Prevention of neonatal herpes

Transcription

1 DOI: /j x Review article Prevention of neonatal herpes C Gardella, Z Brown Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA Correspondence: Dr C Gardella, Department of Obstetrics and Gynecology, University of Washington, Box , Seattle, WA , USA. cgardel@u.washington.edu Accepted 8 October Neonatal herpes can occur when the neonate is exposed to herpes simplex virus in the maternal genital tract during labour. Attack rates are highest when the mother has a newly acquired infection and, therefore, does not have antibodies to protect the neonate. Even with early therapy, there is significant morbidity and mortality associated with neonatal herpes, suggesting that preventing neonatal herpes simplex virus exposure or early recognition of exposure is important. The incidence of neonatal herpes has not declined despite national guidelines for prevention. This suggests that the prevention guidelines need to be re-addressed. Keywords Herpes, neonate, prevention. Please cite this paper as: Gardella C, Brown Z. Prevention of neonatal herpes. BJOG 2011;118: Epidemiology of genital herpes Based on serological data from a large National Health and Nutrition Examination Survey (NHANES), 22% of pregnant women in the USA are infected with herpes simplex virus 2 (HSV-2), 63% are HSV-1 seropositive, 13% have both HSV-1 and HSV-2, and 28% are seronegative. 1 In the general population, for the first time since the 1976 inception of NHANES, the seroprevalence of HSV-2 has decreased; overall, the age-adjusted HSV-2 seroprevalence was 17% in , compared with 21% in , a relative decrease of 19% between the two study periods. Among those infected with HSV-2, the percentage who reported being diagnosed was 14.3% in and 9.9% in , suggesting that more providers are aware of genital herpes, and able to make appropriate diagnoses. 2 However, the vast majority of people infected with HSV-2 remain undiagnosed and, therefore, untreated and able to spread the infection. Between 75% and 90% of HSV-2- infected people are not aware of having the infection. 3 6 This is important because most sexual transmission of HSV occurs during episodes of subclinical reactivation among persons with unrecognized infection. 4,7 10 Virtually all HSV-2 seropositive people have intermittent shedding from the genital mucosa, and most have mild (and hence unrecognized and undiagnosed) disease. 5 In the absence of symptoms, HSV-2 can be detected in the genital tract, by viral culture, on 3% of days for the first year after initial infection, then on 1% of days for the next 2 years. HSV-2 DNA can be detected by polymerase chain reaction testing 15 20% of days. 11,12 Recent data suggest that HSV reactivation may occur much more frequently than previously understood, and may be characterised by frequent short bursts of viral shedding that do not correlate with symptoms. 13 As HSV-2 seroprevalence decreased, HSV-1 seroprevalence in the USA increased to 62% in from 57.7% in Among persons infected with HSV-1 but not HSV-2, a higher percentage reported a diagnosis of genital herpes in compared with (1.8% versus 0.4%). 2 HSV-1 has emerged as a major cause of genital herpes among college-age populations, in which up to 80% of new cases of genital HSV were caused by HSV Epidemiological studies suggest that oral genital contact is the major risk factor for the acquisition of genital HSV Similar findings have been reported worldwide. In Scandinavia, the seroprevalance of HSV-2 among pregnant women was 33%, 18 and in Canada this rate was 17%. 19 Among people attending a sexually transmitted disease clinic in the UK, 25% were seropositive for HSV-2. In developing countries, seroprevalence rates are even higher, reaching 60 90% among commercial sex workers and HIV-positive factory workers in Africa. 20 Data from Australia and Wales similarly suggest that HSV-1 genital infection is becoming more common. 21,22 Neonatal herpes The incidence of neonatal HSV in the USA varies in relation to the source of data, and is probably underestimated. Neonatal HSV is not reportable nationally in the USA, ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology 187

2 Gardella, Brown although in ten states reporting is mandatory. Underreporting and imprecise International Classification of Diseases 9th revision coding result in wide variations in the published rates. Retrospective studies based on hospital discharge data suggest a rate of approximately 12 per in California and as high as 60 per based on a new review of managed care data from 30 plans between 1997 and In our prospective study based on more than women, we observed neonatal HSV at a rate of 30.8 per This rate is consistent with a projected rate of 33 per live births calculated using the recent NHANES data. 1 The incidence of neonatal herpes has remained stable over the past 20 years, 25 suggesting that current prevention recommendations are not adequate. Reported neonatal herpes rates are lower in the UK, where active surveillance by the British Paediatric Surveillance Unit demonstrated an incidence of one in live births annually (95% CI ). This rate was estimated to be 50% that of Europe and Japan. 27 The reported incidence rate of neonatal herpes in Canada from a prospective study was 0.59 per live births. 