- Email: [email protected]
Perinatal viral infections
Semin Neonato11996; 1:107-118
Perinatal viral infections Jennifer Royle Department of hnmunology and Infectious Diseases, Royal Alexandra Hospital for Children, Westmead, NSW 2145, Australia
Key words: herpes simplex virus, encephalitis, varicella zoster virus, ZIG (zoster immune globulin), enterovirus, echovirus, coxsackievirus, perinatal
Perinatal viral infections may cause catastrophic neonatal illness with significant morbidity and mortality. The presentation may be non-specific and appropriate treatment delayed because the diagnosis is frequently unrecognized. Recent advances have been made in understanding the natural history of perinatal viral infections, rapid diagnostic techniques, preventative measures and treatment. This chapter outlines the presentation, diagnosis, management and outcome of perinatally acquired herpes simplex virus, varicella zoster virus and the enteroviruses, echovirus and coxsackievirus. Greater awareness of these infections in the perinatal period is required. Early treatment may reduce the morbidity and mortality and limit the spread of infection.
Herpes simplex virus Herpes simplex virus (HSV) is a DNA virus which can cause devastating disease in the newborn. Even with the availability of antiviral medications, morbidity and mortality from disseminated disease is significant. Prevention of infection and early diagnosis and treatment of local lesions to prevent dissemination is of paramount importance. HSV can remain latent for months or years and periodically reactivate. Two major subtypes, HSV-I and HSV-2, are recognized: HSV-1 primarily causes oral lesions and HSV-2 usually affects genital areas and is therefore a commoner cause of neonatal vertical infections. Both subtypes can affect the genital area and cause neonatal infections. The incidence of neonatal HSV varies Widely. In the UK the estimated rate is approximately 2 per 100 000 [1] whereas rates 25 times higher have been reported from the USA [2].
Transmission Neonatal HSV occurs secondary to maternal genital lesions in about 85% of cases [3]. Transplacental infection can occur, causing congenital HSV infection, but is rare. The virus is most frequently acquired by passage through an infected 1084-2756/96/020107+12$12.00/00
birth canal. Ascending infection following rupture of membranes has been documented, as has infection following caesarean section with apparently intact membranes. Postnatal horizontal infection is uncommon. Cross-infection can occur from one infected baby to another in the nursery or from an oral or skin lesion in a mother or relative or infected staff member. Despite countless nosocomial exposures, the incidence of horizontal spread and neonatal unit outbreaks is very low [4].
Risk of infection Infants bom to mothers with active primary HSV are at the greatest risk of developing neonatal infection. Birth through an infected canal with a recurrent lesion can still cause neonatal infection though the chance is far less, only about 3% [5-7]. Primary HSV around the time of delivery has about a 50% chance of neonatal infection with vaginal delivery [8, 9]. The risk is thought to be lower if caesarean section is performed within 24 hours of membrane rupture [2], although there are no firm data. Symptomatic genital infection is manifest by pain and dysuria and is associated with vesicles and ulcers or both. However, about 70% of mothers of © 1996 W.B. Saunders Company Ltd
108
J. Royle
affected babies are asymptomatic at the time of delivery [10, 11] and give no history of ever having had herpetic lesions. Presumably primary HSV infection is more infectious for the baby because of a lack of antibodies to HSV and because the asymptomatic cervical shedding of HSV continues for longer after the primary episode [9]. The viral load is also larger. There is an increased risk of neonatal HSV associated with the use of fetal-scalp electrodes [7].
Clinical features Transplacental infection can lead to microcephaly and keratoconjunctivitis in the congenitally affected newborn but this is rare [2]. HSV has been isolated from some aborted fetuses and is thought to be associated with an increased risk of spontaneous abortion. Likewise, Whitley reported that in nearly 50% of infants with HSV, the pregnancy ended in premature labour, usually between 30 and 37 weeks gestation [10]. HSV infection is implicated as a cause of premature labour. Neonatal HSV has four clinical pictures. It can be localized (skin, mouth, eyes), generalized (liver, adrenals, lungs, brain and other organs), localized to the lung (pneumonitis) or localized to the central nervous system (meningoencephalitis). Skin involvement is the commonest manifestation of HSV infection. This may be an isolated finding or part of disseminated infection. The skin vesicles occur most often between one and two weeks of life although they have been noted at birth or delayed up to one month. The skin manifestations vary from one or two vesicles, to crops of vesicles, or there may be a large bullous lesion (Fig. 1). Less common skin manifestations are zosteriform eruptions, a generalized petechial rash, areas of denuded skin or erythema multiforme [12]. Progression of disease from isolated skin vesicles to the involvement of other sites occurs in about 70% of infected babies with no treatment [2, 10]. This dissemination occurs over an average of 7 days. Of note, a clinical picture of dissemination or local encephalitis is not always preceded by skin involvement and 20% are thought to have had no preceding skin lesion [10]. Other local sites of HSV neonatal infection include the mouth and eyes. Classical herpetic ulceration may involve the gingiva, tongue, palate (Fig. 2) and even the larynx. Local eye infection is most commonly manifest as keratoconjunctivitis.
Fig. I, Herpes simplex virus infection. A crop of vesicular skin lesions.
Dendritic conjunctival and corneal ulcers may be seen. Chorioretinitis may be present at birth or can develop secondary to keratoconjunctivitis. Uveitis, cataracts, microphthalmia and optic atrophy have all been described as sequelae of HSV eye infection. Disseminated disease usually presents in the first week of life although occasionally is seen at birth or up to 2 weeks of age. Its presentation is nonspecific with fever, vomiting, lethargy and poor feeding. If there is a concomitant CNS infection (seen in about 50%) irritability and convulsions may occur [12]. Other variable features include acidosis, respiratory distress, cyanosis, apnoea, generalized erythema, purpura, jaundice and hepatomegaly. One quarter of patients with disseminated disease develop a bleeding diathesis with disseminated intravascular coagulopathy (DIC), which may precede shock and death [12]. Disseminated disease is often fulminant. Pneumonitis is sometimes the presenting feature, usually at 3-7 days, which distinguishes it from early respiratory distress syndrome. Lung involvement can be part of multiple organ involvement or may develop as a local infection. Respiratory
Perinatal viral infections
109
Fig. 3. Herpes simplex virus pneumonitis. Term baby presented on day 5 with increasing respiratory distress. Chest X-ray demonstrating bilateral opacifications.
Fig. 2. Solitary oral herpes simplex virus lesion.
deterioration will be accompanied by perihilar radiographic changes progressing to extensive bilateral opacifications (Fig. 3). Early treatment can be life-saving, so HSV infection should be considered in a baby with later-onset respiratory distress. Diagnosis can be made rapidly by immunofluorescence on a nasopharyngeal aspirate. Meningoencephalitis (local CNS infection) presents later, mean age 11 days (range 7-30 days) [2, 13]. Presentation may be non-specific, but focal seizures may occur and the gag reflex may be absent [12]. Focal seizures may become generalized and intractable.
Diagnosis A high level of suspicion is required to diagnose neonatal HSV. Failure to commence early antiviral treatment dramatically increases mortality and morbidity. Careful examination of the skin, mouth and eyes may reveal diagnostic lesions in a nonspecifically unwell infant.
