Effect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes

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1 Acta Obstetricia et Gynecologica. 2007; 86: ORIGINAL ARTICLE Effect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes ELIZABETH L. BROWN 1, CAROLYN GARDELLA 2, GUNILLA MALM 3, CHARLES G. PROBER 4, MARIANNE FORSGREN 5, ELIZABETH M. KRANTZ 6, ANN M. ARVIN 4, LINDA L. YASUKAWA 4, KATHLEEN MOHAN 7, ZANE BROWN 2, LAWRENCE COREY 6,8 & ANNA WALD 1,6,8 1 Department of Epidemiology, 2 Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA, 3 Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden, 4 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA, 5 Department of Clinical Virology, Karolinska University Hospital, Stockholm, Sweden, 6 Department of Laboratory Medicine, University of Washington, Seattle, WA, USA, 7 Virology Division, Children s Hospital and Regional Medical Center, Seattle, WA, USA, and 8 Department of Medicine, University of Washington, Seattle, WA, USA Abstract Background. Neonatal herpes simplex virus (HSV) is a rare but devastating disease. We have conducted pooled analyses of data from 3 cohorts to evaluate the effects of maternal HSV serostatus and HSV type on risk of neonatal HSV acquisition and severity. Methods. Data from cohorts in Seattle, WA, and Stanford, CA, USA, and Stockholm, Sweden were pooled using Mantel Haenszel methods. Results. Seventy-eight infants with documented neonatal HSV and known maternal HSV serostatus were included. The risk of neonatal HSV-2 infection was similar in infants born to HSV seronegative women compared with HSV-1 seropositive women (pooled OR: 1.6; 95% CI: ). The odds of neonatal HSV infection was increased in the presence of exposure to maternal HSV-1 versus HSV-2 (adjusted pooled OR: 19.2; 95% CI: ). An elevated odds of disseminated HSV in infants born to women with newly acquired genital herpes was observed in Stockholm (OR/13.5; 95% CI: ), but not in Seattle or Stanford. Conclusion. Our results suggest that maternal HSV-1 antibody offers little, if any, protection against neonatal HSV-2 infection. During reactivation, HSV-1 appears more readily transmissible to the neonate than HSV-2, a concerning finding given the rising frequency of genital HSV-1 infection. Key words: neonatal herpes, HSV serology, herpes in pregnancy, pooled analysis Abbreviations: CI: confidence interval, CNS: central nervous system, ELISA: enzyme-linked immunosorbent assay, HSV: herpes simplex virus, HSV-1: herpes simplex virus type 1, HSV-2 herpes simplex virus type 2, NPFE: non-primary first episode, OR: odds ratio, SEM: skin, eyes and mouth, STD: sexually transmitted disease Introduction Herpes simplex virus (HSV) infection of the neonate is the most serious consequence of genital herpes. Previously identified predictors of transmission of HSV to the neonate include isolation of HSV from the maternal genital tract at delivery (1), and maternal HSV serostatus (1 3). In infants born to women who acquire genital HSV near the time of delivery, the risk of neonatal HSV is 3050% (4,5), compared with5/1% in infants born to women with recurrent HSV at delivery (2,4). Neonatal HSV is a relatively rare disease, with an estimated 5002,500 cases occurring annually in the USA (1,6 8), making prospective studies costly and time-consuming. Thus, we took advantage of previously collected serologic and culture data from two Correspondence: Anna Wald, University of Washington Virology Research Clinic, 600 Broadway, Suite 400, Seattle, WA 98122, USA. annawald@u.washington.edu (Received 25 March 2006; accepted 4 December 2006) ISSN print/issn online # 2007 Taylor & Francis DOI: /

