Prevalence and burden of illness of treated hemolytic neonatal hyperbilirubinemia in a privately insured population in the United States

Neonatal hyperbilirubinemia (NHB), a common condition in newborn infants, results from elevated blood bilirubin levels. The excessive bilirubin manifests as yellowing of the skin and the normally white outer layer of the eyeballs [1‐3]. While most cases resolve quickly without intervention, NHB is a common reason for inpatient readmissions, and admission to the neonatal intensive care unit (NICU) [4, 5]. The prevalence of NHB is not precisely known, however, estimates suggest that approximately 50% full-term and 80% preterm [6] newborns develop some form of NHB. High-risk NHB occurs in 8–9% of neonates during the first week after birth [5, 7].

The origin of NHB may be physiologic or pathologic. Physiologic NHB may be caused by neonate immaturity and the resulting inability to cope with elevated levels of bilirubin [8]. This benign form resolves itself in 2–3 weeks following birth, and usually without treatment [1, 2]. Pathologic NHB may be caused by hemolytic disease of the newborn (HDN), red blood cell (RBC) enzyme deficiency, or impaired bilirubin excretion [9]. HDN results from incompatibilities between maternal and fetal blood types (Rh, ABO or a minor blood group), which may cause ruptures in fetal RBCs and elevated bilirubin levels. Hemolytic NHB usually appears within 24 h after birth [1, 2, 4].

The American Academy of Pediatrics (AAP) clinical practice guidelines address the assessment, screening, and treatment of NHB among infants at ≥35 weeks of gestation [10]. Risk assessment and treatment nomograms based on total serum bilirubin level, postnatal age in hours, and gestational age of the newborn with the presence or absence of risk factors are available to guide patient management [10]. Similar guidelines are not available for neonates at less than 35 weeks of gestation because of scant evidence-based data, differences in clinical manifestations and unclear treatment outcomes [11].

When treatment is indicated, AAP guidelines recommend phototherapy as the initial treatment [6, 10]. In cases where bilirubin levels continue to increase despite phototherapy, the guidelines recommend adding exchange transfusion of whole blood to the treatment regimen, typically in the NICU [2, 10]. For hemolytic cases, AAP guidelines recommend the administration of intravenous immunoglobulin (IVIg) as adjunctive therapy when bilirubin levels continue to rise despite intensive phototherapy [2, 10]. These challenges in management of high-risk hyperbilirubinemia substantially increase the urgency for safer and more effective screening and/or treatment options, especially when viewed against the knowledge that the permanent sequelae of kernicterus spectrum disorders (KSDs) might be prevented.

To the best of our knowledge, the prevalence of hemolytic NHB newborns receiving treatment has not been well characterized, and economic burden at the population level is poorly understood. Our study aimed to address this knowledge gap. We focused on newborns with hemolytic NHB who received treatment because the receipt of intervention indicated that those neonates met the AAP guideline for the recommendation of intervention in order to prevent severe NHB and the spectrum of associated complications [10, 12‐14].

To the best of our knowledge, this is the first study to estimate the prevalence of high-risk hemolytic NHB newborns receiving intervention, and to quantify the burden of hemolytic NHB in the US. The proportions of newborns with hemolytic NHB who received treatment were 0.46 to 0.55% in a privately insured population in the US. Although not prevalent, those high-risk hemolytic NHB neonates who received treatment were associated with substantial healthcare resource utilization and incremental economic burden.

NHB research in the U.S. has been limited, and prevalence estimates vary markedly in the handful of studies in the literature. In a systematic review that included 14 studies to examine the effects and outcomes of phototherapy, Woodgate and Jardine noted that about 50% of full-term and 80% preterm newborns developed jaundice [6]. In a survey at medical centers that practiced universal pre-discharge total serum bilirubin (TSB) screening, Bhutani et al. reported jaundice in 84% of healthy newborns ≥35 weeks GA [20]. Another study, which used inpatient data from the Healthcare Costs and Utilization Project (HCUP), reported 15.6% of newborns had jaundice [21]. These variations could, in part, be due to differences in the study population, case definitions (e.g., TSB level vs. visible jaundice), data sources, and underdiagnosis or underreporting of mild cases. Mild NHB typically resolves without intervention, and may not be fully captured in administrative claims (used in our study) and hospital discharge data (HCUP). Such cases may not be reflected in reimbursements because of bundled payments, which could result in an underestimation of general NHB prevalence.

Our study focused on NHB specifically with etiology of hemolytic diseases, and we found that approximately 7% of the NHB cases were hemolytic NHB. Our estimated prevalence of treated hemolytic NHB (ranging from 0.46–0.55%) was comparable to < 1% of significant hemolysis reported by Wagle and Deshpande [22]. Chang et al. estimated that about 6% of newborns ≥35 weeks GA received phototherapy at Kaiser Permanente hospitals [23]. Using our estimate that 7% of the NHB newborns in this study had hemolytic NHB along with the assumption that all the newborns in the Chang et al. study had NHB, we inferred that approximately 0.42% of newborns in Chang et al. were phototherapy-treated hemolytic NHB — which is close to our estimate. Treatment rates could vary remarkably as treatment practice across hospitals/institutions differ in how cases are identified and when treatment should be initiated [24, 25]. Additionally, prior literature suggested that NHB patients could be under-treated. One U.S. study showed that only approximately half (54%) of healthy term newborns for whom AAP clinical practice guidelines recommended phototherapy received treatment [26].

