The use of transcutaneous bilirubin nomograms for the prevention of bilirubin neurotoxicity in the neonates.

Purpose: Although neonatal jaundice is a ubiquitous and predominantly benign phenomenon, the risk of neurotoxicity exists in a number of infants with unconjugated hyperbilirubinemia. Plotting bilirubin values on nomograms enables clinicians to employ an anticipatory and individualized approach with the goal of avoiding excessive hyperbilirubinemia and preventing acute bilirubin encephalopathy and its progression to kernicterus. We aimed to construct nomograms for White term infants based on transcutaneous bilirubin (TcB) measurements using a JM-105 device. Methods: TcB measurements were taken in infants at ages ranging from 0 to 96 postnatal hours. We then constructed hour-specific TcB nomograms from forehead and sternum measurements in infants who did not require subsequent phototherapy. Results: We included 2,981 TcB measurements taken on the forehead and 2,977 measurements taken on the sternum in 301 White term newborn infants. We assessed the predictive abilities of the nomograms at six postnatal time intervals using receiver operating characteristic curves. The areas under the curves indicated reasonable prediction of hyperbilirubinemia requiring phototherapy, except for the forehead measurement taken within the first 12 h of life. Sensitivity tended to rise as postnatal age increased. Conclusion: The nomograms illustrate dermal bilirubin dynamics in White term neonates during the first 4 days of life. They may be useful tools to predict individualized risk of hyperbilirubinemia requiring treatment, and to plan optimal follow-up of infants at risk of bilirubin neurotoxicity.

Chemoprevention of bilirubin encephalopathy with a nanoceutical agent.

BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.

Use of prophylactic phototherapy for RhD neonatal disease in a referral service.

OBJECTIVE: This study aimed to describe the effect of prophylactic phototherapy in the treatment of infants with Neonatal Hemolytic Disease. METHOD: A retrospective cohort study was carried out with 199 RhD-positive infants, born to RhD-negative mothers, alloimmunized for RhD antigen, between January 2009 and December 2018. RESULTS: The incidence of exchange transfusions in the study population was 9.5%, with a mean maximum bilirubin value of 11.3 mg % (± 4.3mg %). Bilirubin's maximum peak was achieved with a mean of 119.2 life hours (± 70.6h). CONCLUSION: The low incidence of exchange transfusion, the extended maximum bilirubin peak for later ages, and the low mean of the maximum bilirubin values may indicate a positive effect of prophylactic phototherapy in the treatment of this disease. Further studies must be carried out to confirm these findings.

Association between neonatal phototherapy and future cancer: an updated systematic review and meta-analysis.

Phototherapy is the main treatment of neonatal hyperbilirubinemia to prevent encephalopathy. It is generally believed to be safe; however, some studies have shown it might be associated with cancer development. In this systematic review and meta-analysis, we aimed to assess the effect of neonatal phototherapy on future cancer risk. A systematic search in 13 databases was conducted in December 2018 and updated in August 2022 to identify studies that report cancer development after exposure to phototherapy. Throughout the study period, regular manual searches were also conducted to include new studies. A meta-analysis using R programming language was done in which the odds ratios (ORs) with 95% confidence intervals (CIs) were estimated and pooled using the reported adjusted and unadjusted data. Fifteen studies were included. A statistically significant association was detected between neonatal phototherapy and any type of cancer (OR 1.24; 95% CI 1.1, 1.4), any hematopoietic cancer (OR 1.49; 95% CI 1.17, 1.91), any leukemia (OR 1.35; 95% CI 1.08, 1.67), and myeloid leukemia (OR 2.86; 95% CI 1.4, 5.84). The other investigated cancers (lymphoid leukemia, Hodgkin's lymphoma, kidney cancer, nervous system cancer, and skin cancer) were not associated with phototherapy.  Conclusions: Phototherapy may carry a possible risk of future cancers. Future research is needed to quantify the magnitude of the cancer risk. These future studies should consider predictors of preterm birth or exclude premature babies from their analysis. What is Known • There were various reports about the possible association between phototherapy in neonates and the increased risk of cancer in the future. What is New • A statistically significant association between phototherapy and various hematopoietic cancers (especially myeloid leukemia) was recorded. • The effect of the duration of phototherapy on the increased risk of hematopoietic cancers is yet unclear.

