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Original Studies

Incidence and Characteristics of Neonatal Herpes: Comparison of Two Population-Based Data Sources, New York City, 2006–2015

Lao, Steven MPH*†; Flagg, Elaine W. PhD, MS; Schillinger, Julia A. MD, MSc†‡

Author Information
doi: 10.1097/OLQ.0000000000000923

BACKGROUND

Neonatal herpes (nHSV) infection is an uncommon but serious disease with a high case-fatality rate (CFR), caused by herpes simplex virus (HSV) type 1 (HSV-1) or type 2 (HSV-2) acquired during the neonatal period. The majority of cases (~85%) are vertically transmitted during delivery, ~5% of cases are congenitally acquired, and ~10% of infections are thought to be postnatally acquired.1 In recent years, direct orogenital suction (DOS) performed as part of some ritual Jewish circumcisions has been a well-documented cause of postnatal HSV-1 transmission to male infants in New York City (NYC) and elsewhere.2–5

Neonatal herpes infections are associated with substantial mortality. Although infections localized to the skin, eyes, or mouth (SEM) are rarely fatal, 14% of central nervous system (CNS) infections and 54% of disseminated infections result in death before 1 year of age, even with antiviral treatment.6,7 Moreover, 69% and 17% of survivors with CNS and disseminated disease, respectively, do not have normal development by 12 months of age.8

Despite the significant morbidity associated with nHSV infection, it is not a nationally notifiable disease, and there are few data with which to describe the epidemiology of nHSV infections in the United States, including incidence.9 Although an assessment of state surveillance practices during 2000 to 2005 found that nHSV infection was a reportable condition in 9 states, only one used a standard surveillance case definition and another had never received report of a case, suggesting incomplete data.10

Neonatal herpes is one of the most devastating and financially costly outcomes of genital herpes infections.11 A number of HSV vaccines are in clinical and preclinical development, and a point-of-care diagnostic test to identify neonates exposed to HSV at delivery is under evaluation.12 It will be important to be able to monitor nHSV incidence before and after these tools become available to assess impact and missed opportunities for prevention.13 Recognizing the value of establishing the incidence of nHSV infection and characterizing reported cases, the NYC Department of Health and Mental Hygiene (DOHMH) mandated reporting of nHSV infections in 2006.14 However, surveillance activities can be costly and time-intensive and may not be feasible in many jurisdictions. In contrast, administrative hospital discharge data are often used by hospitals to request health insurance payments and are available in most states.15 Access to both routinely collected public health surveillance data and a statewide administrative hospital discharge database with individual-level records provides a unique opportunity to determine the feasibility of using administrative data to monitor trends in laboratory-confirmed nHSV infection.

METHODS

Data Sources

Surveillance Data

Neonatal herpes infection has been a mandated reportable disease in NYC since April 2006.14 Clinical laboratories are required to report to DOHMH any specimen collected from an infant aged 60 days or younger in which HSV infection is detected, and healthcare providers are required to report any diagnosis of HSV infection in an infant aged 60 days or younger, regardless of laboratory confirmation. A threshold of 60 days was used to account for infections that may have been acquired during the conventional neonatal period (28 days), but did not present clinically until afterward. The DOHMH investigates every newly reported nHSV infection, abstracting maternal and infant medical records and interviewing medical providers and, in some cases, parents and other caregivers. A standard case investigation form is used to collects data, including: maternal demographic characteristics, maternal and infant clinical information, infant physical examination findings, laboratory testing, imaging studies, treatment, and vital status. Clinical syndrome is assigned using established surveillance case definitions (Supplemental Table 1 https://links.lww.com/OLQ/A308).

Laboratory-confirmed nHSV infections (ie, surveillance cases) were defined as direct detection of HSV [culture, nucleic acid amplification test, Tzanck test, direct fluorescent antibody test (DFA)] in a specimen collected from a NYC-resident infant aged 60 days or younger.16 The duration of hospitalization was calculated using the first recorded hospitalization with an nHSV diagnosis, combined with any consecutive admissions within 60 days of birth (suggesting a transfer in care).

