Andrea C. Wickremasinghe

Incidence, Etiology, and Outcomes of Hazardous Hyperbilirubinemia in Newborns

BACKGROUND AND OBJECTIVES: Total serum bilirubin (TSB) levels ≥30 mg/dL are rare but potentially hazardous. A better understanding of their incidence, causes, and outcomes could help inform preventive efforts. METHODS: We identified infants born ≥35 weeks’ gestational age from 1995–2011 in Kaiser Permanente Northern California (n = 525 409) and examined the medical records of infants with a TSB ≥30 mg/dL to determine etiology and the occurrence of acute bilirubin encephalopathy. We reviewed inpatient and outpatient encounters through 2013 for evidence of sensorineural hearing loss (SNHL) or cerebral palsy (CP). RESULTS: We identified 47 infants with TSB ≥30 mg/dL (8.6 per 100 000 births). In 44 infants (94%), the hyperbilirubinemia occurred after the initial birth hospitalization. The etiology was not identified in 33 (70%). Glucose-6-phosphate dehydrogenase (G6PD) activity was measured in only 25 (53%) of whom 10 (40%) were deficient. Four children had acute bilirubin encephalopathy of whom 2 developed both CP and SNHL, and 1 developed isolated SNHL. These 3 infants all had G6PD deficiency and TSB >40 mg/dL. One additional 35-week infant with TSB 38.2 mg/dL had SNHL. CONCLUSIONS: Hazardous (≥30 mg/dL) hyperbilirubinemia is a rare event. No etiology could be identified from the clinical record in most cases. G6PD deficiency was the leading cause of hazardous hyperbilirubinemia when an etiology was identified, but many were not tested. Chronic, bilirubin-induced neurotoxicity was uncommon and occurred only in the setting of additional risk factors and TSB values well over (>15 mg/dL) the American Academy of Pediatrics exchange transfusion thresholds.

Neonatal Phototherapy and Infantile Cancer

OBJECTIVE: To determine whether neonatal phototherapy is associated with cancer in the first year after birth. METHODS: We analyzed a data set from the California Office of Statewide Health Planning and Development that was created by linking birth certificates, death certificates, and hospital discharge abstracts up to age 1 year. Subjects were 5 144 849 infants born in California hospitals at ≥35 weeks’ gestation from 1998 to 2007. We used International Classification of Diseases, Ninth Revision codes to identify phototherapy at <15 days and discharge diagnoses of cancer at 61 to 365 days. We adjusted for potential confounding variables by using traditional and propensity-adjusted logistic regression models. RESULTS: Cancer was diagnosed in 58/178 017 infants with diagnosis codes for phototherapy and 1042/4 966 832 infants without such codes (32.6/100 000 vs 21.0/100 000; relative risk 1.6; 95% confidence interval [CI], 1.2–2.0, P = .002). In propensity-adjusted analyses, associations were seen between phototherapy and overall cancer (adjusted odds ratio [aOR] 1.4; 95% CI, 1.1–1.9), myeloid leukemia (aOR 2.6; 95% CI, 1.3–5.0), and kidney cancer (aOR 2.5; 95% CI, 1.2–5.1). The marginal propensity-adjusted absolute risk increase for cancer after phototherapy in the total population was 9.4/100 000 (number needed to harm of 10 638). Because of the higher baseline risk of cancer in infants with Down syndrome, the number needed to harm was 1285. CONCLUSIONS: Phototherapy may slightly increase the risk of cancer in infancy, although the absolute risk increase is small. This risk should be considered when making phototherapy treatment decisions, especially for infants with bilirubin levels below current treatment guidelines.

