Phototherapy Alters the Plasma Metabolite Profile in Infants Born Preterm with Hyperbilirubinemia.

OBJECTIVE: To investigate the effects of gestational age (GA) and phototherapy on the plasma metabolite profile of preterm infants with neonatal hyperbilirubinemia (NHB). STUDY DESIGN: From a cohort of prospectively enrolled infants born preterm (N=92), plasma samples of very preterm (VPT; GA, 28+0 to 31+6 weeks, N =27) and moderate/late preterm (M/LPT; GA, 32+0 to 35+6 weeks, N =33) infants requiring phototherapy for NHB were collected prior to the initiation of phototherapy and 24 hours after starting phototherapy. An additional sample was collected 48 hours after starting phototherapy in a randomly selected subset (N=30; VPT N=15; M/LPT N=15). Metabolite profiles were determined using ultraperformance liquid chromatography tandem mass spectroscopy. Two-way ANCOVA was used to identify metabolites that differed between GA groups and timepoints after adjusting for total serum bilirubin (TSB) levels (FDR q-value<0.05). Top impacted pathways were identified using pathway over-representation analysis. RESULTS: Phototherapy was initiated at lower TSB (mean ± SD mg/dL) levels in VPT compared with M/LPT infants (7.3 ± 1.4 vs. 9.9 ± 1.9, p<0.01). We identified 664 metabolites that were significant for a phototherapy effect, 191 metabolites significant for GA, and 46 metabolites significant for GA x phototherapy interaction (FDR q-value<0.05). Longer duration phototherapy had a larger mean effect size (24 hours post-phototherapy: d=0.36; 48 hours post-phototherapy: d=0.43). Top pathways affected by phototherapy included membrane lipid metabolism, one-carbon metabolism, creatine biosynthesis, and oligodendrocyte differentiation. CONCLUSION: Phototherapy alters the plasma metabolite profile more than GA in preterm infants with NHB, affecting pathways related to lipid and one-carbon metabolism, energy biosynthesis, and oligodendrocyte differentiation.

Adrenal hemorrhage in neonates: Incidence, perinatal characteristics and follow-up outcomes.

BACKGROUND AND OBJECTIVES: Neonatal adrenal hemorrhage (NAH) is relatively uncommon in neonates and it is often noted accidently by abdominal ultrasonogram. Few studies discussed risk factors for and impacts of NAH. This study aimed to assess incidence, perinatal characteristics and follow-up outcomes in neonates with adrenal hemorrhage. METHODS: This was a retrospective cohort study in a single institute from April 2008 to August 2018. All neonates who received abdominal ultrasonogram within seven days-of-life were recruited and divided in to 2 groups according to the presence of NAH. The perinatal characteristics and anthropometric measurements, the follow-up course and the clinical impact of NAH were reviewed in detail. RESULTS: 7217 neonates had received abdominal ultrasonogram within seven days-of-life and 29 of them (0.4%) were diagnosed with NAH. Mean gestation age was 38 ± 1.2 weeks and mean birth weight was 3406 ± 403 g. Most infants (96.6%) had unilateral hemorrhage over the right adrenal gland. Compared with the control group, infants with NAH were significantly heavier (3406 vs. 3094 gm, p < 0.001), longer in body length (50.1 vs. 48.8 cm, p < 0.001) and wider in chest girth (33.2 vs. 32.4 cm, p = 0.006). They also tended to be delivered via vaginal delivery with vacuum-extraction rather than cesarean section. The prevalence of nuchal cord, neonatal jaundice and subgaleal hemorrhage was higher in the NAH group. The hemorrhage area of adrenal gland had a positive correlation with the peak bilirubin level (r = 0.422, p < 0.001) and the days to resolution (r = 0.198, p = 0.033). All infants had resolution of AH before 7 months of age. CONCLUSIONS: NAH occurred more frequently in heavier neonates that were delivered via vaginal delivery with vacuum extraction. The hemorrhage involved mostly over the right adrenal gland. Neonatal jaundice was the major comorbidity. All infants had spontaneous resolution of AH before 7 months of age.

Neonatal jaundice incidence, risk factors and outcomes in 54 referral-level facilities in Nigeria.