Administrative Hospital Discharge Data

Individual-level administrative hospital discharge data for New York State (NYS) were obtained from the Statewide Planning and Research Cooperative System (SPARCS), an all-payer reporting system that collects patient-level characteristics and details regarding diagnoses, procedures, and services for each inpatient and outpatient visit to all hospital facilities in NYS.17 It is audited yearly to ensure data completeness and has been used extensively for research studies.18

The SPARCS data set does not contain clinical data or laboratory results. Cases of nHSV infection in SPARCS (ie, SPARCS cases), were defined as an infant aged 60 days or younger at the time of an inpatient admission to a NYS hospital with: a NYC address, and a primary or secondary diagnosis of HSV infection as classified under the 9th revision of the International Statistical Classification of Diseases, Clinical Modification (ICD-9-CM). Because there is no specific ICD-9-CM code for neonatal infection with HSV, we used the 054.xx series of ICD-9-CM codes for HSV (Supplemental Table 2 https://links.lww.com/OLQ/A309).

For SPARCS cases, we used demographic information from their first admission with an HSV diagnosis. The duration of hospitalization was calculated using the first recorded hospitalization with an nHSV diagnosis, combined with any consecutive admissions within 60 days of birth with an nHSV diagnosis (suggesting a transfer in care). Maternal characteristics were ascertained from the mother's delivery record in SPARCS, which was found using identifying information in the infant's record.

Neonatal Herpes Infections Following Ritual Jewish Circumcision With Confirmed or Probable DOS

Male infants diagnosed with laboratory-confirmed HSV infection due to HSV-1 or untyped HSV, with an earliest specimen collection date of 8 days or older after birth and who underwent ritual Jewish circumcision, were classified as following ritual Jewish circumcision with confirmed or probable DOS. Information regarding the performance of DOS during circumcision was almost always available from medical records or parental interviews; however, some parents declined to provide information about the circumcision procedure. In order to maximize the generalizability of our findings to other parts of the United States where DOS is unlikely to occur, we decided a priori to exclude DOS cases from most analyses. However, we wanted to take the opportunity to characterize the DOS cases in comparison to all other surveillance cases. The DOS cases were matched to individual-level records in SPARCS using identifying information: infant's and mother's name, infant date of birth, address, hospital, medical record number, and admission/discharge dates. These cases were then excluded from both data sources for all subsequent analyses.

Analysis

All analyses were conducted using SAS version 9.4 (SAS Institute, Carey NC). Pearson’s χ2 test of independence was performed to compare distributions of categorical variables between surveillance and SPARCS cases; Fisher exact test was performed when sample sizes were small. Student t tests were used to compare continuous variables.

We limited our analysis to inpatient admissions starting April 2006 through September 2015 (the latest date ICD-9-CM coding was used) and compared concurrent years of nHSV surveillance data with SPARCS data.19 Annual live-birth statistics (number of births by maternal characteristics) were used as the denominator for incidence estimates for both data sources. For the partial calendar years (2006 and 2015), we used live-birth statistics only for the relevant months.

Incidence was calculated separately for surveillance and SPARCS cases overall, by infant sex, and by maternal race/ethnicity and age group. To determine whether the distribution of nHSV incidence by both maternal race/ethnicity and age group varied between the 2 data sources, a fully-saturated binomial model was created using the SAS Genmod procedure. A statistically significant contribution of the 3-way term to this model would indicate the distribution of nHSV incidence for this combination of maternal factors differed between data sources. The absence of statistical significance would allow us to examine reduced models, as appropriate, to determine the relative contributions of maternal race/ethnicity and age group to nHSV incidence.

We did not use a capture-recapture methodology because we used different case definitions for each data source, and laboratory-confirmed cases would have a greater probability of being hospitalized than cases lacking laboratory confirmation. For those reasons, our approach did not meet one of the underlying assumptions of a capture-recapture analysis—that cases in either data source have the same probability of being captured.20

Human Subjects Considerations

This secondary analysis of routinely collected surveillance data was considered surveillance by the NYC DOHMH and determined to be nonresearch by the US Centers for Disease Control.

