Review

Journal of Perinatology (2009) 29, S61–S67; doi:10.1038/jp.2008.213

A proposal to prevent severe neonatal hyperbilirubinemia and kernicterus

V K Bhutani1 and L Johnson2

  1. 1Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Stanford, CA, USA
  2. 2Pennsylvania Center for Kernicterus, Philadelphia, PA, USA

Correspondence: Dr VK Bhutani, Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital, 750 Welch Ave no. 315; Stanford, CA 94304, USA. E-mail: bhutani@stanford.edu

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Abstract

To address systems failures and promote a safer management of newborn jaundice, we propose an ‘aviation safety standard’ for newborn health-care services during the first week after birth. Systems failure in newborn jaundice management has been characterized by lapses in concern, loss of continuity, and delays in care by multiple providers at multiple sites. Components for a six-step national strategy to prevent severe neonatal hyperbilirubinemia and possibly kernicterus are being implemented as delineated in the 2004 AAP guidelines. The clinical guidelines for safer and evidence-based practice have been characterized by both healthcare and societal communities. Professional and community organizations are optimizing outreach resources and facilitating institutionalization of these practices. Nationwide implementation at individual birthing hospitals concurrent with surveillance feedback needs to be initiated. Implementation of a ‘six-sigma’ approach, as proposed to the current Center for Disease Control and Prevention-initiated partnership (health-care providers, public health and community advocates) may be achieved through collaboration with state and national agencies.

Keywords:

newborn jaundice, kernicterus, bilirubin, hyperbilirubinemia, well babies, bilirubin-induced neurologic dysfunction

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Statement of the problem

Of the 4 million infants born each year in the United States, over 3.2 million are over 35 weeks in gestation and should have benign outcomes with little or no threat of neurological compromise from medical conditions during the first year after their birth. Proven preventive health measures provided in the well baby nurseries have been effective in reducing infant mortality and morbidities in this group of infants. Among the leading causes of neurological morbidities during infancy, kernicterus remains the most easily prevented disorder. Traditional epidemiological investigations have failed to track the national incidence of kernicterus or recognize its recent surge. Innovative investigative strategies are needed to seek more sensitive predictive surrogates for kernicterus (often diagnosed late in infancy) and to overcome the limitations of retrospective recognition of adverse neonatal experiences due to severe hyperbilirubinemia. All neonates have some hyperbilirubinemia (total serum bilirubin (TSB) level >2mg per 100ml) and most have benign outcomes when monitored and treated, if necessary, in a timely manner. Jaundice may be recognized in about 60% of healthy infants during the first week after birth. Neonatal hyperbilirubinemia increases by age in hours soon after birth and usually peaks at age 96 to 120h when infants are home and not under direct medical supervision. Newborns with unrecognized jaundice or hyperbilirubinemia represent a vulnerable population deprived from preventive and treatment health-care services in their transition from birthing hospital to home. When monitored and treated in a timely manner, progression of severe hyperbilirubinemia can be curtailed and prevent kernicterus, a life long athetoid cerebral palsy and/or sensori-neural hearing impairment. The available medical interventions and concurrent preventable strategies are amenable to target an ‘aviation safety standard’ for newborn care services during the first week after birth (Figure 1). However, practicing pediatricians and neurologists continue to see cases of acute and chronic bilirubin encephalopathy. Now, a better understanding of the systems failure1, 2 has led to a considerable progress and allows for a six-step national strategy (Figure 2).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Medical and preventive strategies to reduce hyperbilirubinemia.

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Figure 2.
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Approaches to achieve aviation safety standards to prevent extreme hyperbilirubinemia.

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Background analysis

The underlying root cause for kernicterus has been identified as a systems failure in neonatal care, especially during the first week after birth. Primarily, multiple providers provided health services at multiple sites. Second, there was insufficient understanding and knowledge about the potential of neonatal bilirubin neurotoxicity among the community of physicians, nurses, maternal child health-care providers, child health advocates, lactation consultants, and third-party payors as well as the lay society. The resultant interacting root causes included the following: (a) early hospital discharge at age <72h (before extent of jaundice and hyperbilirubinemia is known); (b) lack of adequate concern for the risks of severe jaundice in healthy term and late preterm newborns; (c) a laudable increase in breast feeding but without support and counseling or adequate and optimal lactation; (d) perceived medical cost constraints complicating reimbursement for follow-up at age 3 to 5 days; (e) paucity of educational materials to enable and empower families; and (f) limitations within health-care systems to provide pre-discharge screening, identification of families and infants at increased risk to ensure post-discharge follow-up. AAP Guidelines for management of newborn jaundice now recommend universal systematic implementation to severe neonatal hyperbilirubinemia and possibly acute bilirubin encephalopathy and kernicterus.2

