- Executive summary

A practical guideline for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns has been adapted to fit the Egyptian healthcare system. This process of customizing existing evidence-based clinical practice guidelines for local contexts offers a practical alternative to creating new ones from scratch, potentially enhancing their usefulness while conserving resources. This guideline aims to provide practical guidance for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns in Egypt, as well as the adaptation methods employed to create Egyptian National Guideline for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns using the Adapted ADAPTE method. The entire adaptation process, encompassing the setup, adaptation, and finalization phases, is thoroughly described. This involved a guideline adaptation group (GAG) and an external review group by experts in clinical content.

The finalized adapted CPG provides pediatricians and healthcare workers in the field of neonatology in Egypt with practical, evidence-based guidance for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns. This initiative underscores the effectiveness of the Adapted ADAPTE method and emphasizes the significance of collaboration between clinical and methodological experts in adapting national guidelines.

Guideline’s development and methods:

·       After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

Clinical practice guideline revision: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. AAP 2022.

·       We conducted Adolopment for these guidelines: (Adoption and Development):

Ø Adoption for most of the guideline recommendations.

Ø Development of Good Practice Statements.

Guideline registration:

Will be registered in: http://www.guidelines-registry.org.

 Recommendations and Good Practice Statements (GPS):

·   All pregnant women should be tested to determine their ABO blood group and Rh (D) type and receive an antibody screen to determine the need for Rh (D) immunoglobulin (RhIG) and to assess the potential for isoimmune hemolytic disease of the fetus or newborn. SoR: GPS

·   If the maternal antibody screen is positive or unknown because the mother did not have prenatal antibody screening, the infant should have a direct antiglobulin test (DAT) and the infant’s blood type should be determined as soon as possible using either cord or peripheral blood. SoR: Strong

· If the maternal blood group is unknown, testing for maternal and infant blood group as well as DAT is essential in any case of early jaundice. SoR: GPS

·       Clinicians should promote frequent breastfeeding on demand and recommend starting  within the first hour after birth and should provide breastfeeding support for all mothers. SoR: GPS

·       Oral supplementation with water or dextrose water should NOT be provided to prevent hyperbilirubinemia or decrease bilirubin concentrations. SoR: Strong

·       All infants should be visually assessed for jaundice at least every 12 hours following delivery until discharge. TSB or TcB should be measured as soon as possible for infants noted to be jaundiced < 24 hours after birth. SoR: GPS

·       TcB or TSB should be measured for ALL babies between 24 and 48 hours after birth or before discharge if that occurs earlier. SoR: Conditional

·       If appropriate follow up cannot be arranged for an infant recommended to have an outpatient follow up bilirubin measure, discharge may be delayed. SoR: Conditional

·       Before discharge, all families should receive WRITTEN and VERBAL EDUCATION about neonatal jaundice. SoR: GPS

·       Beginning at least 12 hours after birth, if discharge is being considered, the difference between the bilirubin concentration measured closest to discharge and the phototherapy threshold at the time of the bilirubin measurement should be calculated and used to determine follow-up appointments. SoR: conditional

·       Infants with risk factors for hyperbilirubinemia (Table-8) as determined by history of risk factors, family history, examination and laboratory results require closer monitoring than infants without risk factors. SoR: GPS

·       Elevated TSB in a formula fed infant or late onset jaundice should raise the possibility of G6PD. SoR: GPS

·       Use TSB as the definitive test to guide phototherapy and escalation-of-care decisions, including exchange transfusion. SoR: GPS

·       Decisions to initiate phototherapy or escalate care are guided by the gestational age, the TSB, and the presence of risk factors for bilirubin neurotoxicity (Table-9). SoR: GPS

·       A TSB measurement should be performed on every infant who is jaundiced in the first 24 hours after birth. SoR: Strong

·       TSB should be measured if TCB exceeds or is within 3 mg /dl of phototherapy treatment threshold or if TcB is ≥ 15mg/dL. SoR: Conditional

·       If more than 1 TcB or TSB measure is available, the rate of increase of bilirubin may be used to identify infants at higher risk of subsequent hyperbilirubinemia.  A rapid rate of increase (≥ 0.3 mg/dL per hour in the first 24 hours or ≥ 0.2 mg/dL per hour thereafter) is exceptional and suggests hemolysis. In this case, a DAT should be performed if not previously done. SoR: Conditional

·       The formal assessment of babies with gestational age ≥35 weeks presenting with indirect neonatal hyperbilirubinemia:

-   History and family history (risk factors for hyperbilirubinemia and risk factors for neurotoxicity)

-   Clinical examination (general / signs of neurotoxicity (BIND score).

-   Laboratory assessment:

-  Complete blood count and reticulocyte count.

-  TSB

-  Maternal and child blood group and Rh.

-  DAT test.

-  Further investigations as required. SoR: GPS

·  - Assessment for acute bilirubin encephalopathy should be done in every jaundiced baby with risk factors for neurotoxicity (Table-9) or any severely jaundiced baby using modified BIND score. SoR: Conditional

·  For breastfed infants who are still jaundiced at 3-4 weeks of age and for formula fed infants who are still jaundiced at 2 weeks of age, the total and direct reacting or (conjugated) bilirubin concentration should be measured to identify possible pathologic cholestasis. SoR: Conditional

·   Infants who have an elevation of direct reacting or conjugated bilirubin should have a urine analysis and culture. Additional laboratory evaluation for sepsis should be performed if indicated by history and physical examination (Table-11). SoR: Stong

·       All nurseries and NICUs treating infants should have the necessary equipment to provide intensive phototherapy (Table-12). SoR: Conditional

·       Intensive phototherapy is recommended at the TSB threshold in (Figures-4 & 5) on the basis of gestational age, hyperbilirubinemia neurotoxicity risk factors and age of infant in hours. SoR: GPS

·       The direct reacting or conjugated bilirubin value should not be subtracted from the total bilirubin value when determining management. SoR: GPS

·       In breastfed infants on conventional phototherapy, it is recommended that, if possible, breastfeeding should be continued while withholding phototherapy for the duration of the feed (max 20 minutes). If TSB is approaching escalation of care level, the infant should not come out of phototherapy to feed, as this is a medical emergency. SoR: Strong

·       In breastfed infants receiving phototherapy, supplementation with expressed breast milk or formula is appropriate if the infant’s intake seems inadequate, weight loss is excessive, or the infant is dehydrated. SoR: Strong

·       Routine intravenous fluids are NOT necessary for term or near-term infants receiving phototherapy unless there is evidence of dehydration or if TSB is approaching escalation of care threshold. SoR: Strong

·       For hospitalized infants, TSB should be measured within 12 hours after starting phototherapy. The timing of the initial TSB measurement after starting phototherapy and the frequency of monitoring during phototherapy should be guided by the age of the child, the presence of hyperbilirubinemia neurotoxicity risk factors, the TSB concentration and TSB trajectory. SoR: GPS

·       For infant requiring phototherapy measure the hemoglobin concentration, hematocrit, or complete blood count to assess the presence of anemia and to provide a base line in case subsequent anemia develops. SoR: GPS

·       Evaluate the underlying cause or causes of hyperbilirubinemia:

-  In infants who require phototherapy by obtaining a DAT.

-   In infants whose mother had a positive antibody screen.

-   Or whose mother is blood group O, regardless of Rh status.

-   Or whose mother is Rh (D) negative. SoR: GPS

·       G6PD activity should be measured in:

·        Any infant with jaundice of unknown cause whose TSB:

-  increases despite intensive phototherapy.

-  increases suddenly

-  increases after an initial decline or who requires escalation of care.

·       Any infant who requires escalation of care. SoR: GPS

·       Monitoring TSB for infants receiving intensive phototherapy without signs of ABE:

·       If TSB ≥ 25 mg/dL, repeat TSB within 2–3 h.

·       If TSB 20–25 mg/dL, repeat within 3–4 h.

·       If TSB <20 mg/dL repeat in 4–6 h.

·       If TSB continues to fall, repeat in 8–12 h.

·       Consider exchange transfusion if TSB is not decreasing or is moving closer to the level for exchange transfusion. SoR: Strong

·      Discontinuing phototherapy is an option when TSB has decreased by at least 2 mg / dL below the hour specific threshold at the initiation of phototherapy. A longer period of phototherapy is an option if there are risk factors for rebound hyperbilirubinemia (e.g. Gestational age < 38 weeks, age < 48 hours at the start of phototherapy, hemolytic disease. SoR: Conditional

·       Repeat bilirubin measurement after phototherapy is based on the risk of rebound hyperbilirubinemia. Risk factors are:

·       Infants who received phototherapy before 48 hours.