28 Little is known regarding the risk of neonatal herpes in immunocompromised populations. There are emerging data that HSV-2 may increase the risk of mother to child transmission of HIV although the converse has not been studied. 29 HIV-positive women have a high rate of HSV-2 infection (80 90%), and may be at increased risk for HSV shedding from the genital tract, and genital lesions at the time of delivery. 30,31 Disease manifestations of neonatal herpes Neonatal herpes is categorized as skin, eye, mouth infection, central nervous system (CNS) disease, or disseminated disease depending on clinical manifestations. Skin, eye, mouth infection accounts for 45% of infants and is characterized by vesicular lesions on the skin, eye or mouth without CNS or organ-system involvement. Skin, eye, mouth infection may progress to CNS or disseminated disease without intravenous acyclovir treatment. With treatment, outcome is good although these children may have recurrent outbreaks of cutaneous herpes during childhood. 32,33 Infection of the CNS accounts for 30% of infected infants and presents as lethargy, feeding difficulty and seizures with or without skin lesions. With intravenous acyclovir therapy, there is a 6% mortality rate, and 50% of survivors have moderate-to-severe neurological abnormalities. 32,33 The remaining 25% have disseminated infections that involve multiple organs and present with clinical sepsis. With intravenous acyclovir treatment, mortality is 30%. For all infants, prompt diagnosis and initiation of therapy are critical to neonatal outcome. 32,33 Pathogenesis of neonatal HSV Rarely, congenital neonatal herpes occurs from viral infection before the onset of labour. These infants manifest with microcephaly, hydrocephalis and chorioretinitis at birth. Postnatal acquisition is almost exclusively from HSV-1 contracted from hospital personnel or family members. Neonatal herpes refers to the acquisition of infection at the time of delivery by exposure to the virus in the maternal genital tract and is diagnosed within the first 28 days of life. 34 Neonatal HSV can occur in women regardless of HSV antibody status in pregnancy. 26 However, as shown in Table 1, the risk of neonatal HSV varies by maternal HSV status and is highest among women who are HSV seronegative. This apparent contradiction is the result of the extremely high efficiency of HSV transmission in women with newly acquired genital HSV-1 or HSV-2 in late pregnancy (30 50% transmission rate among women who have HSV detected in the genital tract at delivery) compared with relatively low efficiency of HSV-2 transmission among women who have established HSV-2 (<1% of women with established HSV-2 who shed at delivery transmit neonatal HSV). Maternal HSV antibody crosses the placenta and provides neonatal protection from infection. Overall, most neonatal HSV results from women who acquire genital HSV in late pregnancy because these women lack antibody to protect the neonate and are at high risk of viral shedding at the time of delivery. Risk factors for neonatal herpes are shown in Table 2. Notably, the main risk factor for neonatal herpes is detection of HSV in the genital tract at the time of labour, followed by maternal antibody status, and HSV type. Intrapartum interventions that break the neonatal skin, such as application of a fetal scalp electrode or forceps delivery, increase the risk of neonatal infection. Increasing importance of neonatal HSV-1 The incidence of genital HSV-1 has continued to increase in the last decade. The increase in genital HSV-1 initially was observed in Europe, and more recently in the USA and Australia. 15,21,22 The increase is thought to be the result of both less frequent acquisition of HSV-1 in childhood and more frequent oral genital contact at the initiation of sexual activity. 35,36 Not surprisingly, the increase in genital HSV-1 infection has resulted in an increase in neonatal HSV-1 in proportions that meet or exceed that caused by HSV-2. HSV-1 caused 63% of neonatal HSV in Canada 28 and 50% in 188 ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology

3 Neonatal herpes prevention Table 1. Transmission rates of neonatal HSV by maternal status in a cohort of pregnant women 26 Maternal HSV status Table 2. Risk factors for neonatal herpes 26 Risk factor Rate/ live births (95% CI) HSV seronegative 54 ( ) HSV-1 seropositive only 26 (9.3 56) HSV-2 seropositive (±HSV-1) 22 (4.4 64) Odds ratio HSV in the genital tract at the 346 ( ) time of labour Stage of maternal infection 59 ( ) (primary versus recurrent) Type of HSV isolated from the genital 35 ( ) tract HSV1 versus HSV2 Invasive obstetric procedures 3.5 (0.6 19) Seattle. 