El contacto piel a piel como promotor de la lactancia materna, y su posible relación con la disminución de la hiperbilirrubinemia / Skin-to-skin contact as a promoter of breastfeeding, and its possible relationship with the reduction of hyperbilirubinemia

INTRODUCCIÓN: El contacto piel a piel (CPP) postparto es una práctica de atención de salud fuertemente aconsejada por la OMS, por los beneficios a largo y a corto plazo que conlleva tanto para la salud de la madre como para la del recién nacido. OBJETIVO: Realizar una búsqueda bibliográfica con el objetivo de determinar los beneficios que tiene la CPP durante el periodo del postparto inmediato sobre la lactancia materna (LM) y la ictericia neonatal (IN). RESULTADOS: Los resultados muestran que el CPP aumenta diversos indicadores de éxito de lactancia materna, dentro de los cuales destacan: aumento en la efectividad de la primera lactancia, mayor probabilidad de mantener la LM a 4 meses, aumento del periodo de LM en promedio, mayor probabilidad de LM exclusiva a 6 meses. No se encontraron mayores beneficios al iniciar el CPP antes de los 10 minutos, ni al prolongarlo más de 60 minutos. Además, el CPP indirectamente disminuye la probabilidad de presentar IN, debido a que aumenta la frecuencia de LM, indicador que se asocia de manera indirecta a los niveles de bilirrubina en el recién nacido. CONCLUSIÓN: La revisión de la literatura especializada nos permite concluir que el contacto temprano entre la madre y su hijo en sala de partos, piel a piel, tiene efectos significativamente positivos en la lactancia materna y puede llegar a representar un factor protector de la hiperbilirrubinemia no conjugada en el RN.

Postpartum skin-to-skin contact (SSC) is a health care practice strongly advised by the WHO because of the long- and short-term benefits for both maternal and newborn health. This update summarizes the main findings supporting the recommendation to perform SSC during the immediate postpartum period, specifically the benefits on breastfeeding (BF) and neonatal jaundice (NI). The results show that SSC increases several indicators of breastfeeding success, including: increased effectiveness of the first breastfeeding, greater probability of maintaining BF at 4 months, increased BF period on average, greater probability of exclusive BF at 6 months. No greater benefits were found when initiating SSC before 10 minutes, nor when prolonging it for more than 60 minutes. In addition, SSC indirectly decreases the probability of presenting NI, because it increases the frequency of BF, an indicator that is indirectly associated with bilirubin levels in the newborn. CONCLUSION: A review of the specialized literature allows us to conclude that postpartum skin-to-skin contact (SSC) has significantly positive effects on breastfeeding and may represent benefits in bilirubin levels in the newborn.

Sunlight for the prevention and treatment of hyperbilirubinemia in term and late preterm neonates.

