The HCUP KID is the largest publicly available all-payer pediatric inpatient care database in the US, yielding national estimates for hospital stays of patients under 21 years old.⁹ The dataset encompasses approximately 3.1 million hospitalizations (weighted=5.9 million) and includes clinical and resource data extracted from hospital billing discharge records. The KID consists of 10% of normal newborns born within the hospital and 80% other newborns/pediatric cases selected from each hospital.⁹ Its extensive sample size allows for analysis of rare pediatric conditions,⁹ such as nHSV.

The study population included all neonates in the 2019 HCUP KID born in a hospital or admitted ≤28 days from birth. nHSV associated hospitalizations were defined as a hospital admission ≤28 days of life where the patient had ≥1 International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for HSV infection (Table 1). To address the 2015 transition from ICD-9-CM to ICD-10-CM, codes from the Flagg study⁶ were converted using a mapping and deduplication process with the ICD10Data.com tool and clinical review by two reviewers. Neonates with signs of sepsis may be preemptively diagnosed with nHSV and treated empirically with intravenous acyclovir, the recommended treatment for nHSV, until test results return. To reduce including probable cases and maintain consistency with prior nHSV surveillance studies, we restricted our analysis to patients with a length of stay (LOS) >5 days or who died ≤5 days.⁸

Since each record in the dataset represented a hospital discharge, we combined records associated with readmissions and transfers. For readmissions, we matched records indicating an admission at birth to those indicating admissions ≤28 days of life using race, sex, hospital region, patient median household income per ZIP code, admission month, and LOS. Matches were validated through manual review of the Diagnosis Related Group (DRG) and diagnosis codes. Transfers were similarly identified, matching records involving transfers to other hospitals with records of transfers from other hospitals. In instances of readmission or transfer, we counted matched records for a unique individual as a single record by combining LOS and hospitalization cost.

The crude nHSV incidence rate (per 100,000 hospital births) was calculated by dividing the number of estimated nHSV cases by the total number of hospital births, overall and by hospital region (Northeast, Midwest, South and West). We further stratified by other covariates including: sex (male, female), race/ethnicity (based on AHRQ’s uniform coding¹⁰; Non-Hispanic White [NHW], Non-Hispanic Black [NHB], Hispanic, “Additional Race, Non-Hispanic” [combining Asian or Pacific Islander, Native American, and Other due to small case counts]), median household income for patient’s ZIP Code (<$48,000, $48,000 – $60,999, $61,000 – $81,999, >$82,000), primary payer (public insurance, private insurance, self-pay, no charge/other), and hospital location/teaching status (rural, urban non-teaching, urban teaching).

We also assessed nHSV incidence by gestational age at delivery, using ICD-10-CM codes P07.20-P07.26 for extreme immaturity and P07.30-P07.39 for gestation <37 weeks, classifying a record as preterm birth (gestational age <37 weeks). Records not containing these codes were considered representing term births (gestational age ≥37 weeks). Route of delivery (Cesarean or vaginal) was also evaluated for those infants diagnosed during the birth admission with information on route of delivery.

We assessed nHSV healthcare utilization by examining LOS and associated payments for each case, using variables already included in the 2019 HCUP KID. In addition to estimating hospital charges (amount billed by hospitals) associated with nHSV, we also estimated hospital costs (actual expenses incurred by hospitals), using the HCUP Cost-to-Charge Ratio (CCR).¹¹ We included both hospital charges and costs to allow for fair comparison to Flagg’s study and to provide a more realistic cost estimate, respectively. For cases where matched readmissions or transfers were identified, the total LOS and total hospital charges/costs were calculated as the sum of days or costs for all relevant hospitalizations. To make costs comparable across years, we adjusted all cost data to 2019 US dollars using the Personal Consumption Expenditures (PCE) index for hospitals.^12,13

Furthermore, we calculated the proportion of nHSV cases diagnosed at birth by dividing the number of cases diagnosed at birth admission by the total number of identified cases. We also determined the CFR for nHSV by dividing the number of deaths during hospitalization by the total number of identified cases.

Incidence rates and 95% confidence intervals (CI) were calculated overall for the US, as well as by US census region of the hospital. We stratified based on all covariates described above. For continuous data, we reported the interquartile range (IQR), mean, median, total values and 95% CIs. All rates and 95% CIs are unadjusted. We inferred statistical significance when 95% CIs did not overlap. All analyses were performed using SAS version 9.4 (SAS Institute Inc) and weighted using HCUP KID discharge weights⁹ for national estimation.

We estimated 815 patients were admitted to a US hospital with an associated HSV ICD-10-CM code ≤28 days of life, regardless of LOS (Table 2, Figure 1). Among these, we estimated 561 patients who had a hospital stay of >5 days or died ≤5 days. Nearly half (49.7% [95% CI: 44.9–54.5%]) of the nHSV patients were diagnosed during birth admission.

We estimated an incidence rate of nHSV of 15.7 per 100,000 hospital births (95% CI: 14.5 – 17.1) in the US in 2019. All subsequent incidence rates are provided per 100,000 hospital births. The highest incidence rate was in the South (21.3; 95% CI: 19.0 – 23.9) and lowest in the West (8.7; 95%: 6.8 – 11.0, Table 2). Incidence rates for males (16.3; 95% CI: 14.5 – 18.2) and females (15.2; 95% CI: 13.4 – 17.1) were not significantly different (Table 3).