OBJECTIVE: To determine the incidence, risk factors and outcomes of babies with neonatal jaundice in a network of referral-level hospitals in Nigeria. DESIGN: A cross-sectional analysis of perinatal data collected over a 1-year period. SETTING: Fifty-four referral-level hospitals (48 public and 6 private) across the six geopolitical zones of Nigeria. POPULATION: A total of 77 026 babies born at or admitted to the participating facilities (67 697 hospital live births; plus 9329 out-born babies), with information on jaundice between 1 September 2019 and 31 August 2020. METHODS: Data were extracted and analysed to calculate incidence and sociodemographic and clinical risk factors for neonatal jaundice. MAIN OUTCOME MEASURES: Incidence and risk factors of neonatal jaundice in the 54-referral hospitals in Nigeria. RESULTS: Of 77 026 babies born in or admitted to the participating facilities, 3228 had jaundice (41.92 per 1000 live births). Of the 67 697 hospital live births, 845 babies had jaundice (12.48 per 1000 live births). The risk factors associated with neonatal jaundice were no formal education (adjusted odds ratio [aOR] 1.68, 95% CI 1.11-2.52) or post-secondary education (aOR 1.17, 95% CI 0.99-1.38), previous caesarean section (aOR 1.68, 95% CI 1.40-2.03), booked antenatal care at <13 weeks or 13-26 weeks of gestation (aOR 1.58, 95% CI 1.20-2.08; aOR 1.15, 95% CI 0.93-1.42, respectively), preterm birth (aOR 1.43, 95% CI 1.14-1.78) and labour more than 18 hours (aOR 2.14, 95% CI 1.74-2.63). CONCLUSIONS: Hospital-level and regional-level strategies are needed to address newborn jaundice, which include a focus on management and discharge counselling on signs of jaundice.

A Multicenter Pilot Study of Biliary Atresia Screening Using Digital Stool Color Imaging.

Purpose: The presence of alcoholic stool in biliary atresia (BA) patients is the basis of a stool color card (SCC), a screening tool that has led to more patients receiving Kasai portoenterostomy earlier. This study aimed to evaluate the color image processing of stool images captured using smartphones. We propose that measuring digital color parameters is a more objective method for identifying BA stools and may improve the sensitivity of BA screening. Methods: A prospective study was conducted in five hospitals in Thailand between October 1, 2020, and December 31, 2021. Stools from infants presenting with jaundice, acholic stool, or dark-colored urine were photographed. Digital image color analysis was performed, and software was developed based on the color on the original SCC. Sensitivity and specificity for predicting BA stools were compared between the SCC and the software. Results: Of 33 infants eligible for data collection, 19 were diagnosed with BA. Saturation and blue were two potential digital color parameters used to differentiate BA stools. The receiver operating characteristic curve was used to determine the optimum cutoff point of both values, and when saturation ≤56 or blue ≥61 was set as a threshold for detecting BA stool, high accuracy was achieved at 81.8% and 78.8%, respectively. Conclusion: Digital image processing is a promising technology. With appropriate cutoff values of saturation in hue, saturation, value and blue in red, green, blue color models, BA stools can be identified, and equivocal-colored stools of non-BA patients can be differentiated with acceptable accuracy in infants presenting with jaundice.

Neonatal jaundice detection in low-resource Mexican settings: possibilities and barriers for innovation with mobile health.

BACKGROUND: Neonatal jaundice is a common condition that can lead to brain damage and disabilities when severe cases go undetected. Low- and middle-income countries often lack accurate methods for detecting neonatal jaundice and rely on visual assessment, resulting in a higher incidence of adverse consequences. Picterus Jaundice Pro (Picterus JP), an easy-to-use and affordable smartphone-based screening device for the condition, has demonstrated higher accuracy than visual assessment in Norwegian, Philippine and Mexican newborns. This study aimed to identify the barriers and facilitators to implementing Picterus JP in public health services in low-income settings in Mexico by exploring the current process of neonatal jaundice detection and stakeholders' perspectives in that context. METHODS: Qualitative data collection techniques, including one focus group, 15 semi-structured interviews and four observations, were employed in urban and rural health facilities in Oaxaca, Mexico. The participants included medical doctors, nurses and health administrators. The data were analysed by thematic analysis guided by the Consolidated Framework for Implementation Research. RESULTS: The analysis yielded four main themes: (I) the current state of neonatal care and NNJ detection, (II) the needs and desires for enhancing NNJ detection, (III) the barriers and facilitators to implementing Picterus JP in the health system and (IV) HCWs' expectations of Picterus JP. The findings identify deficiencies in the current neonatal jaundice detection process and the participants' desire for a more accurate method. Picterus JP was perceived as easy to use, useful and compatible with the work routine, but barriers to adoption were identified, including internet deficiencies and costs. CONCLUSIONS: The introduction of Picterus JP as a supporting tool to screen for neonatal jaundice is promising but contextual barriers in the setting must be addressed for successful implementation. There is also an opportunity to optimise visual assessment to improve detection of neonatal jaundice.