RESULTS

Surveillance Cases

Between 2006 and 2015, 120 laboratory-confirmed cases of nHSV infection were detected and reported: 90 confirmed by culture (with or without a positive NAAT), 24 by NAAT only, and 6 only by tests other than culture or NAAT (eg, DFA, Tzanck) (Table 1). Overall, 21 cases died (17.5% CFR). Eighteen fatalities were among cases with disseminated disease (60.0% CFR). One of the 15 cases with SEM disease, and 1 of the 2 cases with congenital infection, died. There were no deaths among the 23 cases with CNS infection. Among 10 cases missing information for clinical syndrome, there was 1 death (10.0% CFR).

TABLE 1
TABLE 1:
Characteristics of Cases of Neonatal Herpes Infection Detected Through Routine Public Health Surveillance—Comparison of Cases That Did, and Did Not, Follow Ritual Jewish Circumcision With Confirmed/Probable DOS: NYC, 2006–2015

Comparison of Cases of Neonatal Herpes Infections Which Did, and Did Not, Follow Ritual Jewish Circumcision With Confirmed or Probable DOS

Of the 120 laboratory-confirmed cases, 13 were determined to be DOS-related. Cases of neonatal herpes infection with DOS differed significantly from other nHSV cases by sex (P < 0.001), maternal race/ethnicity (P < 0.001), viral type (P = 0.004), and borough of residence (P < 0.001) (Table 1). All cases with DOS were male, the majority (92.3%) were born to non-Hispanic white women, and 11 of the 13 with HSV typing had HSV-1 infection. In contrast, 40.2% of other surveillance cases had HSV-1, 46.7% HSV-2, and 13.1% untyped infection. Excluding the 13 DOS-related cases resulted in a final analytic data set of 107 laboratory-confirmed surveillance cases (Fig. 1).

Figure 1
Figure 1:
Determination of neonatal herpes cases for analysis in 2 population-based data sources: New York City, 2006–2015.

SPARCS Cases

Using the described linkage procedures, we identified 11 of the 13 cases with DOS in the SPARCS data set, and excluded them. The final SPARCS analytic data set contained 131 cases (Fig. 1), of which 51 (38.9%) matched to surveillance cases.

Characteristics of Surveillance Cases Compared With SPARCS Cases

Table 2 displays the characteristics of nHSV cases identified in each data source after exclusion of DOS-related cases. There were no statistically significant differences between the distribution of surveillance and SPARCS cases by infant sex or duration of hospitalization. A majority of both surveillance (79 [87.8%] of 107 cases) and SPARCS (103 [78.6%] of 131 cases) cases were hospitalized for nHSV within 30 days of birth, and surveillance cases were most frequently diagnosed during their birth admission (38.9%). The SPARCS cases had an older mean age at hospital admission (surveillance, 10.7 days; SPARCS, 16.7 days; P = 0.006). The majority of SPARCS cases (87 [66.4%] of 131 cases) were admitted 8 days or more after birth compared with surveillance cases (42 [39.3%] of 107 cases). The majority of the surveillance cases (65.0%) were delivered vaginally (delivery mode was only available in SPARCS for birth admissions). Birth weight, available for SPARCS cases hospitalized within the first 28 days of life, was less than 2500 g for 16.3% of those cases. Surveillance cases had a significantly higher CFR (18.7%) than SPARCS cases (8.4%; P = 0.019). Surveillance cases were also more likely to have multiple nHSV-related inpatient admissions within 60 days after birth (P = 0.032).

TABLE 2
TABLE 2:
Comparison of the Characteristics of Laboratory-confirmed Surveillance Cases to the SPARCS Cases: NYC, 2006–2015

Maternal information was available for all surveillance cases and we identified maternal delivery records for 77.9% of SPARCS cases. Surveillance and SPARCS cases differed significantly by maternal race/ethnicity (P = 0.046). In both data sources, the majority of cases were born to black or Hispanic women (surveillance, 67.3%; SPARCS, 55.9%). There was no significant difference between the data sources with regard to the distribution of maternal age (P = 0.51).

