Updated Clinical Practice Guidelines for Management of Hyperbilirubinemia in Infants Born at 35 Weeks or More Gestation.

Given the prevalence of jaundice in newborns, and the consequences of untreated hyperbilirubinemia, the long-awaited revised clinical practice guidelines for hyperbilirubinemia were finally released in August 2022 by the American Academy of Pediatrics as an update to the 2004 guidelines on the same topic. As new evidence and data become available, it is important for pediatricians and neonatologists to re-assess their clinical decision-making over time to ensure that patients are receiving the best care possible. With improvements in medical equipment and medical technology, and growing concerns about the overtreatment of hyperbilirubinemia, the newest clinical practice guidelines attempt to tackle the prevention, risk assessment, monitoring, and treatment of hyperbilirubinemia with these things in mind. [Pediatr Ann. 2023;52(12):e436-e439.].

Clinical and genetic definition of serum bilirubin levels for the diagnosis of Gilbert syndrome and hypobilirubinemia.

BACKGROUND AND AIMS: Gilbert syndrome (GS) is genotypically predetermined by UGT1A1*28 homozygosity in Europeans and is phenotypically defined by hyperbilirubinemia using total bilirubin (TB) cutoff ≥1mg/dL (17 µmol/L). The prevalence of illnesses associated with GS and hypobilirubinemia has never been studied prospectively. As TB varies with UGT1A1*28 genotyping, sex, and age, we propose stratified definitions of TB reference intervals and report the prevalence of illnesses and adjusted 15 years survival. METHODS: UK Biobank with apparently healthy liver participants (middle-aged, n=138,125) were analyzed after the exclusion of of nonhealthy individuals. The stratified TB was classified as GS when TB >90th centile; <10th centile indicated hypobilirubinemia, and between the 10th and 90th centile was normobilirubinemia. We compared the prevalence and survival rates of 54 illnesses using odds ratio (OR), logistic regression, and Cox models adjusted for confounders, and causality by Mendelian randomizations. RESULTS: In women, we identified 10% (7,741/76,809) of GS versus 3.7% (2,819/76,809) using the historical cutoff of ≥1 mg/dL (P<0.0001). When GS and hypobilirubinemia participants were compared with normobilirubinemia, after adjustment and Mendelian randomizations, only cholelithiasis prevalence was significantly higher (OR=1.50; 95% CI [1.3-1.7], P=0.001) in men with GS compared with normobilirubinemia and in causal association with bilirubin (P=0.04). No adjusted survival was significantly associated with GS or hypobilirubinemia. CONCLUSIONS: In middle-aged Europeans, the stratified TB demonstrates a careless GS underestimation in women when using the standard unisex 1 mg/dL cutoff. The prevalence of illnesses is different in GS and hypobilirubinemia as well as survivals before adjusting for confounding factors. With the exception of cholelithiasis in men, these differences were no more significant after adjustment and Mendelian randomization.

Cardiovascular and metabolic effects of hyperbilirubinemia in a cohort of Italian Olympic athletes.

INTRODUCTION: Bilirubin was supposed to have cardio-metabolic protective role by signaling functions. Indeed, mild hyperbilirubinemia has immunosuppressive and endocrine activities and may offer protection against oxidative stress-mediated diseases. Gilbert syndrome (GS) has been hypothesized to provide cardio-metabolic benefits. OBJECTIVE: To investigate the prevalence of hyperbilirubinemia and its cardio-metabolic effects in a cohort of elite Italian athletes engaged in different sports disciplines. METHODS: We enrolled 1492 elite athletes (age 25.8 ± 5.1) practising different disciplines (power, skills, endurance, and mixed) underwent blood, echocardiographic, and exercise tests. GS was diagnosed per exclusionem in athletes with isolated asymptomatic unconjugated hyperbilirubinemia. RESULTS: GS was highlighted in 91 athletes (6%; globally 9% male and 2.4% female); 82% were males (p < 0.0001) showing higher indirect bilirubin (0.53 ± 0.4 vs. 0.36 ± 0.24 mg/dL in females, p < 0.0001). GS athletes had fewer platelets (201 ± 35 vs. 214 ± 41, p = 0.01), higher iron (male: 124 ± 44 vs. 100.9 ± 34 mcg/dL, p < 0.0001; female: 143.3 ± 35 vs. 99.9 ± 42 mcg/dL, p < 0.0001), and lower erythrocyte sedimentation rate, (1.93 ± 0.9 vs. 2.80 ± 2.7 mm/H, p = 0.03). At multivariate analysis, male (OR 3.89, p = 0.001) and iron (OR 3.47, p = 0.001) were independently associated with GS. No significant differences were found in cardiac remodeling, heart rate, blood pressure, arrhythmias, or power capacity at stress test. Endurance athletes (313) presented higher total (p = 0.003) and indirect bilirubin (p = 0.001). CONCLUSION: Bilirubin has several metabolic effects (including immunosuppressive and endocrine) and plays a role in regulating antioxidant pathways exercise-related with hematological consequences but seems not to affect significantly cardiovascular remodeling. Endurance athletes present higher bilirubin concentrations, likely as an adaptive mechanism to counteract increased oxidative stress.

