blood type of Rh was CCDee, the mather's was ccDEE, and CcDEe for the baby. After intensive phototherapy and double volume exchange transfusion, the total bilirubin remained at 303 µmol/L. At day 10, the bilirubin level was 303.5 µmol/L, intensive phototherapy was continued, and intravenous immunoglobulin was used again. The test for thyroid hormones at day 10, the TSH was 13.334mIU/L. And the screening for congenital hypothyroidism showed the TSH was 33mIU/L. Because of the palpable abdominal mass, ultrasound and MRI was done, showed a huge mass in the right adrenal gland. Brainstem auditory evoked potential was performed at day 7, which indicated hearing impairment (65db for left ear and 70db for the right). Euthyrox and intermittent phototherapy were given as following treatment. The jaundice did not subside until the 12th day. CONCLUSION: Even if their parents' ABO blood group and Rh (d) are consistent, a Coomb test is required for newborns with hyperbilirubinemia since they may have minor blood group incompatibilities. When bilirubin rises rapidly or the clinical treatment effect is inadequate, additional causes should be aggressively screened. Adrenal ultrasound should be performed on newborns with palpable abdominal mass, anemia and jaundice to determine whether there is adrenal hemorrhage.

Home phototherapy of term neonates improves parental bonding and stress: Findings from a randomised controlled trial.

AIM: We aimed to evaluate whether in-home phototherapy for hyperbilirubinaemia could reduce the poorer parent-infant bonding and increased parental stress associated with neonatal hospital treatment. METHODS: In this multicentre randomised controlled trial, we allocated families to either home phototherapy or standard hospital care. The primary outcome was parent-infant bonding measured on the Postpartum Bonding Questionnaire directly after therapy and 4 months later. Secondary outcomes were results on four other instruments measuring parental bonding, quality of life and mental health. RESULTS: We randomised 78 of 147 newborn infants to intervention and 69 to the control group. No significant differences were detected in length of stay, mean bilirubin, or weight gain. Parents in the intervention group had better scores on bonding both at discharge (p = 0.034) and at 4 months (p = 0.008; effect size r = 0.2) and lower levels of stress at 4 months (p = 0.024) than controls. No statistically significant outcomes were found for the secondary outcomes. CONCLUSION: In-home phototherapy improved bonding and reduced parental stress in comparison with usual in-hospital treatment. Caregivers should consider offering home phototherapy to families of non-immunised term infants with hyperbilirubinaemia.

The effect of hospital phototherapy on early breastmilk feeding.

BACKGROUND: The effect of phototherapy on breastmilk feeding is unclear. OBJECTIVE: To estimate the effect of inpatient phototherapy on breastmilk feeding at 2-month well-child visits. METHODS: We performed a retrospective cohort study using electronic health record data. From births at 16 Kaiser Permanente Northern California hospitals (2013-2017), we identified a cohort of infants ≥ 35 weeks' gestation with total serum bilirubin levels close to the American Academy of Pediatrics 2004 phototherapy threshold during their birth hospitalisation. We compared self-reported breastmilk feeding at 2-month well-child visits among those who had and had not received birth hospitalisation phototherapy, adjusting for bilirubin levels and other confounding variables. We used multiple imputation (K = 200) to address missing data. RESULTS: Approximately a quarter of infants in the cohort (24.5%) received phototherapy during their birth hospitalisation. At the 2-month visit, exclusive breastmilk feeding was less common (RR 0.91, 95% interval [CI] 0.88, 0.95) among those who received phototherapy (41.3%) than those who did not (45.2%). However, no association remained after adjusting for potential confounders (RR 0.99, 95% CI 0.95, 1.04; average treatment effect on the treated [ATET] -0.2%, 95% CI -2.0%, 1.5%). In contrast, any breastmilk feeding was similar between infants who did (76.8%) and did not get phototherapy (77.9%). After adjusting for confounders, phototherapy had a slightly positive association with any breastmilk feeding at 2 months (RR 1.02, 95% CI 1.00, 1.04). Among infants who received phototherapy, the proportion being fed any breastmilk at the 2-month visit was an estimated 1.6 percentage points higher than it would have been if they had not received phototherapy (ATET 1.6%, 95% CI 0.1%, 3.1%). Multiple imputation results were similar. CONCLUSIONS: Birth hospitalisation phototherapy can be delivered in a way that does not adversely affect breastmilk feeding at 2 months.

