Infection with herpes simplex virus type-1 (HSV-1) or type-2 (HSV-2) during the neonatal period, or neonatal herpes (neonatal HSV), causes severe morbidity and high mortality rates even when treated.1,2 The majority of infections (85%) are acquired perinatally, although postnatal (10%) and congenital (5%) infections do occur.3 There is evidence that an increasing proportion of adult genital HSV infections are attributable to HSV-14,5; however, approaches for preventing neonatal HSV are limited and focused on HSV-2.1,2,6
Experts have advocated for making neonatal HSV a nationally notifiable disease; however, neonatal herpes is currently only reportable in a few jurisdictions in the United States (US).7–10 Estimates of national incidence from other countries range from 1.15/100,000 to 8/100,000 live births.11–16 Incidence estimates from different parts of the United States are higher, ranging from 8.4/100,00017 to 69/100,000 live births9; this range includes estimates that are not population based, as well as a nationally representative incidence estimate gleaned from a database of pediatric hospital admissions.18,19,20 Given variability in the prevalence of genital herpes across geographic regions of the United States,5 variation in incidence of neonatal HSV is expected. Variations are also likely caused by differences in methods used to measure neonatal HSV disease burden. We present findings from a population-based surveillance system for neonatal HSV for the first time in the United States, and compare these findings with analyses of administrative data for the same population.
MATERIALS AND METHODS
In late March 2006, neonatal HSV infection became a reportable disease in New York City (NYC).21 Clinical laboratories were required to report positive results for HSV on specimens from infants aged ≤60 days who were residents of NYC, and healthcare providers were required to report diagnoses of neonatal HSV infection for the same age group, regardless of whether laboratory results confirmed infection. Certificates of birth, death, and spontaneous termination of pregnancy (fetal death before delivery) were obtained from the NYC Bureau of Vital Statistics for all cases. To identify cases not reported by a provider or laboratory report, a retrospective search of vital records was performed at regular intervals.
The NYC Department of Health and Mental Hygiene investigated reported cases using a standard form. Investigations included confirmation of laboratory testing, telephone interviews with providers involved with each case, review of infant medical records, and maternal labor and delivery records. Interviews with parents were conducted only where postnatal infection was considered probable. Data collected regarding infant patients included demographics; gestational age; birth weight; circumcision status and date (males only); whether ill at birth; presence and anatomical distribution of lesions; comorbidities; HSV test and its results; acyclovir treatment; cerebrospinal fluid (CSF) and liver function tests and their results; and dates of: first symptom, first seeking medical attention, hospital admission and discharge, specimen collection, diagnosis, and treatment initiation and completion. Data collected regarding infant patients' mothers included demographics, gravidity and parity, history of HSV infection, prenatal HSV serologic testing status, antiviral medication during pregnancy, and presence of genital herpes lesions at delivery. Data collected regarding delivery of infant patients included presentation (vertex or breech), mode of delivery (vaginal or cesarean section), interval between rupture of membranes and delivery, and artificial rupture of membranes or any invasive obstetric procedures.
We defined a confirmed case of neonatal HSV infection as one occurring in an infant aged ≤60 days who tested positive for HSV by culture, direct immunofluorescence assay or other antigen detection test, or polymerase chain reaction. The upper limit for the age range was 60 days to test our hypothesis that some perinatally transmitted cases may not appear until shortly after the neonatal period. We defined a probable case of neonatal HSV as one occurring in an infant aged ≤60 days with no laboratory confirmation of HSV infection, but who had each of the following: (1) a diagnosis of HSV, (2) treatment with acyclovir for ≥7 days, (3) illness clinically compatible with neonatal HSV, and (4) no alternative diagnosis. In NYC, postnatal HSV-1 infections have occurred after ritual Jewish circumcision practices in which the ritual circumciser (mohel) uses his mouth to suck blood away from the incision on the newly circumcised penis.22 Infection after ritual circumcision was defined as a confirmed case of HSV-1 or untyped HSV, or a probable case, in a male infant who had been circumcised outside of a hospital, with date of illness onset occurring after circumcision; if the date of illness onset was missing, then the date of first specimen collection for HSV testing was used.