Impact of restricting early-term deliveries on adverse neonatal outcomes: a statewide analysis.

BACKGROUND: The "39-Week Rule" was adopted by the American College of Obstetricians and Gynecologists in 2009 to eliminate nonmedically indicated (elective) deliveries before 39 weeks in an effort to improve neonatal outcomes. OBJECTIVE: Our primary objective was to quantify the effect of this policy change on adverse neonatal outcomes among a cohort of term births in South Carolina. STUDY DESIGN: Deidentified data from all births in the state of South Carolina from 2000 to 2008 (before the 39-week rule) and from 2013 to 2017 (after statewide implementation and enforcement of the rule) were obtained from the South Carolina Revenue and Fiscal Affairs Office. Demographic data and International Statistical Classification of Diseases and Related Health Problems Ninth/Tenth Revision codes were obtained for each birth. Our primary outcome was admission to a neonatal intensive care unit. Our secondary outcomes were respiratory morbidities (including respiratory distress syndrome and transient tachypnea of the newborn), hypoxic-ischemic encephalopathy, seizure, sepsis, birth injuries, hyperbilirubinemia, hypoglycemia, and feeding difficulties. Propensity score analysis was used to control for maternal age, body mass index, race, gestational hypertension, infection, placental abruption, and gestational and pregestational diabetes mellitus. After stratification by propensity score, the Cochran-Mantel-Haenszel test was used to compare groups. RESULTS: A total of 620,121 infants were liveborn at term during the 2 study periods. After implementation of the 39-week rule, there was a significant reduction in early-term deliveries. In adjusted analyses, neonatal intensive care unit admission was significantly more common in the postimplementation period. Respiratory morbidities were also significantly more common postimplementation. In contrast, there were significant reductions in birth injuries and hyperbilirubinemia in the postimplementation period. CONCLUSION: Implementation of the 39-week rule was associated temporally with an increase in adverse neonatal outcomes. The outcomes intended to be reduced by the 39-week rule, including neonatal intensive care unit admission and respiratory morbidity, seem to have increased in incidence despite adherence to the proposed guidelines.

Evaluation of a mobile application tool (BiliNorm) to improve care for newborns with hyperbilirubinemia in Indonesia.

BACKGROUND: Severe hyperbilirubinemia is more frequent in low- and middle-income countries such as Indonesia than in high-income countries. One of the contributing factors might be the lack of adherence to existing guidelines on the diagnosis and treatment of hyperbilirubinemia. We developed a new national guideline for hyperbilirubinemia management in Indonesia. To help healthcare workers use this guideline, a web-based decision support tool application may improve both the adherence to the guideline and the care for infants with hyperbilirubinemia. METHODS: We developed a web-based application (BiliNorm) to be used on a smartphone that displays the bilirubin level of the patient on the nomogram and advises about the treatment that should be started. Healthcare workers of two teaching hospitals in East Java, Indonesia, were trained on the use of BiliNorm. At 6 months after the introduction, a questionnaire was sent to those who worked with the application enquiring about their experiences. An observational study was conducted in two time epochs. A chart review of infants with hyperbilirubinemia in the two hospitals was sent. The appropriateness of hyperbilirubinemia management during a 6-month period before BiliNorm introduction was compared to that during a 7-month period after its introduction. RESULTS: A total of 43 participants filled in the questionnaire, the majority (72%) of them indicated that BiliNorm was well received and easy to use. Moreover, 84% indicated that BiliNorm was helpful for the decision to start phototherapy. Chart review of 255 infants before BiliNorm introduction and that of 181 infants after its introduction indicated that significantly more infants had received treatment according to the guideline (38% vs 51%, p = 0.006). Few infants received phototherapy, but bilirubin level was not measured (14% vs 7%, p = 0.024). There was no difference in the proportion of infants who were over- and under-treated (34% vs 32% and 14% vs 10%, respectively). CONCLUSIONS: The web-based decision tool BiliNorm appears to be a valuable application. It is easy to use for healthcare workers and helps them adhere to the guideline. It improves the care for infants with hyperbilirubinemia and may help reduce the incidence of severe hyperbilirubinemia in Indonesia.