·       Infants who had a positive DAT.

·       Infants who had known or suspected hemolytic disease.

·       Infants with risk for hyperbilirubinemia and hyperbilirubinemia neurotoxicity risk factors (Table-8 and 9). SoR: GPS

·       In the presence of one of the above risk factors: TSB should be measured for rebound at 6-12 hours after phototherapy discontinuation. All other infants should be followed up for TSB after 24 hours of discontinuation of phototherapy. SoR: GPS

·      Care should be escalated when an infant’s TSB reaches or exceeds the escalation of care threshold defined as 2 mg /dl below the exchange transfusion threshold. The direct reacting or conjugated bilirubin value should not be subtracted from the total bilirubin value when determining management. SoR: GPS

·       For infants requiring escalation of care, blood should be sent STAT for total and direct reacting serum bilirubin, a complete blood count, serum albumin, serum chemistries and blood type and cross match. SoR: GPS

·       Infants requiring escalation of care should receive intravenous hydration and emergent intensive phototherapy. A neonatologist should be consulted about urgent transfer to a NICU that can perform an exchange transfusion. SoR: Conditional

·       TSB should be measured at least every 2 hours during the escalation period. Once the TSB is lower than the escalation of care threshold, continue phototherapy according to the bilirubin level. SoR: GPS

·       Intravenous immunoglobulin (IVIG) (0.5-1 g/kg over 2 hours) may be provided to infants with isoimmune hemolytic disease (i.e., positive DAT) whose TSB reaches or exceeds the escalation of care threshold.  This dose can be repeated in 12 hours. SoR: Conditional

·       Urgent exchange transfusion should be performed for infants with signs of intermediate or advanced stages of acute bilirubin encephalopathy (Table-10). SoR: Conditional

·       An urgent exchange transfusion should be performed for infants if the TSB ≥ the exchange transfusion threshold (Figure-7 and 8). If while preparing for exchange transfusion but before starting the exchange transfusions, a TSB concentration is below the exchange transfusion threshold and the infant does NOT show signs or intermediate or advanced stages of ABE, then the exchange transfusion may be deferred while continuing intensive phototherapy and following TSB every 2 hours until the TSB is below the escalation of care threshold. SoR: Conditional

·       Use the following medications with caution in a baby with hyper-bilirubinemia as they may cause bilirubin to be displaced from albumin binding sites and increase the risk of ABE:

·       Konakion.

·       Digoxin.

·       Diazepam.

·       Salicylates.

·       Diuretics e.g., furosemide and hydrochlorothiazide.

·       Ceftriaxone.

·       Ibuprofen.

·       Sulfamethoxazole such as in trimethoprim/sulfamethoxazole (cotrimoxazole). SoR: Conditional

·       The use of any of the following medications for the treatment of hyperbilirubinemia is NOT RECOMMENDED (Phenobarbitone, Agar, Clofibrate, albumin, charcoal, cholestyramine, D penicillamine, glycerine, riboflavin, homeopathy, and metalloporphyrins). SoR: Conditional

·       Any infant with severe neonatal hyperbilirubinemia should receive a hearing screen including brainstem auditory evoked potentials (ABR) for the early diagnosis of auditory dys-synchrony or sensory neural hearing loss and timely intervention. SoR: Conditional

·       Infants who required exchange transfusion or those who exhibit neurological abnormalities with history of neonatal jaundice require regular neurological follow up. SoR: Conditional

·       Infants with isoimmunization are at risk of severe anemia after several weeks (up to 8-12 weeks of age); Repeat hemoglobin measurement should be performed at two weeks if it was low at discharge and at four weeks if it was normal. SoR: Conditional

·       Infants suspected to have G6PD deficiency (elevated TSB in formula infants or late onset jaundice) should be tested at 3 months of age. SoR: Conditional

- Recommendations

Table-3: Recommendation statements with level of evidence & strength of recommendations:

- Acknowledgments

The authorship group would like to thank Professor Ashraf Abdel Baki, Head of the EPG, for initiating the idea of adapting the international guidelines to produce specific Egyptian clinical practice guidelines that will help standardize patient care.

The authorship group would also like to thank Professor Tarek Omar, Alexandria University, for his constant support and guidance through every step of formulating this work. We would not have completed it without his help. We would also like to thank Prof. Raghdaa Mahmoud Ali, Ahmed Maher Hospital, for her valuable effort in valuable contribution & support during this work.

A special thank you goes to Prof. Hoda Basheer Head of the Pediatrics Department of Al Galaa Teaching Hospital for her suggestion and implementation of the parent follow up card and to the 5^th year medical students (2017/2018), Ain Shams University for their creativity and commitment in the parent information leaflet.

We are also deeply indebted to Professor Vinod Bhutani, Professor of paediatrics and neonatal medicine; Stanford University and Professor Jon F Watchco, Professor of Pediatrics, Obstetrics and Gynaecology at the University of Pittsburgh, both world-renowned experts in the topic, for their guidance and meticulous review of these guidelines. Their comments, critique and support have been invaluable.

We extend our deep gratitude to the external review group from different universities for their precious time and valuable revision and of this guideline.

Endless gratitude goes to the American Academy of Paediatrics (AAP) since they were the original sources from which this guideline was adapted.

Finally, we thank all our patients and their mothers who have taught us so much without noticing, it is for them that this work is being finalized.

The Authorship Group

Funding:

This work is not related to any pharmaceutical or industrial company. The members of the GDG/ GAG and their institutes and universities volunteered their participation and contributions.

- ABBREVIATIONS

AAP	American Academy of Pediatrics
ABE	Acute bilirubin encephalopathy
ABO	ABO blood group type
ABR	Auditory brainstem response
ADAPTE	The International Collaboration for Guideline Adaptation
AGREE II	Appraisal of Guidelines, Research and Evaluation II
B/A ratio	bilirubin/ albumin ratio
BCSH	British Committee for Standards in Hematology
BIND	Bilirubin induced neurologic dysfunction
BN	Bilirubin nomogram
CBE	Chronic bilirubin encephalopathy
CEBCPGs	Center for Evidence Based Clinical Practice Guidelines
CMV	Cytomegalovirus
CPG	Clinical Practice Guideline
CGAG	Clinical guideline adaptation group
DAT	Direct anti-globulin test
DOB	Date Of Birth
EBCPG	Evidence based clinical practice guidelines
EBM	Evidence-Based Medicine
ENHG	Egyptian Neonatal Hyperbilirubinemia Group
ETCO2	End tidal carbon monoxide
FBC	Full blood count
G6PD	Glucose 6 phosphate dehydrogenase
GA	Gestational age
GDG/GAG	Guideline Development/ Adaptation Groups
GOTHI	General Organization For Teaching Hospitals and Institutes
GPP	Good practice point
HDFN	Hemolytic disease of the fetus and newborn
IUTs	Intrauterine transfusions
IVIG	Intravenous immunoglobulin
LEDs	Light-emitting diodes
LFTs	Liver function tests
M-BIND	Modified bilirubin-induced neurologic dysfunction score
MCHC	Maternal child health center
MMA	Military Medical Academy
MTI	Modern University for Technology and Information
MUST	Misr University for Science & Technology
NICUs	Neonatal Intensive Care Units
NJ	Neonatal jaundice
NPCPGC	National Pediatric Clinical Practice Guidelines Committee
PIPOH	Population, Intervention, Professionals, Outcomes and outcome measures, Healthcare setting and context
PT	Phototherapy
RBC	Red blood cell
RC	Review Committee
RCTs	Randomized controlled trails
Rh (D)	Rhesus Factor blood type D
SBR	Serum Bilirubin
SNH	Severe neonatal hyperbilirubinemia
SNHL	Sensorineural hearing loss
SNJ	Severe neonatal jaundice
SpO2	Oxygen saturation
T4	Free tetra-iodothyronine
TcB	Transcutaneous bilirubinometry
TSB	Total serum bilirubin
TSH	Thyroid stimulating hormone

- INTRODUCTION

Neonatal jaundice (NJ) refers to yellow discoloration of the skin and sclera of newborn babies ⁽⁷⁾. It is generally considered a benign self-limiting condition, affecting more than 60% of healthy term and 80% of preterm infants ^(8,9). However, in some cases, severe neonatal hyperbilirubinemia (SNH) can lead to irreversible brain damage and kernicterus ⁽¹⁰⁾. Surviving infants may acquire long-term neuro-developmental sequelae such as cerebral palsy, sensorineural hearing loss, intellectual difficulties or gross developmental delays. Acute bilirubin encephalopathy (ABE) and Chronic bilirubin encephalopathy (CBE) are largely preventable if SNH is identified early and treated promptly with effective phototherapy, or, if indicated, exchange transfusion.