We assess the feasibility of implementing these guidelines for healthy infants discharged from well baby nurseries using an adapted six-sigma approach: an industry (such as, aviation) measure of quality and safety. We define occurrence of defect per critical encounters (based on critical-to-quality characteristics). Using earlier reports of adverse icteric experiences,3 we calculated the defect-rate per encounter as the critical-to-quality index, converted to defect-rate per million well baby discharges and determined the specific sigma values. Successful implementation of ‘aviation’ safety and quality standards could allow a defect-free experience for 99.99966% to achieve a six (6.0)-sigma level of care. Sigma level of 4 to 4.5 represent safety standards prevalent in the US steel industry in the 1960s. Using TSB level >25mg per 100ml as a surrogate, we calculated a 4.5-sigma level in the pre-phototherapy era of 1960s and at 4.45-sigma level in 1990s.4, 5 Rates for readmission (1988 to 1998) show a 4-sigma level performance. The Danish population-based report of kernicterus,6 six cases over a 5-year period (estimated at 1:38000 well-babies), suggest 5.5-sigma level. A coordination of current multiorganizational strategies could limit nation-wide adverse experiences of TSB >30mg per 100ml to 3 to 4 well babies per million live-births and achieve a six-sigma level care. Steps for these strategies are described below.

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Proposal for a coordinated national strategy

Step I: Identification of kernicterus as a newborn health-care systems failure

Kernicterus occurs in otherwise healthy infants in the United States of America. This is evident from reports of infants who had been discharged as healthy from their birthing hospitals. Systems failure from multiple providers at multiple sites was a key factor in occurrence of these cases. Pediatricians who have managed babies with neonatal hyperbilirubinemia that progress to acute or chronic bilirubin encephalopathy often feel stigmatized and are disinclined to report, discuss, review or publish their experience. Thus, the scope of the true incidences of overt kernicterus as well as possible ‘subtle’ neurological deficits cannot be ascertained without a formal, innovative and non-adversarial approach. Societal expectation for a universally available safe birthing experience includes a safe experience with newborn jaundice.7 Thus, the public health community considers kernicterus or its surrogate: TSB level greater than or equal to30mg per 100ml (Table 1), a potential catastrophic event that is largely preventable.3, 6


Step II: Characterization of evidence-based clinical guidelines

Health-care perspectives
 

The 2004 AAP guidelines, based on a comprehensive review of the evidence including a comprehensive literature review (of nearly 5000 original research articles in the English language) by the New England Medical Center Evidence-based Practice Center commissioned by AHRQ13 states that ‘most jaundice is benign but, because of the potential toxicity of bilirubin, newborn infants must be monitored to identify those who might develop severe hyperbilirubinemia and, in rare cases, acute bilirubin encephalopathy or kernicterus’. The focus of the 2004 guideline is to reduce the incidence of severe neonatal hyperbilirubinemia and bilirubin encephalopathy by providing a framework for the prevention and management of hyperbilirubinemia in newborn infants greater than or equal to35 weeks of gestation.2 For every infant, the guidelines recommend several preventive strategies as well as a treatment guideline for ‘phototherapy or exchange transfusion to prevent the development of severe neonatal hyperbilirubinemia and, possibly, bilirubin encephalopathy (kernicterus)’. At present, there is sufficient and immutable laboratory and clinical literature that the use of phototherapy and/or exchange transfusion used in infants with excessive hyperbilirubinemia can prevent extreme hyperbilirubinemia and kernicterus and that in infants with acute bilirubin encephalopathy, exchange transfusion (with and without phototherapy) can prevent or minimize the chronic sequelae of bilirubin-induced dysfunction.1, 2, 3 Overall, present laboratory and clinical data indicates, ‘bilirubin damages brain tissue cells by necrosis and apoptosis, either alone or in combination, in a neuroanatomical distribution dependant on the amount, duration and the developmental timing of exposure of sensitive brain tissue to free bilirubin’. Optimization of the 2004 AAP guidelines is ongoing14 and provides framework current clinical management strategies.

Community perspectives
 

No standardized or formal national surveillance or mechanisms for health assessment are available following an experience with extreme hyperbilirubinemia. A parent support group, Parents of Infants and Children with Kernicterus (PICK), has advocated for improved system-based health-care services for infants at risk for extreme hyperbilirubinemia.7 These include addressing issues of delays in diagnosis of kernicterus, delays in recognition of hearing impairment, delays in diagnosis of athetosis, motor development, onset of cerebral palsy and need for specific medical attention to sleeping disorders, feeding complications and ability to thrive. Consequences of inadequate surveillance and health-care assessments continue to present challenges to clinicians and families as well as state and local health departments, years after occurrence of an extreme hyperbilirubinemia event. Inappropriate and delayed use of health-care resources to identify and manage infants at risk have led some families to resort to the medico-legal system to seek support for their health-care burden. Often, a single clinician bears the individual responsibility for a systems failure. The medico-legal recourse provides the family limited and often inequitable compensation for their overall life-long health-care burden.