HSV immunofluorescence is the single most useful test, providing a rapid diagnosis within hours. Viral culture can confirm the diagnosis within 2-4 days. Cultures should be taken from skin lesions, the nasopharynx, conjunctiva and, if clinically indicated, cerebrospinal fluid (CSF). Sampling a vesicle involves swabbing the base of the vesicle once the roof has been removed. This swab should be smeared on a slide which is sent for urgent immunofluorescent staining. The swab should then be placed in viral transport medium for culture. Cultures may reveal cytopathic changes in 1-4 days. There is often a raised CSF white cell count (WCC), predominantly lymphocytes (range 50-200 ~l), although the WCC can be up to 2500 [12]. Viral cultures of CSF have been found to be positive in just over half the cases of local CNS infection and less than 20% in disseminated infection, most of whom had CNS infection [10]. CSF polymerase chain reaction (PCR) is now available and can speed the diagnosis, but results need to be interpreted with care, since both false positive and negatives can occur. Serology is generally unhelpful other than in confirming a diagnosis retrospectively. Whitley found the presence or absence of antibodies was
110
not predictive of presentation or outcome of infection [10, 14]. The use of CSF antibodies is controversial. A specific rapid HSV IgM in the CSF can assist an early diagnosis, otherwise CSF antibodies at 4-6 weeks post infection may retrospectively confirm a diagnosis. EEG changes of a temporal or parieto-temporal focus are non-specific, although may assist diagnosis. Computed tomography (CT) scans may be normal initially then within a few days may show unilateral or bilateral temporal lobe changes. Other cerebral imaging abnormalities include cerebral atrophy and the loss of grey-white differentiation. Brain biopsy which was once used to confirm the diagnosis of HSV encephalitis is now seldom performed.
Treatment Acyclovir and adenosine arabinoside (vidarabine, ara-A) are equally effective in neonatal HSV infection [15]. The daily dose of both drugs is 30 mg k g - ~ per day, acyclovir being given intravenously 8 hourly and vidarabine 12 hourly for 10-14 days. A study by Whitley et al [15] found no difference in morbidity, mortality and drug toxicity for acyclovir and vidarabine in treating babies with localized, disseminated disease or encephalitis [15]. Acyclovir is usually preferred because of its much lower volume of administration. Eye lesions should also be treated topically with antiviral agents under the supervision of an ophthalmologist.
Prognosis Without treatment, 70% of local skin lesions disseminate [2, 10]. Mortality without treatment is reported at 74% for disseminated disease and 50% for local CNS disease [16]. Treatment has reduced the mortality of disseminated disease to between 35 and 60% [15-17] and for local CNS disease, 10% [16]. Factors that increase the risk of death include prematurity, DIC, and if the infant is in or near coma when treatment is commenced [18]. Disseminated disease with pneumonitis is also associated with greater mortality [18]. Treatment of local skin, eye or oral infections has greatly reduced the numbers of children reported with disseminated disease. Although
J. Royle
mortality from HSV seems to be declining, severe consequences occur in many of the survivors. Major sequelae are seen in 86% of treated survivors of disseminated disease and 50-75% of treated survivors of meningoencephalitis [12, 17]. The sequelae include major neurological and developmental impairment. Factors which increase the risk of morbidity are encephalitis, seizures, DIC, and infection with HSV-2 rather than HSV-1 [18]. There is concern that HSV may cause a persistent or periodically reactivating infection that continues to cause neurological damage after apparent resolution of the initial acute illness. Gutman et al [19] described infants with neonatal HSV encephalitis who deteriorated after completion of antiviral treatment or who had progressive deterioration over the first year of life. Whitley et al [18] reported 4 of 71 infants with neonatal HSV localized to the skin, eyes or mouth who had long term neurological damage; all four patients had three or more recurrences of HSV-2 skin vesicles in the first year of life. Long term oral acyclovir prophylaxis should therefore be considered for infants with encephalitis and possibly for those with local HSV-2 with three or more recurrences.
Prevention of infection The risk to the fetus of stillbirth or intrauterine infection when the mother has primary genital herpes in the first trimester is unknown, but is probably small [9]. Acyclovir appears to cross the placenta in small quantities [20]; however, its safety for the fetus has not been proven and antenatal use is not indicated. Primary herpes at the time of delivery poses a 50% chance of infection with vaginal delivery [9]. Caesarean section within 24 hours of rupture of the membranes reduces the risk of neonatal HSV in primary infections, perhaps to less than 20% [2] and has been widely adopted as recommended management. Clinically and historically it is not always definite whether the lesion is a primary or recurrent one. When sufficient time exists, maternal IgM can be sought and if positive a caesarean section may be recommended [3]. When a mother with a history of recurrent genital HSV is symptomatic at the time of delivery or has lesions on examination no consensus on management has been reached. Some recommend caesarean section while others recommend vaginal delivery with cultures performed on the infant's
Perinatal viral infections
111
conjunctiva and nasopharynx at 24-48 hours. There are no trials to compare either practice. Culture positivity at birth reflects exposure to HSV, while culture positivity at 24 hours indicates true colonization rather than surface colonization [21]. In the latter circumstance, if the cultures were positive, it seems reasonable that antiviral treatment should be commenced [3]. Likewise treatment should be commenced promptly if the infant becomes symptomatic. Infants born to asymptomatic women with a history of recurrent genital herpes have a very low risk of developing HSV, less than 3% [7] and in the absence of lesions or symptoms, a vaginal delivery is safe.
Varicella zoster virus Ninety-five per cent of women of child-bearing age have had chicken-pox. Primary VZV infection can have devastating effects on a pregnant woman, fetus and newborn.
VZV and the immune system T cells are of primary importance in recovery from acute VZV infection. People with impaired cellular immunity, such as those on immunosuppressive therapy, tend to develop severe varicella which can be fatal, even with appropriate antiviral treatment. Antibodies can protect against infection or at least against the severity of infection but are not primarily involved in recovery. People with hypogammaglobulinaemia can recover normally from varicella. Neonates with transplacental IgG antibody from a mother with a past history of varicella have a minimal risk of developing postnatally acquired varicella and are extremely unlikely to develop a severe acute infection following exposure [22].
Incidence of varicella in pregnancy A large prospective study in the USA documented maternal varicella in 5 per 10 000 pregnancies [23]. Varicella is not notifiable and even in prospective studies, mild cases are probably not reported; asymptomatic cases may also occur. The incidence varies in different parts of the world; adults from tropical and sub-tropical areas are more likely to be susceptible to varicella [24, 25].
Fig. 4. Congenital varicella syndrome. Skin lesion scarring in a dermatomal distribution.
Primary matemal varicella in pregnancy appears to be abnormally severe. This is presumably due to depressed cellular immunity in pregnancy. Lifethreatening pneumonitis in women with gestational varicella has been reported by many, but such reports tend to be highly selective [26, 27]. It is not clear whether the risk is truly greater than that for normal adults.
Congenital varicella syndrome La Foret and Lynch were the first to describe an association between maternal varicella infection in early pregnancy and congenital anomalies in 1947 [28]. Alkalay et al assigned the term, congenital varicella syndrome [29]. Characteristically, there are cicatricial skin lesions of a limb, usually a leg, in a dermatomal distribution. This may be associated with limb hypoplasia. The zig-zag scar is presumed to be secondary to viral reactivation with the appearance of a scarred zoster ('shingles') site (Fig. 4). Other congenital malformations involve the brain (microcephaly, cerebellar hypoplasia, cortical atrophy) and the eye (microphthalmia, optic atrophy, cataracts, chorioretinitis and nystagmus).
112
(a)
J.
Royle
(b)
Fig. 5. Perinatal varicella. (a) Baby born with maternal antibody and rash but well; maternal chickenpox 10 days before delivery. (b) Baby born well, developed rash on day 5 with fatal pneumonitis, despite ZIG and acyclovir; maternal chickenpox 3 days before delivery.