Incidence was calculated for infants aged ≤60 days and for infants aged ≤42 days using the number of cases reported during 4.5 years as the numerator. In the denominator, we added three-quarters the number of live births in 2006 plus the number of live births for 2007 to 2009 plus three-quarters the number of live births in 2009 to estimate the number for January to September 2010. Maternal age and race/ethnicity-specific incidence were calculated using maternal age and race-ethnicity data obtained from birth certificates. To obtain a denominator for these incidence calculations, we used a similar method as described earlier and the number of live births by age and race/ethnicity from 2008 to estimate the numbers for 2009 and 2010, since more current data were not available. Case-fatality rates were calculated overall and by viral type.
Pearson chi-square testing was performed by using SAS 9.1 (SAS Institute, Inc., Cary, NC) to identify statistically significant differences in distribution of characteristics among cases with regard to viral type, fatality, infant sex, clinical manifestation, presence of lesions and fever, delivery mode, maternal race, and age at presentation.
We classified cases as follows: skin, eye, or mucous membranes (SEM) infections were those in which herpetic lesions were present or SEM specimens tested positive for HSV with no evidence of central nervous system (CNS), disseminated, or congenital infection. CNS infections were those that were CSF-positive for HSV with no evidence of disseminated or congenital infection. Disseminated infections were those in which there was no evidence of congenital infection, and both aspartate aminotransferase and alanine aminotransferase levels were elevated.23 Congenital infections were those with signs of HSV-related illness or those from which HSV-positive specimens were collected within 24 hours of birth, or those with stigmata of congenital infection (e.g., microcephaly, microphthalmia, or retinal scarring) noted at birth.
We measured delays in seeking care, diagnosis, and treatment, as well as instances of inappropriate medical treatment. We defined a delay in seeking medical care as >1 day between date of first symptom and date medical care was first sought, a delay in diagnosis as >1 day between date medical care was first sought and date of diagnosis or first specimen collection for HSV testing, and a delay in treatment as >1 day between herpes diagnosis or first specimen collection and beginning treatment with acyclovir. Cases were classified as adequately evaluated if lumbar puncture and liver-function testing were recorded as performed. Inappropriate treatment was defined as administration of less than the recommended course of acyclovir (60 mg/kg/d of intravenous acyclovir for 14 days for SEM cases and 21 days for CNS and disseminated cases); we considered 21 days appropriate therapy for congenital neonatal HSV.24
To explain how HSV might have been transmitted despite the protective effect of cesarean delivery, we recorded obstetric factors that might have increased risk for disease transmission before the cesarean delivery. An interval of >4 hours between rupture of membranes and delivery was considered to pose a risk for HSV transmission,25 as were artificial rupture of membranes, vacuum extraction, and use of fetal scalp electrodes, intrauterine pressure catheters, or forceps.
We used hospital discharge data to measure number of cases of neonatal HSV diagnosed among infants with an NYC zip code of residence who had been discharged from a New York State hospital during January 1997 to December 2008 and who were aged ≤60 days at time of admission, and included any hospital discharges listing an International Classification of Diseases (ICD) Version 9 (ICD-9) code for herpes (codes 054.0–054.9) as the principal, primary, or other diagnosis code. A unique identifier was created by concatenating the encrypted date of birth, sex, and the zip code of the patient's residence to identify infants with more than one hospital discharge listing a herpes ICD-9 code, and only the first such admission was counted. Annual incidence was calculated using annual neonatal HSV hospital discharges as the numerator and annual number of live births in NYC as the denominator.
