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Kernicterus Follow-up

  • Author: Shelley C Springer, JD, MD, MSc, MBA, FAAP; Chief Editor: Ted Rosenkrantz, MD  more...
 
Updated: Apr 02, 2014
 

Further Outpatient Care

To help ensure that infants may reach their maximum neurodevelopmental potential, referring babies with bilirubin-induced neurologic dysfunction (BIND) to a neurodevelopmental pediatrician skilled in caring for these patients is important. Early identification of and intervention for neurodevelopmental deficits has been shown to positively impact an infant's long-term neurodevelopmental prognosis.

The numerous areas of uncertainty surrounding the diagnosis and treatment of hyperbilirubinemia in the infant, coupled with the infrequency of sequelae, make it easy to become cavalier about the evaluation of an infant with jaundice. However, remember that physiologic hyperbilirubinemia is a diagnosis of exclusion, and kernicterus, when it occurs, is a devastating and legally indefensible sequela.

Sepsis must always be excluded in the infant with jaundice. Uncommon, but treatable, metabolic causes of jaundice include hypothyroidism and galactosemia. The first sign of occult immune or nonimmune hemolytic disease may be hyperbilirubinemia.

In its 2004 clinical practice guideline, the AAP included recommendations regarding interval between hospital discharge and outpatient follow-up evaluation by a qualified health care professional.[23] Recommendations are based on the infant's age (in hours of life) at discharge, presence or absence of risk factors for exaggerated hyperbilirubinemia, and the presence of other neonatal problems. Recommendations for follow-up range from as early as prior to 72 hours of life (if discharged before 24 h) to no later than 120 hours (5 d) if discharged before 72 hours.

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Further Inpatient Care

Phototherapy induces a conformational change in the bilirubin molecule, rendering it water-soluble. Formation of lumirubin is irreversible, whereas the formation of other water-soluble isomers is reversible upon cessation of phototherapy. Postphototherapy rebound is a well-recognized phenomenon that must be considered in all patients receiving phototherapy for hyperbilirubinemia due to a hemolytic process or prematurity.

One series of 226 term and near-term neonates treated in Israel between January 2001 and September 2002 reported significant rebound hyperbilirubinemia in 13.3% of patients.[33] Risk factors of excessive rebound included a positive direct Coombs test and a gestation less than 37 weeks.

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Transfer

Reported cases of kernicterus have occurred in near-term or term infants who were discharged from the hospital fewer than 48 hours after birth.

Most infants discharged at fewer than 72 hours after birth have clearly not reached their physiologic peak bilirubin level prior to discharge.

Any infant at risk for significant hyperbilirubinemia and possible neurotoxicity should be cared for in a nursery capable of rendering appropriate care for the hyperbilirubinemia and any contributing diagnoses.

A published nomogram predicts which babies may be at risk for significant disease, based on hour-of-life–specific bilirubin levels (see image below).[23] Infants whose levels fall in the high-intermediate and high-risk zones should be closely monitored in a nursery capable of caring for sick newborns; they may require transfer from the birth hospital to a regional perinatal center.

Hour-specific nomogram for total serum bilirubin a Hour-specific nomogram for total serum bilirubin and attendant risk of subsequent severe disease in term and preterm infants. Used with the permission of the Academy of Pediatrics.
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Deterrence/Prevention

Prevention

Prevention of hyperbilirubinemia is the best way to minimize the incidence of kernicterus. However, because some babies develop kernicterus with relatively modest bilirubin levels, no known absolute level of bilirubin below which the infant is completely safe is recognized. Additionally, because other factors contribute to the ability of bilirubin to cross the blood-brain barrier, management of these components must be appropriately considered.