2 524 E.L. Brown et al. sites in the USA and one site in Sweden to conduct pooled analyses aimed at further defining the risk factors associated with perinatal HSV transmission. We assessed the effects of heterologous maternal HSV antibody and maternal HSV type on risk of transmission to the neonate, and evaluated whether maternal HSV serostatus at delivery affects neonatal disease severity. primary and NPFE infections were grouped together as newly acquired infection. Sources of data Data were collected at each site with informed consent and with the approval of the site s Human Subjects Review Committee. Materials and methods To identify datasets for inclusion in our pooled analysis, we conducted a literature search in May 2001 using MEDLINE with key words (neonat* OR infant) AND (HSV OR genital herpes OR herpes simplex), and limiting the search to articles published after This produced a total of 1,828 abstracts, 78 of which were relevant to our proposed analysis and were reviewed for eligibility. Eligibility criteria included adequate assessment of the outcome (clinical diagnosis of neonatal HSV infection) and adequate exposure information (type-specific HSV serology using either Western blot or an acceptable gg2-based test, and type-specific culture from mothers of exposed, uninfected infants at delivery). We made no language requirements for the full publications, but required the abstract to be in English. Most of the 78 articles reviewed were ineligible. Investigators from three site-seattle, WA; Stockholm, Sweden; and Stanford, CA-had eligible studies and provided us with individual-level data. Neonatal HSV cases were defined as infants with the diagnosis of HSV infection with onset of symptoms before 28 days of life. Infants that presented after day 28 were excluded as they were thought to have most likely acquired the infection postnatally. Infants were categorised by their most severe (highest mortality rate) disease type; thus, an infant who had both SEM and CNS disease was classified as having CNS disease, while an infant with both SEM and disseminated disease was classified as having disseminated disease. We classified maternal HSV serostatus as primary, nonprimary first episode, or recurrent at or near delivery. Women who lacked antibodies to both HSV-1 and HSV-2 were classified as having primary infection, while those with antibodies heterologous to the genital HSV strain were classified as having non-primary first episode (NPFE) infection. Women with antibodies homologous to the genital HSV strain were classified as having recurrent infection. Due to the small number of cases, and the substantially elevated risk of transmission to the neonate among women with primary and NPFE infection compared with women with recurrent infection, Seattle Data were collected during a prospective cohort study of pregnant women between 1982 and 1999 (1,2,4,9). Briefly, the study was conducted at the University of Washington Medical Center in Seattle from 1982 to 1999, and at Madigan Army Medical Center in Tacoma between 1990 and Maternal sera were collected prenatally and/or at delivery. Maternal HSV serotesting was performed using Western blot (10). Genital HSV cultures were collected at delivery. Stockholm We obtained data on all neonatal HSV cases born between 1973 and 2001 in Stockholm and the neighbouring city Visby (11). Sera were collected from case mothers prenatally and/or postpartum. Additionally, sera were collected during the first obstetrical visit from 3,700 women from the same catchment area, who did not transmit HSV to the neonate. HSV serotesting was performed using an ELISA method that could differentiate between persons who are HSV seronegative, HSV-1 seropositive, or HSV-2 seropositive, but could not determine whether an HSV-2 seropositive person also had antibodies against HSV-1. Stanford Data were originally collected during a study of the use of routine cultures at delivery to identify neonates exposed to HSV (3,12 14). The study was performed at Stanford University Medical Center and Santa Clara Valley Medical Center, and included case babies born in the surrounding region who received care at Stanford. Neutralising antibody tests and a HSV-2 type-specific ELISA (12), were performed on sera collected prenatally and/or postpartum and/or on neonatal cord blood. Western blot (10) was performed in cases that were not classified with the ELISA for which sera were still available at the time of the pooled analysis. Maternal cultures at delivery were performed as described previously (12).