BACKGROUND: Acute bilirubin encephalopathy (ABE) and the other serious complications of severe hyperbilirubinemia in the neonate occur far more frequently in low- and middle-income countries (LMIC). This is due to several factors that place babies in LMIC at greater risk for hyperbilirubinemia, including increased prevalence of hematologic disorders leading to hemolysis, increased sepsis, less prenatal or postnatal care, and a lack of resources to treat jaundiced babies. Hospitals and clinics face frequent shortages of functioning phototherapy machines and inconsistent access to electricity to run the machines. Sunlight has the potential to treat hyperbilirubinemia: it contains the wavelengths of light that are produced by phototherapy machines. However, it contains harmful ultraviolet light and infrared radiation, and prolonged exposure has the potential to lead to sunburn, skin damage, and hyperthermia or hypothermia. OBJECTIVES: To evaluate the efficacy of sunlight administered alone or with filtering or amplifying devices for the prevention and treatment of clinical jaundice or laboratory-diagnosed hyperbilirubinemia in term and late preterm neonates. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search CENTRAL (2019, Issue 5), MEDLINE, Embase, and CINAHL on 2 May 2019. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCTs), quasi-RCTs, and cluster RCTs. We updated the searches on 1 June 2020. SELECTION CRITERIA: We included RCTs, quasi-RCTs, and cluster RCTs. We excluded crossover RCTs. Included studies must have evaluated sunlight (with or without filters or amplification) for the prevention and treatment of hyperbilirubinemia or jaundice in term or late preterm neonates. Neonates must have been enrolled in the study by one-week postnatal age. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. We used the GRADE approach to assess the certainty of evidence. Our primary outcomes were: use of conventional phototherapy, treatment failure requiring exchange transfusion, ABE, chronic bilirubin encephalopathy, and death. MAIN RESULTS: We included three RCTs (1103 infants). All three studies had small sample sizes, were unblinded, and were at high risk of bias. We planned to undertake four comparisons, but only found studies reporting on two. Sunlight with or without filters or amplification compared to no treatment for the prevention and treatment of hyperbilirubinemia in term and late preterm neonates One study of twice-daily sunlight exposure (30 to 60 minutes) compared to no treatment reported the incidence of jaundice may be reduced (risk ratio [RR] 0.61, 95% confidence interval [CI] 0.45 to 0.82; risk difference [RD] -0.14, 95% CI -0.22 to -0.06; number needed to treat for an additional beneficial outcome [NNTB] 7, 95% CI 5 to 17; 1 study, 482 infants; very low-certainty evidence) and the number of days that an infant was jaundiced may be reduced (mean difference [MD] -2.20 days, 95% CI -2.60 to -1.80; 1 study, 482 infants; very low-certainty evidence). There were no data on safety or potential harmful effects of the intervention. The study did not assess use of conventional phototherapy, treatment failure requiring exchange transfusion, ABE, and long-term consequences of hyperbilirubinemia. The study showed that sunlight therapy may reduce rehospitalization rates within seven days of discharge for treatment for hyperbilirubinemia, but the evidence was very uncertain (RR 0.55, 95% CI 0.27 to 1.11; RD -0.04, -0.08 to 0.01; 1 study, 482 infants; very low-certainty evidence). Sunlight with or without filters or amplification compared to other sources of phototherapy for the treatment of hyperbilirubinemia in infants with confirmed hyperbilirubinemia Two studies (621 infants) compared the effect of filtered-sunlight exposure to other sources of phototherapy in infants with confirmed hyperbilirubinemia. Filtered-sunlight phototherapy (FSPT) and conventional or intensive electric phototherapy led to a similar number of days of effective treatment (broadly defined as a minimal increase of total serum bilirubin in infants less than 72 hours old and a decrease in total serum bilirubin in infants more than 72 hours old on any day that at least four to five hours of sunlight therapy was available). There may be little or no difference in treatment failure requiring exchange transfusion (typical RR 1.00, 95% CI 0.06 to 15.73; typical RD 0.00, 95% CI -0.01 to 0.01; 2 studies, 621 infants; low-certainty evidence). One study reported ABE, and no infants developed this outcome (RR not estimable; RD 0.00, 95% CI -0.02 to 0.02; 1 study, 174 infants; low-certainty evidence). One study reported death as a reason for study withdrawal; no infants were withdrawn due to death (RR not estimable; typical RD 0.00, 95% CI -0.01 to 0.01; 1 study, 447 infants; low-certainty evidence). Neither study assessed long-term outcomes. Possible harms: both studies showed a probable increased risk for hyperthermia (body temperature greater than 37.5 °C) with FSPT (typical RR 4.39, 95% CI 2.98 to 6.47; typical RD 0.30, 95% CI 0.23 to 0.36; number needed to treat for an additional harmful outcome [NNTH] 3, 95% CI 2 to 4; 2 studies, 621 infants; moderate-certainty evidence). There was probably no difference in hypothermia (body temperature less than 35.5 °C) (typical RR 1.06, 95% CI 0.55 to 2.03; typical RD 0.00, 95% CI -0.03 to 0.04; 2 studies, 621 infants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Sunlight may be an effective adjunct to conventional phototherapy in LMIC settings, may allow for rotational use of limited phototherapy machines, and may be preferable to families as it can allow for increased bonding. Filtration of sunlight to block harmful ultraviolet light and frequent temperature checks for babies under sunlight may be warranted for safety. Sunlight may be effective in preventing hyperbilirubinemia in some cases, but these studies have not demonstrated that sunlight alone is effective for the treatment of hyperbilirubinemia given its sporadic availability and the low or very low certainty of the evidence in these studies.