The Effect of Breastfeeding and an Intensive Breast Milk Nutritional Support Program on Hospitalization Rates for Hyperbilirubinemia in Term Newborns: An Open Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to determine the effect of breastfeeding and intensive breast milk nutritional support program (IBNSP) on hospitalization rates for hyperbilirubinemia in normal term newborns. METHODS: This study's sample consisted of 68 newborn infants (experimental group: 34; control group: 34) born at a university hospital from October 2020 to April 2021. Five steps of breastfeeding and IBNSP were administered to the experimental group for the first 48 h after birth. This program starts at the postpartum first hour and continues until the 48th hour. It includes face-to-face training, practical support on breastfeeding, and one-to-one demonstration and practice methods. The control group received the standard care recommended by the World Health Organization. Both groups' bilirubin levels were measured 24 and 72 h after birth. Participants in both groups were hospitalized for risky (according to bilirubin values) situations. The groups' bilirubin levels and hospitalization rates for hyperbilirubinemia were compared. RESULTS: There was no statistically significant difference between the experimental (5.19 ± 1.27) and the control (5.83 ± 1.52) groups' bilirubin levels at 24 h after birth, (t = -1.881, p = 0.064); however, the control group infants (12.03 ± 3.67 mg/dl) had higher bilirubin levels than the infants in the experimental group 72 h after birth (9.55 ± 2.82 mg/dl) (t = -3.122, p = 0.003). The experimental group's hospitalization rate for hyperbilirubinemia (n: 1, 2.9%) was lower than the control group's rate (n: 8, 23.5%), and this difference was statistically significant (X2 = 6.275, p = 0.014). CONCLUSIONS: Breastfeeding and IBNSP effectively prevent hospitalization for hyperbilirubinemia and reduce newborns' bilirubin levels.

Role of Hyperbilirubinaemia as a Predictor of Complicated Appendicitis in Paediatric Population.

BACKGROUND: Acute appendicitis is a common surgical emergency amongst the paediatric population. Available diagnostic tools are focussed to make a diagnosis of acute appendicitis. A definitive predictive factor for the diagnosis of complicated appendicitis is lacking. Thus, this aims to analyse hyperbilirubinaemia as a predictor of complicated appendicitis amongst the paediatric population. MATERIALS AND METHODS: A prospective observational study was conducted in a tertiary hospital from November 2018 to October 2019. All children undergoing emergency appendectomy were included in the study. Preoperatively, patients were evaluated clinically, and routine investigations including total and direct serum bilirubin were sent. All patients were grouped as 'simple appendicitis' or 'complicated appendicitis' based on intra-operative and histological findings. Bilirubin level was compared between these groups and analysed. RESULTS: A total of 52 children fulfilling the inclusion criteria were included. The mean age was 13.2 ± 4.2 years, and the male: female ratio was 2.1:1. Thirty-four (65.4%) had simple appendicitis and 18 (34.6%) had complicated appendicitis. Total bilirubin was 23.83 ± 5.94 mmol/L in the complicated appendicitis group and 13.15 ± 3.29 mmol/L in the simple appendicitis group. Direct bilirubin was 5.28 ± 2.22 mmol/L in complicated appendicitis and 2.62 ± 0.83 mmol/L in simple one. Both total and direct bilirubin were significantly high in the complicated group (P < 0.001) compared to the simple appendicitis group. On the Receiver operating curve (ROC), the best cutoff value for total and direct bilirubin was 21 and 5.5 mmol/L, respectively. The sensitivity and specificity of total and direct bilirubin were 72.2%, 100%, and 61.1%, and 85.3%, respectively. CONCLUSION: It is concluded that hyperbilirubinaemia is a good predictor for paediatric complicated appendicitis.

Direct hyperbilirubinemia and cholestasis in trisomy 13 and 18.

Trisomy 13 and 18 are common chromosomal abnormalities that affect multiple organ systems. There is a paucity of published data, however, on the hepatic complications seen in these patient populations. One of the most common pathologic hepatobiliary issues seen in the newborn period is direct hyperbilirubinemia (DH). Thus, this study sought to estimate the incidence and evaluate possible etiologies of DH in neonates with trisomy 13 or 18. This retrospective cohort study included all infants admitted to our two neonatal intensive care units between 2012 and 2020 with the diagnosis of trisomy 13 or 18. DH is most commonly diagnosed as a direct bilirubin >1 mg/dl but a cutoff of >2 mg/dl is more specific for cholestasis, so both cutoffs were evaluated. Continuous data were compared using Fisher's exact test and categorical variables by the Mann-Whitney U test. Thirty-five patients met inclusion: 13 with trisomy 13 and 22 with trisomy 18. DH of >2 mg/dl was seen in seven (53.8%) patients with trisomy 13 and five (22.7%) with trisomy 18. Using a cutoff of >1 mg/dl, the rate of trisomy 13 was unchanged, but the rate in trisomy 18 increased to 9/22 (40.9%). There was a trend toward more DH in trisomy 13 patients (p = 0.079) versus trisomy 18 and higher rates in infants who received total parenteral nutrition (TPN) (50.0 vs. 13.3%, p = 0.026). The presence of cardiac or ultrasound-defined hepatobiliary abnormalities was not correlated with DH. Due to the high rates of DH in hospitalized neonates with trisomy 13 and 18, we recommend screening newborns with trisomy 13 or 18 for DH starting in the first week of life and continuing at least weekly until 4 weeks of life or until completion of TPN, whichever comes later. Future studies should further evaluate possible etiologies of DH in this population.