Incidence of nHSV Infection

Figure 2 presents the numbers of nHSV cases by year and data source. The number of cases did not differ significantly by year across data sources (P = 0.86). Table 3 displays the incidence of nHSV infection measured using surveillance compared to that measured using SPARCS data, stratified by infant sex and by maternal race/ethnicity and maternal age at delivery. After excluding DOS-related cases, the overall incidence of laboratory-confirmed nHSV cases in NYC between 2006 and 2015 was 9.9 per 100,000 live births using surveillance and 12.1 per 100,000 live births using SPARCS.

Figure 2
Figure 2:
Comparison of the frequency of laboratory-confirmed surveillance cases to the SPARCS cases by year of hospitalizationa: New York City, 2006–2015.
TABLE 3
TABLE 3:
Incidence of Neonatal Herpes Measured Using Laboratory-confirmed Surveillance Compared With Administrative Data From the SPARCS: NYC, 2006–2015

Binomial modeling indicated that the distribution of nHSV incidence by the combination of maternal race/ethnicity and age group did not vary significantly between the surveillance and SPARCS data sources (P = 0.997). Neonatal herpes incidence was highest among infants born to the youngest mothers in each race/ethnicity group; distribution of incidence by maternal age group did not vary significantly between each maternal race/ethnicity group (P = 0.121). When restricted to cases among mothers younger than 20 years, nHSV incidence was highest among infants born to non-Hispanic black mothers (surveillance, 57.2 per 100,000 live births; SPARCS, 31.2 per 100,000 live births); this difference was of borderline statistical significant (P = 0.054).

DISCUSSION

We present the case characteristics and incidence of nHSV infection in NYC measured using 2 different population-based data sources. Our results suggest that administrative data can provide a reasonable measure of nHSV incidence compared to routine, public health surveillance for laboratory-confirmed infections. The numbers of cases identified each year, and overall incidence, were similar across data sources and comparable to most estimates reported in the scientific literature. Both approaches identified the same population at highest risk—incidence was highest among infants born to young, non-Hispanic black mothers. However, the death rate was under-estimated using administrative data, possibly due to the fact that SPARCS did not identify all the cases (and deaths) detected by surveillance. In addition, these data lacked clinically important information regarding viral type, clinical syndrome, and delivery mode.21

The distribution of incidence by infant sex, maternal race/ethnicity, and maternal age at delivery were similar across data sources and reflect previously reported nHSV risk factors.22 However, there were significant differences in several characteristics between surveillance and SPARCS cases, and the number of cases did not match exactly by year, which may indicate that the 2 data sources did not identify the same infants.

Although DOS cases were not included in incidence calculations, the contribution of DOS cases to disease burden was substantial. Excluding DOS cases decreased the calculated incidence by 10.8% overall and by 19.4% among male infants. This resulted in a more generalizable distribution of characteristics by eliminating the bias toward male infants previously reported.16 The distribution of clinical syndrome and CFR among the remaining 107 surveillance cases closely mirrors the distributions reported in the scientific literature.8

Compared with surveillance, the main advantages of administrative hospital data are low cost and widespread availability. Most states have population-based hospital discharge databases collected for billing purposes (eg, Medicare, Medicaid, commercial health insurance).15 These data are increasingly being used for a variety of purposes, including quality assessment, disease surveillance, and health policy research. However, delays in the availability of administrative data may limit their public health utility.

The availability of individual-level data allowed us to account for neonates hospitalized multiple times with an nHSV diagnosis within 60 days of birth. It also allowed us to identify DOS cases and locate the maternal hospital records of SPARCS cases. A comparison of nHSV surveillance and administrative data has been previously reported from NYC.16 However, that analysis was limited to 3 years, compared to nearly 10 years in the current analysis, and included nHSV cases that were not laboratory-confirmed as well as DOS-related cases.

