Predictive Ability of a Predischarge Hour-specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near-term Newborns

Predischarge Jaundice as a Predictive Vector for Subsequent Hyperbilirubinemia

Early visual recognition of jaundice and accurate estimation of its severity is crucial for effective implementation of the AAP guidelines.¹⁹ Unfortunately, the presence of excessive jaundice for age is often missed clinically, which means that the trigger for measuring the first serum bilirubin level and electing subsequent AAP algorithm recommendations is not set. This is a potentially serious problem. Variability in the time of appearance of jaundice from newborn to newborn and in the ability of the professionals to see jaundice and estimate its severity, coupled with the considerable range of TSB values associated with its cephalo-caudal progression, have been the subject of articles spanning nearly 60 years.^47–49 Even in the present study, with health care providers sensitized to the significance of clinical jaundice, there were several instances when its early appearance was missed (often attributable to confounding skin coloring) or a measured TSB was not considered excessive for the newborn's age in hours. Additionally, in most of the recently reported healthy term newborns who developed kernicterus, significant jaundice was almost certainly present before the first hospital discharge, judging from the height of TSB for age in hours at readmission.^1–6 Either the early icterus had not been noted or its pathologic intensity for postnatal age was not appreciated. TSB values must be excessive for age in hours in otherwise healthy term and near-term newborns to be at potential risk for BIND. It is in the context of identifying such newborns before dangerous levels are reached that a universal TSB screen, before discharge, is recommended as a more specific predictive vector than clinically recognized jaundice.

Statistical Approach

The statistical steps we have used to guide clinical decision-making are based on a nonparametric assessment and make no distributional assumptions. The nomogram has been specifically devised to be intuitively appealing to the clinician in daily practice. The clinician is interested in the probability that the newborn will or will not develop significant hyperbilirubinemia. In this scenario, data on sensitivity and specificity, ROC curves, and negative or positive predictive values do not always suffice. Also, the application of sensitivity and specificity to test results that can have a continuous distribution of values is not clinically practical.³¹ In contrast, the LR has the ability to revise the prior probability of disease upwards or downwards based on the subsequent test result. For continuous variables, the LR (or likelihood quotient) is the ratio of two probabilities, the probability that a given predischarge TSB value predicts the risk of disease (the true positive fraction) divided by the probability of the same test result when there is no disease (the false-positive fraction). The use of LR for predicting an outcome of clinically significant hyperbilirubinemia or disease (outcome of a TSB level in the high-risk zone) encompasses the impact of clinical and demographic risk factors. These contributory factors affect the density distribution of the TSB values and therefore the LR summarizes all these factors into a single clinically relevant index.^31–33 Because TSB values reflect the combined effects of bilirubin production and hepatic excretion, the reasons why successive TSB values that jump track require further evaluation.

Universal Screening

Based on our data (Table 3), the probability of subsequent hyperbilirubinemia in our study population as a whole may be expressed as a ratio of 1:22 for disease and no disease (126 with and 2714 without disease). The overall risk is none in the low-risk zone, nearly halved (1:45) in the lower-intermediate zone, tripled in the upper-intermediate zone (1:7) and increased 14-fold in the high-risk zone (2:3) newborns. Considering the threshold used to rationalize predischarge screening for a variety of congenital inherited disorders, these statistics provide justification for institution of a policy of universal TSB screening. Our recommendation for universal TSB screening performed at the time of the universal metabolic screening would be cost-effective because of the targeted bilirubin follow-up facilitated and encouraged by the nomogram as opposed to medical decisions not based on risk assessment.^{51 ,52} Low-risk zone newborns who were screened between 18 to 72 hours age comprised 61.8% of our study population. They represent newborns who either were in the low-risk zone or moved into the low-risk zone postdischarge. None of these newborns moved into the high-risk zone, required phototherapy or other than minimal intervention, such as counseling on feeding techniques. Bilirubin follow-up of this large component of the population, once screened, could be safely limited to a visual assessment of jaundice by an experienced observer. In the future, significantly more accurate noninvasive technologies now under development to measure bilirubin staining of the skin and its relation to serum bilirubin level may suffice for both predischarge and postdischarge TSB measurements and may theoretically offer an additional estimate of toxic risk.^{30 ,52}

This nomogram, developed from a diverse population, attempts to anticipate risk of an errant experience for a newborn who unexpectedly develops significant hyperbilirubinemia. We initially labeled the low-risk zone by the 50th percentile. Its predictive ability was nearly similar to that of the 40th percentile. However, in view of the unavoidable problems^25–27 in measurement of TSB (at least ±0.5 mg/dL), and the fact that many near-term newborns (35/36 weeks GA) are discharged as if they were at term (as in the clinical case described in the “Results” section), the 40th percentile was considered a safer demarcator. We made painstaking efforts to maintain accuracy and precision in bilirubin measurements by using a single laboratory. A consistent liaison and communication between a local laboratory and the pediatrician would also be effective in monitoring for variation in bilirubin accuracy. The conservative definition of the 40th percentile low-risk zone demarcator minimizes the prospect of an errant experience that might occur in a near-term newborn with multiple risk factors, or when a universal screen is performed at 18 rather than at age 24 hours or more. The low-risk zone designated by our data, as below the 40th percentile track, may not be applicable worldwide. However, the LR for each of the bilirubin defined risk zones in our nomogram can be used at geographic sites with different prior probabilities of significant hyperbilirubinemia to calculate site-specific risk assessment (see Table 3 legend).

Newborns Who Are Placed in the High-risk Zone Before Discharge

As described earlier, we observed 18 newborns who for no identified reason were in the high-risk zone and needed phototherapy before age 60 hours. They were kept in the hospital for further evaluation and interventions. Because their predischarge serial TSB values had already placed them in the disease category, they did not belong in the nomogram to predict disease. Similarly, newborns with known increased risk secondary to ABO and Rh incompatibility with a positive Coombs test were excluded. However, when included in the nomogram, the predischarge and prephototherapy TSB values did not appear to alter the 95th percentile demarcator. Instead, they appeared to effect the low-risk demarcator at age 18 to 30 hours. As expected, the TSB values were located disproportionately in the high-risk or upper- or intermediate-risk zones depending on their rate of bilirubin production and capacity for hepatic excretion. Subsequent tracking of these newborns was markedly aided by the use of the nomogram. Further diagnostic evaluation of any newborn placed in the high- and intermediate-risk zone newborns would help characterize their hyperbilirubinemia as related to increased production (measurement of carbon monoxide production) versus a range of hepatic excretion defects compounded by an increased entero-hepatic circulation, or to a combination of all three.⁵⁴ Furthermore, any newborn who reaches and remains in the high-risk zone would benefit from long-term follow-up for sequelae of both acute and chronic BIND.