Skeletal, gastrointestinal and genitourinary anomalies are less commonly associated. Maternal serology confirming recent infection (VZV IgM) combined with evidence of infection in the infant (a persistently raised VZV IgG) provide evidence to support the association between varicella and congenital malformations. The risk of the congenital varicella syndrome after first trimester varicella is about 2% [27, 30--33]. There are reports of congenital varicella syndrome occurring after second and third trimester varicella [34, 35] and first trimester material zoster [36], although this is less common than following first trimester varicella. Pregnant women with exposure to varicella in the first trimester with no past history of chickenpox and negative varicella serology should be given zoster immunoglobin (ZIG). ZIG is an immunoglobin preparation from donors with a high antibody titre to VZV. It is generally effective in
ameliorating the severity of infection following a recent exposure, although it does not usually prevent infection. The rationale of giving ZIG is to modify the severity of the disease in the mother and to reduce the risk of congenital varicella syndrome in the fetus. Perinatal maternal varicella Maternal peripartum varicella can lead to a lifethreatening illness in the newborn. About 25% of infants whose mothers develop varicella during the last ).I days of pregnancy become infected [26]. The spectrum of illness in the neonatal period varies from a well baby with a few vesicles to a fulminant rash, visceral lesions and pneumonitis [371 (Fig. 5). The incubation period for congenital varicella (time between mother's and infant's rash) is about
Perinatal viral infections
113
Table 1. Timing of chickenpox in mother and baby in relation to severity [38]. Onset of mother's rash in relation to delivery
Onset of baby's rash in relation to delivery (days after)
Died (n)
Survived (n)
Neonatal mortality (%)
0-4 5-10
0 7
27 16
0 30
5-21 days before 4 days before to 2 days after
9-15 days. It can, however, be much shorter if the mother is significantly viraemic. One study noted that if an infant was born with a rash or a rash appeared within four days of birth, the survival was 100%. An infant with a rash developing 5-10 days after birth had a 30% mortality from disseminated varicella usually complicated by severe pneumonitis (Table 1) [38]. The severity of the infant's illness is determined by the timing of the mother's illness in relation to delivery. An infant born with no maternal VZV ]gG who has just received a large inoculum of virus is at the most risk of developing severe disease. These infants are usually born well and become severely ill at 5-10 days. Miller et al have shown that if mothers develop a rash six or more days before delivery, then their infants will have detectable VZV IgG antibody. If the mother's rash develops five or fewer days prior to delivery, antibody is often undetectable [39].
Management of perinatal maternal varicella Considering the importance of the timing of the maternal rash it may be worthwhile delaying labour, where feasible, for a few days when the mother has a varicella rash of recent onset. Additional intrauterine time could increase the chance for transplacental passage of protective maternal antibody. Infants whose mothers develop a varicella rash, up to and including, 5 days prior to delivery, or up to two days after delivery, should be given intramuscular ZIG. Hanngren et al gave ZIG to 95 infants with perinatal exposure and 50% developed varicella. Of the 4I infants in the maximum risk group (mothers' rash onset 5 days before to 2 days after delivery) 21 infants (51%) became infected, of which only two cases were severe [40]. Infants with severe varicella and those of seronegative mothers who were not given ZIG should be treated with acyclovir (60 mg k g - I per day
given 8 hourly). Deaths from severe pneumonitis have occurred despite acyclovir being given early [41]. There have been no controlled studies of acyclovir treatment for mothers with peripartum varicella.
Postnatal exposure to varicella About 95% of mothers in industrialized countries have had chicken-pox and pass protective IgG to the fetus prenatally. The risk to infants of mothers with a history of varicella, is minimal. Unprotected infants may be at increased risk of severe varicella infection, although the risk is difficult to quantify because of selective reporting [42, 43]. Rubin et al [44] reported a case of severe neonatal varicella 8 days after delivery and reviewed a number of case reports of severe postnatally acquired neonatal varicella. They suggested that babies of seronegative mothers exposed to varicella in the neonatal period should be given ZIG, although no data are currently available to support this recommendation. Severe varicella can develop in healthy children (albeit rarely) and adults; hence it is not clear that the few neonatal cases reported truly indicate an increased susceptibility of neonates to severe disease. If an infant is retuming home to a family where, for example, a sibling has chicken-pox, a history of maternal varicella should be sought, and if negative, maternal VZV antibodies should be measured. It would be reasonable to give the infant ZIG prior to discharge if the maternal antibody titre was negative [12, 45]. Checking maternal serology in this situation is to be encouraged; serology can be performed rapidly, many women with no clinical history of varicella (i.e. past history of subclinical infection) have VZV IgG, and although ZIG is relatively safe, it is a blood product and should not be given unless truly indicated. There is never any indication
114
for separating a mother from her baby, or a baby from other siblings.
Nursery outbreaks Nursery outbreaks need special consideration. The degree of exposure will determine the appropriate action to be taken. Infants less than 32 weeks are likely to have low or undetectable levels of VZV IgG even if the mothers have a past history of varicella. These preterm infants should be given ZIG following significant exposure. Term infants with no maternal history of varicella may be considered for ZIG depending on the degree of exposure, maternal serology of the infants would confirm which infants truly are at risk. Infected infants and mothers should be isolated and nursed by immune st~'fff. Infants born to mothers with perinatal varicella should be isolated from birth to help reduce the chance of a nursery outbreak. If a child who had visited the nursery develops chicken-pox, the timing of the visits determines the action to be taken. Children are only infectious for up to a day before the rash appears, but not during the rest of the incubation period. If, say, the rash appeared 2 or more days after the last visit, then no action is needed.
Long term effects of VZV Infants exposed perinatally to varicella, even if they do not have clinical infection, have an increased risk of developing infection early in childhood [12]. It has been suggested that intrauterine varicella could lead to an increased risk of leukaemia and other malignancies [46]. Fine et al [47] reported the incidence of malignancy to be 2.3-fold greater than expected in a follow-up study of infants exposed in utero to VZV or CMV.
VZV vaccine A live attenuated vaccine is available in some countries (e.g. USA, Germany). This vaccine, when more widely available, may have a role for VZV IgG negative women during early adolescence [27]. Immunization of this important target population may greatly reduce the incidence of maternal, fetal and neonatal varicella infection.
J. Royle
Enteroviruses The enteroviruses (echovirus, coxsackievirus, and polioviruses) are RNA viruses which can cause devastating infection in the newbom. Poliovirus is now exceedingly rare in developed countries and becoming less common in developing countries due to immunization. Echoviruses (of various serotypes) can cause fulminant neonatal infection characteristically associated with hepatic necrosis and a bleeding diathesis. Type B coxsackieviruses may cause myocarditis, which is frequently fatal in the newborn period.
Epidemiology Enterovirus infections can occur any time of year, although in temperate climates are more common in the summer and autumn [48, 49]. Irregular epidemics may occur. Enterovirus infections commonly occur during community outbreaks in infants of mothers who have acquired infection near term. Disease in the newborn is uncommon but reflects the frequency of infections in the population. Estimating the incidence is difficult since many cases are asymptomatic and many symptomatic infants may not be diagnosed if the appropriate viral cultures are not performed. Neonatal echovirus and coxsackievirus infections have been described world-wide, coxsackie infections have been reported extensively from South Africa due to their frequent epidemics [50].