During the first 4.5 years (April 2006–September 2010) of neonatal HSV surveillance in NYC, 75 reported cases met our case definitions. One additional case was identified by death certificate search, providing 76 cases for analysis. Overall incidence of neonatal HSV was 13.3/100,000 live births or 1/7519 live births; among infants aged ≤42 days, incidence was 12.4/100,000 live births or 1/8065 live births. Among 72/76 (94.7%) cases with information regarding maternal age at delivery, median maternal age was 25 years (range, 16–43 years). Age-specific incidence was highest among infants born to women aged <20 years (47.4/100,000 live births or 1/2110) and declined thereafter (Table 1). Infants born to black non-Hispanic mothers were 1.5 times as likely to be infected with HSV as those born to white non-Hispanic or Hispanic mothers. Black non-Hispanic mothers had the youngest median age at delivery (20 years, as compared with 27.5 years for white non-Hispanic and 26 years for Hispanic mothers).
Among the 76 cases, 69 (90.8%) were confirmed and 7 (9.2%) were probable; all had laboratory testing performed. Among the 69 confirmed cases, 28 (40.5%) patients were infected with HSV-1; 27 (39.1%) with HSV-2; and 14 (20.3%) had positive laboratory results that were not type specific. No statistically significant differences between HSV-1 and HSV-2 cases were identified with regard to sex, fatality, clinical manifestation, presence of lesions or fever, delivery mode, or maternal race. In all, 43 (56.6%) of the cases were boys. Of the 13 deaths, 8 (61.5%) were among girls; 9 (69.2%) occurred within the first 2 weeks of life (Table 2). Although not statistically significant, the fatality rates differed by HSV type (21.4% among HSV-1 cases and 18.5% among HSV-2 cases). Most of the cases (56.5%) were SEM; 23.2% were disseminated, 17.4% were CNS infections, and 2.9% were congenital infections. Lesions were present among 41 (60.3%) of the 68 cases for which lesion data were available. Fever was present among 19 (31.1%) of the 61 cases for which data were available. Among the 61 cases with known fever and lesion data, 19.7% had neither fever nor lesions (Table 3). In all, 27 (69.2%) SEM cases had lesions noted, compared with 5 (41.7%) CNS cases, 7 (43.8%) disseminated cases, and both (100%) of the congenital cases.
Four (9.3%) of the 43 male patients met the definition for infection after ritual Jewish circumcision. All 4 case patients had lesions on the penis or the scrotum (2 on the penis only, 1 on the scrotum only, and 1 on both the penis and the scrotum); 3 of the 4 case-patients were laboratory-confirmed HSV-1 cases. The interval between circumcision and illness onset ranged 2 to 12 days (median, 3.5 days).One of the case-patients had CNS infection, the remaining 3 had SEM disease.
Of all cases, 56 (73.7%) were diagnosed at age ≤14 days; 12 (15.8%) at age 14 to 30 days; 3 (3.9%) at age 31 to 42 days; and 5 (6.6%) at age 43 to 60 days. Case-patients diagnosed at age ≤14 days had a higher fatality rate than those diagnosed at age ≥15 days (21.4% vs. 5%; P = 0.094). Of the 5 cases diagnosed among infants >42 days, 2 were HSV-1 (delivered by cesarean section); 2 were HSV-2 (one vaginally, and the other with unknown mode of delivery); and 1 was a probable case (cesarean section). Among the 57 case mothers for whom we had data, 11 (19.3%) had a known history of HSV, and 5/52 (9.6%) of those for whom data were available had lesions at delivery. None of the 8 cases diagnosed after 30 days of age were born to a mother with a known history of HSV or acyclovir use during pregnancy.
We found a delay in seeking care for 12/59 (20.3%) cases (median: 2 days; range: 2–10 days), a delay in diagnosis for 26/66 (39.4%) cases (median: 4.5 days; range: 2–21 days), and a delay in initiating acyclovir treatment for 18/61 (29.5%) cases (median: 3 days; range: 2–18 days). Overall, 38/54 (70.4%) cases with complete information with which to judge delays had one or more delays. Of the 38 cases where there were delays, 12 (31.6%) had fever, 27 (71.1%) had lesions, and 4 (10.5%) had neither fever nor lesions. Of 66 liveborn infants with complete information regarding lumbar puncture, 57 (86.4%) received lumbar puncture with HSV testing. Of 63 infants, 50 (79.4%) with available information had liver-function tests performed. Only 19 (51.4%) of the 37 patients for whom we had data related to treatment had received an appropriate acyclovir regimen; all of these had received an adequate evaluation. Over half (68%, or 52/76) of all cases lacked timely or ideal diagnostics or treatment.
