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Med Microbiol Immunol (2007) 196:89–94 DOI 10.1007/s00430-006-0031-0 O RI G I NAL IN VE S T I GA TI O N Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 1: Herpes simplex virus infections A. Sauerbrei · P. Wutzler Received: 24 August 2006 / Published online: 13 December 2006 © Springer-Verlag 2006 Abstract Primary herpes simplex virus (HSV) infection may lead to severe illness in pregnancy and may be associated with transplacental virus transmission and fetal infection. The consequences may be abortion, stillbirth and congenital malformations. In neonates, the clinical Wndings after intrauterine HSV infection are characterized by skin lesions, diseases of the eye and neurologic damage. Herpes genitalis of pregnant women at the time of labor may result in life-threatening neonatal herpes. Currently, neither active nor passive immunization is available to prevent HSV infections during pregnancy and in the newborn infant. Therefore, antiviral treatment using aciclovir and/or valaciclovir must be considered in all primary episodes of genital herpes as well as in neonates who show signs of either infection. Clinical herpes lesions of the genitalia and/or positive test for virus detection at the time of delivery are an indication for cesarean section. However, this surgical intervention may be reduced by suppressive treatment of recurrent genital herpes with aciclovir or valaciclovir. Keywords Herpes simplex virus infection · Pregnancy · Neonate · Prevention · Diagnosis · Therapy Introduction Herpes simplex virus (HSV) and varicella-zoster virus (VZV) induce a wide variety of diseases, which are nor- A. Sauerbrei (&) · P. Wutzler Institute of Virology and Antiviral Therapy, Friedrich-Schiller University of Jena, Hans-Knoell-Strasse 2, 07745 Jena, Germany e-mail: [email protected] mally mild and can be treated satisfactorily. During pregnancy, both pathogens are able to infect the mother as well as the fetus leading occasionally to disastrous maternal, fetal and neonatal diseases. Most infections are a great challenge to medical doctors since the potential beneWts of therapeutic and prophylactic measures to the mother and the potential risks to the fetus or the nursing infant have to be weighed up. Whilst varicella can be generally prevented by vaccination, special diagnostic and therapeutic measures are needed in case of HSV infections. As a Wrst part, the present paper reviews the clinical consequences of HSV infections during pregnancy and summarizes the currently available concepts of prevention, diagnosis and therapy. VZV infections during pregnancy and in newborn infants will follow as the second part of the manuscript. Herpes simplex virus infections during pregnancy The HSV has been considered as one of the most common viral infectious agents in humans. There are two closely related viral types, the HSV type 1 (HSV-1) and the HSV type 2 (HSV-2), which are genetically diVerent. In Germany, the prevalence of HSV-1 antibodies reaches high levels of more than 90% in adults whereas nearly 15% of the adult population possess antibodies to HSV-2 [44]. The number of women, who acquire HSV-1 or HSV-2 infection during pregnancy, has been calculated as 0.5–2% [8, 10]. Primary infections Primary HSV infections in pregnant women can result in more severe diseases than in nonpregnant ones. In 123 90 Med Microbiol Immunol (2007) 196:89–94 particular, gingivostomatitis and vulvovaginitis herpetica tend towards dissemination. As a result, women can develop disseminated skin lesions associated with visceral involvement such as hepatitis, encephalitis, thrombocytopenia, leucopenia and coagulopathy [45]. Although disseminated HSV infection is uncommon in pregnancy, the mortality is about 50%. In particular, pregnant women with primary mucous membrane infection during the third trimester have an increased risk for dissemination [32]. The most important HSV infection during pregnancy is the primary genital HSV infection (Fig. 1), since it can cause the most severe neonatal diseases. However, a Wrst manifestation of genital herpes during pregnancy is in most cases not a primary infection [17]. In principle, genital herpes can be caused by either HSV-2 or by HSV-1, which is the usual agent of orolabial herpes. While genital infection with HSV-1 is clinically indistinguishable from that caused by HSV-2, it is less likely to cause recurrent diseases [5]. Primary symptomatic genital herpes presents with blistering and ulceration of the external genitalia and cervix leading to vulval pain, dysuria, vaginal discharge and local lymphadenopathy. Infection may be complicated by systemic symptoms such as fever and myalgia and occasionally by autonomic neuropathy resulting in urinary retention and meningitis. In some cases, systemic clinical Wndings may be the only presenting symptoms of infection [37]. In more than half of the patients, primary infection goes unnoticed [38]. Women, who acquire genital herpes during the third trimester, are at risk of transmitting HSV to their babies during vaginal delivery. Studies