Transmission Enteroviruses spread rapidly by the faecal-oral route although respiratory transmission can occur [51]. Vertical transmission from the mother appears to occur at the time of delivery. The mode of infection is almost certainly contact with infected cervical secretions or maternal blood during delivery. Infection following caesarean section, even with intact membranes has been reported, suggesting that infection has occurred from maternal blood or that the virus can cross intact membranes [12]. Enteroviruses can also spread horizontally via secretions carried on hands. When there is no clear index case, infection presumably has started from a staff or family member. Horizontal infections are usually less severe [49, 52]. presumably due to a
Perinatal viral infections
smaller initial viral load and possibly due to the presence of passively acquired maternal antibodies
[12]. Enteroviruses enter the body by attaching to receptors on respiratory or gastrointestinal epithelial cells. Following oral or pharyngeal acquisition, local spread occurs to the submucosal (regional) lymph nodes where the virus replicates. Primary (minor) viraemia occurs within 24 hours. This causes viral dissemination but is usually asymptomatic. The virus then multiplies at many sites and at about 4-5 days the major symptomatic (high level) viraemia commences.
Clinical manifestations Symptoms in children and adults
The common clinical features of enterovirus infection are fever and upper respiratory tract infection. Aseptic (viral) meningitis, often with a rash, is relatively common and can be caused by many of the enterovirus serotypes. There are some less common but well described clinical syndromes usually caused by particular groups of enteroviruses: pleurodynia and myocarditis (coxsackie B virus), hand foot and mouth disease (coxsackie A virus 16 and enterovirus 71), paralysis (polioviruses and occasionally coxsackieviruses) and haemorrhagic conjunctivitis (enterovirus 70). The severity of infection and clinical picture depends on the enterovirus serotype, age, sex, immune competence and previous exposure of the host [53]. Despite the relatively benign clinical manifestations of non-polio enterovirus infections in other age groups, the neonate is uniquely susceptible to severe and potentially fatal infections. The timing of infection in relation to delivery may be very important. Symptomatic and particularly fatal disease is most. likely in infants of women infected within a few days of delivery, before protective antibodies can be transferred to the infant [54]. Generally in half to two-thirds of cases of vertical infection there is a history of peripartum maternal illness, usually mild fever and coryza or gastroenteritis [48, 49]. A characteristic syndrome is described with echovirus 11 infection (and sometimes other serotypes), where there is an acute onset of fever in the pregnant mother associated with severe lower abdominal pain which can masquerade as placental abruption or acute appendicitis [54, 55].
115
Symptoms in the neonate
Vertical (maternally acquired) neonatal infection usually presents at 3-5 days of age. It may occasionally present at birth or as late as 7 days. Horizontal infection with echovirus generally has a much milder clinical course than vertical infection [49, 52]. Coxsackievirus does not share this distinction and can cause fulminant infection horizontally, making nursery outbreaks potentially devastating
[50]. Echovirus
Echovirus infection produces three groups of clinical illness in the neonate, of increasing rarity and severity [51]. The first group is of fever, gastrointestinal upset (manifest by anorexia and vomiting) and mild respiratory symptoms often with an associated rash. The second group is aseptic (viral) meningitis, which is usually mild and characterized by temporary irritability, lethargy, fever and feeding difficulties [48]. Overwhelming meningoencephalitis with focal neurological signs can occur, albeit rarely [53]. The third group is that of severe infection which can lead to fulminant hepatitis, DIC and death [49]. Clinically the initial picture in this third group is a non-specific febrile illness perhaps with a rash, which rapidly progresses to pallor, collapse, apnoea, metabolic acidosis, severe jaundice, hepatospIenomegaly and ascites. A severe bleeding disorder secondary to DIC ensues which may become generalized with bloody ascites and haemopericardium. Bleeding can be catastrophic. Hypotension may not respond to fluid and inotropic support. Accompanying the fulminant hepatitis may be meningoencephalitis, pneumonitis, myocarditis and gastroenteritis. Mortality is about 80% [12]. Liver autopsy reveals centrilobular necrosis suggestive of ischaemia rather than hepatitis, the primary effect on the liver may be infection or ischaemia or both [I2]. Any serotype probably can cause severe infection though the most common reported serotypes have been 11, 6 and 7. Horizontal echovirus infection is usually mild, even in premature babies [49, 52], and does not cause the fulminant clinical picture. Over half the cases are symptom flee. Presentation is later, after 7 days, and often after I4 days. The non-specific illness comprises fever, irritability and apnoeic episodes. Meningitis may develop with a presentation similar to that of bacterial meningitis. Deaths have been reported following horizontal outbreaks though the mortality rate is very low [49].
J. Royle
116
Coxsackievirus
Treatment
The severity of neonatal infection with coxsackievirus does not have the clear distinction between horizontal and vertical infection. Neonatal outbreaks have been reported in which horizontal infection has developed into fatal myocarditis [49,
The treatment of severe enterovirus infection is supportive: blood transfusions, fresh frozen plasma, vitamin K, inotropic support and antiarrhythmic agents as individually required. Babies may have an increased sensitivity to digoxin during enterovirus infection and it should be used with caution and initially at low doses [12]. Use of immunoglobulin has been attempted in severe infection though it appears its use is unlikely to modify the disease once established [12].
50]. Most neonatal coxsackievirus reports are of type B rather than A. Clinically three patterns of severe disease occur: a biphasic illness, an abrupt illness with rapid death, or a progressive illness [56]. The biphasic illness commences with an initial episode of fever, mild anorexia, coryza or diarrhoea lasting 1-3 days. A macular rash (occasionally petechial) is a common accompaniment of the initial phase. A period of apparent recovery occurs, lasting 1-7 days. Abrupt recurrence of fever is seen, with associated tachycardia, cyanosis and circulatory collapse. This myocarditis, when onset occurs more slowly, may cause poor feeding, tachycardia and listlessness. Cardiomegaly is present and there may be a cardiac murmur. An abnormal ECG and echocardiogram assist with confirming the diagnosis [48]. In some cases there is no prodrome or it is so mild as to have been missed. Sudden collapse can occur without warning. In others, no biphasic illness occurs, there is a progressive course over 1-2 weeks with relentless deterioration despite intensive support [56]. Coxsackievirus myocarditis has a high mortality. The illness can also be complicated by encephalitis, hepatitis or coagulopathy [56].
Diagnosis The diagnosis of enteroviral infections is confirmed by culture. The virus is readily cultured from a throat swab, nasopharyngeal aspirate (NPA) and stool in an infected infant. In addition, CSF or ascitic fluid can be cultured for enteroviruses. Importantly, if a mother has a suspicious periparturn illness, maternal stool and throat swabs should be collected for culture and cultures from the infant should include NPA, throat and stool. Viral cytopathic effect in the tissue culture monolayer can sometimes be seen within a few days. PCR for enteroviruses is available in a few centres. Serology should be sent although unless specific enteroviral [gM is present, it may not be immediately helpful.
Prognosis Vertically transmitted echovirus infection has a mortality of greater than 60%, and if hepatic necrosis develops the mortality is greater than 80% [49]. Horizontal echovirus infections have occasionally been fatal in neonates, as they have in infants, older children and adults. However, death from horizontal infections is extremely rare. Estimates of the incidence of residual neurological sequence following echovirus meningitis range from 0% [57] to 15% [58-60]. Echovirus myocarditis usually responds to medical management, whereas coxsackievirus myocarditis has a high mortality
[56].
Prevention Prevention requires the reduction of horizontal cross-infection. Scrupulous handwashing is the most important technique in reducing nursery cross-infection [50, 52]. Whenever possible, infants with known or suspected enterovirus infection should be isolated. In relation to echovirus, the cross-infection cases are usually milder and no active preventative treatment for contacts is recommended other than cohorting and improved handwashing [52]. Coxsackievirus cross-infection is of greater concern and outbreaks should be managed more actively. Use of immunoglobulin has been advocated for use in all neonatal coxsackievirus contacts, especially if more than one case of myocarditis has occurred in the nursery [12]. When prenatal enterovirus infection is strongly suspected on clinical grounds, or if the virus has been isolated from the mother, immunoglobulin should be given to the infant, dosage
Perinatal viral infections
300-400 mg k g - i by infusion [12], and the infant should be isolated.