Length of hospitalization was calculated for 61/76 (80.3%) cases; median was 15 days and varied with clinical manifestation—disseminated cases, median was 11 days (range, 2–39); SEM cases, median was 15 days (range, 0–86 days); and CNS cases, median was 22 days (range, 10–46). The 2 congenital cases were hospitalized for a median of 40.5 days (range, 3–78).
Where mode of delivery was known, 37.5% (27/72) of the infants were delivered by cesarean section. Among the 25 cases delivered by cesarean for whom we had data related to obstetric risks for HSV transmission, 20 (80.0%) had at least one such risk. (17 had >4 hours between rupture of membranes and delivery, 10 had artificial rupture of membranes, 5 had invasive instrumentation including vacuum extraction, fetal scalp electrodes, intrauterine pressure catheters, or forceps.) Only 2 of the cesarean deliveries were performed because of a perceived risk of HSV transmission. In both cases, the mother had a known history of genital HSV, and active genital lesions were noted at delivery. Among 45 cases delivered vaginally, 31 (68.9%) had at least one known obstetric risk for neonatal HSV transmission. (20 had >4 hours between rupture of membranes and delivery; 16 had artificial rupture of membranes; 12 had invasive instrumentation including vacuum extraction, fetal scalp electrodes, intrauterine pressure catheters, or forceps.)
Administrative Data Findings
During the 12-year interval from 1997 through 2008, a total of 179 infants were discharged with an ICD-9 code for herpes after an admission at age ≤60 days; 84/179 (46.9%) were male. Only 20/179 (11.2%) infants had been admitted at age >42 days. Median duration of admission was 14 days. During 1997 to 2008, annual incidence of neonatal HSV ranged from 5.6/100,000 live births (in 2001) to 18.3/100,000 live births (in 2006); median annual incidence was 11.8/100,000 live births. For infants aged ≤42 days, incidence ranged from 4.8/100,000 live births (in 2001) to 15.1/100,000 live births (in 2006); median incidence was 11.0/100,000 live births (Fig. 1).
We present the first population-based surveillance findings for neonatal HSV in the United States, as well as a comparison with findings from an administrative data set for the same population. Both methods yielded similar incidence rates, and were within the range of previously reported estimates. Our findings provide insight into neonatal HSV epidemiology. Laboratory-confirmed cases were diagnosed well after the first 30 days of life, and these included HSV-2 infections, suggesting a longer-than-expected incubation period. Our findings also reveal a substantial proportion of cases attributable to HSV-1.
The similarity in incidence estimates gleaned from NYC surveillance, and administrative data indicate that the latter may provide a reasonable means of measuring HSV disease burden in jurisdictions without resources to implement neonatal HSV surveillance. However, administrative data are often untimely and therefore do not allow for a public health response to epidemiologic findings. In addition, administrative data can be difficult to deduplicate, rely on ICD-9 codes that are not specific to neonatal HSV, and often lack detailed clinical and laboratory information, thereby limiting accuracy and utility.
Disparities in risk for neonatal HSV by maternal age and race/ethnicity were apparent in our findings. Younger mothers might be less likely to be infected with HSV at the start of a pregnancy and at increased risk for acquiring HSV during pregnancy. Moreover, because genital HSV-2 infections are particularly prevalent among black non-Hispanic New York residents,26 they might be more likely than women of other races/ethnicities to be exposed to HSV.