Step III: Optimization of clinical practices

Professional and community outreach initiatives have been optimized since the 2004 AAP guidelines.2 A Center for Disease Control and Prevention (CDC) video transcript has distilled the community message to ‘three main things to learn about jaundice and understand these facts. (i) Know if your baby's at risk for problems with jaundice. (ii) Ask about a jaundice bilirubin test for your baby before you go home from the hospital. (iii) Make a follow-up doctor's appointment for your baby that is within 48h after you take your baby home from the hospital’.15 Guidelines, tool-kits, parent and provider information materials are now available on the website with direct access to the American public. Table 2 lists some of the community-based resources that are optimizing the prevention of kernicterus.


Step IV: Implementation of 2004 AAP guidelines and the JCAHO sentinel alert

Regional and practice variations impact barriers to health-care services, newborn screening, timely intervention. Universal risk assessment for subsequent severe hyperbilirubinemia (Figure 3) is a key recommendation of the 2004 AAP guidelines.2 As shown in Table 1, infants with TSB levels greater than or equal to30mg per 100ml (greater than or equal to510μmol) have ranged from zero11, 12, 16 to about 1 in about 140009, 10 to 1 in 100008 and may be decreased to zero with systems approach for newborn care and jaundice management at birthing institutions. Similarly, the frequency range of extreme TSB values greater than or equal to25mg per 100ml (greater than or equal to427μmoll−1) has ranged from 1 in 650 to 15000 infants to a range of 1 in 15000 to about 18000.8, 9, 10, 11, 12, 16, 17, 18, 19 Two examples of systems programs are described below:

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

An approach to time follow-up for repeat jaundice and bilirubin evaluation based on pre-discharge bilirubin testing.

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Example 1
 

With an objective to prevent kernicterus based on the detection of infants at risk for developing severe neonatal hyperbilirubinemia, Eggert et al.17 initiated a program of pre-discharge bilirubin screening of all neonates and coupled this with a results assessment using a percentile-based nomogram in a for-profit 18-hospital health system, the Inter-Mountain Health Care (IHC). They obtained data during two periods of time, before and after initiating the program, and compared the effect of the program on the incidence of significant hyperbilirubinemia and rehospitalization. The study used a historic cohort study involving all neonates delivered at greater than or equal to35 weeks gestation, within IHC's hospital system, from 1 March 2001 to 31 December 2002, and 1 January 2003 to 31 December 2004. A pre-discharge bilirubin screening program, instituted in December 2002, called for a TSB/TcB to be performed on every neonate either at the recognition of clinical jaundice or before discharge regardless of whether jaundice was observed. For non-jaundiced neonates, the nursery staff was encouraged to obtain the screening TSB at the same time they obtained the state-mandated newborn screen for inborn errors of metabolism. Bilirubin values were plotted on an hour-specific nomogram and the corresponding percentile was used to guide evaluation, therapy and follow-up. Eggert et al.17 reported a study of 101272 neonates of which 48789 were in period 1 and 52483 in period 2. Before the program, 1 in every 77 neonates born at an IHC hospital had 1 or more TSB levels >20mg per 100ml. After initiating the program, the incidence decreased to 1 in 142 and the number of neonates with a TSB >25mg per 100ml decreased from 1 in 1522 before to 1 in 4037 after. The rate of hospital readmission with a primary diagnosis of jaundice decreased from 0.55% in period 1 to 0.43% in period 2. Eggert et al.17 concluded that their systems program of bilirubin screening in a multi-hospital health system, coupled with evaluating the results using a percentile-based nomogram, reduced the proportion of neonates with severe neonatal hyperbilirubinemia and reduced the rate of hospital readmissions with jaundice.

Example 2
 

The Share-Zadek Medical Center in Jerusalem has implemented a newborn screening practice for all term and late-preterm infants that focuses on outpatient follow-up and intensive community awareness.8 Infants are routinely discharged at about 48h of age for vaginal births or at 4 days for cesarean births. The key component of their program is the community awareness of risks of newborn jaundice and an informal but effective cultural/religious infrastructure that reinforces the identification of an at-risk infant. A unique component has been the religious injunction against circumcision of a jaundiced infant on eighth day (checked by a mohel, a ritual circumciser). Kaplan et al. report a cohort of 18079 term and late-preterm infants born and cared over a 2-year period.15 Attributed to this screening and follow-up program, there were no cases of acute kernicterus (acute bilirubin encephalopathy), 1 in 18079 occurrence of infant with total bilirubin level >25mg per 100ml, 1 in 4520 infants undergoing an exchange transfusion, 1.9% incidence for use of hospital-based intensive phototherapy and readmission rate of 0.41% for phototherapy.