In 2009, Newman et al reported the numbers needed to treat with phototherapy to prevent kernicterus, based on the AAP 2004 guideline phototherapy threshold. Assessment of 22,547 infants from a cohort of 281,898 infants born in a California hospital system from 1995-2004 resulted in various NNTs for different subpopulations of infants. Averaging 222 for boys and 339 for girls, the subgroup NNTs ranged from 10 for less than 24-hour-old, 36–week-gestation boys to 3,041 for older than or 3-day-old, 41-week-gestation girls.[34]

Serum bilirubin

Total serum bilirubin comprises a conjugated fraction (loosely called direct bilirubin) and an unconjugated fraction (indirect bilirubin). They are additive. However, the indirect fraction is composed of bound bilirubin (bound to albumin), lumirubin and other isomers if the baby is under phototherapy (unbound but water-soluble and unlikely to cross the blood-brain barrier), and free bilirubin. The free component is potentially toxic, but its exact serum level cannot be readily measured.

Risk of reduction of serum bilirubin

The current level of knowledge does not recognize the physiologic benefits of bilirubin, despite the multiple mechanisms operant in the neonate to promote and preserve hyperbilirubinemia. In vitro experiments have demonstrated a potent antioxidant capability of bilirubin, more so than the currently identified mechanisms.

An emerging field of research in human medicine is the role of oxidative injury in the development of various pathologic processes, which may be contributory to many neonatal diseases, such as retinopathy of prematurity, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis. Recent observational studies in the neonate have demonstrated an inverse correlation between peak serum bilirubin levels and the development of these various pathologies. Investigation into this line of research continues.

Phototherapy

Irradiance with light in the blue-green spectrum (440-480 nm) induces a photochemical reaction that changes the bilirubin molecule into other photoisomers that are water-soluble, readily excretable, and unlikely to cross the blood-brain barrier into the lipid-rich neuronal tissue. Such conversion begins immediately upon exposure of the skin surface to the light.

The most important photoreaction is an irreversible structural isomerization of bilirubin into a water-soluble substance called lumirubin, which is then excreted in the bile. Reversible configurational isomerization and photo-oxidation also contribute somewhat to the effectiveness of phototherapy to reduce free bilirubin in the baby.

To be effective, adequate skin surface must be exposed to the appropriate wavelength, with enough intensity (lux) to induce the desired reaction. The AAP has recently included recommendations for wavelength (430-490 nm) and irradiance (>30 µW/cm2) in their clinical practice guideline.[23]

Serum bilirubin levels should be closely monitored during phototherapy. A 1-mg/dL to 2-mg/dL decrease of measured bilirubin levels over a period of 4-6 hours is an appropriate response to phototherapy. If an inadequate response has been observed, lining the baby's bedding with aluminum foil or white material can increase the surface area of exposure and may increase the effectiveness of phototherapy.

Various devices are commercially available to facilitate provision of phototherapy. Models include overhead lights, blankets, and swaddling devices; selection is based on abilities to cover a broad surface area, ease of administration, and personal preference. The assortment of commercially available phototherapy devices continues to expand, and each new market entry is advertised as superior to the previous entry. Head-to-head clinical trials repeatedly show that time, irradiance, and skin surface area are the most significant factors in efficacy of phototherapy.[35, 36, 37]

In 2004, the AAP revised its clinical practice guideline for the management of hyperbilirubinemia in the healthy infant older than 35 weeks' estimated gestational age.[23] The guideline incorporates a nomogram that delineates serum bilirubin levels by hour of life with subsequent risk for significant disease (see following image).

Hour-specific nomogram for total serum bilirubin a Hour-specific nomogram for total serum bilirubin and attendant risk of subsequent severe disease in term and preterm infants. Used with the permission of the Academy of Pediatrics.

An Internet-based tool, BiliTool, is now available to help clinicians assess and treat hyperbilirubinemia based on the hour-specific nomogram and published guidelines.

This reference should be used when deciding how closely to monitor babies being discharged home before their bilirubin levels have peaked. Since its development, some experts have recommended universal bilirubin screening (performed with the state metabolic screen to minimize blood draws) before discharge.

