Severe Hyperbilirubinemia in Term and Late Preterm Newborns: An Evidence-Based Clinical Practice Guideline Adapted for The Use in Egypt Based on The ‘Adapted ADAPTE’ Methodology

Acknowledgement

The NGAG gratefully acknowledges the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia and the help of the professors who reviewed drafts of this Adapted CPG and provided valuable criticisms, as part of the External Review Panel, whether at the national level: Dr. Nahed Fahmy, Cairo University; Dr. Mohamed Fathalla, Ain Shams University; Dr. Aly Afia, Al-Azhar University; Dr. Hesham Abdel-Hady, Mansoura University and Dr. Abdel Latif Abdel Moez, Assuit University; or at the international level : Dr. Vinny Bhutani, Stanford University and Dr. John Watchco, Pittsburgh University.

Author's contributions

Members of the CPG adaptation group (Clinical subgroup) (searching, screening, AGREE II assessment): Iman Iskander, Mossallam Mohamed Nasser, Afaf Korraa, Ahmed Youssef, Dina Rabie,   Ghada  Gad,  Effat Assar , Eman Almorsy, Mohammed Abdelshafy , Mohamed  Abdel Kader, Nouran  AbdAllah, Safaa Shafik, Suzan Gad.

Methodology Group: Ashraf Abdelbaky, Tarek Omar and Yasser Amer.

Iman F. Iskander was the Chair of the NGAG. Afaf A. Korraa, Iman Iskander and Mossallam Nasser have written the first draft of the manuscript. Ashraf Abdelbaky and Tarek E. Omar conceptualized and designed the study. Yasser S. Amer reviewed the methodology, drafts and the final version of this manuscript. All authors contributed to the data collection, critical appraisal of guidelines and approved the final version of the manuscript.

Conflict of interest

The Armed Forces College of Medicine (AFCM) and The Neonatology Guideline Adaptation Group (NGAG) provided non-financial funding throughout the development of this work in terms of utilization of its facilities. This work is not related to any pharmaceutical company. The members of the NGAG and their universities volunteered their participation.

Funding

The research was self-funded by the authors and no funding was received from any funding body or organization.

Availability of Materials

Any relevant material in addition to future revisions and updates will be made available and downloadable from the official website of the Egyptian Pediatrics Clinical Practice Guidelines Committee (http://epg.edu.eg).

Date received: 24^th April 2021, accepted 17^th July 2021

Introduction

Neonatal jaundice refers to yellow discoloration of the skin and sclera of newborn babies [1]. It is generally considered a benign self-limiting condition, affecting more than 60% of healthy term and 80% of preterm infants [2,3]  . However, in some cases, severe neonatal hyperbilirubinemia (SNH) can lead to irreversible brain damage and kernicterus [4]. Surviving infants may acquire long-term neuro-developmental sequelae such as chorioathetoid cerebral palsy, sensorineural hearing loss, and growth and developmental delays. Acute bilirubin encephalopathy (ABE) and chronic bilirubin encephalopathy (CBE) are largely preventable if severe hyperbilirubinemia is identified early and treated promptly with effective phototherapy or, when indicated, exchange transfusion. In a recent systematic review in which severe neonatal hyperbilirubinemia was defined as that associated with acute bilirubin encephalopathy, exchange transfusion or death. The incidence of severe neonatal hyperbilirubinemia 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 Americans [5].

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 per year a large group could be at risk for severe hyperbilirubinemia and its sequelae [6].

In the neonatal intensive care of Cairo university Children’s hospital, in 2011, 44/249 admitted jaundiced newborns not only had extreme hyperbilirubinemia, but presented with moderate to severe bilirubin encephalopathy and in a recently published follow up study in the same Neonatal Intensive Care Unit (NICU), 23/202 babies admitted with severe hyperbilirubinemia had abnormal neurological examination at follow up [7, 8].

The root causes for these shocking numbers within the Egyptian community include parental ignorance of the risk of severe jaundice, absence of timely follow up for jaundiced newborns, as well as delay in proper intervention [9].