Recognizing and managing hereditary and acquired thrombotic thrombocytopenic purpura in infants and children.

We describe how infants and children with hereditary and acquired autoimmune thrombotic thrombocytopenic purpura (TTP) initially present and how they can be promptly diagnosed and effectively managed. These are uncommon disorders that are commonly misdiagnosed and can be rapidly fatal. TTP is caused by a severe deficiency of the plasma protease, A disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13 (ADAMTS13). Measurement of ADAMTS13 activity is becoming easily accessible. A common presentation of hereditary TTP is neonatal severe hemolysis and hyperbilirubinemia. However, the median age of diagnosis is not until 5.5 years. Plasma is effective treatment for exacerbations and for prophylaxis. Plasma may be replaced by recombinant ADAMTS13 when it becomes available. Acquired TTP is more frequent in older children, in whom it is more common in girls and is commonly associated with systemic lupus erythematosus. For acquired TTP, plasma exchange and immunosuppression are the current treatment for acute episodes; caplacizumab is now commonly used in adults and may replace plasma exchange.

Error simulation modeling to assess the effects of bias and precision on bilirubin measurements used to screen for neonatal hyperbilirubinemia.

OBJECTIVES: Error simulation models have been used to understand the relationship between analytical performance and clinical outcomes. We developed an error simulation model to understand the effects of method bias and precision on misclassification rate for neonatal hyperbilirubinemia using an age-adjusted risk assessment tool. METHODS: For each of 176 measured total bilirubin (TSBM) values, 10,000 simulated total bilirubin (TBS) values were generated at each combination of bias and precision conditions for coefficient of variation (CV) between 1 and 15%, and for biases between -51.3 µmol/L and 51.3 µmol/L (-3 and 3 mg/dL) fixed bias. TBS values were analyzed to determine if they were in the same risk zone as the TSBM value. We then calculated sensitivity and specificity for prediction of ≥75th percentile for postnatal age values as a function of assay bias and precision, and determined the rate of critical errors (≥95th percentile for age TSBM with <75th percentile TBS). RESULTS: A sensitivity >95% for predicting ≥75th percentile bilirubin values was observed when there is a positive fixed bias of greater than 17.1 µmol/L (1.0 mg/dL) and CV is maintained ≤10%. A specificity >70% for predicting <75th percentile bilirubin values was observed when positive systematic bias was 17.1 µmol/L (1 mg/dL) or less at CV ≤ 10%. Critical errors did not occur with a frequency >0.2% until negative bias was -17.1 µmol/L (-1 mg/dL) or lower. CONCLUSIONS: A positive systematic bias of 17.1 µmol/L (1 mg/dL) may be optimal for balancing sensitivity and specificity for predicting ≥75th percentile TSB values. Negative systematic bias should be avoided to allow detection of high risk infants and avoid critical classification errors.