Although falling short of recommending universal bilirubin measurement, the AAP guideline does recommend assessment of risk of severe hyperbilirubinemia in every baby prior to hospital discharge. This assessment can include either a bilirubin measurement (serum or transcutaneous), a clinical assessment of risk factors, or a combination of these 2 approaches. Further prospective analysis of these strategies found that the hour-specific nomogram was a better predictor than a clinical risk factor approach and that predischarge bilirubin level combined with gestational age most accurately predicted an infant's risk of developing severe hyperbilirubinemia.[38, 39]

Current quantization of bilirubin has been limited to direct serum measurement. Transcutaneous measurement devices have recently become commercially available and are slowly being integrated into clinical use. The manufacturers claim excellent reliability and validity in babies of all skin types and colors.

Risks of phototherapy

Phototherapy by itself is generally considered safe in babies, except in some rare genetic skin disorders and congenital porphyria. However, some risks are associated with its use.

Exposure to phototherapy can increase insensible fluid loss and lead to dehydration, especially in babies in open warmers if fluid intake and output are not closely monitored. This, in turn, potentiates hyperbilirubinemia.

Some extremely premature infants have reportedly experienced skin burns from fiberoptic blankets on which they were lying. Such devices should be used cautiously in infants with vulnerable skin.

Of potentially greater concern with respect to extremely premature infants is the report of increased mortality associated with phototherapy. A study conducted by the NICHD Neonatal Network as reported by Watchko evaluated the outcomes of aggressive versus conservative phototherapy in extremely low birth weight infants. Although aggressive phototherapy seemed to improve neurodevelopmental outcomes in the 751- to 1000-g cohort, aggressive phototherapy used in the group with birth weights of 501-750 g showed a 5% higher mortality rate, with a post-hoc Bayesian analysis estimating an 89% probability that aggressive phototherapy increased the rate of death in this cohort. The authors speculate that greater light penetration deeper into subcutaneous tissues and possible oxidative injury to cell membranes may be responsible.[18]

Concern exists about the risk of retinal damage in infants exposed to the extremely bright light of phototherapy. Accordingly, all infants should wear protective eye coverings while being treated.

An observed increase in the prevalence of patent ductus arteriosus (PDA) has been shown to occur in premature infants receiving phototherapy, and foil shields to the chest have been shown to ameliorate this increase. The operant mechanism has not been fully elucidated.

Bilirubin photosensitizes the skin, and skin damage is a theoretical risk. Bullous eruptions have been described in several infants with porphyrin abnormalities; congenital porphyria is a contraindication to the use of phototherapy. In 2011, Csoma et al from Hungary reported on 59 sets of twins, one of which received blue-light phototherapy and the other of which did not. Neonatal phototherapy was associated with a significantly higher prevalence of both cutaneous and uveal melanocytic lesions, after controlling for sun exposure and other confounders.[40]

Bronze baby syndrome occurs in infants with direct hyperbilirubinemia who are exposed to phototherapy. This seems likely to be the result of dermal accumulation of coproporphyrins. Measurement of the direct fraction of total bilirubin should be performed in every baby before starting phototherapy.

Phototherapy can interfere with maternal-child bonding at a critical time in the dyad's development. If a mother is breastfeeding, initiation of phototherapy introduces mechanical barriers to the breastfeeding process, which can be overwhelming at this critical time. Any comments about the role of breast milk in the development of hyperbilirubinemia may further sabotage this process. Altered parental perceptions of their infant from healthy to ill may further influence their short-term and long-term interactions with their infant. The pediatrician should address these issues with the family.

Phototherapy may be associated with ileus and/or feeding intolerance in premature infants treated with overhead (but not fiberoptic) devices. Doppler flow studies of splanchnic blood flow performed on babies receiving overhead phototherapy showed increased resistance to flow in the superior mesenteric artery (SMA) compared with prephototherapy measurements; no such effect was observed in babies being treated with fiberoptic devices. A retrospective review of 52 consecutive extremely low birth weight infants showed a higher incidence of ileus (abdominal distention, bilious aspirates) in babies receiving phototherapy (63.4%) compared with those who did not (9%).[41] Outcomes between the 2 groups were comparable.