Infantile pyknocytosis, a neonatal hemolytic anemia with Heinz bodies: A cohort study.

Infantile pyknocytosis (IP) is a rare, probably misestimated, cause of non-immune neonatal hemolytic anemia evolving in two phases: an initial phase with severe jaundice, followed by a second phase with hemolytic anemia, which may require neonatal intensive care. The diagnosis of IP is based on the transient presence on blood smear of hyperdense, contracted, and/or spiculated red blood cells (pyknocytes), associated with the spontaneous resolution of clinico-biological features and the exclusion of other causes. If the etiology remains undetermined, some contributing factors, such as oxidative stress, have been proposed. We report the description of 16 patients with IP aiming at clarifying the circumstances associated with the development of this acquired disorder. In the acute phase, the mean hemoglobin nadir and pyknocyte count were 7.8 g/dL and 11%, respectively, and strikingly, Heinz bodies were evident in 50% of the newborns, but in 100% after prolonged incubation (4 hours). A high proportion of Mediterranean or African ancestry was noted in newborns, as well as a significant number of peripartum events, such as respiratory distress. If the etiology of IP is certainly multifactorial, our series reinforces the role of oxidative stress, which may, at least in part, find origin in desaturation episodes in newborns.

Development of Non-Invasive Biosensors for Neonatal Jaundice Detection: A Review.

One of the most common problems many babies encounter is neonatal jaundice. The symptoms are yellowing of the skin or eyes because of bilirubin (from above 2.0 to 2.5 mg/dL in the blood). If left untreated, it can lead to serious neurological complications. Traditionally, jaundice detection has relied on invasive blood tests, but developing non-invasive biosensors has provided an alternative approach. This systematic review aims to assess the advancement of these biosensors. This review discusses the many known invasive and non-invasive diagnostic modalities for detecting neonatal jaundice and their limitations. It also notes that the recent research and development on non-invasive biosensors for neonatal jaundice diagnosis is still in its early stages, with the majority of investigations being in vitro or at the pre-clinical level. Non-invasive biosensors could revolutionize neonatal jaundice detection; however, a number of issues still need to be solved before this can happen. These consist of in-depth validation studies, affordable and user-friendly gadgets, and regulatory authority approval. To create biosensors that meet regulatory requirements, additional research is required to make them more precise and affordable.

Innovative approaches to neonatal jaundice diagnosis and management in low-resourced settings.

Persistent challenges in addressing severe neonatal hyperbilirubinaemia in resource-constrained settings have led to ongoing and often unacceptable rates of morbidity, disability and mortality. These challenges stem from limitations such as inadequate, inefficient or financially inaccessible diagnostic and therapeutic options. However, over the past decade, noteworthy innovations have emerged to address some of these hurdles, and these innovations are increasingly poised for broader implementation. This review provides a concise summary of these novel, economically viable diagnostic solutions, encompassing point-of-care assays and smartphone applications, as well as treatment modalities, notably more effective phototherapy and filtered sunlight. These advancements hold promise and have the potential to meaningfully reduce the burden of neonatal hyperbilirubinaemia, signifying a promising shift in the landscape of neonatal healthcare.

Machine Learning to Improve Accuracy of Transcutaneous Bilirubinometry.