Co-inheritance of G6PD deficiency and 211 G to a variation of UGT1A1 in neonates with hyperbilirubinemia in eastern Guangdong.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may manifest as neonatal hyperbilirubinemia, is the most prevalent erythrocytic enzyme-related disease in the world. OBJECTIVE: To investigate the association between neonatal hyperbilirubinemia and co-inheritance of G6PD deficiency and 211 G to A variation of UGT1A1 in Chaozhou city of eastern Guangdong province, the effects of G6PD deficiency and UGT1A1 gene variant on the bilirubin level were determined in neonates with hyperbilirubinemia. METHOD: The activity of G6PD was assayed by an auto-bioanalyzer. PCR and flow-through hybridization were used to detect 14 common G6PD mutations in G6PD deficient neonates. 211 G to A variation of UGT1A1 was determined by PCR and sequencing. The data of neonatal bilirubin was collected and analyzed retrospectively. RESULTS: Seventy four cases of the 882 hyperbilirubinemia neonates were G6PD deficiency (8.39%) while 12 cases of the 585 non-hyperbilirubinemia neonates (control group) were G6PD deficiency (2.05%). The rate of G6PD deficiency in the hyperbilirubinemia group was higher than that of the control group. Moreover, the peak bilirubinin of the G6PD-deficient group of hyperbilirubinemia neonates was 334.43 ± 79.27 µmol/L, higher than that of the normal G6PD group of hyperbilirubinemia neonates (300.30 ± 68.62 µmol/L). The most common genotypes of G6PD deficiency were c.1376G > T and c.1388G > A, and the peak bilirubin of neonates with these two variants were 312.60 ± 71.81 µmol/L and 367.88 ± 75.79 µmol/L, respectively. The bilirubin level of c.1388G > A was significantly higher than that of c.1376G > T. Among the 74 hyperbilirubinemia neonates with G6PD deficiency, 6 cases were 211 G to A homozygous mutation (bilirubin levels 369.55 ± 84.51 µmol/L), 27 cases were 211 G to A heterozygous mutation (bilirubin levels 341.50 ± 63.21 µmol/L), and 41 cases were wild genotypes (bilirubin levels 324.63 ± 57.52 µmol/L). CONCLUSION: The rate of G6PD deficiency in hyperbilirubinemia neonates was significantly higher than that of the non-hyperbilirubinemia neonates in Chaozhou. For the hyperbilirubinemia group, neonates with G6PD deficiency had a higher bilirubin level compared to those with normal G6PD. For hyperbilirubinemia neonates with G6PD deficiency, there was a declining trend of bilirubin levels among 211 G to A homozygous mutation, heterozygous mutation, and wild genotype, but there was no significance statistically among the three groups.

Nationwide survey of late-onset hemolysis in very low birthweight infants.

BACKGROUND: In Japan, some cases of late-onset acute hemolysis in very low birthweight (VLBW) infants have been reported. These cases had common features but the cause of hemolysis was unknown. The incidence and prognosis of this disease are also unknown. However, there are only few reports of such hemolytic episodes in countries other than Japan. Thus, this study aimed to examine the incidence and clinical course of late-onset acute hemolysis and to establish it as a new disease concept. METHODS: A nationwide prospective survey was conducted from 2011 to 2015 as a rare disease surveillance project of the Japan Society for Neonatal Health and Development. RESULTS: Twenty-four cases were confirmed. The median (range) gestational age, birthweight, and onset of hemolytic episodes were 26 weeks and 2 days (23 weeks and 4 days-31 weeks and 2 days), 898 g (627-1,416 g), and 19 days after birth (9-33 days), respectively. Phototherapy, blood transfusion, and exchange transfusion were required in 22 (96%), 24 (100%), and 7 (29%) cases, respectively. During the observation period, no recurrence of the hemolytic episode occurred. All patients survived; however, one case developed kernicterus and suffered severe neurological sequelae. CONCLUSIONS: In this study, at least 1 out of 1,259 VLBW infants developed hemolysis at 9-33 days after birth in Japan. Owing to the risk of kernicterus, this disease should be recognized as among the important pathological conditions of VLBW infants, suggesting the need to manage jaundice and anemia until 5 weeks after birth.

Changes in amplitude-integrated electroencephalography, neuron-specific enolase, and S100B in neonates with brain injury induced by neonatal hyperbilirubinemia and their significance.

OBJECTIVE: To explore the changes in amplitude-integrated electroencephalography (aEEG), neuron-specific enolase (NSE), and S100B in neonates with brain injury induced by neonatal hyperbilirubinemia (NHB). METHODS: 67 neonates with brain injury induced by NHB admitted to our hospital from March 2016 to October 2018 were included in a brain injury group (BIG), and 82 neonates with NHB but without brain injury in our hospital during the same period were included in a non-BIG. The two groups were compared regarding the rates of normal and abnormal aEEG results. RESULTS: The proportion of normal aEEG results in the BIG was significantly lower than that in the non-BIG, and the proportion of moderately and severely abnormal aEEG results in the BIG were both significantly higher than those in the non-BIG. The BIG showed significantly higher NSE and S100B levels than those of the non-BIG. The ROC curve for predicting prognosis showed that the AUC of aEEG, NSE, S100B, and the combined detection are 0.780, 0.754, 0.743, 0.788. The AUC > 0.700 indicated a good predictive value for the prognosis. CONCLUSION: The combination of aEEG, NSE, and S100B has good value in diagnosing injury induced by NHB and can predict prognosis moderately well.