Perinatal viral infections

Clinical

Microbiology Newsletter November 15, 1992

Voi. 14, No. 22

Perinatal Viral Infections Betty A. Forbes, Ph.D. Associate Professor, Pathology Director, Microbiology Laboratories S.U~I.Y. Health Science Center Syracuse, NY 13210 A significant number of viral agents can infect the human fetus during pregnancy-fetal and neonatal infection is found in up to 10% of all live births (1). The clinical manifestations of these infections can range from asymptomatic or nonspecific findings to congenital malformations to a severe and sometimes fatal illness in the neonate. This wide range in severity is in large part a function of the unique, dynamic, and complex relationship between the mother and developing fetus. The significant changes in metabolic, hematologic, and immunologic parameters associated with pregnancy play a role in determining the outcome of viral infections during pregnancy. For example, the virulence of the infecting agent, the susceptibility of the infant, the time of the maternal infection, and the immune status of the mother can influence the outcome of the viral infection during pregnancy. The primary purpose of this article is to review those viruses that are of major importance in causing perinatal infections. In the literature, the viruses identified as causing perinatal infections differ as a result of varying delineation of the perinatal period. For purposes of this review, perinatal infections will refer to those viral infections acquired by neonates at the time just prior to delivery or within the immediC M N E E J 14(22)169-176,1992

ate neonatal period. An in-depth review of each viral agent responsible for perinatal infections is beyond the scope of this article. Therefore, general aspects of these infections will first be considered. Some of the key viral agents will then be reviewed with an emphasis on their mode of acquisition and clinical manifestations to underscore the impact these viruses have on the human fetus by infecting it during the perinatal period. Diagnosis of infection will also be discussed.

General Aspects There is consensus that the process of birth is an extremely traumatic process. As noted by Zeichner and Plotkin (2), the infant is exposed to large volumes of maternal blood and the integrity of the placenta is compromised during birth. Furthermore, as the fetus traverses the birth canal, there is a potential risk to the infant of exposure to a variety of pathogens associated with the genital tract. As expected, a number of the viruses causing perinatal infections are also viewed as significant pathogens of sexually transmitted diseases. The newborn can therefore acquire a perinatal viral infection by one of several major routes: (i) by direct inoculation of organs, such as skin, eyes, or respiratory tract, with potential for dissemination and systemic infection; (ii) transplacentally; (iii) by ingestion of viruses during the time of delivery; or (iv) during the postpartum period. Given these routes of transmission, the sources of perinatally acquired viral Elsevier

infections include the maternal circulation with subsequent transmission through the placenta and on to the fetal circulation, the maternal genital tract, the maternal gastrointestinal tract, breast milk, and nosocomial sources (3). In contrast to other routes of infec"dons acquired in the intrauterine period, transplacentally acquired viral infections are not considered a major source of perinatal infections. This article will not address those perinatal viral infections that are nosocomially acquired. Suffice it to say that the list of viral etiologies capable of nosocomial transmission is extensive. Of note, these same viruses are also capa-

In This Issue

Perinatal Viral Infections . . . . . . Discussion of important viral agents causing infection in the perinatal period, including their mode of acquisition, clinical manifestations, and diagnosis

Herpes Simplex Virus Vaccines: How Close Are We? . . . . . . . . . .

169

173

Review of approaches to developing an effective vaccine for herpes simplex viruses

Pseudomycobacteriosis . . . . . . . .

175

False-positive smears due to nontuberculous mycobacteria present in hospital-distilled water 0196-4399/92/$0.00 + 03.00

ble of causing significant morbidity and mortality among neonates. Agents such as respiratory syncytial virus, influenza and parainfluenza viruses, varicellazoster virus (VZV), and herpes simplex virus (HSV) have been reported to be transmitted to neonates by contact with infected hospital personnel. In addition to contact with infected hospital personnel, another source of nosocomial infection is the transfusion of blood products; both cytomegalovirus (CMV) and human immunodeficiency virus (H/V) have been reported to be transmitted to neonates in this manner (4, 5). K e y Viral A g e n t s