Estimates of nHSV incidence in the US range from 5.8 to 76 cases per 100,000 live births.8,23 Differences in these estimates are likely explained by study design, data sources, case definitions, and geographic variation in the prevalence of genital herpes infection in adults of child-bearing age. The choice of which ICD-9-CM codes to include has also affected measures of incidence in studies using hospital discharge data.24,25 Our incidence calculations relied on live-birth statistics obtained from the DOHMH's Bureau of Vital Statistics. An underestimation of live births in the civil birth registry is unlikely because all live births in NYC are required by law to be reported to the DOHMH—the NYC agency that issues birth certificates. It is unlikely that even undocumented home births would go uncounted, because an unreported birth would result in the lack of a birth certificate—a vital record required for a Social Security.

Although the neonatal period conventionally refers to the first 4 weeks of life, some studies use 42, or 60 days (as did the current analysis), to account for infections that may have occurred during the neonatal period, but did not present clinically until later.25,26 Although the majority of laboratory-confirmed nHSV cases were hospitalized within 28 days (87.78%), there were cases initially hospitalized between 28 and 42 days (6 cases) and others between 42 and 60 days (5 cases) after birth. Given the relative rarity of nHSV infection, our inclusion of cases up to 60 days after birth did not appreciably alter the calculated incidence beyond that reported for shorter neonatal timeframes.

This analysis has several limitations. Administrative data are dependent on physicians accurately determining and recording a diagnosis and hospital personnel assigning appropriate ICD-9-CM codes, and are therefore subject to misclassification.27 We only considered ICD-9-CM codes in the 054.xx series, likely missing cases coded otherwise; there is no ICD-9-CM code specific for nHSV infection.28 This may be particularly problematic for nHSV infections because the clinical presentation is often nonspecific (eg, irritability, lethargy, fever). Now that ICD-10, which includes a specific code for congenital HSV infection, has been implemented, a similar analysis should be performed after a sufficient number of new laboratory-confirmed nHSV surveillance cases have accrued.

We also limited our analysis to inpatient admission records; however, we do not believe this affects our estimates. Because nHSV infection can be life-threatening and treatment guidelines recommend at least 14 days of parenteral acyclovir, it is unlikely cases were not hospitalized for at least 1 day.29 Finally, by limiting our analysis to laboratory-confirmed cases, we may have missed some cases that may have been true infections, but lacked laboratory confirmation (and were possibly detected in SPARCS).

In addition, the P values we presented should be interpreted with caution. The cases included in each data source are not independent—51 (47.7%) of the 107 surveillance cases were detected in both data sources—and incidence rates from each data source used the same population live-birth denominators. Furthermore, while we were able to exclude 11 of the 13 known, laboratory-confirmed DOS cases from the administrative data set, we could not exclude the other 2, and other non–laboratory-confirmed DOS cases may also have remained.

We have demonstrated that administrative data can provide a reasonable means of monitoring the incidence of neonatal herpes in NYC. These findings should be replicated in other settings that have dual data sources with which to measure the burden of this uncommon, but serious, infection. The availability of individual-level administrative hospital discharge data enabled us to link individual surveillance cases with their administrative records. This will allow future work to refine an administrative case definition by including demographic covariates and examining how using other ICD-9-CM codes in addition to the 054.xx series affects the sensitivity and specificity of an administrative case definition for identifying laboratory-confirmed nHSV cases.