While 23.5% of nHSV cases were NHB infants, the incidence rate among NHB infants (27.3; 95% CI: 22.8 – 32.4) was statistically significantly higher compared to all other race/ethnicity groups, including NHW (14.3; 95% CI: 12.6 – 16.3), Hispanic (15.2; 95% CI: 12.3 – 18.5), and other race/ethnicity groups (13.6; 95% CI: 10.4 – 17.4). Regionally, incidence rates among NHB infants were generally higher than other race/ethnicity groups, with a statistically significant difference observed in the Midwest, where the rate among NHB infants (28.0; 95% CI: 18.2–41.1) significantly exceeded that of NHW infants (10.6; 95% CI 7.7–14.2) (Table 3).

Most (71.6%) infants with nHSV were born to a parent covered by public insurance, with an incidence rate over three times that of those covered by private insurance (25.2, 95% CI: 22.8 – 27.8 vs. 7.5, 95% CI: 6.3 – 9.0) (Table 3). Among infants diagnosed with nHSV, 24.7% were born preterm. The incidence rate in the preterm group (41.4; 95% CI: 34.8 – 49.0) was three times that of infants delivered at term (13.1; 95% CI: 11.9 – 14.4) (Table 3). This pattern was observed for each US region. Only neonates diagnosed with nHSV during birth admission (n=279, 49.7%) had delivery information; of those, 46.6% were delivered by Cesarean section and 53.4% were delivered vaginally; of those delivered vaginally, 38.2% were preterm.

Most infants with nHSV were admitted to urban teaching hospitals (86.2%), with an incidence rate of 18.5 (95% CI: 16.9 – 20.2) which was nearly three times that of infants admitted to rural hospitals (6.5; 95% CI: 4.0 – 9.8), and two times that of infants admitted to urban non-teaching hospitals (9.1; 95% CI: 6.8 – 11.8) (Table 3). Stratified by US census region, the incidence rate of nHSV was highest in Southern urban teaching hospitals (24.4; 95% CI: 21.5 – 27.7) compared to urban teaching hospitals in other regions; the second highest incidence rate was in the Midwest (18.4; 95% CI: 14.9 – 22.5) (Table 3).

Almost half (43.2%) of infants with nHSV were from households in zip codes with a median household income in the lowest quartile, where the incidence rate was 24.5 (95% CI: 21.6 – 27.8), three times that of the highest income category (7.8; 95% CI: 6.0 – 10.0) and nearly double that of the second-highest income category (13.0; 95% CI: 10.8 – 15.6) (Table 3). This same trend was observed when stratified by US census region.

The median LOS for infants with nHSV was 15 days (95% CI: 14 – 17 days), and the median and mean hospitalization costs were $27,000 (95% CI: $23,000– $31,000), and $52,000 (95% CI: $44,000– $59,000), respectively (Table 4). Total nHSV hospitalization costs were $28.9 million, and total unadjusted hospitalization charges were $116.9 million. Stratified by US census region, the South had the highest per-region hospitalization cost, estimated at $15.2 million, nearly three times that of the next highest region (Midwest, $5.4 million).

Of the 561 nHSV cases in 2019, we estimated 26 in-hospital deaths (95% CI: 15–37), for an overall 4.6% CFR (95% CI: 2.6–6.6%), slightly higher than the CFR estimated in 2006 (4.1%, 95% CI: 1.6–6.6%).⁶ There were no significant differences in CFRs by US census region. CFRs were similar between nHSV patients admitted at vs. after birth (Table 5). However, the CFR among patients born prematurely was nearly four times that of those born ≥37 weeks (Table 5).

The HCUP KID database only includes data from inpatient hospitalizations, potentially missing cases of nHSV treated in outpatient or not in a hospital setting.¹⁹ However, based on national guidance on the management of nHSV and the accepted standard of care, we assumed all identified cases would commence antiviral treatment in a hospital setting.⁵ Our analysis is further limited to hospitalizations admitted ≤28 days from birth, and the lack of unique patient identifiers in HCUP KID prevents tracking individuals across multiple hospitalizations. These limitations may lead to underestimation of the incidence rate, costs, and CFR. Specifically, the CFR, derived solely from discharge status, only reflects deaths during hospitalization, potentially underestimating the true CFR associated with nHSV infection.

Another limitation is the reliance on ICD-10-CM diagnosis codes for case identification. Although ICD-10 codes are widely used in healthcare settings, they are subject to coding errors and variations in coding practices, which may impact the accuracy of case identification. Furthermore, the database lacks the ability to classify the type of nHSV infection (e.g., SEM, CNS, or disseminated), limiting a more detailed analysis of disease severity and outcomes.

nHSV cases were identified from hospital diagnosis charges, including infants born outside hospitals but admitted at 28 days of life or less. Using hospital births as the denominator may have resulted in a 4.7% higher incidence rate (Supplemental Table 3) compared to using all live births.²⁰

Our estimates of the hospital charges and costs of nHSV do not include professional fees and thus could be underestimates.²¹ We estimated the hospital charges and costs of treating infants with nHSV, without regard to whether these expenses were attributable to nHSV. However, a previous study found that >90% of the costs of treating infants with nHSV were “excess costs” compared to the costs associated with healthy infants.²²