Retrospective Cohort Study of Phototherapy and Childhood Cancer in Northern California

OBJECTIVE: To investigate the association between neonatal phototherapy use and childhood cancer. METHODS: This retrospective cohort study included 499 621 children born at ≥35 weeks’ gestation from 1995 to 2011 in Kaiser Permanente Northern California hospitals, who survived to hospital discharge and were followed ≥60 days. We obtained data on home and inpatient phototherapy, covariates, and cancer incidence from electronic records. We used propensity-adjusted Cox and Poisson models to control for confounding and unequal follow-up times. RESULTS: There were 60 children with a diagnosis of cancer among 39 403 exposed to phototherapy (25 per 100 000 person-years), compared with 651 of 460 218 unexposed children (18 per 100 000 person-years; incidence rate ratio [IRR] 1.4; P = .01). Phototherapy was associated with increased rates of any leukemia (IRR 2.1; P = .0007), nonlymphocytic leukemia (IRR 4.0; P = .0004), and liver cancer (IRR 5.2; P = .04). With adjustment for a propensity score that incorporated bilirubin levels, chromosomal disorders, congenital anomalies, and other covariates, associations were no longer statistically significant: Adjusted hazard ratios (95% confidence intervals) were 1.0 (0.7–1.6) for any cancer, 1.6 (0.8–3.5) for any leukemia, 1.9 (0.6–6.9) for nonlymphocytic leukemia, and 1.4 (0.2–12) for liver cancer. Upper limits of 95% confidence intervals for adjusted 10-year excess risk were generally <0.1% but reached 4.4% for children with Down syndrome. CONCLUSIONS: Although phototherapy use was associated with increased cancer rates (particularly nonlymphocytic leukemia), control for confounding variables eliminated or attenuated the associations. Nonetheless, the possibility of even partial causality suggests that avoiding unnecessary phototherapy may be prudent.

Risk for Cerebral Palsy in Infants With Total Serum Bilirubin Levels at or Above the Exchange Transfusion Threshold: A Population-Based Study

IMPORTANCE Exchange transfusion is recommended for newborns with total serum bilirubin (TSB) levels thought to place them at risk for cerebral palsy (CP). However, the excess risk for CP among these infants is unknown. OBJECTIVE To quantify the risks for CP and CP consistent with kernicterus that are associated with high TSB levels based on the 2004 American Academy of Pediatrics exchange transfusion threshold (ETT) guidelines. DESIGN, SETTING, AND PARTICIPANTS We enrolled 2 cohorts from a population of 525,409 infants in the Late Impact of Getting Hyperbilirubinemia or Phototherapy (LIGHT) birth cohort. Eligible infants were born at a gestational age of at least 35 weeks at 15 hospitals within the Kaiser Permanente Northern California integrated medical care delivery system from January 1, 1995, through December 31, 2011. EXPOSURES The exposed cohort included all 1833 infants with at least 1 TSB measurement at or above the ETT based on age at testing, gestational age, and results of direct antiglobulin testing. The unexposed cohort was a 20% random sample of 104 716 infants with TSB levels below the ETT. MAIN OUTCOMES AND MEASURES A pediatric neurologist blinded to the TSB levels reviewed medical records to determine the presence of CP, defined as a nonprogressive congenital motor dysfunction with hypertonia or dyskinesia. Cerebral palsy was judged to be consistent with kernicterus if magnetic resonance imaging of the brain revealed bilateral globus pallidus injury in the setting of dyskinetic CP. RESULTS We identified CP in 7 of 1833 exposed (0.4%) vs 86 of 104 716 unexposed (0.1%) infants (relative risk, 4.7 [95% CI, 2.2-10.0]). Absolute risk differences were 0.2% (95% CI, 0%-0.5%) for a TSB level 0 to 4.9 mg/dL above the ETT (n = 1705), 0.9% (95% CI, 0.1%-5.3%) for a TSB level 5.0 to 9.9 mg/dL above the ETT (n = 102), and 7.6% (95% CI, 2.1%-24.1%) for a TSB level 10 mg/dL or more above the ETT (n = 26). Cerebral palsy consistent with kernicterus occurred in 3 infants (incidence, 0.57 per 100,000 births); all 3 had TSB levels of more than 5.0 mg/dL above the ETT and at least 2 risk factors for neurotoxicity, such as prematurity, glucose-6-phosphate dehydrogenase deficiency, or hypoxia-ischemia. CONCLUSIONS AND RELEVANCE Cerebral palsy consistent with kernicterus occurred only in infants with 2 or more risk factors for neurotoxicity and TSB levels of more than 5 mg/dL above the ETT. Among infants with lower degrees of TSB level elevation, the excess risk for CP is minimal.