In a recent systematic review in which SNH was defined as that associated with acute bilirubin encephalopathy, exchange transfusion or death; the incidence of SNH per 10,000  live births was found to be highest in the African region at 667.8, compared to 4.4/10,000 in the Americas ⁽¹¹⁾. In Egypt, the numbers are not known; however, in a recent study on 4000 well full-term newborns screened for jaundice, 1.9% had bilirubin levels in the high-risk zone on the Bhutani nomogram. This means that, in a population with 2.5 million new births / year, a large group could be at risk for SNH and its sequelae⁽¹²⁾. In the NICU of Cairo university Children’s hospital, in 2009, 44/249 admitted jaundiced newborns not only had extreme hyperbilirubinemia, but presented with moderate to severe bilirubin encephalopathy ⁽¹³⁾ and in a recently published follow up study in the same NICU, all 23/202 babies admitted with SNH had abnormal neurological examination at follow up⁽¹⁴⁾. The root causes for these shocking numbers within the Egyptian community include parental ignorance ⁽¹⁵⁾ of the risk of severe jaundice, absence of timely follow up for jaundiced newborns, as well as delay in proper intervention. ^(15,16)

While tactics to prevent and treat severe neonatal hyperbilirubinemia must be sensitive to cultural and resource variations, the universality of root causes suggests that a common strategy should be applied to make kernicterus, a very rare event throughout the world. A systematic approach should be developed in Egypt whereby newborn infants should be monitored for risk of  hyperbilirubinemia and prompt interventions should be followed to prevent acute bilirubin encephalopathy and kernicterus.

- Definitions

Acute bilirubin encephalopathy (ABE): A clinical syndrome in the presence of severe hyperbilirubinemia that consists of decreased feeding, lethargy, variable abnormal tone (hypotonia and/or hypertonia), high-pitched cry, retrocollis and opisthotonus, setting sun sign, fever, apnea, seizures, and death. ^{(17, 18)}

Chronic bilirubin encephalopathy (CBE): A clinical tetrad that occurs after the history of severe hyperbilirubinemia consisting of:

(1) A movement disorder consisting of not only athetosis and dystonia, but may also include spasticity and hypotonia.

(2) Auditory dysfunction consisting of sensory neural hearing loss or auditory dys-synchrony.

(3) Oculomotor impairments especially impairment of up-gaze, but also lateral gaze impairments including strabismus.

(4) Dental enamel hypoplasia of the deciduous teeth. ⁽¹⁹⁾

Kernicterus: The pathological finding of deep-yellow staining of neurons and neuronal necrosis of the basal ganglia and brainstem nuclei clinically associated with chronic bilirubin encephalopathy. ^(17,19)

Escalation of care: The intensive care that some infants with elevated or rapid increasing bilirubin concentration require to prevent the need for an exchange  and possibly prevent kernicterus. ⁽⁶⁾

Critical or, Extreme hyperbilirubinemia: A TSB concentration greater than 25 mg/dL during the first 28 days of life. ^(18,19)

Rebound Hyperbilirubinemia: Is defined as a TSB concentration that reaches the phototherapy threshold for the infant’s age within 72-96 hours of discontinuing phototherapy. ^(6,20)

Prolonged unconjugated jaundice: Infants 7 days or older with a persistently elevated TSB within 2 mg/dL of the phototherapy threshold may have prolonged indirect hyperbilirubinemia, which can be confirmed by measuring serum direct-reacting or conjugated bilirubin (i.e., a fractionated bilirubin measure) in addition to total bilirubin. ⁽⁶⁾

Intensive phototherapy: Requires a narrow spectrum LED blue light with an irradiance of at least 30 mW/cm2 per nm at a wavelength around 475 nm. ⁽⁶⁾

- SCOPE AND PURPOSE

Disease condition:

  Neonatal hyperbilirubinemia in late preterm ≥35 weeks and term neonates.

Guideline category:

·       Prediction.

·       Prevention.

·       Management.

Clinical specialty:

·       Pediatricians.

·       Neonatologist.

·       Obstetricians.

·       Family physicians.

Intended users:

This evidence base CPG is intended to guide those involved in the management of neonatal hyperbilirubinemia either in primary or secondary/tertiary care namely:

·       Medical officers and general practitioners.

·       Family medicine specialists.

·       Pediatricians, neonatologists and specialists from related disciplines (Nurses and rural health workers).

·       Obstetricians.

·       Parents and care-givers.

GUIDELINES OBJECTIVES

The objectives of this Clinical Practice Guideline is to provide evidence-based guidance on the prediction, prevention and management of severe neonatal hyperbilirubinemia (SNH) specifically adjusted to the customs of the Egyptian community and to integrate it with the already existing health care system to prevent the occurrence of acute bilirubin encephalopathy and kernicterus through the following:

•        Detection of high-risk groups and prediction of severe hyperbilirubinemia.

•        Targeted follow-up of risk groups.

•        Early diagnosis and timely intervention for severe hyperbilirubinemia.

Target Population:

Inclusion and exclusion criteria:

Inclusion criteria:

Newborns with diagnosis of indirect hyperbilirubinemia or at risk for development of severe hyperbilirubinemia meeting the following criteria:

·       Age ≤ 28 days.

·       GA ≥35 weeks.

Exclusion criteria:

·       Neonate with cholestasis.

·       Age >28 days.

·       GA <35 weeks GA.

Healthcare Settings:

•        Community settings: maternal child health care center (MCHC).

- Evidence

We used the GRADE system (Grading of Recommendations, Assessment, Development and Evaluation) for assigning the quality of evidence and strength of recommendations that includes the following definitions ^[29]. Informed by the evidence required for the GRADE Evidence to Decision (EtD) framework (s) was (were) done while considering changing strength of recommendations according to availability of some resources in the recommendations (both ETD and changing strength of recommendation were not done in this guideline).

Description of the interpretation of the GRADE four levels of certainty of evidence:

Table-1: Classification of the Quality of Evidence:

GRADE EtD’s contextual factors, criteria and considerations that link to the strength of recommendations:

Criteria and Considerations:

1.    Benefits and harms: When a new recommendation is developed, desirable effects (benefits) need to be weighed against undesirable effects (risks/harms), considering any previous recommendation or another alternative. The larger the gap or gradient in favor of the desirable effects over the undesirable effects, the more likely that a strong recommendation will be made.

2.    Certainty of the evidence about the effects: The higher the certainty of the scientific evidence base, the more likely that a strong will be made.

3.    Values and preferences: If there is no important uncertainty or variability in how much people value the main outcomes, it is likely that a strong recommendation will be made. Uncertainty or variability around these values that could likely lead to different decisions, is more likely to lead to a conditional recommendation.

4.    Economic implications: Lower costs (monetary, infrastructure, equipment or human resources) or greater cost-effectiveness are more likely to support a strong recommendation.

5.    Equity and human rights: If an intervention will reduce inequities, improve equity or contribute to the realization of human rights, the greater the likelihood of a strong recommendation.

6.    Feasibility: The greater the feasibility of an intervention to all stakeholders, the greater the likelihood of a strong recommendation.

7.    Acceptability: If a recommendation is widely supported by health workers and program managers and there is widespread acceptance for implementation within the health service, the likelihood of a strong recommendation is greater.

Table-2: Classification of the Strengths of Recommendations:

Developing good practice statements:

The GDG/ GAG also developed good practice statements for this guideline, which are actionable messages relevant to the guideline questions. The justification for each good practice statement was carefully considered by the GDG/ GAG with an emphasis that they are clearly needed. Good practice statements were developed, guided by the following GRADE criteria:

1- Message is really necessary with regard to actual healthcare practice.

2- Have large net positive consequence (relevant outcomes and downstream consequences) (GRADE EtD domains).

3- Collecting and summarizing the evidence is a poor use of time and resources.

4- Include a well-documented, clear rationale connecting indirect evidence.

5- Are clear and actionable statements.

The GDG/ GAG collectively drafted and finalized good practice statements with relevant justifications and remarks to help with their interpretation, with close support and input from the consultant and guideline methodologists.

We have used the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension for adapted guidelines (RIGHT-Ad@pt Tool) as a reporting checklist for this guideline adaptation process as recommended by the EQUATOR network.