References 1 Hall S, Glickman B. The British paediatric surveillance unit. N Engl ] Med 1991; 63: 344-346. 2 Nahmias AJ, Keyserling HL, Kerrick CM. Herpes simplex. In: Remington JS, Klein JO, eds. hlfectious Diseases of the Fetus and Newborn Infant, 2nd edn. Philadelphia: WB Saunders, 1983; 636-678. *3 Mclntosh D, Isaacs D. Herpes simplex virus infection in pregnancy. Arch Dis Child 1992; 67: 1137-1138. 4 Light IJ. Postnatal acquisition of herpes simplex virus by the newborn infant: a review of the literature. Pediatrics 1979; 63: 480-482. 5 Whitley RJ. Herpes simplex virus infection. In: Remington JS, Klein JO, eds. hlfectious Diseases of the Fetus and Newborn Infant. 3rd edn. Philadelphia: WB Saunders, 1990; 282-305. 6 Prober CG, Sullender WM, Yasukawa BS et al. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl ] Med 1987; 316: 240--244. 7 Brown ZA, Benedetti J, Ashley R et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labour. N Engl ] Med 1991; 324: 1247-1252. 8 Nahmias AJ, Josey WE, Naib ZM et al. Perinatal risk factors associated with maternal genital herpes simplex virus infection. Am ]Obstet Gynecol 1971; 110: 825833. 9 Brown ZA, Vontver LA, Benedetti J et aI. Effects on infants of a first episode of genital herpes during pregnancy. N Engl ] Med 1987; 317: 1246-1251. * 10 Whitley RJ, Nahmias AJ, Visintine AM et al. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics 1980; 66: 489-494. 11 Yeager AS, Arvin AM. Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus. Pediatrics 1984; 7.3: 188-193. "12 Isaacs D, Moxon ER. Neonatal Infectiolts. Oxford: Butterworth Heinemann, 1991; 149-166. 13 Nahmias AJ, Whitley RJ, Visitine AM et al. Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. ] Infect Dis 1982; 145: 829-836. 14 Kahlon J, Whitley RJ. Antibody response of the newborn after herpes simplex virus infection. ] Infect Dis 1988; 158: 925-933. * 15 Whitley R, Arvin A, Prober C et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex viral infection. N Engl ] Med 1991; 324: 444-449. 16 Whitley RJ, Nahmias AJ, Seng-Jaw Song et al. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 1980; 66: 495-501. 17 Whitley RJ, Hutto C. Neonatal herpes simplex virus infections. Pediatricsin Review 1985; 7: 119-126.
117
* 18 Whitley RJ, Arvin A, Prober C et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engl ] Med 1991; 324: 450--454. 19 Gutman LT, Wilfert CM, Eppes S. Herpes simplex virus encephalitis in children: analysis of cerebrospinal fluid and progressive neurodevelopmental deterioration. ] hlfect Dis 1986; 154: 415-421. 20 Greffe BS, Dooles SL, Deddish RB et al. Transplacental passage of acyclovir. ] Pediatr 1986; 108: 1020-1021. 21 Overall JC, Whitley RJ, Yeager AS et al. Prophylactic or anticipatory antiviral therapy for newborns exposed to herpes simplex infection. Pediatr Infect Dis 1984; 3: 193-195. * 22 McIntosh D, Isaacs D. Varicella zoster virus infection in pregnancy. Arch Dis CMd 1993; 68: 1-2. 23 Sever JA, White LR. Intrauterine viral infections. Ann Rev Med 1969; 19: 471-486. 24 Gershon AA, Raker R, Steinberg S e t al. Antibody to varicella-zoster virus in parturient women and their offspring during the first year of life. Pediatrics1976; 58: 692-696. 25 Weller TH. Varicella and herpes zoster: changing concepts of the natural history, control, and importance of a not-so-benign virus. N Engl ] Med 1983; 309: 1362-1368, 1434-1440. 26 Gershon AA. Chickenpox, measles and mumps. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fehts and Newborn Infant. 3rd edn. Philadelphia: WB Saunders, 1990; 395-445. 27 Paryani SG, Arvin AM. Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl ] Med 1986; 314: 1542-1546. 28 La Foret, Lynch LL. Multiple congenital defects following maternal variceIla. N Engl ] Med 1947; 236: 534-537. * 29 Alkalay AL, Pomerance JJ, Rimoin DL. Fetal varicella syndrome. ] Pediatr 1987; 111: 320-323. 30 Preblud JR, Cochi SL, Orenstein WA. Varicella-zoster infection in pregnancy. N Engl ] Med 1986; 315: 1416--1417. 31 Siegel M. Congenital malformations following chickenpox, measles, mumps and hepatitis, lAMA 1973; 226: 1521-1524. 32 Enders G. Varicella-zoster virus infection in pregnancy. Prog Med Virol 1984; 29: 166-196. 33 Manson MM, Logan WPD, Loy RM. Rubella and other virus infections during pregnancy. In: Reports o l l Public Health and Medical Nibjects (no. 101). London: Her Majesty's Stationery Office, 1960. 34 Brice JEH. Congenital varicella resulting from infection during second trimester of pregnancy. Arch Dis Child 1976; 51: 474-476. 35 Bai PVA, John TJ. Congenital skin ulcers following varicella in late pregnancy. ] Pediatr 1979; 94: 65-67. 36 Webster MH, Smith CS. Congenital abnormalities and maternal herpes zoster. Br Med ] 1977; ii: 1193. 37 Chapman S, Duff P. Varicella in pregnancy. Semin Perinatol 1993; 6: 403-409. 38 De Nicola LK, Hanshaw JB. Congenital and neonatal varicella. ] Pediatr 1979; 94: 175-176.
118
39 Miller E, Cradock-Watson JE, Ridehalgh MKS. Outcome of newborn babies given anti-varicella-zoster immunoglobulin after perinatal maternal infection with varicellazoster virus. Lancet 1989; ii: 371-373. 40 Hanngren K, Grandier M, Granstrom G. Effect of zoster immunoglobulin for varicella prophylaxis in the newborn. Scand] Infect Dis 1985; 17: 343-347. 41 Holland P, Isaacs D, Moxon ER. Fatal neonatal varicella infection. Lancet 1986; ii: 1156. 42 Preblud SR, Orenstein WA, Bart KJ. Varicella: clinical manifestations, epidemiology and health impact in children. Pediatr Infect Dis J 1984; 3: 505-509. 43 Preblud SR, Bregman DJ, Vernon LL. Deaths from varicella in infants. Pediatr h~fect Dis ] 1985; 4: 503-507. 44 Rubin L, Leggiadro R, Elie MT et al. Disseminated varicella in a neonate: implications for immunoprophylaxis of neonates exposed to varicella. Pediatr h~fect Dis ] 1986; 5: I00--102. 45 Prober CG, Gershon AA, Grose C et al. Consensus: varicella-zoster infections in pregnancy and the perinatal period. Pediatr Infect Dis ] 1990; 9: 865-869. 46 Adelstein AM, Donovan JW. Malignant disease in children whose mothers had chickenpox, mumps or rubella in pregnancy. Br Med ] 1972; 4: 629-63I. 47 Fine PEM, Adelstein AM, Snowman J e t al. Long term effects of exposure to viral infection in utero. Br Med ] 1985; 290: 509-511. 48 Krajden S, Middleton PJ. Enterovirus infections in the neonate. Clin Pediatrics 1983; 22: 87-92. * 49 Modlin JF. Perinatal echovirus infection: insights from a literature review of 61 cases of serious infection and 16 outbreaks in nurseries. Rev Infect Dis 1986; 8: 918-925.