Risk of Sensorineural Hearing Loss and Bilirubin Exchange Transfusion Thresholds

BACKGROUND AND OBJECTIVES: High bilirubin levels are associated with sensorineural hearing loss (SNHL). However, few large studies of relative and excess risk exist. We sought to quantify the risk of SNHL in newborns who had bilirubin levels at or above American Academy of Pediatrics exchange transfusion thresholds (ETT). METHODS: Infants born at ≥35 weeks gestation in 15 Kaiser Permanente Northern California hospitals from 1995-2011 were eligible (N = 525 409). We used a nested double cohort design. The exposed cohort included subjects with ≥1 bilirubin level at or above ETT. The unexposed cohort was a 3.6% random sample of subjects with all bilirubin levels below ETT (10 unexposed per exposed). An audiologist, blinded to bilirubin levels, reviewed the charts of children in whom SNHL had been diagnosed before age 8 years to confirm the diagnosis. We calculated Cox proportional hazard ratios for time to diagnosis of SNHL. RESULTS: SNHL was confirmed in 11 (0.60%) of the 1834 exposed subjects and in 43 (0.23%) of the 19 004 unexposed. Only bilirubin levels ≥10 mg/dL above ETT were associated with a statistically significant increased risk of SNHL (hazard ratio: 36 [95% confidence interval (CI): 13 to 101]). Likewise, only bilirubin levels ≥35 mg/dL were associated with a statistically significant increased risk of SNHL (hazard ratio: 91 [95% CI: 32 to 255]). For subjects with total serum bilirubin levels 0 to 4.9 mg/dL above ETT, the upper limit of the 95% CI for excess risk was 0.5%. CONCLUSIONS: Only bilirubin levels well above ETT were associated with SNHL. At lower bilirubin levels, the excess risk of SNHL was low.

Black Race Is Not Protective Against Hazardous Bilirubin Levels

Although black race is considered protective against hyperbilirubinemia, black infants appear at increased risk of kernicterus. We found that although black infants have a lower risk of developing total serum bilirubin levels ≥ 20 mg/dL than white infants, they appear at greater risk of developing levels ≥ 30 mg/dL.

Catecholamine-resistant hypotension and myocardial performance following patent ductus arteriosus ligation

Objective:We performed a multicenter study of preterm infants, who were about to undergo patent ductus arteriosus ligation, to determine whether echocardiographic indices of impaired myocardial performance were associated with subsequent development of catecholamine-resistant hypotension following ligation.Study Design:A standardized treatment approach for hypotension was followed at each center. Infants were considered to have catecholamine-resistant hypotension if their dopamine infusion was >15 μg kg–1min–1. Echocardiograms and cortisol measurements were obtained between 6 and 14 h after the ligation (prior to the presence of catecholamine-resistant hypotension).Result:Forty-five infants were enrolled, 10 received catecholamines (6 were catecholamine-responsive and 4 developed catecholamine-resistant hypotension). Catecholamine-resistant hypotension was not associated with decreased preload, shortening fraction or ventricular output. Infants with catecholamine-resistant hypotension had significantly lower levels of systemic vascular resistance and postoperative cortisol concentration.Conclusion:We speculate that low cortisol levels and impaired vascular tone may have a more important role than impaired cardiac performance in post-ligation catecholamine-resistant hypotension.

Efficacy of Subthreshold Newborn Phototherapy During the Birth Hospitalization in Preventing Readmission for Phototherapy