Neonatal hyperbilirubinemia and bilirubin neurotoxicity in hospitalized neonates: analysis of the US Database.

OBJECTIVE: The objective of this study was to assess the prevalence and trends for neonatal hyperbilirubinemia, and the development of bilirubin neurotoxicity in the USA. STUDY DESIGN: We used a de-identified national dataset for the years 2002-2017. The study included all newborn inpatients with postnatal age ≤28 days. Cochran-Armitage trend test was used for trend analyses. Regression analyses were performed and adjusted odds ratios (aOR) were reported. RESULTS: The study included 57,989,476 infants; of them 53,259,758 (91.8%) were term infants and 4,725,178 (8.2%) were preterm infants. Bilirubin neurotoxicity decreased over the years in term infants (Z = 0.36, p = 0.03) without change in preterm infants (Z = 42.5, p = 0.12). Black neonates were less likely to be diagnosed with hyperbilirubinemia than White neonates (aOR = 0.77, 95% confidence interval (CI): 0.77-0.78, p < 0.001) and more likely to develop bilirubin neurotoxicity than White neonates (aOR = 3.0.5, 95% CI: 2.13-4.36, p < 0.001). Bilirubin neurotoxicity rate in the overall population was 2.4 per 100,000 live births. CONCLUSIONS: Bilirubin neurotoxicity has significantly decreased in term infants and did not change in preterm infants. Despite the less diagnosis of hyperbilirubinemia in Black newborns, they are disproportionately at increased risk of developing bilirubin neurotoxicity when compared to White newborns. IMPACT: In this article, we analyzed the National Inpatient Database. This is the largest study of its kind using data on 57,989,476 neonates. The article has multiple novel findings: (1) it demonstrated that utilization of phototherapy has increased significantly over the years, (2) the rate of kernicterus for neonates decreased in term infants and did not change in preterm babies, (3) kernicterus was mostly encountered in infants without isoimmunization jaundice, and (4) there is a clear racial disparity in neonatal jaundice; although Black newborns have less neonatal jaundice, they are at increased risk of developing kernicterus.

Incidence, Clinical Characteristics and Outcomes of Early Hyperbilirubinemia in Critically Ill Patients: Insights From the MARS Study.

OBJECTIVE: To investigate the incidence, clinical characteristics and outcomes of early hyperbilirubinemia in critically ill patients. DESIGN AND SETTING: This is a post hoc analysis of a prospective multicenter cohort study. PATIENTS: Patients with measured bilirubin levels within the first 2 days after ICU admission were eligible. Patients with liver cirrhosis were excluded. ENDPOINTS: The primary endpoint was the incidence of early hyperbilirubinemia, defined as bilirubin ≥33 µmol/L within 2 days after ICU admission. Secondary endpoints included clinical characteristics of patients with versus patients without early hyperbilirubinemia, and outcomes up to day 30. RESULTS: Of 4,836 patients, 559 (11.6%) patients had early hyperbilirubinemia. Compared to patients without early hyperbilirubinemia, patients with early hyperbilirubinemia presented with higher severity of illness scores, and higher incidences of sepsis and organ failure. After adjustment for confounding variables, early hyperbilirubinemia remained associated with mortality at day 30 (odds ratio, 1.31 [95%-confidence interval 1.06-1.60]; P = 0.018). Patients with early hyperbilirubinemia and thrombocytopenia (interaction P-value = 0.005) had a higher likelihood of death within 30 days (odds ratio, 2.61 [95%-confidence interval 2.08-3.27]; P < 0.001) than patients with early hyperbilirubinemia and a normal platelet count (odds ratio, 1.09 [95%-confidence interval 0.75-1.55]; P = 0.655). CONCLUSIONS: Early hyperbilirubinemia occurs frequently in the critically ill, and these patients present with higher disease severity and more often with sepsis and organ failures. Early hyperbilirubinemia has an association with mortality, albeit this association was only found in patients with concomitant thrombocytopenia.