26 Although HSV-1 does not reactivate in the genital tract as often as HSV-2, 12,37 when HSV-1 reactivation does occur, the neonate appears more likely to become infected than when HSV-2 reactivation occurs. This was initially observed in our prospective study in which HSV-1 isolation at birth was associated with an adjusted 15-fold higher risk of neonatal HSV than genital HSV-2 isolation, 26 and was confirmed by data from California that showed an adjusted relative risk for HSV-1 versus HSV-2 of A larger proportion of infants with neonatal HSV-1 are developmentally normal (70% with HSV-1 versus 43% with HSV-2); however, disseminated HSV-1 can be fatal in infancy with mortality comparable to disseminated HSV Hence, HSV-1 cannot be ignored as a cause of neonatal HSV, and strategies for prevention need to encompass both HSV-1 and HSV-2 infection. Diagnosis and treatment of maternal genital herpes Most infections of maternal genital herpes are unrecognized and undiagnosed. For women with genital lesions, viral culture or polymerase chain reaction (PCR) should be performed to detect and type the virus. PCR is now preferred because of the relative ease of specimen handling, its improved sensitivity and faster turn around time. In addition, if serological testing is indicated, type-specific testing should be performed to accurately classify the infection as new or recurrent. There are many commercially available tests but the practitioner should be sure that the assay tests for glycoprotein G (gg), the protein that differs between HSV-1 and HSV-2 on the capsule of the HSV virion. 39 If the serology type-specific result is discrepant from the culture or PCR result, a new infection is diagnosed. If the serology type-specific result is the same as the culture or PCR result then a recurrent infection is diagnosed. Relying on symptoms to diagnose genital herpes in pregnancy misses the 70 90% of persons with genital HSV infection who are asymptomatic. The majority of persons with genital HSV infection will shed virus sporadically and unpredictably regardless of whether they have symptoms and most sexual transmission of HSV occurs during episodes of asymptomatic shedding in persons previously undiagnosed with genital herpes. 12 Serological testing of asymptomatic women is an option to detect asymptomatic herpes. If a woman is seropositive for HSV-2, she is diagnosed with genital herpes. However, if she is seropositive for HSV-1 and is without oral or genital symptoms then she may have either oral or genital HSV-1. If she develops oral or genital lesions in the future, virological testing of the lesion is indicated to confirm the site of HSV-1 infection. Routine serological testing for herpes in pregnancy is controversial and is not recommended by the American College of Obstetricians and Gynecologists (ACOG) or the Royal College of Obstetricians and Gynaecologists (RCOG). 40,41 Guidelines do not include serologic testing because it is unclear that it would be cost effective, or effective in reducing the neonatal herpes incidence. Future studies are needed to address these important issues. Studies find that women are amenable to HSV testing as part of routine prenatal care. 42,43 New diagnosis of genital HSV in an asymptomatic person causes mild, transient distress that should not preclude testing 44,45 if it is indicated. Women with new genital HSV infection or with recurrent, symptomatic infection during pregnancy should be offered anti-viral therapy and suppression, consistent with ACOG and RCOG guidelines. 40 Current recommendations for neonatal herpes prevention Published US and Canadian prevention guidelines focus on pregnant women with symptomatic genital herpes and recommend thorough examination for genital lesions at the time of labour with caesarean delivery to avoid contact with infected genital secretions if lesions are identified. 40,46 Additionally, women with frequent recurrent lesions during pregnancy may be offered antiviral suppressive therapy to prevent genital lesions at the time of labour. 40 This is generally given from 36 weeks of gestation until delivery. Suppressive therapy has been shown to decrease the risk of ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology 189

4 Gardella, Brown genital lesions that would lead to caesarean delivery at the time of labour, and to decrease, but not eliminate, the incidence of viral shedding at the time of delivery. 47,48 Studies were underpowered to determine if suppression therapy in these women decreased the risk of neonatal herpes. UK prevention guidelines regarding caesarean delivery for genital lesions focus on the maternal stage of infection. If the mother has a primary infection or had a primary infection within 6 weeks of delivery then caesarean section is recommended. However, in the case of genital lesions caused by an established infection caesarean delivery is not recommended because the risk to the neonate is small. 41 Although it makes empiric sense to focus on women with symptomatic disease, it does not fit with the complex pathophysiology of neonatal herpes. The main risk factor for transmission is detection of HSV in the genital tract at the time of vaginal birth. Relying solely on physical examination is inadequate to detect the presence of virus because most viral shedding episodes are asymptomatic and most cases of neonatal herpes occur among women who were asymptomatic at the time of labour. Further, it focuses on women with established infection, who are least likely to transmit to their neonates (1% risk of transmission), while disregarding women with new infection in pregnancy, who are at highest risk of transmitting. These factors contribute to the lack of progress to decrease the incidence of neonatal herpes over the past 20 years. Proposed strategies for prevention Despite the obvious problems with our current prevention strategies, there are no obvious solutions. It appears that reduction in neonatal herpes will happen only if we widen our focus to include women with newly acquired genital herpes during pregnancy and a primary prevention strategy would be to prevent new infections during pregnancy. In our opinion, there are several possible approaches. 