While tactics to prevent and treat severe neonatal hyperbilirubinemia must be sensitive to cultural and resource variations, the universality of root causes suggest 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 are monitored for risk of hyperbilirubinemia and prompt interventions followed to prevent acute bilirubin encephalopathy and kernicterus [9].

Clinical Practice Guidelines (CPGs) are tools for improving the quality and safety of healthcare services using a standardized process [10]. They are produced by a systematic review of the evidence and assessment of the benefit versus the harm of various care options resulting in statements that optimize patient's care [11]. The production of clinical practice guidelines using this approach is both costly and time consuming. Adaptation of CPG is a valid and efficient alternative to de novo development especially in resource-limited countries. It also provides a means to expedite the process and has been acknowledged by the World Health Organization (WHO) to advance guideline production. To date in Egypt there does not exist a standardized national CPG for the prediction, prevention and management of severe neonatal hyperbilirubinemia.

The aim of this work was to use the Adapted ADAPTE method of Alexandria University to provide an evidence-based CPG tailored to the needs of the Egyptian healthcare context that can be applied at all healthcare levels from outpatients to NICU settings, in order to prevent long-term morbidity and mortality from severe neonatal hyperbilirubinemia.

Definitions used in this Guideline:

• Kernicterus: is the pathological finding of deep-yellow staining of neurons and neuronal necrosis of the basal ganglia and brainstem nuclei; and clinically associated with chronic bilirubin encephalopathy [12].
• Acute bilirubin encephalopathy (ABE): a clinical syndrome, that occurs in the presence of severe hyperbilirubinemia, presenting with various combinations of decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis, opisthotonus, setting sun sign, fever, seizures, and death [12].
• Chronic bilirubin encephalopathy (CBE): a clinical tetrad that occurs after the history of severe hyperbilirubinemia consisting of (1) a movement disorder consisting not only of 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, and (4) dental enamel hypoplasia of the deciduous teeth [12].
• Severe neonatal hyperbilirubinemia (SNH): a total serum bilirubin (TSB) concentration greater than 20 mg/dL in the first 72 hours of life [12].
• Critical or extreme hyperbilirubinemia: a TSB concentration greater than 25 mg/dL during the first 28 days of life [12].

Methods

This study is part of a major project by the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) which was formulated by members of the Departments of Pediatrics from multiple Egyptian Universities. EPG is currently affiliated to the Supreme Council of the Egyptian University Hospitals (http://epg.edu.eg). The committee is guided by a formal CPG adaptation methodology: The “Adapted ADAPTE” [13].

This CPG is prepared using the Adapted ADAPTE method of Alexandria University that was based on the ADAPTE Manual and Resource Tool Kit version 2.0, released by the ADAPTE Collaboration in 2009 [13-15]. This formal CPG adaptation process consists of three phases (i.e., set-up, adaptation, and finalization) and 24 steps with modifications in the steps and tools to suit the local healthcare context in health systems with limited resources like Egypt.

Guidelines adaptation methodology

Phase 1 (Set Up):

The topic of severe neonatal hyperbilirubinemia was chosen as a priority because it has been proven that with implementation of CPG in the western world the incidence of chronic bilirubin encephalopathy has declined dramatically compared to the numbers seen in low- and middle income countries. The patient population included in this CPG was late preterm and term newborns diagnosed with indirect hyperbilirubinemia or at risk for severe hyperbilirubinemia meeting the following criteria; age ≤ 28 days, weight ≥ 2.5 kg and GA ≥35 weeks. Preterm neonates and neonates with cholestasis were excluded from this CPG. This adapted CPG is intended for use by neonatologists, pediatricians, family physicians, physician assistants, advanced practice nurses in outpatient, home visits, inpatient, and NICU settings.

The guideline adaptation group was chosen from multiple Egyptian universities. There was active involvement of a Multidisciplinary Review Committee including clinicians (academic faculty staff and consultant pediatricians and neonatologists) and CPG methodologists.