- Implementation Considerations

·       It has been demonstrated in a variety of settings that patient care consistent with recommendations in evidence- based guidelines leads to improved outcomes. Guidelines are designed to ensure that all members of a patient’s health care team are aware of the goals of treatment and of the different ways of achieving these goals. They help set standards of clinical care, may serve as a basis for audit, and act as a starting point for the education of health professionals and patients.

·       However, in order to effect changes in medical practice and consequent improvements in patient outcomes, evidence-based guidelines must be implemented and disseminated at national and local levels. Dissemination involves educating healthcare providers to improve their awareness, knowledge, and understanding of guideline recommendations. It is a part of implementation, which involves the translation of evidence-based guidelines into real-life practice with improvement of health outcomes for the patient. Implementation remains a difficult problem worldwide. Barriers to implementation range from poor infrastructure that hampers delivery of care to remote parts of a country, to cultural factors that make patients reluctant to use recommended medications and lack of use of guidelines

Guideline Implementation Strategies:

·        Implementing guidelines in practice that result in successful practice changes and positive clinical impact is a complex undertaking.  There are many strategies that can be helpful during implementation, which include the following:

- Identifying an individual to lead the project who is able to provide dedicated time to implementation. This leader will provide support, clinical expertise and should have strong interpersonal, facilitation and project management skills.

- Utilizing a systematic approach to planning, implementation and evaluation of the guideline initiative. A work plan is helpful to keep track of activities and timelines.

- Before a change in practice that can be expected and guideline recommendations implemented, the attitudes, values and beliefs of staff about NNJ must be addressed through a preliminary questionnaire.

- Implementation strategies

Table-5: CPG implementation strategies:

- IMPLEMENTATION TOOLS

Education material was prepared for the implementation of the “Egyptian clinical practice guideline for the prediction, prevention and management of hyperbilirubinemia in term and late preterm newborns”. Each item can be printed out in the form of posters to be hung in different nurseries or NICUs or an information leaflet to be given to parents. Also, it can be utilized within a protocol book of procedures to facilitate its use by physicians in clinics or MCHC.

SUMMARY OF RECOMMENDATIONS:

1.    Antenatal orientation of mothers about neonatal jaundice especially if she is of a risky blood group type (Rh negative or O).

2.    Early promotion and support of successful breastfeeding.

3.    Set protocols for the identification and evaluation of hyperbilirubinemia should be in all nurseries

4.    Any infant jaundiced in the first 24 hours should have his total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) level measured.

5.    All bilirubin levels should be interpreted according to the infant’s age in hours.

6.    Infants < than 38 weeks’ gestation, particularly those who are breastfed, are at higher risk of developing severe hyperbilirubinemia and require closer surveillance and monitoring.

7.    A systematic assessment should be performed on all infants before discharge from maternity hospital for the risk of severe hyperbilirubinemia.

8.    Parents should be provided with written and verbal information about newborn jaundice.

9.    Appropriate follow-up date based on the time of discharge and the risk assessment should always be arranged and written in a follow up card.

10. Any baby presenting with hyperbilirubinemia should be examined for cause as well as signs of ABE.

11. Prompt treatment of newborns, when indicated, with phototherapy or exchange transfusion should be decided based on TSB (without subtracting direct component).

12. Immediate exchange transfusion is indicated in any baby with signs of ABE.

13. Follow up of any baby with severe hyperbilirubinemia should include ABR, neurodevelopmental follow up and follow up for anemia if cause was hemolytic.

Figure-1: Approach to identify newborns with maternal anti-erythrocyte antibodies and to guide early management ⁽⁶⁾

Figure-2: Flow diagram for infants during birth hospitalization to monitor jaundice follow up ⁽⁶⁾

Table-6: Timing of follow up (unless seen earlier according to nomogram):

                                                                                                (AAP guideline, Pediatrics 2004)⁽³⁾

Table-7: Risk Factors for Development of significant hyperbilirubinemia: ⁽⁶⁾

Table-8: Hyperbilirubinemia neurotoxicity risk factors: ⁽⁶⁾

Table-9: Clinical assessment of neurotoxicity using the Modified BIND score: ⁽⁵¹⁾

Choose one number for each domain. Final score out of 12 (zero: Normal, 1-4: mild encephalopathy, 5-6: moderate encephalopathy, 7-12: severe encephalopathy) ⁽⁵⁸⁾

Table-10: Laboratory Evaluation of the Jaundiced Infant of 35 or More Weeks’ Gestation: ⁽³⁾

Treatment:

-        Use intensive phototherapy and/or exchange transfusion

Laboratory tests:

-        TSB and direct-reacting (or conjugated) bilirubin levels.

-        Blood type (ABO, Rh).

-        Direct antibody test (or Coombs’ test).

-        Serum albumin.

-        Complete blood cell count with differential and smear for red cell morphology.

-        Reticulocyte count.

-        ETCO (if available).

-        G6PD if suggested by ethnic or geographic origin or if poor response to phototherapy.

-        Urine for reducing substances.

-        If history and/or presentation suggest sepsis, perform blood culture, urine culture, and cerebrospinal fluid for protein, glucose, cell count, and culture.

Interventions:

-        If TSB ≥25 mg/dL (428 µmol/L) or ≥20 mg/dL (342 µmol/L) in a sick infant or infant ≤ 38 week gestation, obtain a type and cross match, and request blood in case an exchange transfusion is necessary.

-        In infants with isoimmune hemolytic disease and TSB level rising in spite of intensive phototherapy or within 2-3 mg/dL (34-51 µmol/L) of exchange level (Figures-7 & 8), administer intravenous immunoglobulin 0.5–1 g/kg over 2 h, and repeat in 12 h if necessary.

-        If infant’s weight loss from birth is 12% or there is clinical or biochemical evidence of dehydration, recommend expressed breast milk or formula. If oral intake is in question, give intravenous fluids.

- Parent Information leaflet

الصفراء في الأطفال حديثي الولادة:

ما هى الصفراء فى الأطفال حديثى الولادة ؟

هى عبارة عن حدوث اصفرار ببياض العين و الجلد عند المولود ، وهى حالة قد  تتطلب عناية خاصة بحديثى الولادة.

كيف تحدث الصفراء فى حديثى الولادة ؟

تحدث نتيجة  زيادة مستوى المادة المسببة للصفراء في الدم عن الحد الطبيعي. و هي مادة تُنتج عند:

·       تكسير خلايا الدم الحمراء.

·       مشاكل بالكبد (عدم اكتمال نمو الكبد أو وجود التهابات أو اعتلال بالكبد).

·       انسداد القنوات المرارية.

ما هى أنواع الصفراء فى حديثى الولادة ؟

1-    الصفراء الفسيولوجية (الطبيعية):

·       هي عادة تظهر بنهاية اليوم الثالث أو الرابع من الولادة وتستمر لمدة عشرة أيام أو أسبوعين من يوم الولادة على الأكثر.

·       وتحدث لأن إنزيمات الكبد المسئولة عن التخلص من المادة المسببة للصفراء فى الطفل حديث الولادة  تكون غير مكتملة جزئيا .

2-    الصفراء المرضية: وتحتاج لتدخل طبي

·       من أشهر أسبابها: تكسير الدم نتيجة عدم توافق فصيلة دم الطفل مع دم الأم (إذا كان الطفل يحمل فصيلة موجبة والأم تحمل فصيلة سالبة والأب يحمل فصيلة موجبة).

·       يحدث ذلك خلال 24 ساعة من الولادة.

·       تحدث أيضا نتيجة وجود التهابات أو اعتلال بالكبد أو انسداد القنوات المرارية.

الأطفال الأكثر عرضة للإصابة بصفراء حديثي الولادة:

1-    الأطفال المبتسرين (أقل من 9 شهور أو 36 أسبوع حمل).

2-    وجود اخ او اخت عانى سابقا من صفراء حديثي الولادة.

3-    ناقصي النمو.

4-    إذا أصيبت الأم بأي حرارة أو طفح جلدي أثناء الحمل.

5-    إذا كانت فصيلة الام 0 أو الأم تحمل فصيلة سالبة والأب يحمل فصيلة موجبة).

أعراض الصفراء في حديثي الولادة:

·       اصفرار بشرة الطفل.

·       اصفرار بياض العين.

علامات الخطر:

·       ظهور الاصفرار في اليوم الأول من الولادة.

·       تحول لون البراز إلى اللون الفاتح المقارب للبياض.

·       وجود تشنجات أو تقوس بالضهر.