suggest that viral shedding from vulva and cervix persists for a variable time after healing of the primary lesion, and these Pregnant women 0.5-2% Genital HSV infection Primary HSV-2 (HSV-1) Viremic Recurrent HSV-2 (HSV-1) Ascending Intrauterine infection 1st - 20th weeks Intrauterine death of fetus Congenital anomalies of newborn Infection under birth genital herpes in last trimester Postnatal infection Neonatal HSV infection 70-85% HSV-2 and 15-30% HSV-1 Incidence: 7/100,000 life births women may be at increased risk of preterm delivery [9]. Neonates are exposed to virus during the process of birth or shortly thereafter by direct contact with herpetic lesions in the birth canal or genitalia [30]. Infection intrapartum can lead to neonatal herpes, also referred to as herpes neonatorum, which is considered a life-threatening illness of the neonate. Prolonged rupture of membranes could increase the risk of virus transmission to the fetus, probably as the consequence of ascending infection. Transplacental infection has also been reported, especially after primary HSV infection, independent of the localization of herpes lesions [20]. Recurrent infections HSV can reactivate in the genital tract either asymptomatically or symptomatically. Classical signs are grouped vesicles with progression to ulceration and crusting, localized to a small area of external genitalia. Lesions are typically fewer and smaller than in primary disease and constitutional symptoms are rare [38]. The great majority of recurrent genital herpes is due to HSV-2 [33]. Although no clinical signs can be recognized in many HSV-2 infections, there is an asymptomatic viral shedding in most patients. Sexual contacts with such subjects infected subclinically during periods of asymptomatic viral shedding carry a substantial risk of transmitting HSV-2 to sexual partners [29]. Viral shedding is of shorter duration than in primary infection. Although there is a smaller risk of vertical viral transmission than in primary infection, recurrent genital herpes must be regarded as the most common cause of neonatal infections and the passage through an infected birth canal is the most probable route of transmission [14, 26]. In recurrent infections associated with clinical symptoms, the risk of neonatal disease is reduced dramatically by cesarean section [41]. Transmission of HSV by women with asymptomatic viral shedding is of greater signiWcance, since neonates mostly acquire infection without being recognized. Individuals with recurrent HSV lesions outside the genitalia must be regarded as infective for neonates, too. Thus, viral transmission from a mother with lesions of the breast as well as transmission to infants of seronegative mothers from fathers or relatives have been reported. Abortion Clinical findings • Localized infections including skin, eye, and mouth • Involvement of the central nervous system • Generalized infections Fig. 1 Herpes simplex virus infections and their consequences during pregnancy 123 Intrauterine herpes simplex virus infection Intrauterine HSV infection is a rare disorder and accounts for 5% of HSV infections in neonates. The Med Microbiol Immunol (2007) 196:89–94 highest risk of intrauterine infection with about 50% has been observed in pregnant women who develop disseminated HSV infections. Among HSV infections acquired in utero, 90% of those with an identiWed type are due to HSV-2 [30]. Both primary and recurrent maternal infection can result in congenital disease [19], even so the risk after recurrent infection must be regarded as smaller. The danger to intrauterine viral transmission is highest during the Wrst 20 weeks of gestation leading to abortion, stillbirth and congenital anomalies. The diagnostic criteria of intrauterine HSV infection consist of identiWcation of infected infants in the Wrst 48 h of life, virologic conWrmation of infection and exclusion of other pathologic conditions. The classic triad of Wndings is listed in Table 1. In the diVerential diagnosis, other congenital infections such as by the varicella-zoster virus (VZV) have to be considered. Neonatal herpes simplex virus infections In 85–90% of neonatal HSV infections, HSV is acquired at the time of delivery and 5–10% are caused by early postnatal acquisition of the virus. The disease is referred to as neonatal herpes. Neonatal HSV infections of 70–85% are caused by HSV-2 and the remainder cases are due to HSV–1 [34]. Infection with HSV-2 is associated with a poorer prognosis [43], but severe cases have also been found to be caused by HSV-1 [28]. A review of literature suggests that the incidence is around 7/100,000 life births [11] and up to 40% of the suVered infants are premature [43]. Neonatal herpes is a rare disorder in newborn infants, but it belongs due to its high morbidity and mortality to the most severe infections acquired during the perinatal period [12, 39]. Therefore, neonatal HSV infection should be considered in the diVerential diagnosis of each acutely unwell neonate. At the onset, the disease is often diYcult to distinguish from bacterial Table 1 Clinical