J. Royle
50 Editorial. Avoiding the danger of enteroviruses in newborn babies. Lancet I986; i: 194-I96. 51 Nagington J, Wreghitt TG, Gandy G e t al. Fatal echovirus 11 infections in outbreak in special-care baby unit. Lancet 1978; ii: 725-728. 52 Isaacs D, Dobson SRM, Wilkinson AR et al. Conservative management of an echovirus I I outbreak in a neonatal unit. Lancet 1989; h 543-545. * 53 Gilbert GL. hlfectious Disease in Pregnancy and the Newborn hzfant. Vol. 2. Chur: Harwood Academic, 1991; 381-391. 54 Modlin JF. Fatal echovirus 11 disease in premature neonates. Pediatrics 1980; 66: 775-780. 55 Kurnetz R, Cacciarelli A, Egerer R et al. ] Pediatr 198I; 99: 822-826. *56 Kaplan MH, Klein SW, McPhee J et al. Group B coxsackievirus infections in infants younger than three months of age: a serious childhood illness. Rev h~fect Dis 1983; 5: I019-1032. 57 Bergman I, Painter MJ, Wald ER et al. Outcome in children with enteroviral meningitis during the first year of life. ] Pediatr 1987; 110: 705-709. 58 Farmer K, MacArthur BA, Clay MM. A follow-up study of 15 cases of neonatal meningoencephalitis due to coxsackie B5. ] Pediatr I975; 87: 558-571. 59 Sells CJ, Carpenter RL, Ray CG. Sequelae of central nervous system enterovirus infections. N Engl ] Med 1975; 293: I-4. 60 Wilfert CM, Thompson RJ JR, Sunder TRO et al. Longitudinal assessment of children with enterovirus meningitis during the first three months of life. Pediatrics 1981; 67: 811-815.
Perinatal viral infections Jennifer Royle Department of hnmunology and Infectious Diseases, Royal Alexandra Hospital for Children, Westmead, NSW 2145, Australia
Key words: herpes simplex virus, encephalitis, varicella zoster virus, ZIG (zoster immune globulin), enterovirus, echovirus, coxsackievirus, perinatal
Perinatal viral infections may cause catastrophic neonatal illness with significant morbidity and mortality. The presentation may be non-specific and appropriate treatment delayed because the diagnosis is frequently unrecognized. Recent advances have been made in understanding the natural history of perinatal viral infections, rapid diagnostic techniques, preventative measures and treatment. This chapter outlines the presentation, diagnosis, management and outcome of perinatally acquired herpes simplex virus, varicella zoster virus and the enteroviruses, echovirus and coxsackievirus. Greater awareness of these infections in the perinatal period is required. Early treatment may reduce the morbidity and mortality and limit the spread of infection.
Herpes simplex virus Herpes simplex virus (HSV) is a DNA virus which can cause devastating disease in the newborn. Even with the availability of antiviral medications, morbidity and mortality from disseminated disease is significant. Prevention of infection and early diagnosis and treatment of local lesions to prevent dissemination is of paramount importance. HSV can remain latent for months or years and periodically reactivate. Two major subtypes, HSV-I and HSV-2, are recognized: HSV-1 primarily causes oral lesions and HSV-2 usually affects genital areas and is therefore a commoner cause of neonatal vertical infections. Both subtypes can affect the genital area and cause neonatal infections. The incidence of neonatal HSV varies Widely. In the UK the estimated rate is approximately 2 per 100 000 [1] whereas rates 25 times higher have been reported from the USA [2].
Transmission Neonatal HSV occurs secondary to maternal genital lesions in about 85% of cases [3]. Transplacental infection can occur, causing congenital HSV infection, but is rare. The virus is most frequently acquired by passage through an infected 1084-2756/96/020107+12$12.00/00
birth canal. Ascending infection following rupture of membranes has been documented, as has infection following caesarean section with apparently intact membranes. Postnatal horizontal infection is uncommon. Cross-infection can occur from one infected baby to another in the nursery or from an oral or skin lesion in a mother or relative or infected staff member. Despite countless nosocomial exposures, the incidence of horizontal spread and neonatal unit outbreaks is very low [4].
Risk of infection Infants bom to mothers with active primary HSV are at the greatest risk of developing neonatal infection. Birth through an infected canal with a recurrent lesion can still cause neonatal infection though the chance is far less, only about 3% [5-7]. Primary HSV around the time of delivery has about a 50% chance of neonatal infection with vaginal delivery [8, 9]. The risk is thought to be lower if caesarean section is performed within 24 hours of membrane rupture [2], although there are no firm data. Symptomatic genital infection is manifest by pain and dysuria and is associated with vesicles and ulcers or both. However, about 70% of mothers of © 1996 W.B. Saunders Company Ltd
108
J. Royle
affected babies are asymptomatic at the time of delivery [10, 11] and give no history of ever having had herpetic lesions. Presumably primary HSV infection is more infectious for the baby because of a lack of antibodies to HSV and because the asymptomatic cervical shedding of HSV continues for longer after the primary episode [9]. The viral load is also larger. There is an increased risk of neonatal HSV associated with the use of fetal-scalp electrodes [7].
Clinical features Transplacental infection can lead to microcephaly and keratoconjunctivitis in the congenitally affected newborn but this is rare [2]. HSV has been isolated from some aborted fetuses and is thought to be associated with an increased risk of spontaneous abortion. Likewise, Whitley reported that in nearly 50% of infants with HSV, the pregnancy ended in premature labour, usually between 30 and 37 weeks gestation [10]. HSV infection is implicated as a cause of premature labour. Neonatal HSV has four clinical pictures. It can be localized (skin, mouth, eyes), generalized (liver, adrenals, lungs, brain and other organs), localized to the lung (pneumonitis) or localized to the central nervous system (meningoencephalitis). Skin involvement is the commonest manifestation of HSV infection. This may be an isolated finding or part of disseminated infection. The skin vesicles occur most often between one and two weeks of life although they have been noted at birth or delayed up to one month. The skin manifestations vary from one or two vesicles, to crops of vesicles, or there may be a large bullous lesion (Fig. 1). Less common skin manifestations are zosteriform eruptions, a generalized petechial rash, areas of denuded skin or erythema multiforme [12]. Progression of disease from isolated skin vesicles to the involvement of other sites occurs in about 70% of infected babies with no treatment [2, 10]. This dissemination occurs over an average of 7 days. Of note, a clinical picture of dissemination or local encephalitis is not always preceded by skin involvement and 20% are thought to have had no preceding skin lesion [10]. Other local sites of HSV neonatal infection include the mouth and eyes. Classical herpetic ulceration may involve the gingiva, tongue, palate (Fig. 2) and even the larynx. Local eye infection is most commonly manifest as keratoconjunctivitis.
Fig. I, Herpes simplex virus infection. A crop of vesicular skin lesions.