Breastfeeding

The link between hyperbilirubinemia and breastfeeding has long been recognized, and, until recently, breastfeeding was typically interrupted in infants with jaundice. Randomized controlled trials have shown that offering formula or dextrose water to the breastfed infants with jaundice actually increases total serum bilirubin levels and, thus, should not be advocated. The AAP recommends against this practice, with evidence quality B and C in its 2004 clinical practice guideline.[23] Furthermore, this practice has also been shown to result in a decrease in breast milk intake after breastfeeding is reestablished. Study of the effect of continuing breastfeeding versus its interruption has not shown any untoward effect of continued breastfeeding. Because of the clear short-term and long-term advantages to the infant of breast milk feeds, the evidence would indicate that breastfeeding should be continued in the infant who is well enough to have enteral feedings.

Infant massage

In 2011, Chen et al reported from Niigata, Japan the results of a randomized controlled trial of the benefits of infant massage on hyperbilirubinemia. Forty-two healthy term breastfed infants ranging in weight from 2800-3600 g were randomized to massage or no massage (control). Infants receiving massage had a significantly higher frequency of stooling on days 1 and 2 (P < .05) and a lower total serum bilirubin on day 4 compared with the control group.[42]

Clinical algorithms

A Journal of Pediatrics supplement devoted exclusively to hyperbilirubinemia and prevention of kernicterus advocated 2 models for public health policy aimed at eliminating kernicterus from the population.[43, 44] To date, notwithstanding the efforts of some hospital systems and the American Academy of Pediatrics to standardize this aspect of newborn care, approaches to the surveillance and management of hyperbilirubinemia remain individualized, both throughout the United States and elsewhere.[19]

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Patient Education

To facilitate the provision of appropriate evaluation and follow-up for babies without recognized risk factors, the AAP has published an hour-of-age-specific guideline that correlates total serum bilirubin levels with degree of risk and recommendations for follow-up.[23]

The AAP recommends professional medical evaluation in 2-3 days for babies who are discharged from the hospital fewer than 48 hours after birth.[23] Babies discharged fewer than 72 hours after birth may also be at risk, and they should be closely monitored as well. Other risk factors warranting additional vigilance may include unexplained family history of neonatal hyperbilirubinemia, near-term gestation, low birth weight, excessive bruising or hematomata, and ethnicity at risk for exaggerated hyperbilirubinemia.

Parents should be informed of the importance of keeping these appointments, as well as be familiarized with the symptoms of poor feeding in breastfed babies and how to seek help.

For patient education resources, see the Children's Health Center, as well as Newborn Jaundice and Spinal Tap.

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Contributor Information and Disclosures
Author

Shelley C Springer, JD, MD, MSc, MBA, FAAP Professor, University of Medicine and Health Sciences, St Kitts, West Indies; Clinical Instructor, Department of Pediatrics, University of Vermont College of Medicine; Clinical Instructor, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health

Shelley C Springer, JD, MD, MSc, MBA, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Coauthor(s)

David J Annibale, MD Professor of Pediatrics, Director of Neonatology, Director of Fellowship Training Program in Neonatal-Perinatal Medicine, Department of Pediatrics, Medical University of South Carolina

David J Annibale, MD is a member of the following medical societies: American Academy of Pediatrics, National Perinatal Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David A Clark, MD Chairman, Professor, Department of Pediatrics, Albany Medical College

David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Pediatric Society, Christian Medical and Dental Associations, Medical Society of the State of New York, New York Academy of Sciences, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Oussama Itani, MD, FAAP, FACN Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center

Oussama Itani, MD, FAAP, FACN is a member of the following medical societies: American Academy of Pediatrics, American Association for Physician Leadership, American Heart Association, American College of Nutrition

Disclosure: Nothing to disclose.

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Typical patterns of total serum bilirubin levels in neonates of different racial origins. Used with the permission of the Academy of Pediatrics.
Overview of bilirubin metabolism.
Hour-specific nomogram for total serum bilirubin and attendant risk of subsequent severe disease in term and preterm infants. Used with the permission of the Academy of Pediatrics.
Magnetic resonance image of 21-month-old with kernicterus. Area of abnormality is the symmetric high-intensity signal in the area of the globus pallidus (arrows). Courtesy of M.J. Maisels.
Neuronal changes observed in kernicterus. Courtesy of J.J. Volpe.
 
 
 
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