Human Immunodeficiency Virus A number of infectious agents can infect the human fetus during the perinatal period and cause significant disease. Particularly disturbing has been the rapidly rising incidence in the number of children infected with HIV--approximately 80% of pediatric cases of AIDS in the United States are believed to arise from vertical transmission, i.e., from mother to child (6). Although not understood clearly, vertical transmission of HIV is believed to occur transplacentally during pregnancy, during labor and delivery as a resuit of contact with contaminated blood or body fluids, or possibly shortly after birth by postpartum transmission by breast-feeding. Currently, intrauterine transplacental infection of the fetus is considered the important mechanism of vertical transmission for this virus. Regardless of the route of transmission, between 20 and 40% of infants born to HIV-infected mothers will be infected (7). Although many possibilities have been suggested, the factors that influence the transmission of HIV from mother to child are poorly understood. Recent studies have demonstrated that maternal antibodies directed against certain epitopes of the HIV envelope protein gp 120 might play an important

role in preventing vertical transmission (8, 9). If these studies are substantiated, the presence or absence of these antibodies may prove to be highly predictive for infection in neonates born to mothers with HIV infection. Like adults, children with perinatally acquired HIV infection manifest a widely variable clinical outcome: some develop AIDS within the first months of life while others remain asymptomatic or have mild symptoms for years. Nevertheless, the clinical presentation of HIV infection in children can also differ somewhat from that seen in adults. For example, opportunistic infections due to Pneumocystiscariniior CMV are less frequent, while recurrent bacterial infections with Streptococcus pneumoniae or Haemophilus hzfluenzae are more common in HIV-infected children than in adults. Other consistent features of infants who contract AIDS are hepatosplenomegaly and failure to thrive. Virologic and serologic tests for HIV as well as DNA recombinant techniques have been used for the detection and clinical management of H/V-infected patients. However, the diagnosis of HIV infection in neonates can be ambiguous, and, thus, some of these techniques, particularly serologic testing, may be limited in their ability to detect infection in this population. Fol~example, serological tests that measure IgG antibody to HIV are not diagnostic because maternal IgG crosses the placenta. Also, neonatal IgM antibody to HIV is generally absent or only transiently present. Recently, significant progress in early diagnostic testing of neonates employing the polymerase chain reaction (PCR) or other antibodydependent assays has been made (6). The detection of HIV in neonates by PCR appears to be both sensitive and specific. Of particular significance is the potential of this technique to differentiate between intrauterine and perina-

tal infection. If it is determined that a significant number of newborns acquire their infection during delivery, therapeutic intervention might then become a realistic possibility. Aside from the problems in neonates, standard serologic testing to detect HIV infection will not identify all infected pregnant women. Johnson et al. (10) reported that perinatal transmission occurred in two of three women with negative enzyme-linked immunosorbent assays or indeterminate results on Western blot analyses during pregnancy.

Hepatitis B Virus Like HIV infections, infections caused by hepatitis B virus (HBV) represent a serious, worldwide public health problem. This virus causes acute hepatitis with a case-fatality rate of about 1%. Of significance is that 5 to 10% of these infected individuals will become chronic carriers and about 25% will die as a result of cirrhosis and hepatocellular carcinoma. The reservoir of HBV chronic carriers in the world is estimated at more than 200 million people, with 80% of them residing in Asia and the Western Pacific (11). In high-incidence areas, neonates acquire their infections from mothers who are chronic asymptomatic carriers of HBV; 70 to 90% of infants born to hepatitis B surface antigen (HBsAg)and hepatitis B e antigen (HBeAg)-positive mothers will themselves become chronic carriers. In turn, these children then act as community reservoirs for the virus because they are infectious to their later sexual partners and offspring. Maternal transmission of HBV may occur transplacentally, at the time of delivery, or shortly ,after delivery. In contrast to the transmission of HIV infections, it is clear that the majority of HBV infections are acquired at the time of delivery as a result of swallowing maternal blood (11). In terms of the clinical manifesta-

NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or propeay as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, ir~tmctinos or ideas contained in the material herein. No suggested test or procedure should be carried out unless, in the reader's judgment, its risk is justified. Because of rapid advances in medical sciences, we recommend that the independent verification of diagnoses and drug dosages should be made. Discussions, views and recommendations as to medical pmoedures, choice of drugs and drug dosages are the responsibility of the authors.