Our findings differed in several ways from those reported by other North American investigators. We found a lower proportion of CNS cases (17.4%, as compared to 30%) and a higher proportion of SEM cases (56.5%, as compared to 45%) than previously reported.3 The former was surprising, especially because highly sensitive nucleic-acid amplification tests are increasingly being used to test CSF specimens,27,28 and the majority of our cases (76.0%) had CSF testing. However, our findings on distribution of cases by clinical manifestation was similar to what was found in Canadian surveillance.11 Our findings on prevalence of fever (31.1%) was also similar to what has been previously reported.29 We also found a higher case-fatality rate among disseminated cases (62.5%) than previously reported (29%), but no fatalities among CNS cases, in contrast to previous reports of fatality rates of 4% to 15%2,29 among CNS cases. These findings may be explained, at least in part, by our use of a definition for disseminated disease which selects for only very severe disease and by the increasing use of highly sensitive tests (polymerase chain reaction) to test CSF, which may classify as CNS disease cases who might have been considered SEM in the past.
Over one-third of the reported case-patients had been delivered by cesarean section, suggesting that the protective effect of cesarean delivery can be undermined when other obstetric risk factors for transmission have already occurred. Because a majority of neonatal HSV cases were among infants born under circumstances that would not prompt provider suspicion of risk for HSV infection, opportunities for intervention are limited. Prenatal screening of pregnant women and their sex partners could enable providers to counsel seronegative women with seropositive partners about abstinence or safer sex during pregnancy,17 or to recommend acyclovir suppressive treatment during the third trimester to HSV-positive women,30–32 but both of these strategies are unproven, expensive, and carry risks (of undue strain on the woman's relationship and possible toxicity to the infant,1 respectively).
Postpartum infections could be reduced by educating parents and caregivers about ways to avoid transmitting infection. Unfortunately, it is difficult to modify the practice of ritual Jewish circumcision with oral suction because of the religious value attached to it by certain sects.33 A vaccine for HSV would be the best prevention strategy, but the HSV vaccine in Phase III trials has recently proven ineffective.6 To prevent the majority of neonatal HSV cases, a vaccine would have to be effective against both HSV types and be administered before sexual debut.
Opportunities to intervene in the progression of disease were missed, evidenced by delays in diagnosis for over 1/3 of cases and delays in initiating antiviral treatment in nearly 1/3 of cases. A majority (89.5%) of those cases where delays in care seeking, diagnosis, and/or treatment were present had fever or lesions, which may support the case for increased caregiver and provider education. Nonspecific presentation, like the 19.7% of cases we found with neither fever nor lesions, does make diagnosis of neonatal HSV difficult, so pediatric providers should be encouraged to consider neonatal HSV in the differential diagnosis of ill infants, to perform SEM testing, lumbar puncture, and liver function tests, and to initiate intravenous acyclovir treatment immediately when neonatal HSV is suspected.
Our study has several limitations. It is likely that neonatal HSV cases were underreported and those reported might be biased toward more severe disease. The relatively limited number of cases limits our ability to make definitive statistical comparisons among our cases and to those reported in other case series and makes certain statistical analyses unstable. Due to missing information on some cases, there may be some misclassification of disease syndrome; however, that is most likely to have resulted in an overestimate of SEM cases. We lack data concerning lumbar punctures performed at the end of treatment; therefore, we were unable to assess whether follow-up treatment was performed when needed. Length of hospitalization for neonatal HSV might have been overestimated because it includes hospitalization for non-HSV illness, and might appear misleadingly short for disseminated cases, which are more likely to result in death. The number of congenital cases might have been overestimated because we may have included infants' ill at birth with conditions other than neonatal HSV who were colonized with HSV, which might have cleared without treatment. Finally, some of our findings may not be generalizable outside of NYC. For example, the incidence is affected by the prevalence of genital HSV in the population, which varies. However, some of our findings (e.g., delays in diagnosis, treatment, and seeking care, and case fatality rates) are likely to be generalizable.
Administrative data may provide an adequate and inexpensive means to assess local neonatal HSV burden, although such data lack the detail and timeliness of surveillance data. We believe routine surveillance for neonatal herpes is of value; our data provide new insights, give a baseline incidence from which to evaluate the impact of future prevention efforts, and point to the need for parental and provider education regarding neonatal HSV. Challenges remain for reducing incidence of neonatal HSV, as all current prevention strategies are limited.
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