Phase 2 (Adaptation):

The NGAG included 23 Professors of Neonatology in addition to Professors of Pediatrics and a general pediatrician who are experts in evidence-based CPG adaptation methodologies. Clinical questions are identified, using the PIPOH model, including questions for risk factors, prevention, prediction, diagnosis, and treatment (Table 1). The PIPOH model includes the target patient population (P), intervention(s) (I), professionals and clinical specialties (P), outcomes (O), and healthcare settings or context (H). The literature search was conducted using MEDLINE/PubMed and Google Scholar portals. The Appraisal of Guidelines for Research and Evaluation  Instrument (AGREE II) [16] was used to appraise the eligible Source CPGs. AGREE II is considered the gold standard for quality assessment of CPG. It is a reliable tool that consists of 23 items organized in six domains. The neonatology guideline adaptation group (NGAG) studied several CPGs using the criteria of the AGREE II. The American Academy of Pediatrics (AAP) (2004 [17], 2009[18], 2011 [19] CPGs, NICE (2010 [20] , 2016 [21] CPGs, the Australian (Queensland, 2017) [22] CPG as well as Canadian Pediatric Association (2018) [23] CPG were considered. The first draft of the adapted CPG marks the last step of this phase.

Phase 3 (Finalization phase): In phase 3, the first draft of the adapted CPG is finalized after assessing whether it is acceptable and applicable to the Egyptian healthcare context. The draft was then disseminated to a panel of external reviewers of topic experts. Afterwards, the feedback of reviewers was revised and discussed within the NGAG with consideration of the national healthcare context. The finalized version of the adapted CPG included relevant practical implementation tools and strategies.

Ethical approval

Ethics approval and consents: are not applicable in this context.

Results

We identified 19 clinical questions using the PIPOH model. We studied several source original CPGs for prediction, prevention and management of severe neonatal hyperbilirubinemia. Based on the results of the AGREE II appraisal and in-depth content review, there was a consensus among the members of the NGAG to adapt the AAP CPGs (2004, 2009 & 2011) [18-20] to answer the 19 clinical questions posted. For questions not answered within the chosen source, the group searched for other most relevant evidence available providing its grading and reference. The AGREE II ratings of the AAP CPG were 96% (domain 1: scope and purpose), 90.7% (domain 2: stakeholder involvement), 97.9% (domain 3: rigor of development), 98 (domain 4: clarity and presentation), 72.2% (domain 5: applicability), 97.2% (domain 6: editorial independence), 88.8 % (overall assessment 1), and the overall assessment 2 showed that NGAG recommended its use in practice. The summary recommendations of the adapted CPG are highlighted in Table 1. A set of CPG implementation tools were attached to the finalized adapted CPG. These tools were developed and revised by the NGAG group to be used by healthcare providers and families of neonates for education and awareness, so that the tools would be effective in our community. Implementation tools are shown in Appendices 1-5. The most important of which were the summary of recommendations, the discharge card for the parents that shows the possible risk for developing severe jaundice in their babies and the time of follow up. The algorithm for the management of a case presenting with neonatal jaundice, the decision making graphs as well as how to make phototherapy most effective. Future updates to this adapted CPG will review and consider any evidence published after our cut-off date.

Key to Evidence: The evidence presented in this CPG is categorized according to the categorization of the AAP Steering Committee on Quality Improvement and Management [17]

 Table 1: Health Questions

Table 2: Key Recommendations

GPP: Good Practice Point (based on the expertise of the NGAG)

 Discussion

Jaundice is one of the most common conditions requiring medical attention in Egyptian newborn babies [6]. Because it is so common and usually benign, cases of SNH can easily be missed and mistaken for simple physiological jaundice which is known to occur in 60% of term and 80% of preterm babies in the first week of life. The management of neonatal jaundice is a particular challenge to the neonatologist. He/she should learn to avoid over treatment of harmless cases specially with limited resources but at the same time should never miss severe neonatal hyperbilirubinemia which if left untreated can lead to permanent bilirubin-induced neurological damage [24] . The importance of this work lies in using the Adapted ADAPTE method [13] to expedite the production of this adapted evidence-based CPG, for the use in the Egyptian community, to prevent further increase in the number of kernicterus cases by following the instructions provided to healthcare physicians and other medical personnel that deal with newborns. The presence of the Egyptian pediatric guidelines committee has provided support and has been a facilitator for this project and the inclusion of representative professors from multiple universities all over Egypt has enriched the process bringing in different experiences that were essential for the completion of this work.