Combating the Hidden Health Disparity of Kernicterus in Black Infants: A Review.

Importance: Kernicterus is a devastating, permanently disabling neurologic condition resulting from bilirubin neurotoxicity. Black neonates account for more than 25% of kernicterus cases in the US, despite making up only approximately 14% of all births. This is a largely overlooked health disparity. Observations: The black kernicterus health disparity exists despite a lower overall incidence of clinically significant hyperbilirubinemia among black neonates, a paradox recently explained by a previously unrecognized risk for hazardous hyperbilirubinemia. Aligned with national and global health initiatives to reduce or eliminate health disparities, this review highlights the multiple biologic and nonbiologic factors contributing to kernicterus risk in black infants and approaches to reduce this health disparity. This includes both parent-level and clinician-level kernicterus prevention strategies, with an emphasis on improving parental health literacy on neonatal jaundice and acute bilirubin encephalopathy and clinician awareness of the key factors that contribute to hazardous hyperbilirubinemia risk in this vulnerable group. Parent-level prevention strategies include efforts to improve their health literacy on neonatal jaundice and acute bilirubin encephalopathy and empower care seeking for jaundice. Clinician-level prevention strategies include efforts to eliminate community and institutional barriers that impede access to care, heighten clinician awareness of the factors that contribute to kernicterus risk in this vulnerable patient group, and strengthen newborn hyperbilirubinemia management and bilirubin surveillance. Conclusions and Relevance: There are multiple opportunities for intervention to reduce black kernicterus risk. Although kernicterus is a rare disorder, the incidence among black infants is not a trivial matter nor are efforts to prevent kernicterus. While the multiple interacting biologic and nonbiologic contributors to increased kernicterus risk among black infants pose a considerable challenge to clinicians, there are opportunities for intervention to reduce this risk and health disparity. Continued study is imperative to understand the current scope of kernicterus and its occurrence in black neonates.

Delayed cord clamping in Rh-alloimmunised infants: a randomised controlled trial.

Despite advancement in medical care, Rh alloimmunisation remains a major cause of neonatal hyperbilirubinaemia, neuro-morbidity, and late-onset anaemia. Delayed cord clamping (DCC), a standard care now-a-days, is yet not performed in Rh-alloimmunised infants due to paucity of evidence. Hence, we randomised these infants of 28- to 41-week gestation to delayed cord clamping (N = 36) or early cord clamping (N = 34) groups. The primary outcome variable was venous packed cell volume (PCV) at 2 h of birth. The secondary outcomes were incidence of double volume exchange transfusion (DVET) and partial exchange transfusion (PET), duration of phototherapy (PT), functional echocardiography (parameters measured: superior vena cava flow, M-mode fractional shortening, left ventricular output, myocardial perfusion index, and inferior vena cava collapsibility) during hospital stay, and blood transfusion (BT) until 14 weeks of life. Neonates were managed as per unit protocol. The baseline characteristics of enrolled infants were comparable between the groups. The median (IQR) gestation and mean (SD) birth weight of enrolled infants were 35 (33-37) weeks and 2440 (542) g, respectively. The DCC group had a higher mean PCV at 2 h of life (48.4 ± 9.2 vs. 43.5 ± 8.7, mean difference 4.9% (95% CI 0.6-9.1), p = 0.03). However, incidence of DVET and PET, duration of PT, echocardiography parameters, and BT until 14 weeks of postnatal age were similar between the groups.Conclusion: DCC in Rh-alloimmunised infants improved PCV at 2 h of age without significant adverse effects.Trial registration: Clinical Trial Registry of India (CTRI), Ref/2016/11/012572 http://ctri.nic.in/Clinicaltrials, date of trial registration 19.12.2016, date of first patient enrolment 1 January 2017.What is Known:•Delayed cord clamping improves haematocrit, results in better haemodynamic stability, and decreases the need of transfusion in early infancy.•However, due to lack of evidence, potential risk of hyperbilirubinaemia, and exacerbation of anaemia (following delayed cord clamping), early cord clamping is the usual norm in Rh-alloimmunised infantsinfants.What is New:•Delayed cord clamping in Rh-alloimmunised infants improves haematocrit at 2 h of life without any increase in incidence of serious adverse effects.