INTRODUCTION: This study aimed to develop models for predicting total serum bilirubin by correcting errors of transcutaneous bilirubin using machine learning based on neonatal biomarkers that could affect spectrophotometric measurements of tissue bilirubin. METHODS: This retrospective study included infants born at our hospital (≥36 weeks old, ≥2,000 g) between January 2020 and December 2022. Infants without a phototherapy history were included. Robust linear regression, gradient boosting tree, and neural networks were used for machine learning models. A neural network, inspired by the structure of the human brain, was designed comprising three layers: input, intermediate, and output. RESULTS: Totally, 683 infants were included. The mean (minimum-maximum) gestational age, birth weight, participant age, total serum bilirubin, and transcutaneous bilirubin were 39.0 (36.0-42.0) weeks, 3,004 (2,004-4,484) g, 2.8 (1-6) days of age, 8.50 (2.67-18.12) mg/dL, and 7.8 (1.1-18.1) mg/dL, respectively. The neural network model had a root mean square error of 1.03 mg/dL and a mean absolute error of 0.80 mg/dL in cross-validation data. These values were 0.37 mg/dL and 0.28 mg/dL, smaller compared to transcutaneous bilirubin, respectively. The 95% limit of agreement between the neural network estimation and total serum bilirubin was -2.01 to 2.01 mg/dL. Unnecessary blood draws could be reduced by up to 78%. CONCLUSION: Using machine learning with transcutaneous bilirubin, total serum bilirubin estimation error was reduced by 25%. This integration could increase accuracy, lessen infant discomfort, and simplify procedures, offering a smart alternative to blood draws by accurately estimating phototherapy thresholds.

Transcutaneous bilirubin reliability during and after phototherapy depending on skin color.

Measurement of transcutaneous bilirubin (TcB) is a non-invasive, widely used technique to estimate serum bilirubin (SB). However, its reliability in multiethnic populations during and after phototherapy is still controversial even in covered skin. The aim of this study was to determine the reliability of TcB in covered (cTcB) and exposed (eTcB) skin during and after phototherapy in a multiethnic population of term and preterm neonates according to Neomar's neonatal skin color scale. Prospective, observational study comparing SB and TcB. We determined SB when clinically indicated and, at the same time, measured cTcB under a photo-opaque patch and eTcB next to it with a jaundice meter (Dräger JM-105TM). All dyads TcB-SB were compared, both globally and according to skin color. We obtained data from 200 newborns (color1: 44, color2: 111, color3: 41, color4: 4) and compared 296 dyads TcB/SB. Correlation between cTcB and SB is strong during (0.74-0.83) and after (0.79-0.88) phototherapy, both globally and by color group. The SB-cTcB bias depends on gestational age during phototherapy and on skin color following phototherapy. The correlation between eTcB and SB during phototherapy is not strong (0.54), but becomes so 12 h after discontinuing phototherapy (0.78).  Conclusions: Our study supports the reliability of cTcB to assess SB during and after phototherapy, with differences among skin tones after the treatment. The use of cTcB and Neomar's scale during and mainly after phototherapy may help reduce the number of blood samples required. What is Known: • Controversies exist on the reliability of jaundice meters during and after phototherapy in covered skin. Only a few studies have analyzed their accuracy in multiethnic populations, but none has used a validated neonatal skin color scale. What is New: • We verified correlation between serum and transcutaneous bilirubin in covered skin in a multiethnic population depending on skin color based on our own validated neonatal skin color scale during and after phototherapy.

A review of the current policies and guidance regarding Apgar scoring and the detection of jaundice and cyanosis concerning Black, Asian and ethnic minority neonates.

BACKGROUND: Ethnic inequalities in maternal and neonatal health in the UK are well documented. Concerns exist regarding the use of skin colour in neonatal assessments. Healthcare professionals should be trained to recognise symptoms of diverse skin tones, and comprehensive, and inclusive guidance is necessary for the safe assessment of all infants. Disparities in healthcare provision have been emphasised during the COVID-19 pandemic, and additional research is needed to determine whether such policies adequately address ethnic minority neonates. METHODS: A desktop search included searches of guidance produced for the United Kingdom (UK). Further searches of the Cochrane and World Health Organization (WHO) were used to identify any international guidance applicable in the UK context. RESULTS: Several policies and one training resource used descriptors 'pink,' 'pale,' 'pallor,' and 'blue' about neonatal skin and mucous membrane colour. No policies provided specific guidance on how these colour descriptors may appear in neonates with different skin pigmentation. Only the NICE guidance and HEE e-learning resource acknowledged the challenges of assessing jaundice in infants with diverse skin tones, while another guideline noted differences in the accuracy of bilirubin measurements for the assessment of jaundice. Three policies and one training resource advised against relying on visual observation of skin colour when diagnosing neonatal conditions. The training resource included images of ethnic minority neonates, although most images included white infants. CONCLUSIONS: Inadequate consideration of ethnicity in UK policy and training perpetuates disparities, leading to inaccurate assessments. A review is needed for inclusivity in neonatal care, regardless of skin pigmentation.