وعند ظهور أي من هذه العلامات يجب التوجه إلى الطبيب فوراً.

ما هي مضاعفات مرض الصفراء؟

ارتفاع المادة المسببة للصفراء بدم الطفل يؤدي الى وصولها الى أجزاء ومراكز هامة بالمخ ومن ثم حدوث مضاعفات خطيرة مثل:

الاعتلال الدماغي الحاد (الشلل الدماغي): وتكون أعراضه:

·       الخمول أو صعوبة الاستيقاظ.

·       البكاء عال النبرة.

·       قلة الرّضاعة.

·       تقوس الرقبة والجسم للوراء.

·       تأخر تطور النمو العقلي.

·       فقدان السمع.

كيف يتم تشخيص الصفراء في حديثي الولادة:

·       قياس نسبة المادة المسببة للصفراء عبر الجلد.

·       قياس نسبة المادة المسببة للصفراء في الدم.

علاج الصفراء في حديثي الولادة:

عند ملاحظة الاصفرار على بشرة الطفل يجب التوجه الى الطبيب فورا ويحدد الطبيب طريقة العلاج على حسب نسبة الصفراء في دم الطفل:

1-    المتابعة: وتستمر كل 72 ساعة مع استمرار الرضاعة الطبيعية المنتظمة (8:12) مرة يوميا.

2-    العلاج الضوئي في الحضانة.

3-    تغيير دم الطفل في حالات الارتفاع الشديد لنسبة الصفراء في الدم.

4-    فى حالة انسداد القنوات المرارية نتوجه للعلاج الجراحي.

ماذا تفعل بعد خروج الطفل من الحضانة؟

·       يجب متابعة الصفراء بعد 24 ساعة.

·       يجب عمل فحص للسمع لأي طفل عانى من نسبة صفرا مرتفعة.

معتقدات خاطئة:

·       عدم عرض الطفل الأصفر على الطبيب.

·       أن حالة الطفل ستتحسن تحت الإضاءة المنزلية المعتادة (اللمبة النيون). أو في الشمس.

·       ان الفيتامينات أو الجلوكوز أو الاجار أو الاعشاب علاج للصفراء.

·       ان الرضاعة الطبيعية لا يمكن ان تستمر في حالة وجود الصفراء او العلاج الضوئي.

Instructions to parents before discharge from maternity unit:

Parents should be provided with written information to facilitate post discharge care including the date, time and place of follow up appointment and when necessary prescription and appointment for a follow up TcB or TSB.

Birth hospitalization information including the last TcB or TSB and the age at which it was measured and DAT results (if any) should be documented.

Figure-3: Example of parent card

- Appendix

What decline in the Serum Bilirubin can you expect?

·       With extremely high bilirubin (more than 30 mg/dL), and intensive phototherapy, a decline of as much as 10 mg/dL can occur within few hours, and a decrease of at least 0.5 to 1 mg/dL/ hour can be expected in the first 4 to 8 hours.

·       On average, for infants >35 weeks’ gestation readmitted for phototherapy, intensive phototherapy can produce a decrement of 30% to 40% in the initial bilirubin level by 24 hours after initiation of phototherapy.

·       The most significant decline will occur in the first 4 to 6 hours.

·       With standard phototherapy systems, a decrease of 6- 20% of the initial bilirubin level can be expected in the first 24 hours.

Safety and protective measures:

·       A clinician skilled in newborn care should assess the neonate’s clinical status during phototherapy to ensure adequate hydration, nutrition, and temperature control. Clinical improvement or progression of jaundice should also be assessed, including signs suggestive of early bilirubin encephalopathy (ABE).

·       The distance of the phototherapy device from the infant should be safely minimized.

·       It is important to note that the intensity of light decreases at the outer perimeter of the light footprint and to recognize the effects of physical factors that could impede or obstruct light exposure to have maximum exposure.

·       Temperature should be monitored during phototherapy and a neutral thermal environment ensured.

·       Baby should be monitored for adequate hydration by daily weighing and assessment of wet nappies.

·       Phototherapy does not use ultraviolet light and exposure to lights is mostly harmless. Devices must comply with general safety standards.

·       The genitalia should be protected from light during phototherapy.

·       Give baby eye protection and routine eye care.

Other clinical considerations include:

·       Phototherapy is contraindicated in infants with congenital porphyria or those treated with photosensitizing drugs.

·       Prolonged phototherapy is associated with increased oxidant stress and lipid peroxidation and riboflavin deficiency.

When should phototherapy be stopped?

·       There is no standard for discontinuing phototherapy.

·       For infants who are readmitted after their birth hospitalization (usually for TSB levels of 18 mg/dL or higher), phototherapy may be discontinued when the serum bilirubin level falls below 13 to 14 mg/dL.

·       Do not delay discharge to observe the infant for rebound.

·       If phototherapy is used for infants with hemolytic diseases or is initiated early and discontinued before the infant is 3 to 4 days old, a follow-up bilirubin measurement within 24 hours after discharge is recommended.

Intermittent Versus Continuous Phototherapy:

·       NO rationale for intermittent phototherapy exists.

·       If the infant’s bilirubin level is approaching the exchange transfusion zone, intensive phototherapy should be administered continuously until a satisfactory decline in the serum bilirubin level occurs or exchange transfusion is initiated.

·       Phototherapy may be interrupted for breastfeeding or brief parental visits as long as the level of bilirubin is not approaching the exchange zone.

Hydration:

·       No evidence that excessive fluid administration affects the serum bilirubin concentration.

·       If a baby with high bilirubin levels is also mildly dehydrated. This may need supplemental fluid intake to correct the dehydration.

·       Encourage frequent breastfeeding but if baby is dehydrated despite frequent breastfeeding, supplement with a milk-based formula, because it inhibits the enterohepatic circulation of bilirubin and should help to lower the serum bilirubin level.

·       Routine intravenous fluid or other supplementation (e.g., with dextrose water) of term and near-term infants receiving phototherapy is NOT required or indicated unless there is evidence of dehydration or escalation of care is required. ⁽⁶⁾

Safety and state of the art use:

PHOTOTHERAPY IS A DRUG like Pharmacotherapy.⁽²⁰⁾

In order to provide effective PT and improve outcomes, the following rules should be followed:

·       Use photons as a drug when prescribing phototherapy.

·       Use a narrow‐spectrum blue light (450 nm).

·       Measure irradiance for specific wavelength.

·       Use the least irradiance dose to achieve an efficient decrease in bilirubin load.

·       Use phototherapy for the shortest possible time and only when indicated. ⁽⁷¹⁾

Complications:

·       Phototherapy in hospital separates mother and infant. Eye patching is disturbing to parents.

·       Diarrhoea, intestinal hypermotility.

·       Temperature instability.

·       Phototherapy rash.

·       Possible long term effects:

-  Teratogenic effects, one study reported that phototherapy was associated with DNA damage. However, there is no evidence that this effect on DNA at a microscopic level can lead to long-term adverse effects in phototherapy-treated babies.

-  Melanocytic nevus development.

·       Infants with cholestatic jaundice may develop a dark, grayish-brown discoloration of the skin, serum, and urine (the bronze infant syndrome). This syndrome generally has had few deleterious consequences, and if there is a need for phototherapy, the presence of direct hyperbilirubinemia should not be considered a contraindication to its use. This is particularly important in sick neonates.

·       Rarely, purpura and bullous eruptions have been described in infants with severe cholestatic jaundice receiving phototherapy and severe blistering and photosensitivity during phototherapy have occurred in infants with congenital erythropoietic porphyria.

·       Congenital porphyria or a family history of porphyria is an absolute contraindication to the use of phototherapy, as is the concomitant use of drugs or agents that are photosensitizers.

Home phototherapy:

·       Home phototherapy should not be used unless there is quality assurance regarding the  phototherapy device, the implementation and the monitoring of bilirubin at home. Very close supervision of medical practitioners by a regulator of the process is required to avoid malpractice. Since that is currently not available, it is not recommended to have home phototherapy until these rules are fulfilled. 

Escalation of care:

The intensive care that some infants with elevated or rapid increasing bilirubin concentration require to prevent the need for an exchange and possibly prevent kernicterus. ⁽⁶⁾

Figure-6: Approach to escalation of care

Appendix 2: Exchange Transfusion

·       Exchange transfusion is an intensive invasive procedure and should not be performed in a Level 1 NICU.