Baby-Friendly Hospital Initiative Is Associated with Lower Rates of Neonatal Hyperbilirubinemia.

Background: The Baby-Friendly Hospital Initiative (BFHI) advances practices that support exclusive breastfeeding. BFHI practices are associated with increased breastfeeding rates, however, other patient outcomes are not well described. This study examined the association of BFHI practices with hyperbilirubinemia and phototherapy between groups of newborns born before and after BFHI implementation at an urban, tertiary academic medical center in South Carolina. Materials and Methods: We conducted a retrospective study of healthy, term newborns born between July and September 2011 (n = 956), before BFHI implementation, and newborns born during the same period in 2013 (n = 1,131) after BFHI implementation. Primary outcomes were neonatal hyperbilirubinemia, phototherapy treatment, and hospital readmissions for hyperbilirubinemia within 30 days of discharge. We compared rates of outcomes between the study groups using unadjusted and adjusted odds ratios (OR). Results: Among newborns born before versus after BFHI implementation, 20.3% versus 6.98% were diagnosed with hyperbilirubinemia (p < 0.001), 5.75% versus 1.95% received phototherapy (p < 0.001), and 0.31% versus 0.35% were readmitted to the hospital for hyperbilirubinemia within 30 days (p = 0.88). In adjusted analyses, newborns born after BFHI implementation were significantly less likely to develop neonatal hyperbilirubinemia (OR 0.28 [95% confidence intervals; CI 0.20-0.37]) and receive phototherapy treatment (OR 0.27 [95% CI 0.15-0.49]) than newborns born before BFHI implementation. Conclusions: Implementation of BFHI practices is associated with significant decreases in neonatal hyperbilirubinemia and phototherapy without affecting readmission rates. Exclusive breastfeeding has traditionally been considered a risk factor for the development of neonatal jaundice. This study demonstrates that BFHI practices may mitigate that risk.

Prebiotics for the prevention of hyperbilirubinaemia in neonates.

BACKGROUND: Hyperbilirubinaemia occurs in approximately two-thirds of all newborns during the first days of life and is frequently treated with phototherapy. Although generally seen as safe, there is rising concern regarding phototherapy and its potentially damaging effects on DNA and increased side effects particularly for preterm infants. Other methods, such as enteral feeding supplementation with prebiotics, may have an effective use in the management of hyperbilirubinaemia in neonates. OBJECTIVES: To determine whether administration of prebiotics reduces the incidence of hyperbilirubinaemia among term and preterm infants compared with enteral supplementation of milk with distilled water/placebo or no supplementation. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 14 June 2018), Embase (1980 to 14 June 2018), and CINAHL (1982 to 14 June 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: We considered all RCTs that studied neonates comparing enteral feeding supplementation with prebiotics versus distilled water/placebo or no supplementation. DATA COLLECTION AND ANALYSIS: Two reviewers screened papers and extracted data from selected papers. We used a fixed-effect method in combining the effects of studies that were sufficiently similar. We then used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: Three small studies evaluating 154 infants were included in this review. One study reported a significant reduction in the risk of hyperbilirubinaemia and rate of treatment with phototherapy associated with enteral supplementation with prebiotics (risk ratio (RR) 0.75, 95% confidence interval (95% CI) 0.58 to 0.97; one study, 50 infants; low-quality evidence). Meta-analyses of two studies showed no significant difference in maximum plasma unconjugated bilirubin levels in infants with prebiotic supplementation (mean difference (MD) 0.14 mg/dL, 95% CI -0.91 to 1.20, I² = 81%, P = 0.79; two studies, 78 infants; low-quality evidence). There was no evidence of a significant difference in duration of phototherapy between the prebiotic and control groups, which was only reported by one study (MD 0.10 days, 95% CI -2.00 to 2.20; one study, 50 infants; low-quality evidence). The meta-analyses of two studies demonstrated a significant reduction in the length of hospital stay (MD -10.57 days, 95% CI -17.81 to -3.33; 2 studies, 78 infants; I² = 0%, P = 0.004; low-quality evidence). Meta-analysis of the three studies showed a significant increase in stool frequency in the prebiotic groups (MD 1.18, 95% CI 0.90 to 1.46, I² = 90%; 3 studies, 154 infants; high-quality evidence). No significant difference in mortality during hospital stay after enteral supplementation with prebiotics was reported (typical RR 0.94, 95% CI 0.14 to 6.19; I² = 6%, P = 0.95; 2 studies; 78 infants; low-quality evidence). There were no reports of the need for exchange transfusion and incidence of acute bilirubin encephalopathy, chronic bilirubin encephalopathy, and major neurodevelopmental disability in the included studies. None of the included studies reported any side effects. AUTHORS' CONCLUSIONS: Current studies are unable to provide reliable evidence about the effectiveness of prebiotics on hyperbilirubinaemia. Additional large, well-designed RCTs should be undertaken in neonates that compare effects of enteral supplementation with prebiotics on neonatal hyperbilirubinaemia with supplementation of milk with any other placebo (particularly distilled water) or no supplementation.