3 Effect of maternal herpes simplex virus (HSV) serostatus 525 Procedure for handling missing data Prenatal and/or postpartum serologic data were missing for some women. Subjects for whom we could infer maternal HSV serostatus at delivery from documented history of genital herpes or previously documented HSV seropositivity were retained in the analysis, while those for whom we could not infer HSV serostatus were excluded. Control subjects whose HSV isolates at delivery were not typed and who lacked documentation of previous typed genital HSV culture were excluded. Statistical methods The odds ratio (OR) was the effect measure chosen for all comparisons, to allow for case-control analyses as well as adjustment for confounding variables using logistic regression. This effect measure estimates the relative risk for neonatal HSV-2 by maternal HSV-1 serostatus because this outcome is rare. However, the OR for our other two outcomes, neonatal HSV among babies who were exposed at delivery and type of disease among infected babies, are not rare and should not be viewed as estimates of the relative risk. Unadjusted site-specific ORs used exact confidence intervals and were tested for heterogeneity and pooled using Mantel Haenszel methods (15). Adjusted site-specific ORs were calculated using logistic regression, then tested for heterogeneity and pooled using a general variancebased method (15). In analyses where numbers were too small to adjust for Cesarean delivery, we repeated the analyses excluding all neonates born by Cesarean delivery. Intercooled Stata version 8.0 (Stata Corporation, College Station, TX) and Microsoft Excel 2003 were used for statistical analyses. Results Risk of neonatal HSV-2 by maternal HSV-1 serostatus To assess whether maternal HSV-1 antibody protects against transmission of HSV-2 to the neonate, we pooled eligible datasets, including all neonatal HSV cases that occurred in the specified time period and location and contained information about maternal HSV serostatus at delivery. We also required a sample of pregnant women who did not transmit HSV to their infant and whose HSV antibody status was known. In Seattle, we obtained maternal HSV serologic data on 18 cases (15 vaginal deliveries and 3 Cesarean sections) of neonatal HSV (8 HSV-1, 10 HSV-2) and an additional 31,630 women who gave birth to uninfected infants (1) (Table I). HSV serostatus at delivery among women who did not transmit HSV to the neonate is shown in Table II. Compared to HSV seronegative women, HSV-1 seropositive women had similar risk of transmitting HSV-2 to their infant (OR/1.1; 95% CI: ). In Stockholm, maternal serostatus was available for 35 (10 HSV-1 and 25 HSV-2) of the 42 neonates reported that met our case definition for neonatal HSV. Of these 35 cases, 34 were delivered vaginally and 1 was delivered by Cesarean section. HSV-1 and HSV-2 serologic data were also available for an additional 3,700 women who gave birth to uninfected infants (Table II). Risk of neonatal HSV-2 was similar in infants born to seronegative and HSV-1 seropositive women (OR: 1.9; 95% CI: ; Table III). We found no evidence of heterogeneity between the Seattle and Stockholm estimates for risk of neonatal HSV-2 by maternal HSV-1 serostatus (p /0.25). The pooled risk of neonatal HSV-2 was similar in seronegative women compared with HSV- 1 seropositive women (Table 3, Figure 1A). Neonatal HSV by maternal HSV type isolated at the time of delivery For the pooled analysis of neonatal herpes by HSV type to which the neonate was exposed, eligible datasets included maternal serology and clinical history data from which we could determine maternal HSV serostatus at delivery and data from which we could determine to which HSV type the neonate was exposed. For cases we required that the neonate s HSV infection be typed, and for controls we required typed maternal HSV culture at or within 2 days of delivery, as evidence of neonatal HSV exposure. In Seattle, HSV was isolated at delivery from 167 women (100 vaginal deliveries and 67 Cesarean sections) of the 31,630 women who gave birth to uninfected infants. Of the 18 women who gave birth to infected infants, 8 transmitted HSV-1 (4 newly acquired and 4 recurrent), and 10 transmitted HSV- 2 (7 newly acquired and 3 recurrent). In contrast, among the 167 women with serologic data who gave birth to uninfected infants, HSV-1 was isolated at delivery from 10 (1 newly acquired and 9 recurrent), and HSV-2 was isolated from 157 (17 newly acquired and 140 recurrent; Table I). Thus, neonates exposed to HSV-1 during delivery were more likely to become infected than those exposed to HSV-2 during delivery (adjusted OR /14.8; 95% CI: ; Table III).