·       “Exchange transfusion must take place in an intensive care setting with intensive physiological and biochemical monitoring, carried out by staff trained in the procedure following written informed parental consent”, cited by British Committee for Standards in Hematology. ⁽⁷²⁾

·       Exchange transfusion is usually carried out by repeatedly exchanging small samples (5-10 ml/kg) of blood through an umbilical venous catheter and replacing with same volumes by compatible blood.

·       Neonatal exchange transfusion is becoming an infrequent procedure because severe Rh hemolytic disease of the newborn is becoming increasingly rare due to:

-  Maternal anti-D therapy and intrauterine transfusion of affected fetuses.

-   Maximizing phototherapy use prevents the need for exchange transfusion, even at very high level of TSB.  

-  Intravenous immunoglobulin (IVIG) acts by preventing the destruction of sensitized erythrocytes.

Benefits of Exchange Transfusion in severely jaundiced babies:

·       Rapidly lowers the serum bilirubin level and reduce the risk of brain damage and kernicterus.   

·       Corrects anemia and increase the oxygen carrying capacity of the infant’s blood.

·       Removes damaged and antibody coated red cells.

Indication for exchange transfusion in severe hyperbilirubinemia:

·       Any baby showing signs of intermediate or advanced stages of acute bilirubin encephalopathy (e.g., hypertonia, arching, retrocollis, opisthotonus, high pitched cry, or recurrent apnea) irrespective of bilirubin level.

·       If the TSB is at or above the exchange transfusion threshold.

·       If intensive phototherapy is failing to lower TSB and it is approaching exchange level

·       If the bilirubin /albumin ratio is:

-   ≥8.0 If the gestational age is ≥38 weeks’ gestation and there are no hyperbilirubinemia neuro toxicity risk factors,

-  ≥7.2 If the gestational age is ≥38 weeks’ gestation and there is at least 1 hyperbilirubinemia neurotoxicity risk factor,

-  ≥7.2 If the gestational age is 35 through 37 weeks’ gestation with no hyperbilirubinemia neurotoxicity risk factor,

-     6.8 If the gestational age is 35 through 37 weeks’ gestation and at least 1 hyperbilirubinemia neurotoxicity risk factor. ⁽⁶²⁾

 Figure-7: Exchange transfusion threshold by gestational age for infants with no recognized hyperbilirubinemia neurotoxicity risk factors

Figure-8: Exchange transfusion threshold by gestational age for infants with any recognized hyperbilirubinemia neurotoxicity risk factors⁽⁶⁾

Table-14: B/A Ratio at which Exchange Transfusion should be considered: ⁽⁶⁾

·       The bilirubin/ albumin ratio can be used with TSB level to help determine need for exchange transfusion.

·       The bilirubin/ albumin ratio threshold for exchange transfusion, measured as TSB (measured in mg/ dL) divided by serum albumin (measured in g/dL), varies by gestational age and risk.

·       An exchange transfusion may be considered if the bilirubin albumin ratio is:

-  ≥8.0 if the gestational age is ≥38 weeks’ gestation and there are no hyperbilirubinemia neuro toxicity risk factors

-  ≥7. 2 if the gestational age is ≥ 38 weeks’ gestation and there is at least 1 hyperbilirubinemia neurotoxicity risk factors

-  ≥7.2 if the gestational age is 35 through 37 weeks’ gestation with no hyperbilirubinemia neurotoxicity risk factors

-  ≥6.8 if the gestational age is 35 through 37 weeks’ gestation and at least 1 hyperbilirubinemia neurotoxicity risk factors.

Use of IVIG: ⁽⁶⁾

Intravenous immunoglobulin (IVIG) 0.5-1 g/kg over 2 hours:

Provide to infants with isoimmune hemolytic disease (i.e. positive DAT) whose TSB reaches or exceeds the escalation of care threshold.  This dose can be repeated in 12 hours.

Table-15: Procedures for Exchange Transfusion:

Risks/Complications of exchange transfusion

There is a 5% risk of complication ⁽³⁾

Exchange Transfusion Reaction:

·        Tachycardia or bradycardia.

·        Respiratory Distress.

·        Dramatic changes in blood pressure.

·        Temperature irregularity.

·        Rash.

·        Cyanosis or pallor.

·        Hypoglycemia

·        Hypocalcaemia (treatment see below)

·        Cardiac Arrhythmias.

·        Heart failure (fluid overload).

Other risk/complications:

·        Administration of incorrect blood product.

·        Volume overload.

·        Hemodynamic instability.

·        Acid base instability.

·        Apnea.

·        Electrolyte imbalances (hypocalcaemia, hypoglycemia, hypomagnesaemia).

·        Convulsions.

·        Hypotension (volume depletion).

·        Embolism (air/thrombus).

·        Graft versus host reaction.

·        Infection.

·        Necrotizing enterocolitis.

·        Temperature instability.

·        Thrombocytopenia.

·        Thrombosis.

·        Intraventricular hemorrhage.

Table-16: Exchange Transfusion Fluid Chart: ⁽²⁴⁾

- Glossary

1. Acceptability

Is the extent to which the users are likely to adopt a recommendation, based on internal qualities such as clarity, comprehensiveness, and logical reasoning and on external factors such as the burden imposed on the process and system of care, patient and providers attitudes and beliefs, and patients’ needs, expectations, and preferences.

2. Adaptation (of guidelines)

Is the systematic approach to considering the use and/or modification of (a) guidelines(s) produced in one cultural and organizational setting for application in different context? Adaptation can be used as an alternative to de novo guideline development or for customizing (an) existing guideline(s) to suit the local context.

3. Adoption (of a guideline)

Is the acceptance of a guideline as a whole after the assessment of its quality, currency, and content? When health care providers (or other users of recommendations) adopt a guideline, they feel committed to change their practices in accordance with the recommendations of the guideline.

4. Applicability

Is the extent to which the users are able to put a recommendation into practice, based on internal qualities such as a clearly defined eligible patient population that matches the population to which the intervention is targeted in the local setting and external factors such as the availability of the necessary knowledge, skills, provider time, staff, equipment, and other resources.

Applicability is sometimes taken as a synonym for feasibility:

·       Feasibility of the acquisition of necessary skills and knowledge.

·       Feasibility of the necessary increase in provider time, staff, equipment, and so on.

5. Culture

Culture represents the norms and values of a specific group, community, or population.

6. Diffusion

Is a passive means of transferring knowledge; it is not directed towards a target audience (e.g. publication of articles in medical journals).

7. Dissemination

Is more active than diffusion in that it targets a specific audience and involve tailoring the information for that audience (e.g. of dissemination strategies include targeted mailings, presentations, and press conferences.

8. Evidence-based principles

Evidence-Based Medicine (EBM) has been defined as ― the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of EBM means integrating individual clinical expertise with the best available external clinical evidence from systematic research.

9. Evidence tables

Are summaries of the most salient information from studies identified in the systematic review. The elements of evidence tables are dependent on the types of information in studies related to a particular topic but might include information such as the article reference, the study type (e.g. RCT or Cohort), the number of patients and their characteristics, and the intervention, comparison arms, outcome measures, and effect sizes.

10. Guideline or Clinical Practice Guideline (CPG)

Systematically developed statements about specific health problems, intended to assist practitioners and patients in making decisions about appropriate health care.

11. Guideline consistency

Agreement between the evidence and the recommendations, based on the:

§ Comprehensiveness of the study search and selection process,

§ Coherence between the results of the studies and their interpretation by the guideline authors, and

§ Transparency between interpretation and recommendations.

12. Guideline content

In the ‘ADAPTE Manual and Resource Toolkit for Guideline Adaptation’ document, guideline content refers to the recommendations in the source guidelines.

13. Guideline currency

A CPG may be considered up to date ―when (no) new information on interventions, outcomes, and performance justifies updating (it).

14. Guideline quality

By quality of clinical practice guidelines, we mean the confidence that the potential biases of guideline development addressed adequately and that the recommendations are both internally and externally valid and are feasible for practice. This process involves taking into account the benefits, harms and costs of the recommendations, as well as the practical issues attached to them. Therefore, the assessment (of quality) includes judgments about the methods used for developing the guidelines, the content of the final recommendations, and the factors linked to their uptake.

15. Guideline topic

In the ADAPTE Manual and Resource Toolkit for Guideline Adaptation' document, the topic refers to the theme of the guideline, as described in the guideline title, for a targeted population (disease and patients) and intervention. The purpose, the audience, and the setting intended for the guideline, although not necessarily explicitly stated in the title, are also part of the topic. A guideline on a given topic may contain more than one health question.