Step V: Outcome of adverse experiences of extreme hyperbilirubinemia

Consensus for surrogate measures of outcome of successful implementation of the 2004 AAP guidelines include tracking of readmission for neonatal hyperbilirubinemia, rates of exchange transfusion and surrogate TSB levels of >25mg per 100ml.3 Success of programs such as the Jerusalem experience is highly dependent on a partnership between providers and parents in the context of societal participation. Using surrogate measures for program performance, the varying occurrence of extreme hyperbilirubinemia, TSB >25mg per 100ml, is evident in diverse communities and practices.8, 9, 10, 11, 12, 15, 16, 17, 18 Infants with TSB >25mg per 100ml, when identified in a timely manner can be salvaged from a progression to a catastrophic event and may be considered a ‘near-miss’ event. A systems program that is relevant to the community, its health-care infrastructure and a built performance measure could minimize adverse hyperbilirubinemia experiences and possibly prevent kernicterus. A variety of systems-approach to institutional, regional or national programs to prevent severe hyperbilirubinemia have been implemented. The aims of these initiatives are to reduce readmission during the first week after birth, contain cost and reduce the medical burden for communities. Successful institutionalization has led to early identification of infants at risk for nutritional and breast feeding support and targeted use of phototherapy. More importantly, universal and unfettered access to pre-discharge management has led to minimal decision regret for those identified as ‘low-risk’ before discharge from birthing hospital based on the absence of jaundice and bilirubin (TcB/TSB) levels <40th percentile for age in hours.

Step VI: Surveillance for national frequency for extreme hyperbilirubinemia (TSB >25 mg per 100 ml)

Accuracy and precision of TSB measurements have improved substantially in the past decade. College of American Pathologists anticipates a substantial improvement in bilirubin measurements due to the reduction of systematic error.20 Health-societal burden of extreme hyperbilirubinemia and kernicterus are unique but amenable to a national surveillance and oversight with concurrent, improved access to specific health-care services to those families who are at risk for adverse outcomes. In summary, as we balance evidence-based medicine, patient safety and protective care for all newborns entrusted to the care of health professionals, partnership with parents should lead to implementation of a kinder, gentler and protective approach. An effective clinical and community health strategy should allow a clinician to worry and closely follow only those few at-risk infants for severe hyperbilirubinemia.

Statement of the desired action(s) to be taken
 

To reduce the incidence of extreme hyperbilirubinemia affecting newborn with jaundice in the United States and to prevent kernicterus, the following actions may be taken:

  1. Implement proven prevention strategies for severe neonatal hyperbilirubinemia as defined by 2004 American Academy of Pediatrics Guidelines to all newborns in the United States. The highest priority should be given to (i) designating TSB >25mg per 100ml (extreme hyperbilirubinemia) as a reportable condition; (ii) implementation of JCAHO Sentinel Report for kernicterus (2004) and CDC education materials (Table 2); (iii) outreach to communities for education of prospective parents; (iv) development of a pathway to monitor, evaluate and track infants with extreme hyperbilirubinemia.
  2. Develop a national surveillance program for ‘Extreme Hyperbilirubinemia’ using a formal system to receive ongoing feedback from statewide laboratories, to address gaps in the statewide health screening processes at birthing hospitals.
  3. Develop, implement and maintain a kernicterus Electronic Disease Notification (EDN) Data System. This is critical for improving the timeliness and completeness of notifications and for allowing evaluation and interventions at the policy and individual family level.
  4. Convene a multi-agency working group (possible partners include representatives of the Department of Health and Human Services; HRSA; CDC, Council of State and Territorial Epidemiologists, Association of State and Territorial Health Officials, National Association of County and City Health Officials, JCAHO, AAP, AWOHNN to: (i) define comprehensive recommendations for national health assessments and preventive and therapeutic interventions for infants with extreme hyperbilirubinemia; (ii) assess the benefits and risks in terms of public value and cost in comparison with existing mandatory newborn programs that universally screen for rarer disorders or those that are less amenable to effective intervention; (iii) coordinate with these successful programs such as newborn screening for inherited disorders and hearing; (iv) identify areas for policy and regulatory changes to optimize national surveillance and health assessments.

Public health impact
 

The adoption of the action items could reduce the kernicterus as well as ‘catastrophic hyperbilirubinemia’ (TSB >30mg per 100ml) burden on receiving communities in the United States to less than 10 infants annually. It may also indirectly prevent moderate and possibly the subtle effects of excessive hyperbilirubinemia, decrease morbidity and mortality associated with unmonitored and untreated excessive hyperbilirubinemia in infants born in the United States, and improve the overall health of 3.2. million newborns >35 weeks gestational age born each year in the United States of America.

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Disclosure

The authors have declared no financial interests.

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References

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