Dendritic conjunctival and corneal ulcers may be seen. Chorioretinitis may be present at birth or can develop secondary to keratoconjunctivitis. Uveitis, cataracts, microphthalmia and optic atrophy have all been described as sequelae of HSV eye infection. Disseminated disease usually presents in the first week of life although occasionally is seen at birth or up to 2 weeks of age. Its presentation is nonspecific with fever, vomiting, lethargy and poor feeding. If there is a concomitant CNS infection (seen in about 50%) irritability and convulsions may occur [12]. Other variable features include acidosis, respiratory distress, cyanosis, apnoea, generalized erythema, purpura, jaundice and hepatomegaly. One quarter of patients with disseminated disease develop a bleeding diathesis with disseminated intravascular coagulopathy (DIC), which may precede shock and death [12]. Disseminated disease is often fulminant. Pneumonitis is sometimes the presenting feature, usually at 3-7 days, which distinguishes it from early respiratory distress syndrome. Lung involvement can be part of multiple organ involvement or may develop as a local infection. Respiratory
Perinatal viral infections
109
Fig. 3. Herpes simplex virus pneumonitis. Term baby presented on day 5 with increasing respiratory distress. Chest X-ray demonstrating bilateral opacifications.
Fig. 2. Solitary oral herpes simplex virus lesion.
deterioration will be accompanied by perihilar radiographic changes progressing to extensive bilateral opacifications (Fig. 3). Early treatment can be life-saving, so HSV infection should be considered in a baby with later-onset respiratory distress. Diagnosis can be made rapidly by immunofluorescence on a nasopharyngeal aspirate. Meningoencephalitis (local CNS infection) presents later, mean age 11 days (range 7-30 days) [2, 13]. Presentation may be non-specific, but focal seizures may occur and the gag reflex may be absent [12]. Focal seizures may become generalized and intractable.
Diagnosis A high level of suspicion is required to diagnose neonatal HSV. Failure to commence early antiviral treatment dramatically increases mortality and morbidity. Careful examination of the skin, mouth and eyes may reveal diagnostic lesions in a nonspecifically unwell infant.
HSV immunofluorescence is the single most useful test, providing a rapid diagnosis within hours. Viral culture can confirm the diagnosis within 2-4 days. Cultures should be taken from skin lesions, the nasopharynx, conjunctiva and, if clinically indicated, cerebrospinal fluid (CSF). Sampling a vesicle involves swabbing the base of the vesicle once the roof has been removed. This swab should be smeared on a slide which is sent for urgent immunofluorescent staining. The swab should then be placed in viral transport medium for culture. Cultures may reveal cytopathic changes in 1-4 days. There is often a raised CSF white cell count (WCC), predominantly lymphocytes (range 50-200 ~l), although the WCC can be up to 2500 [12]. Viral cultures of CSF have been found to be positive in just over half the cases of local CNS infection and less than 20% in disseminated infection, most of whom had CNS infection [10]. CSF polymerase chain reaction (PCR) is now available and can speed the diagnosis, but results need to be interpreted with care, since both false positive and negatives can occur. Serology is generally unhelpful other than in confirming a diagnosis retrospectively. Whitley found the presence or absence of antibodies was
110
not predictive of presentation or outcome of infection [10, 14]. The use of CSF antibodies is controversial. A specific rapid HSV IgM in the CSF can assist an early diagnosis, otherwise CSF antibodies at 4-6 weeks post infection may retrospectively confirm a diagnosis. EEG changes of a temporal or parieto-temporal focus are non-specific, although may assist diagnosis. Computed tomography (CT) scans may be normal initially then within a few days may show unilateral or bilateral temporal lobe changes. Other cerebral imaging abnormalities include cerebral atrophy and the loss of grey-white differentiation. Brain biopsy which was once used to confirm the diagnosis of HSV encephalitis is now seldom performed.
Treatment Acyclovir and adenosine arabinoside (vidarabine, ara-A) are equally effective in neonatal HSV infection [15]. The daily dose of both drugs is 30 mg k g - ~ per day, acyclovir being given intravenously 8 hourly and vidarabine 12 hourly for 10-14 days. A study by Whitley et al [15] found no difference in morbidity, mortality and drug toxicity for acyclovir and vidarabine in treating babies with localized, disseminated disease or encephalitis [15]. Acyclovir is usually preferred because of its much lower volume of administration. Eye lesions should also be treated topically with antiviral agents under the supervision of an ophthalmologist.
Prognosis Without treatment, 70% of local skin lesions disseminate [2, 10]. Mortality without treatment is reported at 74% for disseminated disease and 50% for local CNS disease [16]. Treatment has reduced the mortality of disseminated disease to between 35 and 60% [15-17] and for local CNS disease, 10% [16]. Factors that increase the risk of death include prematurity, DIC, and if the infant is in or near coma when treatment is commenced [18]. Disseminated disease with pneumonitis is also associated with greater mortality [18]. Treatment of local skin, eye or oral infections has greatly reduced the numbers of children reported with disseminated disease. Although
J. Royle
mortality from HSV seems to be declining, severe consequences occur in many of the survivors. Major sequelae are seen in 86% of treated survivors of disseminated disease and 50-75% of treated survivors of meningoencephalitis [12, 17]. The sequelae include major neurological and developmental impairment. Factors which increase the risk of morbidity are encephalitis, seizures, DIC, and infection with HSV-2 rather than HSV-1 [18]. There is concern that HSV may cause a persistent or periodically reactivating infection that continues to cause neurological damage after apparent resolution of the initial acute illness. Gutman et al [19] described infants with neonatal HSV encephalitis who deteriorated after completion of antiviral treatment or who had progressive deterioration over the first year of life. Whitley et al [18] reported 4 of 71 infants with neonatal HSV localized to the skin, eyes or mouth who had long term neurological damage; all four patients had three or more recurrences of HSV-2 skin vesicles in the first year of life. Long term oral acyclovir prophylaxis should therefore be considered for infants with encephalitis and possibly for those with local HSV-2 with three or more recurrences.
Prevention of infection The risk to the fetus of stillbirth or intrauterine infection when the mother has primary genital herpes in the first trimester is unknown, but is probably small [9]. Acyclovir appears to cross the placenta in small quantities [20]; however, its safety for the fetus has not been proven and antenatal use is not indicated. Primary herpes at the time of delivery poses a 50% chance of infection with vaginal delivery [9]. Caesarean section within 24 hours of rupture of the membranes reduces the risk of neonatal HSV in primary infections, perhaps to less than 20% [2] and has been widely adopted as recommended management. Clinically and historically it is not always definite whether the lesion is a primary or recurrent one. When sufficient time exists, maternal IgM can be sought and if positive a caesarean section may be recommended [3]. When a mother with a history of recurrent genital HSV is symptomatic at the time of delivery or has lesions on examination no consensus on management has been reached. Some recommend caesarean section while others recommend vaginal delivery with cultures performed on the infant's
Perinatal viral infections
111
conjunctiva and nasopharynx at 24-48 hours. There are no trials to compare either practice. Culture positivity at birth reflects exposure to HSV, while culture positivity at 24 hours indicates true colonization rather than surface colonization [21]. In the latter circumstance, if the cultures were positive, it seems reasonable that antiviral treatment should be commenced [3]. Likewise treatment should be commenced promptly if the infant becomes symptomatic. Infants born to asymptomatic women with a history of recurrent genital herpes have a very low risk of developing HSV, less than 3% [7] and in the absence of lesions or symptoms, a vaginal delivery is safe.
Varicella zoster virus Ninety-five per cent of women of child-bearing age have had chicken-pox. Primary VZV infection can have devastating effects on a pregnant woman, fetus and newborn.
VZV and the immune system T cells are of primary importance in recovery from acute VZV infection. People with impaired cellular immunity, such as those on immunosuppressive therapy, tend to develop severe varicella which can be fatal, even with appropriate antiviral treatment. Antibodies can protect against infection or at least against the severity of infection but are not primarily involved in recovery. People with hypogammaglobulinaemia can recover normally from varicella. Neonates with transplacental IgG antibody from a mother with a past history of varicella have a minimal risk of developing postnatally acquired varicella and are extremely unlikely to develop a severe acute infection following exposure [22].