4 526 E.L. Brown et al. Table I. Sources of data on neonatal HSV cases and controls Study site Seattle n (%) Stockholm n (%) Stanford n (%) Total n (%) Neonatal HSV cases (total) Cases with known maternal HSV serostatus at delivery 18 (100) 35 (83) 25 (41) 78 (64) HSV-1 cases Newly acquired Recurrent HSV-2 cases Newly acquired Recurrent Controls: women with positive genital HSV culture at or within 2 days of delivery and known maternal serostatus at delivery Total 167 NA Newly acquired HSV Recurrent HSV Newly acquired HSV Recurrent HSV Neonatal disease severity (maternal HSV serostatus at delivery) Skin, eyes and mucosa Newly acquired Recurrent Unknown Central nervous system* Newly acquired Recurrent Unknown Disseminated$ Newly acquired Recurrent Unknown HSV, herpes simplex virus; CNS, central nervous system. *Central nervous system (CNS) category includes all infants diagnosed with any CNS disease (9/skin, eyes and mucosal disease) $Disseminated category includes all infants diagnosed with disseminated disease (9/CNS disease). At Stanford, 25 neonates met our case definition and provided maternal serostatus at delivery. Among the corresponding 25 mothers, 10 transmitted HSV- 1 to the neonate (7 newly acquired and 3 recurrent) and 15 transmitted HSV-2 to the neonate (8 newly acquired and 7 recurrent; Table I). Of these 25 cases, 22 were delivered vaginally and 3 were delivered by Cesarean section. Among 50 controls with complete data on maternal serologic status at delivery and type of HSV isolated by culture, one was HSV-1 culturepositive (recurrent) and 49 were HSV-2 culturepositive (28 newly acquired and 21 recurrent); 41 Table II. HSV seroprevalence among pregnant women who did not transmit HSV to the neonate sampled in Seattle and Stockholm Maternal HSV serostatus Seattle n (%) Stockholm n (%) HSV seronegative 7,262 (23) 887 (24) HSV-1 seropositive only 15,499 (49) 1,760 (48) HSV-2 seropositive 8,869 (28) 1,053 (28) HSV-1 and -2 seropositive 5,292 (17) Unknown HSV-2 seropositive only 3,577 (11) Unknown Total 31,630 (100) 3,700 (100) were delivered vaginally and 9 were delivered by Cesarean section. Among infants exposed to HSV at delivery, those exposed to HSV-1 had elevated odds of infection compared to those exposed to HSV-2 (adjusted OR: 34.8; 95% CI: ; Table III). We found no evidence of heterogeneity of the ORs (p /0.25) between Seattle and Stanford, so we pooled the data to compare risk of transmission to the neonate when the neonate is exposed to HSV-1 versus HSV-2 at delivery. The pooled OR adjusted for newly acquired maternal disease and for Cesarean section was 19.2 ( ) (Table III, Figure 1B). In a sensitivity analysis that excluded one Stanford case with possible non-vertical transmission of HSV-1, the Stanford site-specific OR and the pooled OR decreased only slightly. Neonatal disease severity by maternal HSV disease status For the pooled analysis of neonatal disease severity by maternal serostatus, we required information on neonatal disease type (skin, eyes and mouth (SEM), central nervous system (CNS), or disseminated (8))

5 Table III. Risk factors for neonatal herpes acquisition and disease severity Effect of maternal herpes simplex virus (HSV) serostatus 527 Seattle Stockholm Stanford Pooled Outcome Exposure Odds ratio (95% CI) Neonatal HSV-2 Any neonatal HSV Disseminated versus other neonatal HSV disease% Seronegative versus HSV-1/ HSV-1 versus HSV-2 isolation at delivery Maternal newly acquired versus recurrent HSV 1.1 (0.17.4) 1.9 (0.57.1) NA 1.6 (0.64.0) 14.8 ( )* NA 34.8 ( )* 19.2 ( )* 0.7 ( ) 13.5 (1.4630) 1.9 (0.1114) Not appropriate to pool *Adjusted for maternal HSV serostatus at delivery and for Cesarean section. %Includes skin, eyes and mouth and central nervous system. and sufficient maternal serology or clinical history data to determine whether maternal disease was newly acquired or recurrent at delivery. The numbers of cases with each disease type by maternal HSV serostatus at delivery are shown in Table I. In Seattle and Stanford, the odds of disseminated disease were similar for infants born to women with newly acquired versus recurrent HSV disease (OR: 0.7; 95% CI: for Seattle; OR: 1.9; 95% CI: for Stanford; Table III). In contrast, the odds of disseminated disease in Stockholm was elevated for infants born to women with newly acquired genital herpes compared with infants born to women with recurrent HSV (OR: 13.5; 95% CI: ; Table III). While we found no statistical evidence of heterogeneity of ORs across all three study sites (p/0.24), it was clear from inspection of the site-specific ORs that pooling was inappropriate. In a sensitivity analysis, exclusion of one Stanford case and one Stockholm case with possible non-vertical transmission did not alter our findings substantially, nor did the exclusion of cases born by Cesarean section. Discussion Our pooled analyses aimed to define more precisely maternal serologic and virologic factors associated with transmission of HSV to the neonate. We did not find evidence for a significantly protective effect of Figure 1. (A) Risk of neonatal HSV-2 in infants born to seronegative women compared with HSV-1 seropositive women. (B) Odds of neonatal HSV in infants exposed to HSV-1 versus HSV-2 at delivery. (C) Odds of disseminated neonatal HSV in infants born to women with newly acquired versus recurrent HSV at delivery. Solid boxes represent site-specific estimates and are sized according to each site s weight (a site s weight is equal to the inverse of the variance). Horizontal bars represent 95% confidence intervals. Diamonds represent the pooled estimates, and their width spans the 95% confidence interval for the pooled estimate. Dotted vertical reference lines mark the pooled point estimates.