REFERENCES

1. Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev 2004; 17:1–13.
2. Distel R, Hofer V, Bogger-Goren S, et al. Primary genital herpes simplex infection associated with Jewish ritual circumcision. Isr Med Assoc J 2003; 5:893–894.
3. Rubin LG, Lanzkowsky P. Cutaneous neonatal herpes simplex infection associated with ritual circumcision. Pediatr Infect Dis J 2000; 19:266–268.
4. Centers for Disease Control and Prevention (CDC). Neonatal herpes simplex virus infection following Jewish ritual circumcisions that included direct orogenital suction—New York City, 2000-2011. MMWR Morb Mortal Wkly Rep 2012; 61:405–409.
5. Gesundheit B, Grisaru-Soen G, Greenberg D, et al. Neonatal genital herpes simplex virus type 1 infection after Jewish ritual circumcision: Modern medicine and religious tradition. Pediatrics 2004; 114:e259–e263.
6. Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 1991; 324:444–449.
7. Kimberlin DW. Advances in the treatment of neonatal herpes simplex infections. Rev Med Virol 2001; 11:157–163.
8. Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med 2009; 361:1376–1385.
9. Protocol for public health agencies to notify CDC about the occurrence of nationally notifiable conditions, 2018. Centers for Disease Control and Prevention. Available at: https://wwwn.cdc.gov/nndss/document/NNC_2018_Notification_Requirements_By_Condition_20171120.pdf. Accessed March 18, 2018.
10. Dinh TH, Dunne EF, Markowitz LE, et al. Assessing neonatal herpes reporting in the United States, 2000-2005. Sex Transm Dis 2008; 35:19–21.
11. Owusu-Edusei K Jr, Flagg EW, Gift TL. Hospitalization cost per case of neonatal herpes simplex virus infection from claims data. J Pediatr Nurs 2015; 30:346–352.
12. Identification of herpes simplex virus (HSV) shedding in the female genital tract of pregnant and nonpregnant women by GeneXpert PCR, routine PCR, and culture. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01878383. NLM Identifier: NCT01878383. Accessed March 17, 2018.
13. Gottlieb SL, Giersing BK, Hickling J, et al. Meeting report: Initial World Health Organization consultation on herpes simplex virus (HSV) vaccine preferred product characteristics, march 2017. Vaccine 2017; In press.
14. Notice of adoption of an amendment to Section 11.03 of the New York City Health Code. New York City Department of Health and Mental Hygiene. Available at: https://www1.nyc.gov/assets/doh/downloads/pdf/public/notice-nh-20060317.pdf. Accessed October 3, 2016.
15. Andrews RM. Statewide hospital discharge data: Collection, use, limitations, and improvements. Health Serv Res 2015; 50(S1):1273–1299.
16. Handel S, Klingler E, Washburn K, et al. Population-based surveillance for neonatal herpes in New York City, April 2006-September 2010. Sex Transm Dis 2001; 38(12):1–7.
17. Statewide Planning and Research Cooperative System (SPARCS). New York State Department of Health. Available at: https://www.health.ny.gov/statistics/sparcs/index.htm. Accessed April 16, 2017.
18. Hospital inpatient discharges. New York State Department of Health. Available at: https://www.health.ny.gov/statistics/sparcs/annual/data_completeness.htm. Accessed April 16, 2017.
19. Protecting Access to Medicare Act of 2014, Pub. L. No. 113–93, 128 Stat. 1040 (2014).
20. Tilling K. Capture-recapture methods—Useful or misleading? Int J Epidemiol 2001; 30:12–14.
21. Brown Z, Wald A, Morrow A. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA 2003; 289(2):203–209.
22. Nahmias AJ, Josey WE, Naib ZM, et al. Perinatal risk associated with maternal genital herpes simplex virus infection. Am J Obstet Gynecol 1971; 110:825–837.
23. Whitley R, Davis E, Suppapanya N. Incidence of neonatal herpes simplex virus infections in a managed-care population. Sex Transm Dis 2007; 34(9):704–708.
24. Xu F, Gee JM, Naleway A, et al. Incidence of neonatal herpes simplex virus infections in two managed care organizations: Implications for surveillance. Sex Transm Dis 2008; 35:592–598.
25. Flagg EW, Weinstock H. Incidence of neonatal herpes simplex virus infections in the United States, 2006. Pediatrics 2011; 127:e1–e8.
26. Morris SR, Bauer HM, Samuel MC, et al. Neonatal herpes morbidity and mortality in California, 1995–2003. Sex Transm Dis 2008; 35:14–18.
27. O'Malley KJ, Cook KF, Price MD, et al. Measuring diagnoses: ICD code accuracy. Health Serv Res 2005; 40(5 Pt 2):1620–1639.
28. Rudnick C, Hoekzema G. Neonatal herpes simplex virus infections. Am Fam Physician 2002; 65:1138–1142.
29. Kimberlin DW, Brady MT, Jackson MA, et al, eds. Herpes simplex. In: Red Book: 2015 Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics, 2015:432–445.

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