Screening and treatment to reduce severe hyperbilirubinaemia in infants in primary care (STARSHIP): a factorial stepped-wedge cluster randomised controlled trial protocol.

INTRODUCTION: Jaundice caused by hyperbilirubinaemia is a physiological phenomenon in the neonatal period. However, severe hyperbilirubinaemia, when left untreated, may cause kernicterus, a severe condition resulting in lifelong neurological disabilities. Although commonly applied, visual inspection is ineffective in identifying severe hyperbilirubinaemia. We aim to investigate whether among babies cared for in primary care: (1) transcutaneous bilirubin (TcB) screening can help reduce severe hyperbilirubinaemia and (2) primary care-based (versus hospital-based) phototherapy can help reduce hospital admissions. METHODS AND ANALYSIS: A factorial stepped-wedge cluster randomised controlled trial will be conducted in seven Dutch primary care birth centres (PCBC). Neonates born after 35 weeks of gestation and cared for at a participating PCBC for at least 2 days within the first week of life are eligible, provided they have not received phototherapy before. According to the stepped-wedge design, following a phase of 'usual care' (visual assessment and selective total serum bilirubin (TSB) quantification), either daily TcB measurement or, if indicated, phototherapy in the PCBC will be implemented (phase II). In phase III, both interventions will be evaluated in each PCBC. We aim to include 5500 neonates over 3 years.Primary outcomes are assessed at 14 days of life: (1) the proportion of neonates having experienced severe hyperbilirubinaemia (for the TcB screening intervention), defined as a TSB above the mean of the phototherapy and the exchange transfusion threshold and (2) the proportion of neonates having required hospital admission for hyperbilirubinaemia treatment (for the phototherapy intervention in primary care). ETHICS AND DISSEMINATION: This study has been approved by the Medical Research Ethics Committee of the Erasmus MC Rotterdam, the Netherlands (MEC-2017-473). Written parental informed consent will be obtained. Results from this study will be published in peer-reviewed journals and presented at (inter)national meetings. TRIAL REGISTRATION NUMBER: NTR7187.

Transcutaneous bilirubin levels of newborn infants performed abdominal massage: A randomized controlled trial.

PURPOSE: This study was designed as a randomized controlled trial to determine the effect of abdominal massage on bilirubin levels of newborn infants. DESIGN AND METHODS: The sample group consisted of 90 newborn infants (experimental group: 44; control group: 46) who were followed in a university hospital after birth between March and August 2017. The data were collected using an Information Form, Observation Form, and Transcutaneous Bilirubin Level Meter. Bilirubin levels were measured 1 hr after the first breastfeeding in both groups. The abdominal massage was performed for 5 min in each session, was continued in three sessions per day; was completed in totally six sessions for 2 days in infants in the experimental group. The second bilirubin measurements were repeated at the 48th hour after the birth and bilirubin levels were compared in two groups. The Student t test was used to evaluate the normally distributed data and the Mann-Whitney U test was used to carry out statistics in nonnormal distribution of quantitative data. RESULTS: The bilirubin levels of the groups (experimental group: 1.06 ± 0.92; control group: 1.01 ± 0.98) were statistically similar before abdominal massage, t(88) = 0.25, p = 0.803. The difference of the bilirubin levels was compared in the groups before and after abdominal massage. The increase of bilirubin levels in the experimental group (1.96 ± 1.69 mg/dl) was statistically significantly lower compared with the control group (2.80 ± 2.30 mg/dl), t(88) = -1.974, p = 0.048. PRACTICE IMPLICATIONS: Abdominal massage is effective to reduce bilirubin levels of newborn infants.