We found that treated hemolytic NHB newborns had significantly longer length of stay during their birth hospitalization, higher 30-day readmission rates, higher NICU use and slightly higher rates of physician office visits, compared to their matched counterparts. Length of stay of mothers’ delivery hospitalizations were also slightly longer in the treated hemolytic NHB cohort (2.9 days vs 2.5 days, data not shown). These findings suggest significant burden to patients, their caregivers, and the healthcare system. Prior studies have shown that NHB was as major cause of readmission. Approximately half (51%) of all readmissions occurring 2 weeks after birth were attributable to NHB [27]. The increase in physician office visits we reported was also consistent with available literature, which found that NHB was associated with increased parental awareness, and newborns receiving phototherapy had higher rates of outpatient visits [28].

We also found that hemolytic NHB newborns who received treatment incurred 2.6 times the average costs of their matched non-NHB counterparts during the first 30 days after birth. The majority of the incremental cost was derived from birth hospitalizations. Indirect costs associated with patients’ and caregivers’ quality of life as well as caregivers’ loss of productivity could not be evaluated using claims data. As of now, no prior study has examined the economic burden of hemolytic NHB. One earlier study estimated the average cost of childbirth via vaginal or caesarian at $18,329 or $27,866, respectively, in a private health plan [29]. Those estimates were close to the average costs, $20,568, of the sum of maternal delivery (mean (SD) = $15,413 ($20,010), data not shown) and newborn birth hospitalization ($5,155 ($50,080), Table 5) in the non-NHB cohort in our study. Such comparability might warrant the representativeness and generalizability of our study results to other privately insured populations. In this study, we found that the majority of treated hemolytic NHB newborns received phototherapy. A total of 15 (1%) newborns received IVIg or ET, which are recommended by AAP when bilirubin levels continue to rise despite intensive phototherapy. This group imposed even greater economic burden with average (SD) total one-month all-cause costs of $81,065 ($133,767) (data not shown).

We extrapolated our findings to the entire U.S. newborn population in 2016. The extrapolation estimated total healthcare expenditure of $271.9 million and incremental costs of $177.0 million among 18,872 treated hemolytic NHB newborns as compared with their counterparts without NHB during the first month after birth. Our extrapolation assumed our estimates were applicable to the U.S. newborn population mainly insured by private insurance plans or Medicaid. This projection should be interpreted with caution as privately insured populations tend to have higher socioeconomic status and healthcare expenditures than the Medicaid population [30]. Further research in the Medicaid newborn population is warranted to examine our assumptions and estimates.

We did not observe significant difference in neurodevelopment delay, language disorders, motor dysfunction, cerebral palsy, abnormal behavior, encephalopathy, hearing and vision loss between treated hemolytic NHB newborns and the matched non-NHB cohort during the first year of birth. However, the observation period was likely too short as many of these conditions might not be identifiable nor noticeable in the first year of life. Kernicterus, a brain injury resulting from severe NHB, was found in nine newborns, approximately 1.2% of all treated hemolytic NHB newborns during the one-year follow up. Kernicterus has been reported from 1.0 to 3.7 cases per 100,000 live birth in the literature [31, 32], but these incidence rates were estimated for the general population in contrast to the high-risk hemolytic NHB population (treated) in this study. As hemolytic NHB was strongly correlated with higher incidences of birth trauma, polycythemia, and other subsequent morbidities which could also cause neurodevelopment disorders, neurodevelopment disorders in this population could be due to a combination of hemolytic NHB and other morbidities, rather than hemolytic NHB alone.

Effective management of high-risk hemolytic NHB is critical to reduce the impact of disease burden on patients, their caregivers, and the healthcare system. Several studies have investigated comprehensive approaches, such as pre-discharge bilirubin screening for all newborns [25], or the implementation of a standard pathway including treatment algorithms (e.g., requiring irradiance compliance to ensure consistent delivery of effective phototherapy) and education to increase awareness among clinicians [33]. These comprehensive approaches have demonstrated success in reducing costs, length of stay [33] and hospital readmission rates [25]. In addition, new treatment options are needed. For example, an investigational treatment – stannsoporfin (SnMP, a heme oxygenase inhibitor) with or without phototherapy was studied for use in the management of NHB or hemolytic NHB [34, 35].

This is likely the first study estimating the prevalence of newborns with hemolytic NHB who received intervention in the U.S. This high-risk population imposes a substantial burden of healthcare resource utilization and incremental costs on newborns, their caregivers, and the healthcare system. Effective management protocols and emerging new treatments may help to mitigate the overall burden of hemolytic NHB.