After completing this article, readers should be able to:
List potential reasons for the resurgence in cases of kernicterus since 1990 in otherwise well-appearing term and near-term infants.
List maternal and infant risk factors for increased frequency and severity of hyperbilirubinemia in breastfed infants.
Describe the key components of daily follow-up visits for infants discharged fewer than 48 hours after birth.
Describe the laboratory test that can be used to determine the risk of developing subsequent severe hyperbilirubinemia and help guide acute therapy and follow-up plans.
Explain why near-term infants born at 35 to 37 weeks’ gestation are at particularly high risk for developing severe hyperbilirubinemia and kernicterus.
A clinician in a well-baby nursery is asked daily to make decisions involving hyperbilirubinemia, breastfeeding, and early newborn discharge. In most cases today, a newborn is at home when lactogenesis is occurring and bilirubin levels are peaking. With the less aggressive approach to managing bilirubin advocated in the 1990s, there has been a dramatic rise in cases of acute bilirubin toxicity and kernicterus in otherwise well-appearing, healthy term and near-term newborns. There have been 120 cases reported to the Pilot Kernicterus Registry in the last 12 years, probably an underestimate of the true incidence. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) issued a Sentinel Event Alert in 2001 notifying all hospitals that kernicterus does threaten healthy newborns. Kernicterus has been called a “never event,” identified on a list of “serious, egregious, preventable adverse events” by The Agency for Healthcare Research and Quality. Policies and protocols are needed in well-baby nurseries to ensure the safety of newborns from this entirely preventable and devastating outcome. In this article, we review the history of jaundice and kernicterus; the key interplay between hyperbilirubinemia, dehydration, and breastfeeding failure; and how a systematic approach to the prevention of kernicterus might be implemented.
History of the Problem
The term “vigintiphobia” (the fear of the number 20) was coined by Watchko in 1983 in a review that summarized the evolution and evidence by which practitioners historically have managed hyperbilirubinemia. Retrospective studies by Hsai and associates in infants who had Rh isoimmunization reported that 18% of infants who had total serum bilirubin (TSB) levels of 16 to 30 mg/dL (274 to 510 mcmol/L) and 50% of those whose TSB levels were greater than 31 mg/dL (530 mcmol/L) developed kernicterus. These numbers were consistent with data from Mollison and colleagues, who reported a 46% incidence of kernicterus in Rh-isoimmunized babies when the level of TSB was higher than 18 mg/dL (308 mcmol/L). It was based on these data that the traditional guideline of exchange transfusion when the bilirubin level in the infant who had Rh disease reached 20 mg/dL (342 mcmol/L) was established. The same guideline was then applied to all infants, including those who were otherwise healthy and without hemolytic disease. This approach, along with the use of Rho(D) immune globulin, resulted in the near disappearance of kernicterus until the mid-1980s.
Although the benefit of exchange transfusion in Rh disease is well established, controversy surrounds such an aggressive approach to hyperbilirubinemia in a nonhemolytic newborn for several reasons. Evidence to suggest the same risk in healthy newborns without hemolysis was lacking. Small studies in the 1960s that retrospectively evaluated infants who did not have Rh disease and developed TSB higher than 20 mg/dL (342 mcmol/L) found no evidence for kernicterus. Furthermore, exchange transfusion carries an approximately 2% mortality risk and a 12% risk of serious morbidity, including thrombocytopenia, portal vein thrombosis, necrotizing enterocolitis, electrolyte imbalance, and infection. The Collaborative Perinatal Project provided evidence to support the concept that higher bilirubin levels were associated with lower developmental scores, lower intelligence quotients (IQs), and increased neurologic abnormality. However, these data included all infants (term, preterm, and those who had hemolytic disease). Newman and Maisels reviewed the evidence from the Collaborative Perinatal Project in 1990 and eliminated all but those infants considered healthy who did not have hemolytic disease. These data supported a clinically insignificant difference, showing only 1 point of IQ change for each 5-mg/dL (86-mcmol/L) increment of bilirubin and no association with cognitive impairment or hearing loss. A “kinder, gentler approach” to treatment of hyperbilirubinemia was recommended, which included less rigorous evaluation of TSB when there was no evidence of hemolysis and higher TSB levels before phototherapy and exchange transfusion were undertaken.
The American Academy of Pediatrics (AAP) followed with a practice parameter for hyperbilirubinemia in 1994. Some of the salient points include maternal ABO and Rh typing and antibody screening for all women, subsequent blood type and Coombs test in the newborn at risk for hemolysis (mother O+ or Rh-), visible jaundice in the first 24 hours after birth as an absolute indication to check a TSB and no longer categorizing that infant as “healthy,” and a strong recommendation for follow-up within 2 to 3 days of discharge if the infant is discharged before 48 hours of age. Guidelines for phototherapy and exchange transfusion use recommended a TSB as high as 25 mg/dL (428 mcmol/L) before considering exchange transfusion.
Simultaneously, other fundamental practices regarding the routine care of the well newborn were changing. The number of women choosing to breastfeed was growing from 30% in 1973 to 52% in 1990 and 60% in 1995. The AAP Work Group on Breastfeeding advocates human milk as the preferred feeding because of its benefits, including less diarrhea, less frequent lower respiratory infections and otitis media, and lower incidences of bacteremia and necrotizing enterocolitis. Breastfed infants have higher bilirubin levels due to increased enterohepatic circulation; 12.9% of breastfed infants compared with 4% of formula-fed infants exhibit moderate hyperbilirubinemia of 12 mg/dL (205 mcmol/L). Hyperbilirubinemia is the most commonly reported morbidity associated with early inadequate breastfeeding.
Another factor in the equation is the standard early (<48 h) and very early (<24 h) postpartum hospital discharge for routine vaginal deliveries. The length of stay for all deliveries decreased by 37% (from 4.1 to 2.6 days) between 1970 and 1992. Although federal legislation mandates that insurers allow hospital stays of up to 48 hours for vaginal deliveries and 72 hours for cesarean sections, very early and early discharges continue to be common. Infants are now at home when TSB levels are peaking and lactogenesis is occurring. The combination of an apparent loss of concern for jaundice, increased breastfeeding, and shorter hospital stays has led to the resurgence of kernicterus in apparently healthy, nonhemolytic newborns.
The Reappearance of Kernicterus
The clinical evolution of kernicterus begins with changes in behavior (somnolence progressing to lethargy or increasing irritability), followed by poor feeding, abnormal cry, abnormalities in muscle tone, opisthotonos, and seizures. Bhutani and associates have proposed a bilirubin neurologic dysfunction (BIND) score to estimate the degree of bilirubin toxicity and risk for progression to kernicterus (Table 1). Late sequelae of kernicterus are devastating, with an often bright mind trapped within a totally uncontrollable body, wracked by painful muscle spasms. Late sequelae also include gaze abnormalities, sleep disturbances, feeding difficulties, dystonia, incoordination and choreoathetosis, enamel dysplasia, and sensorineural hearing loss.
|Condition||1 Point||2 Points||3 Points|
|Mental Status||Sleepy, poor feeding||Lethargy, irritability||Semicoma, seizures|
|Muscle Tone||Slight decrease||Hyper- or hypotonia, depending on arousal state, mild arching||Markedly increased or decreased, opishotonus, bicycling|
|Cry||High-pitched||Shrill or too infrequent||Inconsolable or only with stimulation|
Total score: 1 to 3 points = minimal signs of encephalopathy; 4 to 6 points = progressive, but reversible with treatment; 7 to 9 points = advanced, largely irreversible, severity decreased with treatment
Adapted from Johnson L, Brown AK, Bhutani VK. BIND—a clinical score for bilirubin-induced neurologic dysfunction in newborns. Pediatrics. 1999;104(suppl):746–747.
The Pilot Kernicterus Registry has accumulated more than 120 infants who had evidence of acute bilirubin toxicity and kernicterus since 1990. The cases demonstrate the “loss of concern for jaundice,” with evidence that early follow-up appointments were not made, clinicians ignored parental concerns about poor feeding and lethargy in their newborns, and treatment of infants who had severe hyperbilirubinemia was delayed. Johnson summarized the findings from 61 infants in the Registry who were readmitted within fewer than 7 days after birth for severe hyperbilirubinemia and acute bilirubin toxicity. A total of 59 were breastfed, and 41 had no early follow-up appointment in place. Of the 14 babies who did have early follow-up, seven were noted to be jaundiced but no TSB was measured, demonstrating the limited reliability of visual estimation of severity based only on clinical examination. Alarmingly, seven infants had TSBs less than 30 mg/dL (513 mcmol/L), but with acute signs of toxicity, and four progressed to permanent sequelae of kernicterus. No definitive cause was identified for the severe hyperbilirubinemia among 31% of the 61 readmissions at fewer than 7 days of age. These data underscore that term, healthy, breastfed newborns are at risk for kernicterus. These reports were followed by a JCAHO Sentinel Event Alert notifying all hospitals that kernicterus threatens healthy newborns and suggesting that hospitals put systems in place to prevent further occurrences. The root causes identified by JCAHO are listed in Table 2.
Data from Sentinel Event Alert: Kernicterus Threatens Health Babies. Issue 18, April 2001.
It is worth noting two special genetic circumstances that dramatically increase the risk for bilirubin toxicity: glucose-6-phosphate dehydrogenase (G6PD) deficiency and Gilbert syndrome. Among the 61 babies detailed in the original Kernicterus Registry report, 31% were later found to have G6PD deficiency. The AAP Practice Parameter for hyperbilirubinemia makes special mention for physicians to raise their awareness for this disorder and its potential for neonatal hyperbilirubinemia. It affects primarily African-American, Greek, Italian, and Southeast Asian males, although a small percentage of females may be affected through X inactivation. The pathogenesis of hyperbilirubinemia from this X-linked enzyme defect is debated. It is either the result of impaired conjugation of bilirubin via decreased action of uridine diphosphate glucuronyl transferase (UDPGT) or reduced protection of red cells from oxidative damage due to lack of G6PD and resultant hemolysis. Gilbert syndrome is manifested by decreased UDPGT activity in adults. It has not been linked directly to higher peak bilirubin levels in the neonate, but there has been some evidence that G6PD deficiency in combination with a variant in the UGT1A1 promoter encoding UDPGT may increase the risk for severe hyperbilirubinemia. Kaplan and Hammerman have recommended a protocol for neonates at high risk for G6PD deficiency by virtue of ethnic background. A biochemical screening test within the first 24 hours after birth may be helpful in these infants, followed by frequent serum bilirubin testing and more aggressive therapy in the G6PD-deficient neonate.
The Relation of Breastfeeding to Jaundice
Breastfed infants have the potential for increased frequency and severity of hyperbilirubinemia, and excessive jaundice may be a warning sign of inadequate breastfeeding. Both endocrine and autocrine pathways control milk production. Endocrine control involves stimulation of the breast by suckling, activation of a neural reflex path to the hypothalamus, and subsequent release of oxytocin and prolactin from the pituitary, resulting in milk production and the let-down reflex. The most important determinant, however, of the volume of milk produced is the autocrine control of lactation. A peptide feedback inhibitor of lactose and casein synthesis is present in the whey of human milk. This inhibitory substance, if not removed effectively with each feeding, will result in decreased milk production. It is, therefore, crucial for successful breastfeeding to include effective emptying of the breast.
Inadequate human milk production is the result of either failure of lactogenesis (primary insufficiency) or inadequate emptying (secondary insufficiency). Mothers who desire to breastfeed should be screened prenatally for risk factors for primary insufficient lactation (Table 3). Failure of lactogenesis is rare and affects fewer than 5% of women. The more common problem, occurring in about 10% of women, is secondary lactation insufficiency caused by either infant or maternal factors resulting in ineffective or infrequent emptying and a diminished milk supply. The predisposing infant risk factors are also listed in Table 3. Latch-on difficulties are common and can occur even without anatomic risk factors. Methods of preventing this problem include early initiation of breastfeeding within the first hour after birth, rooming-in, lactation counseling, and avoidance of pacifiers and unnecessary supplementation. Occasionally a nipple shield can be of assistance, when used under the guidance of a trained nurse or lactation consultant. Breast engorgement occurs in 20% of primiparous mothers and can lead to difficulty with infant latch-on and poor milk transfer. Frequent breastfeeding, warm compresses, and brief pumping to establish flow can help with this temporary problem. Sore nipples are often the result of poor breastfeeding technique and an insufficient amount of areolar tissue taken by the baby during the latch-on process. If the pain is severe enough, the mother can dread nursing, leading to fewer nursing sessions and, therefore, decreased milk production. Proper positioning of the infant, lanolin cream, and temporary use of a breast pump while the nipples heal are common therapies. Ensuring a calm, pain- and embarrassment-free environment in the hospital and in the early days at home can help to avoid inhibition of the let-down reflex. Rarely, mastitis can develop in the breastfeeding mother, which may require systemic antibiotic therapy. Continuation of breastfeeding during that time should be encouraged.
|Infant Risk Factors|
|Intrauterine growth retardation|
|Cardiac or respiratory problems|
|Maternal Risk Factors|
|Failure to undergo prenatal breast enlargement|
|Flat or inverted nipples|
|Anatomic breast variation|
|Previous breast surgery|
|Minimal postpartum breast enlargement|
|Serious medical illness|
Adapted from Neifert M. Early assessment of the breastfeeding infant. Contemp Pediatr. 1996;13:146
Distinguishing breastfeeding jaundice and human milk jaundice is crucial when evaluating a jaundiced neonate. Human milk contains several factors that increase levels of unconjugated bilirubin. Pregnanediol, fatty acids, and lipase can inhibit hepatic excretion of bilirubin. Human milk also contains B-glucuronidase, which produces unconjugated bilirubin by cleaving the ester linkage of bilirubin glucuronide, resulting in increased enterohepatic circulation. Although necessary in utero for clearing bilirubin through the placenta, B-glucuronidase in extrauterine life can increase serum bilirubin levels. These factors result in human milk jaundice, a term that should be used only for the healthy, thriving breastfed infant of 1 to 3 weeks of age who is gaining weight well and has no other cause for persistent jaundice. Exaggerated hyperbilirubinemia in the first postnatal week is not human milk jaundice, but rather breastfeeding jaundice (or “lack of human milk” jaundice) and can be a clear warning sign of inadequate breastfeeding.
The lactation specialists at The Children’s Hospital of Denver have developed a clinical care pathway for breastfeeding mothers, reprinted with permission in Figure 1. It can be given to breastfeeding mothers to use at home as they track the normal course for lactogenesis, baby’s activity, feeding routines, and baby’s urine output and stools. Education and availability of follow-up resources to new mothers cannot be emphasized enough to ensure the safety of newborns who are at home during this critical transition.
A Systematic Approach to the Prevention of Kernicterus in the Well-Baby Nursery
A large percentage of well newborns undoubtedly have some degree of hyperbilirubinemia. How can clinicians provide a rational, cost-effective approach to identifying and following those infants at highest risk for severe hyperbilirubinemia and potentially kernicterus? First, the risk must be recognized with every newborn-mother combination. A clever mnemonic was created in a Centers for Disease Control Weekly Update to help clinicians remember the common risk factors for severe hyperbilirubinemia:
J - Jaundice within first 24 hours
A - A sibling who was jaundiced
U - Unrecognized hemolysis
N - Nonoptimal nursing/Near-term infant
D - Deficiency in G6PD
I - Infection
C - Cephalohematomas/bruising
E - East Asian or Mediterranean descent
Bhutani and colleagues proposed the use of an hour-specific bilirubin nomogram to stratify infants further at low (<40%), intermediate (40% to 95%) and high (>95%) risk for subsequent hyperbilirubinemia in the first postnatal week. The nomogram was created based on 2,840 healthy term newborns eligible for early discharge, of which 43% were white, 41% African-American, 3% Hispanic, and 4% Asian. About 50% were breastfed and 50% were bottle-fed. The nomogram (Fig. 2) can anticipate the risk of an infant developing subsequent severe hyperbilirubinemia based on a predischarge bilirubin level and help guide anticipatory therapy and follow-up planning. More studies are needed to evaluate the cost-effectiveness and utility of screening all newborns who have a TSB drawn at the time of the newborn screen with application of the hour-specific bilirubin nomogram.
The promotion of successful breastfeeding from the time of birth onward is a crucial part of the systematic approach to the prevention of kernicterus. Risk factors for both primary and secondary lactation insufficiency always should be identified in both mother and newborn. Hospital routines to maximize breastfeeding success, such as early initiation of nursing, rooming-in, and avoiding interruption of breastfeeding, should be instituted at all hospitals. Knowledgeable lactation support staff and access to electric breast pumps should be provided to all lactating mothers. Objective measures to ensure adequate breastfeeding, including test weights, evaluation of pumped amounts, and daily infant weights, should be used whenever possible.
Finally, as the AAP Practice Parameter states, “Follow-up should be provided to all neonates discharged less than 48 hours after birth by an experienced health care professional in an office, clinic or at home within 2 to 3 days of discharge.” There is some evidence that there is no difference in the risk of readmission to the hospital among infants discharged at fewer than 48 hours and those discharged between 48 and 72 hours, arguing that the recommendations for 2- to 3-day follow-up appointments should apply to all infants discharged at fewer than 72 hours after birth. The early follow-up examination should include the unclothed infant weight and calculated percent change from birthweight. The upper limit of normal weight loss is 8% in the first few days after birth. Babies should not continue to lose weight after lactogenesis occurs. Assessing the frequency and duration of feedings can raise potential warning flags for the undernourished baby. Early in life an infant should be breastfeeding 8 to 12 times in a 24-hour period. A frequency that is much greater or much less may signal a problem with lactation insufficiency. Signs of lactogenesis should be obtained from mother, such as pre- and postfeeding changes in the breast, tingling, or signs of milk let-down with uterine cramping. Again, objective measures such as the infant’s weight or pumped volumes can be more useful than subjective reports from the mother. The elimination history also should be obtained. Once lactogenesis has occurred, the infant should be having about four stools daily for the next 4 weeks. Only then can it be “normal” for the breastfed infant to go several days without a bowel movement. Also after lactogenesis, there should be six to eight wet diapers per day. A full physical examination of the baby should assess hydration and the cardiovascular and neurologic systems. Finally, a TSB should be considered, especially if there is a presence of risk factors or if a predischarge TSB was obtained and use of the nomogram indicates elevated risk.
A final note must be made regarding near-term infants of 35 to 37 weeks’ gestation. These infants should not be considered term. They are much more likely to have difficulty nursing, poorer caloric intake, less energy reserve, greater weight loss, and less effective hepatic clearance of bilirubin. For all of these reasons, a near-term infant can become more severely jaundiced. Several studies have shown that they carry 5 to 10 times the risk for readmission with excessive weight loss or jaundice as an infant who is more than 38 weeks’ gestation. Near-term infants do not meet either AAP or American College of Obstetricians and Gynecologists criteria for early hospital discharge at fewer than 48 hours. We recommend a hospital stay of at least 3 days for this age group and up to 5 days in the 35 weeks’ gestation infant to ensure adequate feeding patterns and observation during bilirubin peak.
Kernicterus is devastating and completely preventable condition when severe hyperbilirubinemia is recognized early and treated aggressively. Because prevention is the key, clinicians need a systematic approach to identify the infant who may develop severe hyperbilirubinemia, acute bilirubin toxicity, and kernicterus. A simple start to prevention of kernicterus should include use of the “JAUNDICE” mnemonic to identify infant risk factors, promotion of successful breastfeeding in both the hospital and in the home, and more rigorous use of the hour-specific bilirubin nomogram. Making a 2- to 3-day follow-up appointment is essential for all infants prior to discharge from the hospital. Recognition of mild prematurity with lengthened hospital stay is prudent. Further research is required regarding the cost-effectiveness and generalizability of universal TSB screening and use of the hour-specific nomogram in all healthy term and near-term infants. Hopefully, we can truly make kernicterus a “never event.”
- Copyright © 2003 by the American Academy of Pediatrics
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