Magnitude and its associated factors of neonatal jaundice among neonates admitted to the neonatal intensive care unit of Dessie Town public hospitals, Amhara region, Ethiopia, 2020: a multicenter cross-sectional study.

Background: Neonatal jaundice is a prevalent illness affecting approximately 60%-80% of newborns. In severe cases, it can result in severe neurological distress. Approximately 1.1 million neonates are affected annually on a global scale, with the vast majority living in sub-Saharan Africa and southern Asia. It is common in newborns in the first week of life. This study aims to assess the magnitude and determinants of jaundice in newborns admitted to the neonatal intensive care unit (NICU) of public hospitals in the city of Dessie in northern Ethiopia. Methods: An institutional cross-sectional study was conducted at the NICU at Dessie town public hospitals from 30 March to 30 April 2020. A systematic random sampling procedure was used to select the study participants. Data were collected through face-to-face interviews with mothers using a structured questionnaire and by reviewing neonatal medical records using a checklist. Binary logistic regression analysis was used to identify the determinants of neonatal jaundice. A significance level of less than 0.05 was used to declare the statistical significance in the final model. Results: A total of 218 neonates with their mothers were included in the study. The prevalence rate of neonatal jaundice was found to be 28.4%. The major associated factors for neonatal jaundice were sepsis [adjusted odds ratio (AOR): 10.13, 95% confidence interval (CI) = 2.36, 43.56], preterm < 37 weeks (AOR: 6.03, 95% CI = 1.41, 25.79) low APGAR score < 7 (AOR: 7.34, 95% CI = 1.34, 39.65), ABO incompatibility (AOR: 24.55 95% CI = 1.58, 68.83), prolonged labor (AOR 9.03, 95% CI = 1.67, 48.33), and Rh incompatibility (AOR = 30.40, 95% CI = 2.01, 66.20). Conclusion: The magnitude of neonatal jaundice among neonates was determined to be high. Therefore, both maternal and neonatal factors contributed significantly to the management of neonatal jaundice and also influenced the use of phototherapy treatment. Proper consideration of these factors is crucial for the prevention and treatment of neonatal jaundice.

Validity of BiliDx as a point-of-care bilirubin measurement device to diagnose and monitor neonatal jaundice at Muhimbili National Hospital, an observational study.

BACKGROUND: Neonatal jaundice is a condition caused by elevated levels of bilirubin in the bloodstream. Laboratory determination of serum bilirubin concentration by total serum bilirubin (TSB) test is still considered as gold standard for clinical guidance and practice. In developed countries, diagnosis of neonatal jaundice is shifting towards point-of-care medical devices. BiliDx is a device developed to allow a fast, blood-based determination of bilirubin levels at the point of care. This study aimed to determine the accuracy of the BiliDx device relative to a standard laboratory total serum bilirubin to diagnose and monitor jaundice among neonates admitted at Muhimbili National Hospital (MNH). MATERIAL AND METHODOLOGY: This was a prospective hospital-based observational study conducted at the Neonatal Ward - MNH, Dar-es-Salaam, Tanzania from November 2022 to January 2023. A total of 180 neonates admitted at the neonatal ward with jaundice and whose parents consented were enrolled in the study. Blood samples were collected; 2 ml of venous blood into the vacutainer bottle for standard laboratory measurement of total serum bilirubin (TSB) and 25µL blood collected into a transfer pipette tube and applied to BiliDx. STATA version 15.1 was used for data analysis. RESULTS: Out of 180 neonates, 39.4% (71/180) had birth weight between 1500 - 2499.9 g, approximately 2/3rd (120/180) were preterm, 92/180 (51.1%) were males and 100/180 (55.6%) were undergoing phototherapy treatment the moment sample taken. The mean bilirubin concentration was 92 mmol/l for BiliDx and 118 mmol/l for standard laboratory TSB. The minimum and maximum values obtained with BiliDx were, 3.4 and 427.5 mmol/l respectively, compared with 10.7 and 382.1 mmol/l using standard laboratory TSB. A linear relationship and correlation coefficient of 0.8408 (p = 0.000) between BiliDx and standard laboratory TSB was found. The regression analysis showed the presence of constant error [coefficient of BiliDx/slope = 0.91, 95% CI (0.82-0.99), p = 0.000] and random error exclusively [coefficient of constant/y-intercept = 48.52, 95%CI (37.70-59.34), p = 0.000]. The Bland-Altman plot showed an acceptable mean difference of 39.1mmol/l, limits of agreement of -48.3mmol/l to 126.4mmol/l, and 179 points (179/180 = 99.4%) lying inside the limits of agreement. CONCLUSION: The results support the use of BiliDx for rapid and accurate testing of elevated levels of bilirubin in the bloodstream among neonates since 99.4% of the differences between BiliDx and standard laboratory TSB lie between the lines of agreement.