Clinical Microbiology Newsletter OSSN 0196-4399) is issued twice monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, NY 10010. Subscription price per year. $135.00 including postage and handling in the United States, Canada, and Mexico. Add $52.00 for postage in the rest of the world. Second-class postage paid at New York, NY and at additional mailing offices. Postmaster. Send address changes to Ch'nical Microbiology Newsletter, Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, ICY I O0I0.

170

0196-4399/92~0.00 + 03.00

© 1992 Elsevier Science Publishing Co., Inc.

Clinical Microbiology Newsletter 14:22,1992

tions of perinatal HBV infections, infants can develop clinical hepatitis with elevated transaminases, chronic active hepatitis, or even fulminant hepatitis. However, most neon~ites are asymptomatic or exhibit only mild or transient symptoms. Despite .the lack of clinical symptoms among perinatally infected infants, a prospective study of asymptomatic HBV-carrier children indicated that some pathologic changes in the liver following perinatal infection begin very early (12). During the last decade, maternal HBeAg and HBV-DNA have been shown to be reliable predictors of perinatal transmission of HBV infection. A majority of infants (85 to 90%) born to HBeAg-positive mothers will develop HBV infection following birth and most will develop chronic infection. In contrast, infants born to anti-HBe-positive mothers are much less likely to become infected, and, of those who are infected, most do not become chronic carriers (13). The circulating level of HBV-DNA also corresponds well with infectivity and in one study was shown to be a more reliable indicator of perinahal transmission than HBeAg (14). Importantly, because most infants acquire their infections not transplacentally but rather at or near the time of delivery, post-exposure prophylaxis against perinatal HBV infection is possible. Combined administration of hyperimmune globulin directed ag,'-finst HBV (HBIG) and the inactivated HBV vaccine immediately following birth (within 12 h) has proved to be highly effective for infants identified to be at risk for perinatal HBV infection. Of course, testing of women for HBsAg in their third trimester of pregnancy is prerequisite. The Centers for Disease Control is now suggesting universal vaccination of all infants (15).

Herpesviruses The herpesviruses, CMV and HSV, can both cause perinatal viral infections. As members of the herpesvirus family, both viruses have the ability to cause a primary infection and then establish a latent or persistent infection in the human host. CMV is considered the leading cause of perinatally acquired infections; perinatal acquisition occurs in Clinical Microbiology Newsletter 14:22,1992

4 to 10% of all deliveries. The primary sources of perinatal CMV infections are the maternal genital tract at the time of delivery, breast milk, and blood transfusion. Approximately 10% of CMV-seropositive American women excrete CMV from the genital tract at delivery, and 14 to 27% of postpartal women excrete CMV in breast milk (3, 4, 16). The incubation period of perinatal infection ranges from 4 to 12 wk. Interestingly, the quantity of virus excreted by infants with perinatal infection is less than that of infants with congenital or intrauterine acquisition and is characterized by persistent viral shedding for years (16). Fortunately, the majority of neonates with perinatally acquired CMV infections remain asymptomatic. However, the risk of CMV disease is significantly greater for small, premature infants who acquire their infection by blood transfusion (4). Symptoms lbr these infants include hepatosplenomegaly, thrombocytopenia, neutropenia, and pulmonary morbidity. Given the possible role of maternally derived CMV passive antibody, perinatal CMV infeclions are more common and more severe if acquired from a non-maternal source by infants born to seronegative mothers. To establish the diagnosis of a perinatal CMV infection, congenital infection must first be excluded by showing the absence of viral excretion during the first 2 wk of life. Laboratory diagnosis of CMV infection is accomplished through a variety of virological and immunological techniques for detecting viral infectivity, structural components, or humoral and cellular immune responses. Although not as frequent as CMV perinatal infections, HSV infections can cause considerable mortality and morbidity among neonates. Also, ,as with CMV infections, newborns who acquire an HSV infection usually contract the virus in the birth canal by coming in direct contact with infected maternal tissues or fluids rather than transplacentally. Recent studies indicate that most infants with perinatal HSV have mothers with subclinical genital HSV infection with asymptomatic shedding of the virus at the time of delivery (17). How© 1992 Elsevier Science Publishing Co., hlc.