Trends in hospitalizations of newborns with hyperbilirubinemia and kernicterus in United States: an epidemiological study.

BACKGROUND: Hyperbilirubinemia is one of the most common diagnosis in newborn nurseries in United States. Universal pre-discharge bilirubin screening decreased the incidence of extreme hyperbilirubinemia and risk of kernicterus. OBJECTIVES: We sought to assess temporal population trends of hyperbilirubinemia, kernicterus and usage of phototherapy, intravenous immunoglobulin (IVIG), and exchange transfusion. DESIGN/METHODS: Data from Healthcare Cost and Utilization Project (HCUP)-the Kids' Inpatient Database (KID) obtained for years 1997-2012. All neonatal discharges with ICD-9 codes for neonatal jaundice (774.2, 774.6), kernicterus (773.4, 774.7) and procedure codes for phototherapy (99.83), IVIG infusion (99.14), exchange transfusion (99.01) were extracted. We compared the trends of diagnosis of hyperbilirubinemia, kernicterus, use of phototherapy, IVIG, and exchange transfusion. RESULTS: During the study period, the proportion of infants diagnosed with hyperbilirubinemia increased by 65% (9.4% vs. 15.5%; p<.001) in term infants and 34.5% (33.5% vs. 45%; p<.001) in preterm infants, respectively. Rate of kernicterus discharges significantly reduced from 7 to 1.9 per 100,000 newborns. Overall, the number of exchange transfusions has decreased by 67% during study period while phototherapy and IVIG use increased by 83% and 170%, respectively. CONCLUSIONS: In last two decades, there was a significant decrease in neonatal discharges with a history of exchange transfusion or with a diagnosis of kernicterus. However, there was a significant increase in number of neonates discharged home with a history of phototherapy during birth hospitalization and decreased number of exchange transfusions were observed during the study period. Incremental implementation of universal predischarge bilirubin screening and treatments based on 2004 AAP recommended risk-based strategies might have contributed to timely interventions in infants with significant hyperbilirubinemia.

Risk factors analysis of hyperbilirubinemia after off-pump coronary artery bypass grafting: a retrospective observational study.

BACKGROUND: Hyperbilirubinemia is a common complication after off-pump coronary artery bypass grafting (OPCAB), but the incidence and the risk factors are unclear. This study aimed to analyze the incidence and risk factors of postoperative hyperbilirubinemia in patients undergoing OPCAB. METHODS: From December 2016 to March 2019, a total of 416 consecutive patients undergoing OPCAB were enrolled in this single-center retrospective study. Patients were divided into the normal serum total bilirubin group and the hyperbilirubinemia group based on the serum total bilirubin levels. Perioperative variables between the two groups were compared by univariate logistic regression analysis. Then, multivariate binary logistic regression analysis was used to analyze the independent risk factors of developing hyperbilirubinemia in patients underwent OPCAB. P < 0.05 was considered as statistically significant. RESULTS: Thirty two of 416 (7.7%) patients developed postoperative hyperbilirubinemia. Univariate regression analysis showed significant differences in gender (73.96% vs. 93.75%, P = 0.012), preoperative total bilirubin levels (11.92 ± 4.52 vs. 18.28 ± 7.57, P < 0.001), perioperative IABP implantation (22.66% vs. 43.75%, P = 0.008), perioperative blood transfusion (37.50% vs. 56.25%, P = 0.037) between the two groups. Multivariate logistic regression analysis revealed that elevated preoperative serum total bilirubin levels (OR = 1.225, 95% CI 1.145-1.310, P < 0.001), perioperative blood transfusion (OR = 4.488, 95% CI 1.876-10.737, P = 0.001) and perioperative IABP implantation (OR = 4.016, 95% CI 1.709-9.439, P = 0.001) were independent risk factors for hyperbilirubinemia after OPCAB. CONCLUSIONS: Hyperbilirubinemia is also a common complication after OPCAB. Elevated preoperative serum total bilirubin levels, perioperative blood transfusion, and perioperative IABP implantation were independent risk factors for patients developing hyperbilirubinemia after OPCAB. Further studies need to be conducted to confirm the risk factors of hyperbilirubinemia after OPCAB procedure.

Hyperbilirubinemia as an Indicator of Perforated Acute Appendicitis in Pediatric Population: A Prospective Study.