manifestations of intrauterine [15, 18, 20, 31] and neonatal herpes simplex virus (HSV) infections [25] Intrauterine HSV infections • Skin vesicles or scarring • Eye lesions (chorioretinitis, microphthalmia, cataract) • Neurologic damage (microcephaly, intracranial calciWcations, seizures, encephalomalacia) Neonatal HSV infections • Localized infections of skin, eye and mucous membranes • Infections of the central nervous system • Disseminated systemic infections 91 sepsis and the maternal infection may be completely asymptomatic [21]. Clinical manifestations are divided into three major categories summarized in Table 1. Localized infections have been found in 50% of the aVected neonates, involvement of the central nervous system (CNS) in 33%, and generalized infections in 17% of the cases [25]. Several studies have demonstrated that generalized HSV infections can present with the major symptom of liver failure associated with shock symptoms and disseminated intravascular coagulopathy [16, 28]. Despite the availability of antiviral drugs for treatment of neonatal HSV infections, the outcome remains poor, particularly for babies with disseminated multi-organ infections or manifestations of CNS [42]. The course predominantly involving the CNS is the neonatal hemorrhagic-necrotizing encephalitis that manifests as lethargy and seizures. Although the mortality rate is only 5% for neonates with encephalitis, over 50% of survivors are left with signiWcant neurological impairment [42]. After a neonatal herpes infection, cutaneous recurrences may occur for some time [24]. Prevention, diagnosis and therapy for herpes simplex virus infections during pregnancy Preventive measures The most eVective measure to prevent perinatal herpes infections is to avoid exposure to virus since there is highest risk to the neonate after primary genital herpes during late pregnancy. In case of recurrent genital herpes, the risk of severe neonatal infection can be regarded as small. However, all women should be asked at their booking visit if they or their partners have ever had genital herpes. Female partners of men with genital herpes, but who do not themselves have a history of genital herpes, should be strongly advised not to have sexual intercourse at the time of recurrence. Conscientious use of condoms throughout pregnancy should be advised to minimize the risk of viral acquisition. Diagnostic procedures The diagnosis of genital herpes is conWrmed by detection of HSV DNA using polymerase chain reaction (PCR) or by isolating the virus by culture from the genital tract [18]. Viral antigen can also be detected using commercially available antigen test kits. Serological procedures are only useful in the diagnosis of primary genital infection when the virus-speciWc immunoglobulin (Ig) M is expected to be positive and when a reliable diVerentiation between primary and latent infection 123 92 Med Microbiol Immunol (2007) 196:89–94 with HSV-1 and HSV-2 is desirable. The viral envelope glycoprotein G of HSV-1 and HSV-2, used as aYnity puriWed or recombinant antigens in several commercially distributed enzyme immunoassays, have been recognized as type-speciWc antigens [6, 35]. In molecular biological studies, a unique region was identiWed in the glycoprotein G-2–encoding gene, which could not be found in the glycoprotein G-1 [27]. Type-speciWc enzyme immunoassays can be recommended to identify mothers at high risk of infecting their infants as well as silent HSV-2 carriers, who may be an important reservoir for viral transmission. When HSV-2 has been detected in pregnant women several weeks before delivery, type-speciWc HSV serology can be useful to distinguish primary from recurrent episodes of genital herpes [7]. This is possible by detection of seroconversion after testing samples are taken sequentially. Women who acquire genital HSV infection during pregnancy, but who do not complete their seroconversion prior to the time of labor, will most likely infect their neonates and, therefore, cesarean section should be considered [8]. On the other hand, a cesarean section is not necessary if the seroconversion is completed at the time of delivery. In this case, the neonate is likely to be protected by maternal antibodies. Therapeutic measures All primary episodes of genital herpes in pregnant women should be treated with aciclovir or valaciclovir at the recommended dosage [3, 38] (Table 2). Results from the aciclovir-in-pregnancy registry do not show teratogenic eVects of the drug [2]. Comparable data have been reported for the oral administration of valaciclovir [13], whereas no data about other nucleoside analogous compounds such as famciclovir during Table 2 Antiviral treatment of genital herpes in pregnancy and of neonatal herpes simplex virus infection pregnancy are available. As aciclovir and valaciclovir are not oYcially approved for the treatment of pregnant women, patients should be informed about the limited information and give consent before the drug is used. Randomized studies have shown that suppressive treatment with aciclovir (Table 2) from the 36th week of