ever, not all infants exposed to HSV at the time of delivery acquire neonatal herpes infections. In an attempt to define the risk factors associated with neonatal HSV infection, Brown et al. (17) reported that in a prospective study of asymptomatic women who shed HSV in early labor, about a third of these women had recently acquired genital HSV, and their infants were 10 times more likely to have neonatal HSV than the infants of those women with asymptomatic reactivation of HSV; the presence of maternal antibody specific to HSV-2 but not HSV-1 appeared to reduce the neonatal transmission of HSV-2. Perinatal HSV infections in infants usually present after the first 24 to 48 h of life. The mucocutaneous form of the infection is recognized by a vesicular appearance of the lesions, which may occur as a single lesion or cluster of lesions of the skin or scalp or involve the mucous membranes of the eyes or mouth. Disseminated herpes is characterized by the onset of symptoms within 7 to 10 d after birth, with fever and signs usually associated with bacterial sepsis in the newborn. The course of disease is often fulminant, producing severe hepatitis, thrombocytopenia, coagulopathy, meningoencephalitis, or pneumonia, In contrast, herpes encephalitis usually occurs in infants who have been well the first 10 d to 4 wk of age. Typically, the infant presents with fever, lethargy, and poor feeding followed by the onset of seizures. Unless the infant has skin lesions, early diagnosis of HSV encephalitis requires a brain biopsy for direct immunofluorescent staining and culture. In contrast to CMV, serological assays are not indicated for possible neonatal HSV infections. Demonstration of the virus by direct immunofluorescent staining of HSV antigens and/or viral culture of lesions, tissues, or in the event of disseminated disease, cultures of blood, oropharyngeal secretions, or cerebrospinal fluid are the mainstays for diagnosis of perinatal herpes infections. Finally, another member of the herpes family, variceila-zoster virus (VZV), merits a brief comment as to its ability to cause perinatal virus infections. Maternal chickenpox near term, 0196-4399/92/$0.00 + 03.00

171

or soon after delivery, can cause severe or fatal illness in the newborn. Fortunately, VZV is an unusual cause of perinatal infection in the U.S. because more than 90% of women of childbearing age are immune. Since the pathogenesis of varicella involves the transmission of virus by the respiratory route followed by local replication and ultimately a viremia, the fetus acquires VZV infection transplacentally. The risk is said to be greatest for mothers who had the onset of varicella during the last 5 d of pregnancy or within 2 d of birth; neonatal infection is most likely a consequence of the newborn's not receiving protective transplacental antibodies and the immaturity of the immune system. Diagnosis of chickenpox is still usually made by history and physical examination.

Human Papilloma Virus This group of viruses is recognized as among the most common sexually transmitted agents. Perinatal infections are presumed to be due to maternalinfant transmission at delivery. Following birth, human papilloma virus (HPV)-infected infants may develop respiratory papillomatosis. Of note, the presence of maternal condylomata acuminata has been reported in 55 to 65% of children with respiratory papillomatosis (18). The means by which transmission occurs remains unknown; transmission typically follows vaginal delivery, but has also been documented after Cesarean section (19). To date, the relative risk of perinatal HPV infection for developing subsequent HPV-associated lesions has not been determined by prospective studies. Papillomatosis follows an extremely variable clinical course in terms of onset and rapidity of disease progression. Nevertheless, hoarseness and respiratory distress are the usual presenting features. And although one study showed no associated mortality among 23 patients followed from 4 to 45 yr, pulmonary involvement by HPV may be severe (20).