Healthcare workers' perceptions about the use of mobile health technologies in public health facilities in Lagos, Nigeria.

Background: Mobile health has enormous potential in healthcare due to the increasing use of mobile phones in low- and middle-income countries; its effective deployment, uptake, and utilization may result in improved health outcomes, including a reduction in neonatal deaths. However, there is a suboptimal uptake of mobile health technologies among healthcare workers in low-resource settings like Nigeria, which are often context-specific. Objective: To investigate healthcare workers' perceptions of mobile health technologies in public health facilities in Lagos, Nigeria. Method: A qualitative study was conducted, and data were collected through six focus group discussions with 26 healthcare workers (doctors, nurses, and community health extension workers) from three public health facilities in Lagos, Nigeria. The collected data were analyzed using a thematic approach, where themes and subthemes were created. Results: Although the participants acknowledged that mobile health enhances patient-provider communication and saves time, they identified altering of healthcare workers' routine practices, information overload, power and network failure, skepticism, lack of trust, and concerns over diagnostic accuracy as potential barriers to its uptake. Conclusion: Addressing healthcare workers' perceptions of mobile health technologies may enhance the deployment and uptake of such solutions in Nigeria and similar low-resource settings. Developers and implementers of such can use them to create new or enhance existing mobile health solutions to better meet the needs and requirements of healthcare workers in low- to middle-income health settings, such as Lagos, Nigeria.

Factors associated with neonatal jaundice among neonates admitted at referral hospitals in northeast Ethiopia: a facility-based unmatched case-control study.

BACKGROUND: Neonatal jaundice is a significant contributor to illness and death in newborns, leading to frequent admissions to neonatal intensive care units. To better understand this issue, a study was conducted to identify the factors contributing to neonatal jaundice among newborns admitted to Dessie and Woldia comprehensive specialized hospitals in northeast Ethiopia. METHODS: The study took place from April 1 to May 30, 2022, using unmatched case-control design. A total of 320 neonates paired with their mothers were involved, including 64 cases and 256 controls. Data were collected through a structured interviewer-administered questionnaire and a review of medical records. The collected data were analyzed using SPSS Version 23, and a multivariate logistic regression model was employed to understand the relationship between independent factors and the occurrence of neonatal jaundice. Statistical significance was determined at a threshold of P value less than 0.05. RESULTS: The study findings revealed that maternal age over 35 years, residing in urban areas [adjusted odds ratio (AOR) = 2.4, 95% confidence interval (CI): 1.23, 4.82], male gender (AOR = 4.3, 95% CI: 1.90, 9.74), prematurity (AOR = 3.9, 95% CI: 1.88, 8.09), and ABO incompatibility (AOR = 2.6, 95% CI: 1.16, 5.96) were significant determinants of neonatal jaundice. Conversely, the study indicated that cesarean birth was associated with a 76% lower likelihood of infant jaundice compared to vaginal delivery (AOR = 0.24, 95% CI: 0.08, 0.72). CONCLUSION: To prevent, diagnose, and treat neonatal jaundice effectively, efforts should primarily focus on managing ABO incompatibility and early detection of prematurity. Additionally, special attention should be given to neonates born through vaginal delivery, those with mothers over 35 years old, and those residing in urban areas, as they are at higher risk of developing newborn jaundice. Close monitoring of high-risk mother-infant pairs during the antenatal and postnatal periods, along with early intervention, is crucial for reducing the severity of neonatal jaundice in this study setting.

Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single-gene testing and next-generation sequencing in East Asia.

BACKGROUND AND AIM: Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel-based next-generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single-gene testing and next-generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. METHODS: From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single-gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. RESULTS: Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin-Johnson syndrome, 5 with arthrogryposis-renal dysfunction-cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann-Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl-tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single-gene testing and next-generation sequencing. CONCLUSIONS: Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single-gene testing and next-generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.

Minocycline attenuates the bilirubin-induced developmental neurotoxicity through the regulation of innate immunity and oxidative stress in zebrafish embryos.

When liver or intestinal function is impaired, bilirubin accumulates in the body and leads to neonatal jaundice. However, the potential negative effects caused by excessive accumulation of bilirubin such as developmental immunotoxicity and neurotoxicity remain unclear. We used a zebrafish model to establish bilirubin-induced jaundice symptoms and evaluated the toxic effects of bilirubin in aquatic organisms. Firstly, our results suggested that bilirubin exposure markedly decreased the survival rate, induced the developmental toxicity and increased the yellow pigment deposited in the zebrafish tail. Meanwhile, the number of macrophages and neutrophils was substantially reduced in a concentration-dependent manner. Besides, the antioxidant enzyme activities were greatly elevated while the inflammatory genes were significantly decreased after bilirubin exposure. Secondly, transcriptome analysis identified 708 genes were differentially expressed after bilirubin exposure, which animal organ morphogenesis, chemical synaptic transmission, and MAPK / mTOR signaling pathways were significantly enriched. Thirdly, bilirubin exposure leads to a significant decrease in the motility of zebrafish, including a dose-dependent decrease in the travelled distance, movement time, and average velocity. Moreover, the innate immune genes and apoptosis-related genes such as TLR4, NF-κB p65, STAT3 and p53 were elevated at a concentration of 10 µg/mL of bilirubin. Finally, our results further revealed that the anti-inflammatory and neuroprotective minocycline could partially rescue the bilirubin-induced neurobehavioral disorders in zebrafish embryos. In conclusion, our study explored the bilirubin-induced immunotoxicity and neurotoxicity in aquatic organisms, which will provide a theoretical basis for the treatment of neonatal jaundice in clinical practice.

Modified Kramer's versus Kramer's Method for Clinical Assessment of Jaundice in Term and Near-Term Neonates.

OBJECTIVES: To compare the performance of Modified Kramer's and Kramer's methods in terms of agreement with total serum bilirubin (TSB). METHODS: This cross-sectional study was done in Level-III neonatal unit in New Delhi. Visibly jaundiced neonates born at ≥35 wk of gestation were enrolled and examined by (i) conventional Kramer's, (ii) Modified Kramer's in artificial (MK-A) and (iii) natural daylight (MK-N), and finally sampled for estimation of TSB by point-of-care spectrophotometry. The primary outcomes were agreement of Kramer's and Modified Kramer's with TSB and accuracy in terms of proportion of bilirubin estimates lying within ±2 mg/dL of TSB; secondary outcome was agreement of MK-A and MK-N with TSB. RESULTS: A total of 144 neonates with median gestation of 37 wk and mean birth weight of 2788 g were enrolled. Bland Altman analysis between Kramer's and TSB yielded mean difference of 1.7 mg/dL, 95% limits of agreement (LOA) -3.1 to 6.6 mg/dL. For Modified Kramer's and TSB, mean difference was -0.02 mg/dL, 95% LOA -4.7 to 4.7 mg/dL under artificial light; 0.02 mg/dL, 95% LOA -4.2 to 4.2 mg/dL under natural daylight. MK-N had highest proportion of bilirubin estimates lying within ±2 mg/dL of TSB (68.7%) as compared to MK-A (59.7%) [OR, 1.77; 95% CI, 1.09 to 2.86] and Kramer's (45.8%) [OR, 1.65; 95% CI, 1.27 to 2.15]. CONCLUSIONS: Though all the three methods had poor agreement with TSB, Modified Kramer's method when performed in natural light had reasonable accuracy, however limited clinical utility, in evaluation of clinical jaundice.

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.