SMOFlipid Protects Preterm Neonates against Perinatal Nutrition-Associated Cholestasis.

OBJECTIVE: Intravenous lipid infusions improve both short- and long-term outcomes of premature neonates. However, prolonged infusion of lipids has been implicated in the development of parenteral nutrition-associated cholestasis (PNAC). We speculated that the multicomponent SMOFlipid would be hepatoprotective against PNAC. STUDY DESIGN: This is a retrospective review comparing the incidence and severity of direct hyperbilirubinemia in preterm infants <1,500 g who were hospitalized for a minimum of 2 weeks during a 20-month period in which all preterm infants on total parenteral nutrition (TPN) received fat as Lipofundin with the following 20-month period in which all preterm infants on TPN received SMOFlipid. RESULTS: Infants in the SMOFlipid period had a lower incidence of PNAC (6 vs. 13%; p = 0.022), lower peak direct bilirubin levels (3.2 vs. 7.1 mg/dL; p = 0.018), and a shorter length of stay (51 vs. 60 days; p = 0.019). The relative risk of developing direct hyperbilirubinemia during the Lipofundin period was 2.22 (1.1-4.3) as compared with period 1; p = 0.018; NNT-14. CONCLUSION: SMOFlipid was hepatoprotective in our population of preterm neonates <1,500 g receiving long-term TPN as compared with those receiving Lipofundin, despite similar levels of exposure to both intravenous lipid load and duration in the two groups.

Role of massage therapy on reduction of neonatal hyperbilirubinemia in term and preterm neonates: a review of clinical trials.

BACKGROUND: Neonatal hyperbilirubinemia (NNH) is one of the leading causes of admissions in nursery throughout the world. It affects approximately 2.4-15% of neonates during the first 2 weeks of life. AIMS: To evaluate the role of massage therapy for reduction of NNH in both term and preterm neonates. METHOD: The literature search was done for various randomized control trials (RCTs) by searching the Cochrane Library, PubMed, and EMBASE. RESULTS: This review included total of 10 RCTs (two in preterm neonates and eight in term neonates) that fulfilled inclusion criteria. In most of the trials, Field massage was given. Six out of eight trials reported reduction in bilirubin levels in term neonates. However, only one trial (out of two) reported significant reduction in bilirubin levels in preterm neonates. Both trials in preterm neonates and most of the trials in term neonates (five trials) reported increased stool frequencies. CONCLUSION: Role of massage therapy in the management of NNH is supported by the current evidence. However, due to limitations of the trials, current evidences are not sufficient to use massage therapy for the management of NNH in routine practice.

Recomendaciones para la prevención, la detección y el manejo de la hiperbilirrubinemia en los recién nacidos con 35 o más semanas de edad gestacional / Guidelines for prevention, detection and management of hyperbilirubinaemia in newborns of 35 or more weeks of gestation

La hiperbilirrubinemia representa la causa más común de reingreso hospitalario en la primera semana de vida. Su detección continúa siendo un desafío, debido especialmente al alta precoz que puede asociarse con un retraso en el diagnóstico. La identificación de los niños con riesgo de desarrollar hiperbilirrubinemia significativa es una de las principales prioridades de la sanidad pública. En este documento, se presenta un enfoque para el manejo de la ictericia del recién nacido, según recomendaciones basadas en la evidencia médica y en la opinión del Comité de Estándares de la Sociedad Española de Neonatología (AU)

Hyperbilirubinaemia is one of the most frequent causes of hospital readmission during the first week of life. Its detection is still a big challenge, mainly due to the early discharge from the hospital that can be associated with a delay of the diagnosis. The identification of those newborns at risk of developing significant hyperbilirubinaemia is one of the main priorities in the public health care system. An approach to the management of newborn jaundice is presented in this article, following the recommendations based on the medical evidence and on the opinion of the Standards Committee of the Spanish Society of Neonatology (AU)

Role of oral zinc supplementation for reduction of neonatal hyperbilirubinemia: a systematic review of current evidence.