172

0196-4399/92/$0.00 + 03.00

Conclusion Many infectious agents, including both viruses and bacteria, can be important causes of perinatal infections. Perinatal virus infections are common and are important causes of perinatal morbidity and/or mortality. These viral infections, which occur just prior to and immediately after birth, usually infect the fetus as it passes through the birth canal; infection usually occurs by direct inoculation of infected foci or direct contact with infected maternal body fluids. As a fortunate consequence of this timing, there are opportunities for effective therapeutic interventions in some of these infections. However, many of these viral infections require further concerted efforts to understand their pathobiology so that improved means of diagnosis, treatment, and prevention may be provided.

9.

10.

11.

12.

13.

14.

References 1. Ingall, D. 1990. Introduction to the symposium on perinatal infectious diseases update. Pediatr. hffect. Dis. J. 9:761762. 2. Zeiclmer, S. L. and S. A. Plotkin. 1988. Mechanisms and pathways of congenital hffections. Clin. Pefinatol. 15:163-188. 3. Prober, C. G. and A. M. Arvin. 1987. Perinatal viral infections. Eur. J. Clin. Microbiol. 6:245-261. 4. Alford, C. A. et al. 1990. Congenital and perinatal cytomegalovirus infections. Rev. Infect. Dis. 12:$745-$753. 5. MacGregor, S. N. 1991. Human hmnunodeficiency virus infection in pregnancy. Clin. Perinatol. 18:33-50. 6. Gwinn, M. et al. 1991. Prevalence of HIV infection in childbearing women in the United States. JAMA 265:1704-1708. 7. Blanche, S. et al. 1989. A prospective study of infants bom to women seropositive for human hmnunodeficiency virus type I. N. Engl. J. Med. 320:1643-1648. 8. Devash, Y. et al. 1990. Vertical transmission of htunan hmnunodeficiency virus is correlated with the absence of high-alTmity maternal antibodies to the gp 120 principal neutralizing domain. Proc. Natl. Acad. Sci. USA 87:3445-3449.

© 1992 Elsevier Science Publishing Co., Inc.

15.

16.

17.

18.

19.

20.

Rossi, P., V. Moschese, and P. Broliden. 1989. Presence of maternal antibodies to human hmnunodeficiency virus 1 envelope glycoprotein gp 120 epitopes correlates with the uninfected status of children born to seropositive mothers. Proc. Natl. Acad. Sci. USA 86:8055-8058. Johnson, J. P. et al. 1991. Vertical transmission of human hmnunodeficiency virus from seronegative or indetenninate mothers. Am. J. Dis. Child. 145:12391241. Ghendon, V. 1987. Perinatal transmission of hepatitis B virus in high incidence countries. J. Virol. Methods 17:69-79. Chang, M. H. et al. 1988. Prospective study of asymptomatic HBsAg carrier children infected in the perinatal period: clinical and liver histologic studies. Hepatology 8:374-377. Zanetti, A. R. et al. 1982. Perinatal transmission of the hepatitis B virus and of the HBV-associated delta agent from mother to offspring in northern Italy. J. Med. Virol. 9:139-148. Bemigner, M. et al. 1982. An assay for the detection of the DNA genome of hepatitis B virus in serum. J. Med. Virol. 9:57-68. Centers for Disease Control. 1991. A comprehensive strategy for elhninating transmission in the United States through universal childhood vaccination. Morbid. Mortal. Weekly Rep. 40 (suppl.): 1-10. Stagno, S. et al. 1983. Congenital and perinatal cytomegalovirus infections. Semin. Perinatol. 7:31-42. Brown, Z. A. et al. 1991. Neonatal herpes shnplex virus infection in relation to as)nnptomatic matemal infection at the thne of labor. N. Engl. J. Med. 324:1247-1252. Schwartz, D. B. et al. 1987. The management of genital condylomas in pregnant women. Obstet. Gynecol. Clin. North Am. 14:589-599. Brodsky, L., S. Y. Siddiqui, and J. F. Stanievich. 1987. Massive oropharyngeal papillomatosis causing obstructive sleep apnea in a child. Arch. Otolaryngol. Head Neck Surg. 113:882884. Chi'istiensen, P. L., K. Jorgensen, and A. Grontved. 1984. Juvenile papillomatosis of the larynx. Acta Otolaryngoi. Suppl. (Stockh) 412:37-39.

Clinical Microbiology Newsletter 14:22,1992