The aim of this project was to produce an available evidence-based document that caters to the need and increases the awareness of Egyptian physicians managing newborn babies regarding the risk of developing severe neonatal hyperbilirubinemia and kernicterus and to provide them with a standardized practical framework for the prediction, prevention and management of SHB through the use of this adapted CPG.

Testing the blood group and RH type of the mother can identify risky blood groups; and health education at that point in the antenatal care clinic can raise awareness of the mother to the possible risks her baby may be exposed to if she belongs to a risky blood group. Also, clear instructions regarding breast feeding support as well as date of follow up for jaundice are essential. Education of the mother for red flags her baby might show that require urgent medical advice can allow timely medical intervention that would prevent acute bilirubin encephalopathy which is the consequence of neglected severe neonatal hyperbilirubinemia.

Measuring a predischarge TSB or TcB for newborn infants, and plotting it on the Bhutani hour-specific nomogram  [25] provides an excellent guide for timely follow up and for predicting which infants are at increased risk for developing severe hyperbilirubinemia and its sequelae. Once baby is clinically jaundiced, the CPG encourages mothers to seek medical advice and decision making should be guided according to the clinical examination for signs of acute bilirubin encephalopathy as well as plotting the serum bilirubin on specific graphs to decide whether phototherapy is sufficient or the baby requires exchange transfusion. In the latter case, this newborn should be managed as a medical emergency where intensive phototherapy is started while preparations for exchange transfusion are made using the crash cart approach.

The preparation not only of the adapted CPG but also the attached implementation tools, though tedious is essential. Implementation tools facilitate the use of this adapted CPG. The Arabic explanation of jaundice and its sequelae in a small flyer that parents can receive on discharge, facilitates communication with the parents and also increases awareness to the importance of follow up and the risks of severe jaundice. Other tools, like the summary of recommendations when printed on a small card and made available in every nursery as well as the decision charts can make the life of physicians much easier and facilitate correct decision making.

Limitations: Although the achievement of producing this adapted Egyptian CPG for the prediction, prevention and management of SNH newborns is a huge one; there are limitations to its effectiveness in reducing the number kernicterus cases in our community. These include the limited financial resources required for the wide dissemination of the CPG, and for the continuous medical training and workshops essential for neonatal healthcare providers to be effective in its application in Egypt. The difficult collaboration with Obstetric colleagues which is essential for educating the mothers during antenatal care regarding risky blood groups and the seriousness of neglecting early neonatal jaundice and the importance of close follow up after delivery. Also, resources are required for providing points of care, bilirubin measuring devices, affordable phototherapy and training personnel on how to make it more effective.

Conclusions

Using the Adapted ADAPTE method facilitated the production of an adapted evidence-based CPG for the predication, prevention and management of severe neonatal hyperbilirubinemia in late preterm and term newborns in prompt time, and with the required implementation tools. The effectiveness of this CPG should be assessed by monitoring the impact of the use of these CPGs in the reduction of cases of kernicterus that still occur in our country

Abbreviations

AAP: American Academy of Pediatrics

ABE: Acute bilirubin encephalopathy

AGREE II: Appraisal of Guidelines for Research and Evaluation Instrument

BIND score: Bilirubin induced neurological damage score

CBE: chronic bilirubin encephalopathy

CPG: clinical practice guideline

EPG: Egyptian Pediatric Clinical Practice Guidelines Committee

NGAG: Neonatal guideline adaptation group

NICU: Neonatal intensive care unit

PIPOH model: population (P), intervention(s) (I), professionals and clinical specialties (P), outcomes (O), and healthcare settings or context (H)

SNH: severe neonatal hyperbilirubinemia

TSB: total serum bilirubin

WHO: World health organization