pregnancy until delivery reduces the frequency of clinical manifestation and virus shedding at the time of delivery. Thus, the cesarean section rate can be decreased signiWcantly [36]. Prevention, diagnosis and therapy for herpes simplex virus infections in neonates Preventive measures If clinical herpes lesions, positive tests for virus detection, or both are present at the time of delivery, then a cesarean section is indicated as an eVective measure for prevention of neonatal herpes infection [10]. In case of acute recurrent genital herpes, a vaginal delivery can be considered when the oral administration of 2 £ (200-) 400 (-800) mg aciclovir was started two days before delivery [40]. At membrane rupture, if it may be assumed that the fetal lungs are mature, a cesarean section should be performed as quickly as possible and no more than 4–6 h later [1]. In case of immature lungs, there is no established basis for the decision [38]. Neonates with a conWrmed or suspected HSV infection should be isolated. Direct contact with skin and mucosal lesions as well as excretions and body Xuids should be avoided. Since neonatal herpes can also be acquired postnatally, women or relatives with active herpes lesions should be advised about the risk of viral transmission. Medical staV and visitors with recur- Primary genital herpes Aciclovir Orally: 5 £ 200 mg Valaciclovir Orally: 2 £ 500 mg Recurrent genital herpes Aciclovir Orally: 5 £ 200 mg Valaciclovir Orally: 2 £ 500 mg Suppressive treatment of genital herpes Aciclovir Orally: 3 £ 400 mg Valaciclovir Orally: 2 £ 250 mg Neonatal herpes Aciclovir Length of therapy: 10 days Length of therapy: 10 days Length of therapy: 5 days Length of therapy: 5 days Maintenance therapy Length of therapy: from week 36 until delivery Intravenously: Length of therapy: 14–21 days 3 £ 10–15 (¡20) mg/kg Suppressive treatment of cutaneous recurrences after neonatal herpes Aciclovir Orally: 2–3 £ 300 mg/m2 Length of therapy: for weeks to months 123 Med Microbiol Immunol (2007) 196:89–94 rences of herpes should take necessary precautionary measures to prevent direct contact with the skin or mucosa of the neonate or should be excluded from the neonatal unit until the lesions are fully healed. Diagnostic procedures Because HSV infection in neonates can mimic other neonatal diseases including VZV infection, laboratory diagnosis is indispensable. In case of manifest genital herpes or known maternal virus shedding at the time of delivery, it is advisable to cultivate swabs from the neonate’s conjunctiva, oropharynx and rectum [38]. If the neonate exhibits suspicious symptoms, diagnosis must be rapid and reliable. PCR technology has to be regarded as the “gold standard” for detecting HSV [22]. Vesicular, conjunctival, oropharyngeal, stool/rectal swabs, urine and cerebrospinal Xuid serve as specimens. The detection of HSV in the blood can allow an early diagnosis and can speed up decision to initiate antiviral treatment. Although serological methods have traditionally been widely used for the diagnosis of HSV infections, studies have shown that the determination of antibodies including virus-speciWc IgM does not allow an early diagnosis of neonatal HSV infections [18]. In most cases, serological studies are only convenient for retrospective diagnosis. However, detection of type-speciWc antibodies can be of great signiWcance to conWrm a clinical diagnosis of HSV-2 infection without using relatively expensive and labor-intensive methods for virus detection. Therapeutic measures There is clear evidence that intravenous administration of high-dose aciclovir signiWcantly reduces the mortality of babies with either encephalitis or disseminated disease [42] (Table 2). Nevertheless, neonatal herpes infection is still associated with high residual mortality and morbidity. The point in time, at which treatment is started, is crucial for prognosis especially in case of disseminated infection. Thus, antiviral treatment must be introduced before an irreversible damage in particular of CNS and liver tissue is present [4]. An empiric treatment with aciclovir (Table 2) has been recommended in neonates with (1) typical HSV lesions of the skin, eyes or mouth, (2) encephalitis or sepsis with negative bacterial cultures and (3) the combination of hepatitis and pneumonitis [30]. Suppressive antiviral treatment using aciclovir is indicated when cutaneous recurrences are observed after neonatal HSV infection [23] (Table 2). 93 References 1. American Academy of Pediatrics (2003) Herpes simplex. In: Pickering LK (ed) Red Book: 2003 Report of the Committee on Infectious Diseases, 26th edn. American Academy of Pediatrics, Elk Grove Village, pp 836–843 2. Andrews EB (1994) Acyclovir does not increase risk in pregnancy. Am Pharm NS34:6 3. Anonymous (2004). Deutsches Herpes Management Forum. Chemother J 13:27–37 4. Benador N, Mannhardt W, Schranz D, Braegger C, Fanconi S, Hassan S, Talebzadeh V, Cox J, Suter S (1990) Three cases of neonatal herpes simplex virus infection presenting as fulminant hepatitis. 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