6 528 E.L. Brown et al. maternal HSV-1 antibodies against neonatal HSV-2 infection. We did observe substantially higher odds of neonatal HSV in infants exposed to maternal HSV-1 compared with HSV-2. To our knowledge, this is the largest study of neonatal HSV to include maternal serologic and culture data as predictors of neonatal outcome. Our finding that the risk of neonatal HSV-2 infection is similar in infants born to HSV-seronegative women compared with HSV-1 seropositive women has not been well established in the literature-the number of cases in previous studies addressing this issue have been very small, and results have been inconsistent (9,16). It has been hypothesised that heterologous antibody might provide sufficient viral neutralisation to prevent HSV infection in the neonate. We found no evidence for such protection, as we observed a similar risk of neonatal HSV-2 in infants born to women with and without HSV-1 antibody. In this study, HSV-1 was more readily transmissible to the neonate than HSV-2 when present in the genital tract at delivery, even after controlling for maternal serostatus and Cesarean delivery. This result is concerning given that HSV-1 is an increasingly common cause of genital herpes (5,17 19), possibly as a consequence of decreasing rates of orolabial HSV-1 in childhood and changes in patterns of sexual behavior (20,21). The increase in the proportion of neonatal HSV cases due to HSV-1 in the past three decades (22,23) is likely attributable to both the increasing prevalence of genital HSV-1 infection and the higher transmissibility of HSV-1. The biological basis for increased risk of HSV-1 transmission during reactivation is not understood, and the relevance of this finding to sexual transmission of genital HSV-1 is not known. Despite inclusion of data from three centres, we had a relatively small number of cases. Thus, we grouped primary and NPFE infections together as newly acquired for all analyses except for the analysis of risk of neonatal HSV-2 by maternal HSV-1 serostatus. This grouping is based upon the much higher risk of transmission that occurs among women with primary or NPFE infection (/57% and 25%, respectively) compared with women with recurrent HSV at delivery (/2%) (1). We feel that this grouping is valid, especially given our lack of evidence for protection by heterologous antibodies against neonatal infection. Additionally, while the risks of transmission for these groups may differ by/2-fold, both risks exceed a level that is acceptable. Our finding that infants born to women with newly acquired HSV infection were at elevated odds of disseminated disease was restricted to the cases from Stockholm. The inconsistency in this association across study sites may be a reflection of some of the limitations inherent in pooling data originally collected at separate sites under different circumstances. Classification of maternal serostatus at delivery may vary by study site based on the HSV serology test used, although we relied only on gg-based assays. Furthermore, while we aimed to classify maternal HSV serostatus at the time of delivery, in some cases it was not possible to distinguish between maternal HSV acquisition just prior to delivery versus earlier during pregnancy. Classification of neonatal disease severity involves some degree of clinical judgment, and, thus, may vary by location as well. Our lack of statistical evidence of heterogeneity of ORs between the 3 study sites for the neonatal disease severity comparison may be a reflection of the low power of tests to detect heterogeneity. Identification of women at the highest risk of transmitting HSV to the neonate will allow for appropriate focusing of prevention efforts. Acknowledgements We thank Rhoda Morrow, David Friedrich, Stacy Selke, Judy Zeh, Lisa Frenkel, and Janet Englund for their contributions to this work. Financial support: CG, EK, ZB, LC and AW were supported by NIH grant AI EB was supported by NIH training grant T32 AI GM was supported by grants from the Karolinska Institute Foundation (Sweden) and the Samariten Foundation (Sweden). References 1. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;/289(2):/ Brown ZA. HSV-2 specific serology should be offered routinely to antenatal patients Rev Med Virol. 2000;/10(3):/ Prober CG, Sullender WM, Yasukawa LL, Au DS, Yeager AS, Arvin AM. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital HSV infections. N Engl J Med. 1987;/316: / Brown ZA, Selke SA, Zeh J, Kopelman J, Maslow A, Ashley RL, et al. Acquisition of herpes simplex virus during pregnancy. N Engl J Med. 1997;/337: / Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev. 1999;/12(1):/ Gutierrez KM, Halpern MSF, Maldonado Y, Arvin AM. The epidemiology of neonatal herpes simplex virus infections in California from 1985 to J Infect Dis. 1999;/180:/

7 Effect of maternal herpes simplex virus (HSV) serostatus Handsfield HH, Waldo AB, Brown ZA, Corey L, Drucker JL, Ebel CW, et al. Neonatal herpes should be a reportable disease. Sex Transm Dis. 2005;/32(9):/ Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev. 2004;/17(1):/ Brown ZA, Benedetti J, Ashley R, Burchett S, Selke S, Berry S, et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med. 1991;/324:/ Ashley RL, Militoni J, Lee F, Nahmias A, Corey L. Comparison of Western blot (Immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 and 2 in human sera. J Clin Microbiol. 1988;/26:/ Malm G, Berg U, Forsgren M. Neonatal herpes simplex: clinical findings and outcome in relation to type of maternal infection. Acta Paediatr. 1995;/84(3):/ Prober CG, Hensleigh PA, Boucher FD, Yasukawa LL, Au DS, Arvin AM. Use of routine viral cultures at delivery to identify neonates exposed to herpes simplex virus. N Engl J Med. 1988;/318(14):/ Boucher FD, Yasukawa LL, Bronzan RN, Hensleigh PA, Arvin AM, Prober CG. A prospective evaluation of primary genital herpes simplex virus type 2 infections acquired during pregnancy. Pediatr Infect Dis J. 1990;/9(7):/ Kulhanjian J, Soroush V, Au D, Bronzan R, Yasukawa L, Weylman L, et al. Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N Engl J Med. 1992;/326:/ Petitti D. Meta-analysis, decision analysis, and cost-effectiveness analysis; methods for quantitative synthesis in medicine. Second edition New York: Oxford University Press. 16. Brown Z, Vontver L, Benedetti J, Critchlow C, Sells C, Berry S, et al. Effects on infants of first episode genital herpes during pregnancy. N Engl J Med. 1987;/317:/ Langenberg A, Corey L, Ashley R, Leong W, Straus S. A prospective study of new infections with herpes simplex virus type 1 and type 2. N Engl J Med. 1999;/341:/ Coyle PV, O Neill HJ, Wyatt DE, McCaughey C, Quah S, McBride MO. Emergence of herpes simplex type 1 as the main cause of recurrent genital ulcerative disease in women in Northern Ireland. J Clin Virol. 2003;/27(1):/ Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;/30(10):/ Vyse AJ, Gay NJ, Slomka MJ, Gopal R, Gibbs T, Morgan- Capner P, et al. The burden of infection with HSV-1 and HSV-2 in England and Wales: implications for the changing epidemiology of genital herpes. Sex Transm Infect. 2000;/ 76(3):/ Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;/ 296(8):/ Nahmias AJ. Neonatal HSV infection Part II: Obstetric considerations a tale of hospitals in two cities (Seattle and Atlanta, USA). Herpes. 2004;/11(2):/ Kropp RY, Wong T, Cormier L, Ringrose A, Burton S, Embree JE, et al. Neonatal herpes simplex virus infections in Canada: results of a 3-year national prospective study. Pediatrics. 2006;/117(6):/