1. Tell all pregnant women to abstain from any sexual contact during pregnancy. This approach has been advocated by some as a simple, inexpensive prevention message. Although this may be easy to implement, data suggest that women will not adhere to abstinence in pregnancy. Even among pregnant women known to be HSV-2 seronegative, the frequency of abstinence and unprotected sex was the same as for women with known seroconcordant partners, suggesting that this method is unlikely to work. 2. Add serological testing to routine prenatal care to identify women who are HSV-2 seropositive, and those who are HSV-2 seronegative, and therefore at risk of acquiring the infection during pregnancy. Among serologically at-risk women, safer-sex counselling could advocate for abstinence or condom use, but, as noted above, this did not improve compliance with risk reduction strategies. This approach would also identify women with asymptomatic genital HSV for education. Whether women with asymptomatic genital herpes should be prescribed antiviral suppression therapy is debatable and ACOG does not recommend it at this time. Although acyclovir is thought to be safe in pregnancy, widening exposure to a larger proportion of pregnant women without data to indicate that it will decrease the risk of neonatal herpes seems imprudent without further study. 3. Serotest both the pregnant woman and her partner to identify women at risk for HSV acquisition. This would identify a smaller group of high-risk women for more intensive counselling to prevent infection during pregnancy. About 12 20% of women are at risk of acquiring HSV from their partners during pregnancy. 49 Further, antiviral suppressive therapy could be offered to the infected partner to decrease his risk of viral reactivation and shedding. This approach has worked in non-pregnant couples to reduce the risk of infection by 50% 50 during the 8 months of observation. Partner testing appears to be feasible, at least in a predominately monogamous population, but is unlikely to work among women with multiple partners in pregnancy. 51 The previous prevention possibilities are relatively complicated, requiring serological testing, time and effort to counsel regarding results and safer sex practices, and decision-making regarding antiviral use in pregnancy and are unlikely to be applicable to the broad obstetric population. A more direct prevention strategy would be to identify neonates at risk for exposure to HSV at the time of labour by sampling the genital secretions for HSV of all women in labour. For those with HSV detected in the genital tract, determination of serostatus could be performed using a point of care serological test to identify women with recurrent genital herpes, 99% of whom will not transmit to the neonate, and those with newly acquired infection, 50% of whom will transmit the infection to the neonate. For those with recurrent infection, options could include vaginal delivery with acyclovir prophylaxis, enhanced observation of the neonate, and antiviral prophylaxis for the neonate. There is a risk that unnecessary caesarean deliveries would be performed in this relatively low-risk population. If caesarean delivery was performed reflexively in this population, the number of caesarean deliveries needed to prevent one case of neonatal herpes is 99. However, for women with new infection, every two caesarean deliveries would prevent one case of neonatal herpes. We recently developed a rapid HSV PCR test that can provide results within 2 hours to inform clinical decisionmaking for mode of delivery and postpartum care of the neonate with excellent sensitivity and specificity. 52 Eightyfive percent of women surveyed said that they would be willing to use such a test in labour, suggesting that testing will be feasible. 42 Although the technical development of this test needs to be followed by clinical studies among 190 ª 2010 RCOG No claim to original US government works Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology

5 Neonatal herpes prevention pregnant women, and appropriate management strategies for women who are HSV positive in labour need to be evaluated, we are hopeful that this tool will allow clinical studies to be conducted toward defining effective strategies for reducing the burden of neonatal HSV. Disclosure of interests CG has no potential conflicts of interest. ZB has received grants for educational activities from and has served as a paid advisor or consultant to GlaxoSmithKline. Contribution to authorship CG and ZB wrote this review article. CG was the primary author and ZB edited the paper and provided substantive feedback. Details of ethics approval Not applicable for this review article. Funding None. Acknowledgement None. j References 1 Xu F, Markowitz LE, Gottlieb SL, Berman SM. Seroprevalence of herpes simplex virus types 1 and 2 in pregnant women in the United States. Am J Obstet Gynecol 2007;196:43.e Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmias AJ, et al. 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