Background: This prospective cohort study aimed to investigate the association of hyperbilirubinemia with perforated appendicitis in the pediatric population. Patients and Methods: A total of 284 children in whom the diagnosis of acute appendicitis was established were included in this study. The patients were allocated in study groups in regard to operative findings. The first study group included patients who had perforated appendicitis (n = 64; 22.5%) whereas the patients in the second group had simple appendicitis (n = 220; 77.5%). Blood samples for serum bilirubin levels and acute inflammatory markers were taken before the patients underwent surgery. The primary outcome of the study was to investigate whether the level of serum bilirubin should be used to distinguish between simple and perforated appendicitis. Results: The median level of serum bilirubin in children with perforated appendicitis was 27 mcmol/L whereas the patients with simple appendicitis had lower median levels of serum bilirubin (10 µmol/L; p < 0.001). An area under the receiver operating characteristic (ROC) curve for total serum bilirubin was 0.876 (95% confidence interval [CI], 0.820-0.929) in the patients who had a perforated appendicitis. An ROC analysis showed the best sensitivity (92%) and specificity (77.3%) for a cutoff value of 15.5 mcmol/L for total serum bilirubin (p < 0.001). Hyperbilirubinemia at admission was found in 35 patients (54.7%) with complicated appendicitis and in 14 patients (6.4%) with non-perforated appendicitis (p < 0.001). The modeling of collected data by multivariable logistic regression identified serum bilirubin concentration (odss ratio [OR] = 1.12; 95% CI, 1.07-1.18; p < 0.001), serum sodium concentration (OR = 0.64; 95% CI, 0.51-0.81; p < 0.001), body temperature (OR = 2.48; 95% CI, 1.05-0.84; p < 0.001), and duration of symptoms (OR = 1.06; 95% CI, 1.02-1.09; p < 0.001) as risk factors for perforated appendicitis. Conclusion: Elevateds level of total serum bilirubin may be useful as an indicator of perforated appendicitis in children. Levels of bilirubin in serum is an inexpensive, simple, and available laboratory marker and should therefore be recommended in the initial evaluation for acute appendicitis in pediatric patients.

The incidence, risk factors, and prognosis of postoperative hyperbilirubinemia after cardiac surgery: a systematic review and meta-analysis.

BACKGROUND: The purpose of the present systematic review was to evaluate the incidence, risk factors, and outcome of hyperbilirubinemia after cardiac surgery. METHODS: The Population, Interventions, Comparators, Outcomes, and Study design (PICOS) framework was employed to develop the search strategy, and the findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed, Embase, and the Cochrane Library were systematically searched for studies that provided data on the incidence, risk factors, and outcomes of hyperbilirubinemia in cardiac surgery patients from January 1960 to May 2020. Publication bias was graphically explored through funnel plots, and the Newcastle-Ottawa quality assessment scale (NOS) was used to evaluate the quality of the included studies. RESULTS: Ten studies with 6,100 patients were included in our systematic review. The pooled incidence of hyperbilirubinemia was 23% [95% confidence interval (CI), 0.13-0.32]. Preoperative factors, including right atrial pressure [mean difference (MD), 4.65; 95% CI, 4.43-4.88], total bilirubin (TB) concentration (MD, 0.72; 95% CI, 0.65-0.79), alkaline phosphatase (MD, 27.38; 95% CI, 12.94-41.82), and alanine aminotransferase (MD, 12.02; 95% CI, 10.73-13.31), and intraoperative factors, including cardiopulmonary bypass (CPB) time (MD, 1.57; 95% CI, 0.52-2.63), aortic cross-clamping (ACC) time (MD, 11.82; 95% CI, 9.50-14.14), and the amount of blood transfused (MD, 3.77; 95% CI, 0.68-6.85), were the most robust risk factors for hyperbilirubinemia after cardiac surgery. Additionally, postoperative hyperbilirubinemia was associated with increased in-hospital mortality [odds ratio (OR), 9.9; 95% CI, 5.00-19.60, P<0.0001]. DISCUSSION: Hyperbilirubinemia was common and was associated with increased in-hospital mortality. Preoperative high right atrial pressure, high TB concentration, prolonged CPB and ACC time, and a large amount of blood transfused were the commonly observed risk factors for postoperative hyperbilirubinemia in cardiac surgery patients. Addressing these risk factors may be helpful to lower the occurrence of postoperative hyperbilirubinemia.

Association of Maternal SARS-CoV-2 Infection in Pregnancy With Neonatal Outcomes.