BACKGROUND: Neonatal hyperbilirubinemia is frequently seen condition in the NICU. Oral zinc has been tried for the prevention of hyperbilirubinemia. AIMS: To evaluate the role of oral zinc supplementation for reduction of neonatal hyperbilirubinemia in term and preterm infants. METHOD: The literature search was done for various randomized control trial (RCT) by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Scopus, Index Copernicus, African Index Medicus (AIM), Thomson Reuters (ESCI), Chemical Abstracts Service (CAS) and other data base. RESULTS: This review included six RCT that fulfilled inclusion criteria. One study evaluated the role of zinc in very low birth weight (VLBW) infants and remaining enrolled neonates ≥35 weeks of gestation. The dose of zinc varied from 5 to 20 mg/day and duration from 5-7 days. All the studies used zinc sulfate, only one study used zinc gluconate. The total neonates enrolled in these different RCT are 749. CONCLUSION: Role of zinc in the prevention of neonatal hyperbilirubinemia is not supported by the current evidence. Only one study was able to show reduction in the mean TSB level and requirement of phototherapy with zinc, and the remaining studies did not report any positive effect. None of the studies showed any effect on the duration of phototherapy, incidence of phototherapy, age of starting of phototherapy and any serious adverse effect.

Hyperbilirubinemia in Preterm Neonates.

Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion. Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin. In this article, we review the evolving evidence for bilirubin-induced brain injury in preterm infants and highlight the clinical approaches that minimize the risk of bilirubin neurotoxicity.

Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model.

BACKGROUND: Increased bilirubin production due to hemolysis can lead to neonatal hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants. METHODS: After 24 h of heme administration (30 µmol/kg s.c.), 4-d-old mice were given 30 µmol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT-PCR, respectively. RESULTS: After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 µmol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed. CONCLUSION: ZnPP-Lipid is effective and thus has potential for treating neonatal hyperbilirubinemia due to hemolysis.

Oral zinc for the prevention of hyperbilirubinaemia in neonates.

BACKGROUND: Between 6% and 15% of neonates develop hyperbilirubinaemia requiring treatment. Successful management of neonatal hyperbilirubinaemia relies on prevention and early treatment, with phototherapy being the mainstay of treatment. Oral zinc has been reported to decrease the serum total bilirubin (STB), presumably by decreasing the enterohepatic circulation. OBJECTIVES: To determine the effect of oral zinc supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life and to assess the safety of oral zinc in enrolled neonates. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014). SELECTION CRITERIA: Randomised controlled trials were eligible for inclusion if they enrolled neonates (term and preterm) to whom oral zinc, in a dose of 10 to 20 mg/day, was initiated within the first 96 hours of life, for any duration until day seven, compared with no treatment or placebo. DATA COLLECTION AND ANALYSIS: We used the standard methods of The Cochrane Collaboration and its Neonatal Review Group for data collection and analysis. MAIN RESULTS: Only one study met the criteria of inclusion in the review. This study compared oral zinc with placebo. Oral zinc was administered in a dose of 5 mL twice daily from day 2 to day 7 postpartum. The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or with a spoon. Incidence of hyperbilirubinaemia, defined as serum total bilirubin (STB) ≥ 15 mg/dL, was similar between groups (N = 286; risk ratio (RR) 0.94, 95% confidence interval (CI) 0.58 to 1.52). Mean STB levels, mg/dL, at 72 ± 12 hours were comparable in both the groups (N = 286; mean difference (MD) -0.20; 95% CI -1.03 to 0.63). Although the duration of phototherapy in the zinc group was significantly shorter compared to the placebo group (N = 286; MD -12.80, 95% CI -16.93 to -8.67), the incidence of need for phototherapy was comparable across both the groups (N = 286; RR 1.20; 95% CI 0.66 to 2.18). Incidences of side effects like vomiting (N = 286; RR 0.65, 95% CI 0.19 to 2.25), diarrhoea (N = 286; RR 2.92, 95% CI 0.31 to 27.71), and rash (N = 286; RR 2.92, 95% CI 0.12 to 71.03) were found to be rare and statistically comparable between groups. AUTHORS' CONCLUSIONS: The limited evidence available has not shown that oral zinc supplementation given to infants up to one week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.