Importance Treatment of jaundiced newborns with subthreshold phototherapy (phototherapy given to newborns with bilirubin levels below those recommended in American Academy of Pediatrics [AAP] guidelines) is common. However, the use of subthreshold phototherapy may have risks and increase costs, and, to date, it has not been systematically studied in newborns. Objectives To estimate the efficacy of subthreshold phototherapy for newborns with total serum bilirubin (TSB) levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold during the birth hospitalization in preventing readmissions for phototherapy, and to identify predictors of readmission for phototherapy. Design, Setting, and Participants Retrospective cohort study of 25 895 newborns born at 35 or more weeks’ gestation, born in 1 of 16 Kaiser Permanente Northern California hospitals from January 1, 2010, through December 31, 2014, with at least 1 TSB level from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold and not exceeding the threshold during the birth hospitalization. Data were analyzed from November 1, 2015, to November 28, 2017. Exposure Subthreshold phototherapy during the birth hospitalization. Main Outcomes and Measures Readmission for phototherapy. Results Among 25 895 newborns with qualifying TSB levels from 0.1 to 3.0 mg/dL below the appropriate AAP phototherapy threshold, 4956 (19.1%) received subthreshold phototherapy and 241 of these (4.9%) were readmitted for phototherapy compared with 2690 of 20 939 untreated newborns (12.8%) (unadjusted odds ratio [OR], 0.35; 95% CI, 0.30-0.40). In a logistic regression model, adjustment for confounding variables, including gestational age, race/ethnicity, formula feedings per day, and the difference between the TSB level and the phototherapy threshold, strengthened the association (OR, 0.28; 95% CI, 0.19-0.40). Estimated numbers needed to treat ranged from 60.8 in the lowest quintile of predicted risk to 6.3 in the highest quintile. Newborns who received formula feedings had lower adjusted odds of readmission for phototherapy compared with exclusively breastfed newborns (OR, 0.58; 95% CI, 0.47-0.72 for >0 to <2 formula feedings per day; OR, 0.24; 95% CI, 0.21-0.27 for ≥6 formula feedings per day). Subthreshold phototherapy was associated with a 22-hour longer length of stay (95% CI, 16-28 hours). Conclusions and Relevance Subthreshold phototherapy during the birth hospitalization is effective in preventing readmissions for phototherapy; however, for each readmission prevented, many newborns require phototherapy who would otherwise not need it.

Phototherapy and Risk of Type 1 Diabetes

BACKGROUND AND OBJECTIVE: Increases in both phototherapy use and the incidence of type 1 diabetes mellitus (DM-1) have been reported. One large study has suggested a strong association between them. Our objective was to quantify any association between neonatal phototherapy and DM-1 in a northern California integrated health care system. METHODS: This retrospective cohort study included 499 642 children born at ≥35 weeks’ gestation in 15 Kaiser Permanente Northern California hospitals from 1995 to 2011 and followed until March 31, 2014. We ascertained phototherapy, bilirubin levels, and other covariates from electronic records. We identified DM-1 cases using a diabetes registry and inpatient and outpatient diagnoses. We used traditional and propensity-adjusted Cox models to quantify associations. RESULTS: Phototherapy use increased from 2.7% in 1995 to 16.0% in 2011. DM-1 was diagnosed in 37 of 39 406 children who had received phototherapy (15.1 per 100 000 person-years; mean follow-up 6.2 years) and 712 of 460 236 who had not (18.8 per 100 000 person-years; mean follow-up 8.2 years). There was no evidence of increasing diabetes incidence. We found no association between phototherapy and DM-1 in either unadjusted analyses (incidence rate ratio 0.81; 95% confidence interval, 0.56 to 1.12) or analyses adjusted for hyperbilirubinemia and other covariates (hazard ratio 1.06; 95% confidence interval, 0.78 to 1.45). DM-1 incidence was most strongly associated with race and ethnicity, with whites at highest risk (25.6 per 100 000) and Asians at lowest risk (8.9 per 100 000). CONCLUSIONS: We found no evidence of increased DM-1 risk in children who had received phototherapy.

Invited Commentary: Does Neonatal Hyperbilirubinemia Cause Asthma?

In an analysis of data from the US Collaborative Perinatal Project, Huang et al. (Am J Epidemiol. 2013;178(12):1691-1697) report an association between neonatal total serum bilirubin levels and childhood asthma. To consider the implications of this finding, we need to evaluate whether the association is causal. The results do not appear to be due to chance or any obvious biases. It is likely that the observed association is the result of a common cause of both hyperbilirubinemia and asthma (confounding). Polymorphisms in the glutathione S-transferase gene are a potential genetic confounder. The glutathione S-transferase M1-null phenotype has been linked to both neonatal hyperbilirubinemia and asthma in several studies. Before making any changes in practice aimed at lowering peak bilirubin levels to reduce asthma risk, it is vital to determine not only whether the association between higher bilirubin levels and asthma risk is causal, but also whether interventions to reduce peak bilirubin levels (or their duration) are associated with decreased risk of asthma (without evidence of other adverse effects). The study by Huang et al. should encourage further investigation of these questions.