Importance: The outcomes of newborn infants of women testing positive for SARS-CoV-2 in pregnancy is unclear. Objective: To evaluate neonatal outcomes in relation to maternal SARS-CoV-2 test positivity in pregnancy. Design, Setting, and Participants: Nationwide, prospective cohort study based on linkage of the Swedish Pregnancy Register, the Neonatal Quality Register, and the Register for Communicable Diseases. Ninety-two percent of all live births in Sweden between March 11, 2020, and January 31, 2021, were investigated for neonatal outcomes by March 8, 2021. Infants with malformations were excluded. Infants of women who tested positive for SARS-CoV-2 were matched, directly and using propensity scores, on maternal characteristics with up to 4 comparator infants. Exposures: Maternal test positivity for SARS-CoV-2 in pregnancy. Main Outcomes and Measures: In-hospital mortality; neonatal resuscitation; admission for neonatal care; respiratory, circulatory, neurologic, infectious, gastrointestinal, metabolic, and hematologic disorders and their treatments; length of hospital stay; breastfeeding; and infant test positivity for SARS-CoV-2. Results: Of 88 159 infants (49.0% girls), 2323 (1.6%) were delivered by mothers who tested positive for SARS-CoV-2. The mean gestational age of infants of SARS-CoV-2-positive mothers was 39.2 (SD, 2.2) weeks vs 39.6 (SD, 1.8) weeks for comparator infants, and the proportions of preterm infants (gestational age <37 weeks) were 205/2323 (8.8%) among infants of SARS-CoV-2-positive mothers and 4719/85 836 (5.5%) among comparator infants. After matching on maternal characteristics, maternal SARS-CoV-2 test positivity was significantly associated with admission for neonatal care (11.7% vs 8.4%; odds ratio [OR], 1.47; 95% CI, 1.26-1.70) and with neonatal morbidities such as respiratory distress syndrome (1.2% vs 0.5%; OR, 2.40; 95% CI, 1.50-3.84), any neonatal respiratory disorder (2.8% vs 2.0%; OR, 1.42; 95% CI, 1.07-1.90), and hyperbilirubinemia (3.6% vs 2.5%; OR, 1.47; 95% CI, 1.13-1.90). Mortality (0.30% vs 0.12%; OR, 2.55; 95% CI, 0.99-6.57), breastfeeding rates at discharge (94.4% vs 95.1%; OR, 0.84; 95% CI, 0.67-1.05), and length of stay in neonatal care (median, 6 days in both groups; difference, 0 days; 95% CI, -2 to 7 days) did not differ significantly between the groups. Twenty-one infants (0.90%) of SARS-CoV-2-positive mothers tested positive for SARS-CoV-2 in the neonatal period; 12 did not have neonatal morbidity, 9 had diagnoses with unclear relation to SARS-CoV-2, and none had congenital pneumonia. Conclusions and Relevance: In a nationwide cohort of infants in Sweden, maternal SARS-CoV-2 infection in pregnancy was significantly associated with small increases in some neonatal morbidities. Given the small numbers of events for many of the outcomes and the large number of statistical comparisons, the findings should be interpreted as exploratory.

Fluid restriction in the management of transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn (TTN) is caused by delayed clearance of lung fluid at birth. TTN typically appears within the first two hours of life in term and late preterm neonates and is characterized by tachypnea and signs of respiratory distress. Although it is usually a self-limited condition, admission to a neonatal unit is frequently required for monitoring and providing respiratory support. Restricting intake of fluids administered to these infants in the first days of life might improve clearance of lung liquid, thus reducing the effort required to breathe, improving respiratory distress, and potentially reducing the duration of tachypnea. OBJECTIVES: To evaluate the efficacy and safety of restricted fluid therapy as compared to standard fluid therapy in decreasing the duration of oxygen administration and the need for noninvasive or invasive ventilation among neonates with TTN. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 12), in the Cochrane Library; Ovid MEDLINE and electronic ahead of print publications, in-process & other non-indexed citations, Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), on December 6, 2019. We also searched clinical trial databases and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs, and cluster trials on fluid restriction in term and preterm neonates with the diagnosis of TTN or delayed adaptation during the first week after birth. DATA COLLECTION AND ANALYSIS: For each of the included trials, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy, need for continuous positive airway pressure [CPAP], need for mechanical ventilation, duration of mechanical ventilation) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcome considered in this review was the duration of supplemental oxygen therapy in hours or days. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Four trials enrolling 317 infants met the inclusion criteria. Three trials enrolled late preterm and term infants with TTN, and the fourth trial enrolled only term infants with TTN. Infants were on various methods of respiratory support at the time of enrollment including room air, oxygen, or nasal CPAP. Infants in the fluid-restricted group received 15 to 20 mL/kg/d less fluid than those in the control group for varying durations after enrollment. Two studies had high risk of selection bias, and three out of four had high risk of performance bias. Only one study had low risk of detection bias, with two at high risk and one at unclear risk. The certainty of evidence for all outcomes was very low due to imprecision of estimates and unclear risk of bias. Two trials reported the primary duration of supplemental oxygen therapy. We are uncertain whether fluid restriction decreases or increases the duration of supplemental oxygen therapy (mean difference [MD] -12.95 hours, 95% confidence interval [CI] -32.82 to 6.92; I² = 98%; 172 infants). Similarly, there is uncertainty for various secondary outcomes including incidence of hypernatremia (serum sodium > 145 mEq/L, risk ratio [RR] 4.0, 95% CI 0.46 to 34.54; test of heterogeneity not applicable; 1 trial, 100 infants), hypoglycemia (blood glucose < 40 mg/dL, RR 1.0, 95% CI 0.15 to 6.82; test of heterogeneity not applicable; 2 trials, 164 infants), endotracheal ventilation (RR 0.73, 95% CI 0.24 to 2.23; I² = 0%; 3 trials, 242 infants), need for noninvasive ventilation (RR 0.40, 95% CI 0.14 to 1.17; test of heterogeneity not applicable; 2 trials, 150 infants), length of hospital stay (MD -0.92 days, 95% CI -1.53 to -0.31; test of heterogeneity not applicable; 1 trial, 80 infants), and cumulative weight loss at 72 hours of age (%) (MD 0.24, 95% CI -1.60 to 2.08; I² = 89%; 2 trials, 156 infants). We did not identify any ongoing trials; however, one trial is awaiting classification. AUTHORS' CONCLUSIONS: We found limited evidence to establish the benefits and harms of fluid restriction in the management of TTN. Given the very low certainty of available evidence, it is impossible to determine whether fluid restriction is safe or effective for management of TTN. However, given the simplicity of the intervention, a well-designed trial is justified.