16. Health question or clinical question or key question

Is a precisely described health issue (e.g. clinical, professional practice or public health) relating to the topic of the guideline? Guideline may include one or more questions.

17. Implementation

Implementation includes methods to promote the uptake of research findings into routine healthcare in both clinical and policy contexts and hence to improve the quality and effectiveness of healthcare. It includes the study of influences on healthcare professional and organizational behavior.

18. Intra-class correlations

Intra-class correlations provide a measurement of the extent to which two or more raters agree when rating the same set of things. It is a reliability index and is typically a ratio of the variance of interest over the sum of the variance of interest plus error.

19. Recommendation

Any statement that promote or advocate a particular course of action in clinical care.

20. Stakeholder

A stakeholder is an individual, group and/or organization with a stake in your decision to implement a guideline. Stakeholders include individuals or groups who will be directly or indirectly affected by the implementation of a guideline.

21. Source guideline

In the ADAPTE Manual and Resource Toolkit for Guideline Adaptation' document, source guideline refers to those guidelines selected to undergo assessments of quality, currency, content, consistency, and acceptability/applicability and upon which an adapted guideline may be based.

- Limitation of the guidelines

·       Most of the recommendation statements from one source & many recommendations of low strength of evidence (GPS)

·       No data registry in Egypt about neonatal jaundice.

·       The guidelines directed only for term and late preterm newborns

Suggestions:

·       It is essential to have data registry about neonatal jaundice cases and cases with BIND.

- Further research needs

·       To study the actual effectiveness of IVIG in arresting hemolysis and progression of severe hyperbilirubinemia

·       To prepare guidelines for premature babies.

·       To study the safety, practicality and efficacy of home phototherapy remain a research priority.

- Monitoring and evaluating the impact of the guideline

·       Research should be directed toward methods for disseminating the information contained in this guideline to increase awareness on the part of physicians, residents, nurses, and parents concerning the issues of neonatal hyperbilirubinemia and strategies for its management.

·       In addition, monitoring systems should be established to identify the impact of these guidelines on the incidence of acute bilirubin encephalopathy and kernicterus and the use of phototherapy and exchange transfusions.

- REFERENCES

1.     The ADAPTE Collaboration (2009). The ADAPTE Process: Resource Toolkit versions for Guideline Adaptation. Version 2.0 Available from: https://www.g-i-n.net/   2009.

2.     Amer YS, Elzalabany MM, Omar TI, Ibrahim AG, Dowidar NL. The 'Adapted ADAPTE': an approach to improve utilization of the ADAPTE guideline adaptation resource toolkit in the Alexandria Center for Evidence-Based Clinical Practice Guidelines. Journal of evaluation in clinical practice. 2015;21(6):1095-106.

3.     American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297-316.

4.     Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant > or =35 weeks' gestation: an update with clarifications. Pediatrics. 2009;124(4):1193-8.

5.     Bhutani VK, Committee on F, Newborn, American Academy of P. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2011;128(4):e1046-52

6.     Kemper AR, Newman TB, Slaughter JL et al. Clinical practice guideline revision: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics.2022; 150 (3): e2022058859.

7.     Ayyappan S, Philip S, Bharathy N, Ramesh V, Kumar CN, Swathi S, et al. Antioxidant status in neonatal jaundice before and after phototherapy. Journal of pharmacy & bioallied sciences. 2015;7(Suppl 1):S16-21.

8.     Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatric clinics of North America. 2004;51(4):843-61.

9.     Maisels MJ. Epidemiology of neonatal jaundice. In: Maisels MJ, Watchko JF, editors. Neonatal jaundice. Amsterdam: Harwood Academic Publishers; 2000. p. 37–49.

10.  Ebbesen F, Andersson C, Verder H, Grytter C, Pedersen-Bjergaard L, Petersen JR, et al. Extreme hyperbilirubinaemia in term and near-term infants in Denmark. Acta paediatrica. 2005;94(1):59-64.

11.  Slusher TM, Zamora TG, Appiah D, Stanke JU, Strand MA, Lee BW, et al. Burden of severe neonatal jaundice: a systematic review and meta-analysis. BMJ paediatrics open. 2017;1(1):e000105.

12.  Basheer H, Makhlouf M, El Halawany F, Fahmy N, Iskander I. Screening for neonatal jaundice in El Galaa Teaching Hospital: A Egyptian Maternity Hospital &#8211; Can the model be replicated? Journal of Clinical Neonatology. 2017;6(2):128-33.

13.  Gamaleldin R, Iskander I, Seoud I, Aboraya H, Aravkin A, Sampson PD, et al. Risk factors for neurotoxicity in newborns with severe neonatal hyperbilirubinemia. Pediatrics. 2011;128(4):e925-31.

14.  El Houchi SZ, Iskander I, Gamaleldin R, El Shenawy A, Seoud I, Abou-Youssef H, et al. Prediction of 3- to 5-Month Outcomes from Signs of Acute Bilirubin Toxicity in Newborn Infants. The Journal of pediatrics. 2017;183:51-5 e1.

15.  Mostafa MA et al. Knowledge of Neonatal Hyperbilirubinemia Among Primary Health Care Physicians: A Single-Center Experience. Clinical Medicine Insights: Pediatrics. 2019;  13: 1–5.

16.  Iskander I, Gamaleldin R, Kabbani M. Root causes for late presentation of severe neonatal hyperbilirubinaemia in Egypt. Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit. 2012;18(8):882-7.

17.  Shapiro SM. Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). Journal of perinatology : official journal of the California Perinatal Association. 2005;25(1):54-9.

18.  Amin S.B., Bhutani V.K., Watchko J.F. Apnea in acute bilirubin encephalopathy. Semin. Perinatal. 2014;38:407–411. doi: 10.1053/j.semperi.2014.08.003

19.  Shaprio S.M. Chronic bilirubin encephalopathy: Diagnosis and outcome. Semin. Fetal Neonatal Med. 2010;15:157–163

20.  Valinjkar SJ et al, Rebound hyperbiliurbinemia in neonates after phototherapy and factors affecting it. JMSCR 2017;5(3):19003-19014

21.  Taylor JA, Stout JW, de Greef L, Goel M, Patel S, Chung EK, et al. Use of a Smartphone App to Assess Neonatal Jaundice. Pediatrics. 2017;140(3).

22.  Hansen TW. The role of phototherapy in the crash-cart approach to extreme neonatal jaundice. Seminars in perinatology. 2011;35(3):171-4.

23.  Singla DA, Sharma S, Sharma M, Chaudhary S. Evaluation of Risk Factors for Exchange Range Hyperbilirubinemia and Neurotoxicity in Neonates from Hilly Terrain of India. International journal of applied & basic medical research. 2017;7(4):228-32.]\

24.  National Institute for Health and Care Excellence (NICE): Jaundice in the newborn under 28 days  [CG98.1]; 2010.

25.  National Institute for Health and Care Excellence (NICE): Addendum to Jaundice in newborn babies under 28 days. London:; 2016 May. (Clinical Guideline, No. 98.1.) Available from: https://www.ncbi.nlm.nih.gov/books/NBK550520/

26.  Barrington KJ, Sankaran K, Canadian Paediatric Society, Fetus and Newborn Committee. Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants | Canadian Paediatric Society: Canadian Paediatric Society; 2018 [updated 28/2/2018; cited 2018 15/6/2018]. Available from: https://www.cps.ca/en/documents/position/hyperbilirubinemia-newborn.

27.  Queensland Clinical Guidelines. Neonatal jaundice clinical guideline education presentation E22.7-1-V3-R27. Queensland Health. 2018.

28.  Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. Canadian Medical Association Journal. 2010;182(18):E839-E42.

