JAMA Pediatrics Journal Club Slides: Effect of Laboratory Calibration of Neonatal Bilirubin

1. JAMA Pediatrics Journal Club Slides:Effect of Laboratory Calibration of Neonatal Bilirubin Kuzniewicz MW, Greene DN, Walsh EM, McCulloch CE, Newman TB. Association between laboratory calibration of a serum bilirubin assay, neonatal bilirubin levels, and phototherapy use. JAMA Pediatr. Published online April 11, 2016. doi:10.1001/jamapediatrics.2015.4944.

2. Introduction Background • The Vitros BuBc Neonatal Bilirubin assay (Ortho Clinical Diagnostics) is a widely used reflectance spectrophotometry assay for measuring serum bilirubin. • On May 21, 2012, Ortho Clinical Diagnostics notified customers that it had “received customer complaints of positively biased results using Vitros... BuBc Slides.” • Based on customer input and an internal investigation, the company adjusted the calibrator values for the Vitros BuBc Slides. Study Objective • To investigate the clinical effect of recalibration on maximum total serum bilirubin (TSB) levels and phototherapy use in Kaiser Permanente Northern California (KPNC), a large, integrated health care delivery system.

3. Methods Study Design • Descriptive study comparing TSB levels and phototherapy use before and after recalibration. Setting • KPNC, a large, integrated health care delivery system. Intervention • The hospital laboratories implemented the manufacturer-adjusted calibrators between May 24, 2012, and June 13, 2012. Patients • All live births ≥35 weeks’ gestation at 12 KPNC facilities that used universal bilirubin screening with a TSB. • Prerecalibration cohort (January 1, 2010, through April 30, 2012): n = 61 677 • Postrecalibration cohort (July 1, 2012, through December 31, 2013): n = 42 571.

4. Methods Outcomes • TSB ≥15 mg/dL (to convert to micromoles per liter, multiply by 17.104) and TSB ≥American Academy of Pediatrics (AAP) phototherapy threshold. • All TSB values from each infant’s first month after birth were obtained. • Each TSB value was compared with the 2004 AAP phototherapy guideline, based on hour-specific TSB value, gestational age, and direct antiglobulin testing result. • Phototherapy during the birth hospitalization and readmissions. • An admission with either of the following: • An International Classification of Diseases, Ninth Revisioncode for phototherapy (99.83) and an order for phototherapy in the electronic medical record. • An electronic medical record flowsheet entry for phototherapy. Statistical Analysis • Outcomes were compared between the 2cohorts using an autoregressive integrated moving average (ARIMA) time-series model.

5. Results • Infants in the 2 periods were similar in terms of birth weight and percentage born before 37 weeks’ gestation. • The mean maximum TSB in the postrecalibration period was 1.25 mg/dL lower (95% CI, 1.19-1.31; P < .001) than in the prerecalibration period. • In the ARIMA models, the postrecalibration period was associated with the following: • 8.0% (95% CI, 7.1%-8.8%) absolute reduction in infants with a TSB level ≥15 mg/dL. • 4.8% (95% CI, 4.1%-5.4%) absolute reduction in infants with a TSB level ≥AAP phototherapy threshold. • 5.5% (95% CI, 5.1%-6.0%) absolute reduction in infants receiving phototherapy during the birth hospitalization. • 2.0% (95% CI, 1.7%-2.3%) absolute reduction in phototherapy readmissions.

6. Results Monthly Rates of Phototherapy Administration and Hyperbilirubinemia

7. Results TSB Levels and Phototherapy Rates

8. Comment • Modest systematic reductions in TSB values resulted in a major reduction in the percentage of infants with clinically significant hyperbilirubinemia. • Recalibration led to a significant reduction in use. • For every 10 000 deliveries, recalibration resulted in a reduction of 1300 patient-days/year and 4500 fewer TSB tests/year. • Recalibration saved $1.4 million for every 10 000 deliveries (estimating an inpatient hospitalization day at $1000 and the cost of a TSB test and blood draw at $30). • Approximately 380 laboratories across the United States were enrolled in College of American Pathologists proficiency testing for neonatal total bilirubin using the Vitros assay. • KPNC hospital laboratories represented about 6% of those enrolled. • The overall health care resources lost to analytical inaccuracy far exceed what was calculated for the KPNC health care system.

9. Comment • Calibration shifts in laboratory assays can have major clinical implications. • While theoretical models can predict these effects, it is rare to capture the consequential extent of the changes. • This study provides a powerful example of how small changes in measurement methods can lead to large changes in diagnosis and treatment. • The data from the Vitros BuBc assay recalibration highlight the following needs: • Increased integration of laboratory expertise into clinical guidelines. • Support of international initiatives to standardize laboratory measurements.

10. Contact Information • If you have questions, please contact the corresponding author: • Michael W. Kuzniewicz, MD, MPH, Division of Research, Kaiser Permanente Northern California, 2000 Broadway Ave, Oakland, CA 94612 (michael.w.kuzniewicz@kp.org). Funding/Support • This project was supported by grant R01HS020618 from the Agency of Healthcare Research and Quality. Conflict of Interest Disclosures • None reported.