Hepatic Involvement as Hyperbilirubinemia in Patients with COVID-19: Case Series from Iran.

BACKGROUND: After the spread of novel coronavirus disease 2019 (COVID-19) from Wuhan to Iran, gastroenterology clinics, was faced with a large number of patients who were suspected of being infected with the SARS-CoV-2. Among refereed patient, the incidence of pure hyperbilirubinemia as rare gastrointestinal (GI) symptoms was obvious. METHODS: In this case series, we have reported the clinical data in details for patients with COVID-19 who have been admitted to the Shahid Beheshti Hospital in Qom city, from 3 March to 3 August 2020. COVID infection, be confirmed by using real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) and chest computed tomography (CT) scan, as well. RESULTS: According to the clinical findings, pure hyperbilirubinemia may consider as rare gastrointestinal (GI) symptom of COVID-19. However, it is possible that the other GI enzymes values fall in to the normal range. CONCLUSION: In some infected patients, GI physicians may face hepatic involvement as pure hyperbilirubinemia. At the age of COVID-19 crisis, all GI physicians should be aware of the possible occurrence of hepatic involvement as an important prognosis of COVID pneumonia and it should be exactly addressed in new referred patients to GI clinic.

Conjugated hyperbilirubinemia among infants with hyperinsulinemic hypoglycemia.

From clinical practice, we noted that a subset of neonates with hyperinsulinism develop conjugated hyperbilirubinemia. A relationship between these two conditions has not been previously described. We aimed to assess the incidence of cholestasis in a cohort of neonates with hyperinsulinism and describe their clinical characteristics. In a retrospective cohort of 63 neonates with hyperinsulinism, 48% developed cholestasis (conjugated bilirubin > 17 µmol/L) with a median maximum conjugated bilirubin of 81 [21 to 191] µmol/L. A history of fetal distress (RR 2.3 [1.24-4.45], p < 0.01) and prematurity (RR 2.0 [1.23-3.26], p <0.01) was associated with the development of cholestasis, but not parental nutrition or other pharmacological treatments. An underlying etiology for the cholestasis was only found in 1 patient, and in all cases the cholestasis spontaneously improved.Conclusions: A significant percentage of infants with hyperinsulinism develop idiopathic, spontaneously resolving, conjugated hyperbilirubinemia. The association with a history of fetal distress potentially suggests that intrauterine factors leading to hyperinsulinism may also predispose towards conjugated hyperbilirubinemia. While the presence of neonatal cholestatic jaundice warrants timely investigations to exclude important underling etiologies, if validated, these findings may support a less invasive diagnostic workup of conjugated hyperbilirubinemia in infants with co-existent hyperinsulinism. What is Known: • Hyperinsulinism and conjugated hyperbilirubinemia are two common presentations in neonates. • A clinical association between the two conditions has not been described. What is New: • A significant proportion of infants with hyperinsulinism develop idiopathic, spontaneously resolving conjugated hyperbilirubinemia. • Increased risk for cholestasis in this patient population is associated with fetal distress and prematurity but not parental nutrition.