29.  Alshehri A, Almazrou S, Amer Y. Methodological frameworks for adapting global practice guidelines to national context int eh Eastern Mediterranean region. EMHJ, 2023;1:29(7):541-549

30.  Practice bulletin No. Practice bullitin no 181summary: prevention of RHD alloimmunization Obstet gynecol.2017;130(2): 481-483

31.  Vats K, Watchco JF. Coordinating care across the perinatal continuum in hemolytic disease of the fetus and newborn: the timely handoff of a postive maternal antierythrocyte antibody screen. J Pediatr. 2019; 214: 212-216

32.  Erdeve O. Management of neonatal jaundice in low-income and middle-income countries. BMJ Paediatr Open. 2020; 2;4(1):e000845

33.  Chen Yj, Yeh TH, Chen CM. Effect of breast feeding frequency on hyperbilirubinemia in breast fed term neonates. Pediatr Int. 2015;57(6):1121-1125

34.  Porter MLand Dennis BL.Hyperbilirubinemia in the term newborn. Am Fam Phys 2002;65(4):599-606

35.  Kaplan M, Kaplan E, Hammerman C et al, POst photherapy neonatal bilirubin rebound : a potential cause of significant hyperbiliurbinemia . Arch dis child 2006; 9(1):31-34

36.  Maayan-Metzger A, Schwartz T, Sulkes K, Merlob P. Maternal antiD prophylaxis during pregnancy does not cause neonatal hemolysis. Arch Dis Child Fetal Neonatal Ed. 2001; 84(1):F60–F62

37.  Flaherman VJ, Maisels MJ; Academy of Breastfeeding Medicine. ABM clinical protocol #22: guidelines for management of jaundice in the breastfeeding infant 35 weeks or more of gestation — revised. Breastfeed Med. 2017;12 (5): 250-257

38.   Maisels MJ, Clune S, Coleman K et al. The natural history of jaundice in predominantly breastfed infants. Pediatrics. 2014;134(2):e340-345

39.  Meek JY, Noble L. American Academy of Pediatrics, Section on breastfeeding. Breast feeding and use of human milk. Pediatrics 2022; 150(1): e2022057989

40.  Flaherman VJ, Schaefer EW, Kuzniewicz MW, Li SX, Walsh EM, Paul IM. Early weight loss nomograms for exclusively breastfed newborns. Pediatrics 2015; 135 (1) :e16-e23

41.  Newman TB, Liljestrand P, Escobar GJ. Jaundice noted in the first 24 hours after birth in a managed care organization. Arch Pediatr Adolesc Med. 2002;156(12):1244–1250

42.  Hulzebos CV, Vitek L, Coda Zabetta CD, et al. Screening methods for neonatal hyperbilirubinemia: benefits, limitations, requirements, and novel developments. Pediatr Res. 2021;90(2):272–276

43.  Wainer S, Parmar SM, Allegro D, Rabi Y, Lyon ME. Impact of transcutaneous bilirubinometry program on resource utilization and severe hyperbilirubinemia. Pediatr 2012; 129(1): 77-86. 

44.  Konana OS, Bahr TM, Strike HR, Coleman J, Snow GL, Christensen RD. Decision accuracy and safety of transcutaneous bilirubin screening at intermountain healthcare. J Pediatr. 2021;228:53–57

45.  Kuzniewicz MW, Park J, Niki H, Walsh EM, McCulloch CE, Newman TB. Predicting the need for phototherapy after discharge. Pediatrics. 2021;147(5): e2020019778

46.  Maisels MJ, Deridder JM, Kring EA, Balasubramaniam M. Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia. J Perinatol. 2009; 29(9):612–61733.

47.  Elsaie AL, Taleb M, Nicosia A et al. Comparison of end tidal cardon monoxide measurements with direct antiglobin tests in the managmeent of neonatal hyperbilirurbinemia . J Perinatol. 2020; 40(10): 1513-1517.

48.  Amegan-Aho KH, Segbefia CI, Glover NDO, Ansa GA, Afaa TJ. Neonatal Janudice: awareness , perception and preventive practices in expectant mothers. Ghana Med J.2019; 53(4):267-272.

49.  Olusanya BO, Imosemi DO, Emokpae AA. Differences between transcutaneous and serum bilirubin measurements in Black African neonates. Pediatrics. 2016;138(3):e20160907

50.  Engle WD, Jackson GL. Transcutaneous bilirubinometry. Semin Perinatol.2014; 34(7) :438-451.

51.  Radmacher PG, Groves FD, Owa JA, Ofovwe GE, Amuabunos EA, Olusanya BO, et al. A modified Bilirubin-induced neurologic dysfunction (BIND-M) algorithm is useful in evaluating severity of jaundice in a resource-limited setting. BMC pediatrics. 2015;15:28

52.  Watchko JF. Bilirubin-Induced Neurotoxicity in the Preterm Neonate. Clinics in perinatology. 2016;43(2):297-311

53.  Johnson L, Brown AK, Bhutani VK. BIND-a Clinical Score For Bilirubin Induced Neurologic Dysfunction In Newborns. Pediatrics. 1999;104(3):746-7.

54.  Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns. Pediatrics. 1994;93(3):488–494

55.  Wallenstein MB, Bhutani VK. Jaundice and kernicterus in the moderately preterm infant. Clinics in perinatology. 2013;40(4):679-88.

56.  Amin SB, Saluja S, Kler N. Unbound bilirubin and acute bilirubin encephalopathy in infants born late preterm and term with significant hyperbilirubinemia. J Pediatrics 2024;266:113880.

57.  Noorulla F, Dedon R, Maisels MJ. Association of early direct bilirubin levels and biliary atresia among neonates. JAMA Netw Open. 2019;2(10):e1913321

58.  Fawaz R, Baumann U, Ekong U, et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2017;64(1):154–168

59.  Tridente A, De Luca D. Efficacy of light-emitting diode versus other light sources for treatment of neonatal hyperbilirubinemia: a systematic review and meta-analysis. Acta Paediatr. 2012; 101(5):458–465

60.  Sachdeva M, Murki S, Oleti TP, Kandraju H. Intermittent versus continuous phototherapy for the treatment of neonatal non-hemolytic moderate hyperbilirubinemia in infants more than 34 weeks of gestational age: a randomized controlled trial. Eur J Pediatr. 2015;174(2):177–181

61.  Grabenhenrich J, Grabenhenrich L, B€ uhrer C, Berns M. Transcutaneous bilirubin after phototherapy in term and preterm infants. Pediatrics. sive phototherapy. Arch Pediatr Ado lesc Med. 2002;156(7):669–672 119.

62.  Ahlfors CE. Criteria for exchange transfusion in jaundiced newborns.Pediatrics. 1994;93(3):488–494

63.   Louis D, More K, Oberoi S, Shah PS. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Archives of disease in childhood Fetal and neonatal edition. 2014;99(4):F325-31.

64.  Singh M. Vitamin K during infancy: current status and recommendations. Indian Pediatr. 1997 Aug;34(8):708-12. PMID: 9492399

65.  Drew JH, Wells R. The effect of drungs on albumin binding of bilirubin and on free bilirubin concentration as determined by flurescence quenching. Annals of pharmacology 1979;(13)9:486-560.

66.  Ahlfors CE, Shwer ML, Ford KB. Bilirubin-albumin binding in neonatal salicylate intoxication. Dev Pharmacol Ther. 1982;4(1-2):47-60.

67.  Shankaran S, Poland RL. The displacement of bilirubin from albumin by furosemide. J Pediatr. 1977 Apr;90(4):642-6.

68.  Pacifici GM, Marcini G. Clinical Pharmacology of Ceftriaxone in Neonates and Infants: Effects and Pharmacokinetics Systematic Review;2017  5751-5777

69.  Zecca E, Romagnoli C, De Carolis MP, Costa S, Marra R, De Luca D. Does Ibuprofen increase neonatal hyperbilirubinemia? Pediatrics. 2009 Aug;124(2):480-4. doi: 10.1542/peds.2008-2433.    

70.  Martínez-Cruz CF, García Alonso-Themann P, Poblano A, Cedillo-Rodríguez IA. Hearing and neurological impairment in children with history of exchange transfusion for neonatal hyperbilirubinemia. Int J Pediatr. 2014;2014:605828.

71.  Ree, I. M. C., Smits-Wintjens, V. E. H. J., van der Bom, J. G., van Klink, J. M. M., Oepkes, D., & Lopriore, E. (2017). Neonatal management and outcome in alloimmune hemolytic disease. Expert Review of Hematology, 10(7), 607–616

72.  Watchko JF. Emergency release uncross-matched packed red blood cells for immediate double volume exchange transfusion in neonates with intermediate to advanced acute bilirubin encephalopathy: timely but insufficient? J Perinatol. 2018; 38(8):947–953

73.  Sproul A, Smith L. Bilirubin equilibra tion during exchange transfusion in hemolytic disease of the newborn. J Pediatr. 1964;65:12–26

74.   Valaes T. Bilirubin distribution and dynamics of bilirubin removal by exchange transfusion. Acta Paediatr (Stockh). 1963;52(suppl 149):57–69

- Annexes

Declaration of Conflict of Interests:

The members of the guideline development/ adaptation group and the external review group have no academic, financial, or competing interests to declare and none of them were involved in the development of the original source guideline (s).

Annex Table 17: Results of the AGREE II assessment of the source guidelines: