Clinical Laboratory Strategies: November 12, 2009

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Screening for Bilirubin in Newborns
New Recommendations May Cause Confusion
By Bill Malone

Since 2004, the American Academy of Pediatrics (AAP) has recommended that every newborn be examined for hyperbilirubinemia risk by either direct bilirubin measurement or a clinician’s assessment. Now, a group of experts—including several from the AAP subcommittee on hyperbilirubinemia—has refined this recommendation to specify universal screening using TSB or TcB. But at the same time, the USPSTF found insufficient evidence to assess bilirubin screening. This issue of Strategies examines these recent developments.

After birth, bilirubin levels rise in all newborns due to accelerated red blood cell breakdown. However, their livers are not ready to conjugate the bilirubin that results from the breakdown of hemoglobin. Normally newborns’ bilirubin peaks within a week at a harmless level and then drops. But in a few cases, bilirubin peaks at such a high level that irreversible brain damage results, a condition called chronic bilirubin encephalopathy or kernicterus. The consequences of kernicterus are severe and include cerebral palsy, deafness, and vision problems.

While the outcomes of kernicterus are extremely devastating, the condition is also extremely rare, affecting about 1 in every 100,000 live births, according to recent estimates from the United Kingdom. The incidence in the U.S. is not known, as it is not a reportable condition. This situation has made evaluation of screening programs very difficult. "The extreme rarity of chronic bilirubin encephalopathy makes it nearly impossible to design and conduct a study that could directly evaluate the effectiveness of an intervention to reduce the incidence of this condition," wrote the authors from the U.S. Preventive Services Task Force (USPSTF, Pediatrics 2009;124:1172–1177).

While USPSTF acknowledged that several studies in its review showed that measuring total serum bilirubin (TSB) early could predict the likelihood that TSB would later reach a very high peak, none could link TSB screening with kernicterus. With no studies examining the potential harms of screening itself, and little additional evidence about harms of treatment—phototherapy or the more rare exchange transfusion therapy—USPSTF concluded it could make not make a recommendation regarding the use of TSB for screening.

Another problem in linking TSB screening to better outcomes is that the relationship between the disease and hyperbilirubinemia is not totally clear, explained Brad Karon, MD, PhD, director of hospital clinical labs at Mayo Clinic in Rochester, Minn. "One reason for the lack of evidence is that the relationship between bilirubin and the development of kernicterus isn’t 100 percent," he said. "There is a strong relationship—but not every baby with over a certain level of bilirubin will have brain damage."

Despite these challenges, many pediatricians would agree that giving up on screening would eventually lead to more cases of kernicterus, however tenuous the data connecting them, explained Karon. Prior to common use of Rho(D) Immune Globulin treatment, or RhoGAM, in the 1970s, kernicterus was much more common in Rh-positive babies born to Rh-negative mothers. Without RhoGAM, antibody-mediated red cell destruction in the infant can cause a huge increase in the normal level of red cell destruction, leading to even higher bilirubin levels. Once RhoGAM became standard treatment for Rh-negative mothers, the incidence of kernicterus dropped sharply, and bilirubin screening standards were relaxed.

But with the advent of managed care in the 1990s, hyperbilirubinemia became more of a problem. More and more, babies were sent home between 24–48 hours—well before the time that bilirubin levels usually peak. With a baby in the hospital, a physician might notice its jaundiced appearance and order a TSB; at home, parents either didn’t know what to look for or weren’t sure what to do about it. "By 2004, there were reports that the incidence of kernicterus was increasing," said Karon. "Pediatricians felt that with it being a completely preventable disorder, and since we had the ability to screen infants in the hospital before we sent them home, that we should never have a baby that develops kernicterus." So in 2004, AAP revised the guidelines to recommend universal screening by either direct bilirubin measurement or a clinician’s assessment. Now, after 5 years of ramped up screening, the USPSTF aimed to go back and see if the evidence for universal screening had progressed, explained Karon.

On the other side of the fence, M. Jeffrey Maisels, MD, and others from the AAP subcommittee on hyperbilirubinemia continue to argue for universal screening as the best choice, although aware of the same paucity of evidence (Pediatrics 2009;124:1193–1198). Maisels was the lead author of the paper and is professor and chair of the department of pediatrics at Oakland University William Beaumont School of Medicine and physician-in-chief at Beaumont Children’s Hospital, in Royal Oak, Michigan. The historical waxing and waning of bilirubin screening helps explain this position. Even though researchers may not yet have definitive evidence of screening’s ultimate benefit, the medical community understands hyperbilirubinemia well enough to push forward with universal screening in hopes of preventing a terrible outcome for a small number of newborns.

"There really is no conflict with the USPSTF findings," said Maisels. "We recommend that you do this because we think it’s a good idea. By measuring bilirubin before the baby leaves the hospital, there is now good evidence that you’re likely to reduce significantly the number of babies that have very high bilirubin levels. We can’t extrapolate from that to say we’ll reduce the risk of kernicterus. It is such a rare condition, that it would take us years to get that information, but it seems reasonable to expect a reduction in kernicterus if you can reduce the number of infants with extreme hyperbilirubinemia."

Maisels and his coauthors have refocused the 2004 AAP recommendation to advise universal screening using TSB or transcutaneous bilirubin (TcB), together with clinical risk factors, highlighting the role of the lab. Though the authors of the paper are from the AAP subcommittee, their recommendation is not an official statement of AAP, due to the lack of available evidence.

Now more than ever, pediatricians need excellent support from laboratorians, emphasized Maisels. He stressed that labs need to go beyond just reporting a bilirubin level and instead use the nomogram developed by Vinod Bhutani, MD to report risk of hyperbilirubinemia. First published in 1999, the nomogram uses TSB and the age of a newborn in hours to predict which babies are most at risk of severe hyperbilirubinemia in the next few days. "For example, the lab should tell you this baby is 47 hours old, its bilirubin level is 12, and it’s in about the 90th percentile, and therefore you should pay attention to it," said Maisels. "Labs are not regularly using the Bhutani nomogram, but they should be. As a predictive tool it works, and based on this, if the baby’s gestation is such and such, then the lab could suggest that the baby get a bilirubin repeated in 6 hours, 24 hours, 48 hours, or don’t worry about it. There are all sorts of things a lab could do for a pediatrician with this information."

In addition to reporting bilirubin results with risk information from the nomogram, laboratorians also have their work cut out for them with standardization issues, said Karon. "In a way, labs contribute to part of the problem of not having good evidence that these screening programs work because we haven’t standardized our bilirubin screening programs," he said. "We’ve been part of the hindrance, not the help, because our methods are not well-standardized, which means that at every institution that wants to screen with a transcutaneous method, the relationship between the transcutaneous and the lab value will be different."

Notwithstanding the lack of evidence on the one hand and standardization problems on the other, Maisels believes universal screening at hospitals will become more common. He cited the recent move by the Northern California Kaiser Permanente hospitals as well as Hospital Corporation of America—which delivers 5% of all babies in the U.S.—to adopt universal screening in all of their hospitals. All of these screening programs will rely heavily on labs. "Labs have to do better partnering with the pediatric communities in their hospitals and institutions," said Karon. "For both laboratory and transcutaneous values, pediatricians need to feel confident that their bilirubin values are accurate and that they can use them in a reliable way."

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