Incidence of varicella in pregnancy A large prospective study in the USA documented maternal varicella in 5 per 10 000 pregnancies [23]. Varicella is not notifiable and even in prospective studies, mild cases are probably not reported; asymptomatic cases may also occur. The incidence varies in different parts of the world; adults from tropical and sub-tropical areas are more likely to be susceptible to varicella [24, 25].
Fig. 4. Congenital varicella syndrome. Skin lesion scarring in a dermatomal distribution.
Primary matemal varicella in pregnancy appears to be abnormally severe. This is presumably due to depressed cellular immunity in pregnancy. Lifethreatening pneumonitis in women with gestational varicella has been reported by many, but such reports tend to be highly selective [26, 27]. It is not clear whether the risk is truly greater than that for normal adults.
Congenital varicella syndrome La Foret and Lynch were the first to describe an association between maternal varicella infection in early pregnancy and congenital anomalies in 1947 [28]. Alkalay et al assigned the term, congenital varicella syndrome [29]. Characteristically, there are cicatricial skin lesions of a limb, usually a leg, in a dermatomal distribution. This may be associated with limb hypoplasia. The zig-zag scar is presumed to be secondary to viral reactivation with the appearance of a scarred zoster ('shingles') site (Fig. 4). Other congenital malformations involve the brain (microcephaly, cerebellar hypoplasia, cortical atrophy) and the eye (microphthalmia, optic atrophy, cataracts, chorioretinitis and nystagmus).
112
(a)
J.
Royle
(b)
Fig. 5. Perinatal varicella. (a) Baby born with maternal antibody and rash but well; maternal chickenpox 10 days before delivery. (b) Baby born well, developed rash on day 5 with fatal pneumonitis, despite ZIG and acyclovir; maternal chickenpox 3 days before delivery.
Skeletal, gastrointestinal and genitourinary anomalies are less commonly associated. Maternal serology confirming recent infection (VZV IgM) combined with evidence of infection in the infant (a persistently raised VZV IgG) provide evidence to support the association between varicella and congenital malformations. The risk of the congenital varicella syndrome after first trimester varicella is about 2% [27, 30--33]. There are reports of congenital varicella syndrome occurring after second and third trimester varicella [34, 35] and first trimester material zoster [36], although this is less common than following first trimester varicella. Pregnant women with exposure to varicella in the first trimester with no past history of chickenpox and negative varicella serology should be given zoster immunoglobin (ZIG). ZIG is an immunoglobin preparation from donors with a high antibody titre to VZV. It is generally effective in
ameliorating the severity of infection following a recent exposure, although it does not usually prevent infection. The rationale of giving ZIG is to modify the severity of the disease in the mother and to reduce the risk of congenital varicella syndrome in the fetus. Perinatal maternal varicella Maternal peripartum varicella can lead to a lifethreatening illness in the newborn. About 25% of infants whose mothers develop varicella during the last ).I days of pregnancy become infected [26]. The spectrum of illness in the neonatal period varies from a well baby with a few vesicles to a fulminant rash, visceral lesions and pneumonitis [371 (Fig. 5). The incubation period for congenital varicella (time between mother's and infant's rash) is about
Perinatal viral infections
113
Table 1. Timing of chickenpox in mother and baby in relation to severity [38]. Onset of mother's rash in relation to delivery
Onset of baby's rash in relation to delivery (days after)
Died (n)
Survived (n)
Neonatal mortality (%)
0-4 5-10
0 7
27 16
0 30
5-21 days before 4 days before to 2 days after
9-15 days. It can, however, be much shorter if the mother is significantly viraemic. One study noted that if an infant was born with a rash or a rash appeared within four days of birth, the survival was 100%. An infant with a rash developing 5-10 days after birth had a 30% mortality from disseminated varicella usually complicated by severe pneumonitis (Table 1) [38]. The severity of the infant's illness is determined by the timing of the mother's illness in relation to delivery. An infant born with no maternal VZV ]gG who has just received a large inoculum of virus is at the most risk of developing severe disease. These infants are usually born well and become severely ill at 5-10 days. Miller et al have shown that if mothers develop a rash six or more days before delivery, then their infants will have detectable VZV IgG antibody. If the mother's rash develops five or fewer days prior to delivery, antibody is often undetectable [39].
Management of perinatal maternal varicella Considering the importance of the timing of the maternal rash it may be worthwhile delaying labour, where feasible, for a few days when the mother has a varicella rash of recent onset. Additional intrauterine time could increase the chance for transplacental passage of protective maternal antibody. Infants whose mothers develop a varicella rash, up to and including, 5 days prior to delivery, or up to two days after delivery, should be given intramuscular ZIG. Hanngren et al gave ZIG to 95 infants with perinatal exposure and 50% developed varicella. Of the 4I infants in the maximum risk group (mothers' rash onset 5 days before to 2 days after delivery) 21 infants (51%) became infected, of which only two cases were severe [40]. Infants with severe varicella and those of seronegative mothers who were not given ZIG should be treated with acyclovir (60 mg k g - I per day
given 8 hourly). Deaths from severe pneumonitis have occurred despite acyclovir being given early [41]. There have been no controlled studies of acyclovir treatment for mothers with peripartum varicella.
Postnatal exposure to varicella About 95% of mothers in industrialized countries have had chicken-pox and pass protective IgG to the fetus prenatally. The risk to infants of mothers with a history of varicella, is minimal. Unprotected infants may be at increased risk of severe varicella infection, although the risk is difficult to quantify because of selective reporting [42, 43]. Rubin et al [44] reported a case of severe neonatal varicella 8 days after delivery and reviewed a number of case reports of severe postnatally acquired neonatal varicella. They suggested that babies of seronegative mothers exposed to varicella in the neonatal period should be given ZIG, although no data are currently available to support this recommendation. Severe varicella can develop in healthy children (albeit rarely) and adults; hence it is not clear that the few neonatal cases reported truly indicate an increased susceptibility of neonates to severe disease. If an infant is retuming home to a family where, for example, a sibling has chicken-pox, a history of maternal varicella should be sought, and if negative, maternal VZV antibodies should be measured. It would be reasonable to give the infant ZIG prior to discharge if the maternal antibody titre was negative [12, 45]. Checking maternal serology in this situation is to be encouraged; serology can be performed rapidly, many women with no clinical history of varicella (i.e. past history of subclinical infection) have VZV IgG, and although ZIG is relatively safe, it is a blood product and should not be given unless truly indicated. There is never any indication
114
for separating a mother from her baby, or a baby from other siblings.
Nursery outbreaks Nursery outbreaks need special consideration. The degree of exposure will determine the appropriate action to be taken. Infants less than 32 weeks are likely to have low or undetectable levels of VZV IgG even if the mothers have a past history of varicella. These preterm infants should be given ZIG following significant exposure. Term infants with no maternal history of varicella may be considered for ZIG depending on the degree of exposure, maternal serology of the infants would confirm which infants truly are at risk. Infected infants and mothers should be isolated and nursed by immune st~'fff. Infants born to mothers with perinatal varicella should be isolated from birth to help reduce the chance of a nursery outbreak. If a child who had visited the nursery develops chicken-pox, the timing of the visits determines the action to be taken. Children are only infectious for up to a day before the rash appears, but not during the rest of the incubation period. If, say, the rash appeared 2 or more days after the last visit, then no action is needed.
Long term effects of VZV Infants exposed perinatally to varicella, even if they do not have clinical infection, have an increased risk of developing infection early in childhood [12]. It has been suggested that intrauterine varicella could lead to an increased risk of leukaemia and other malignancies [46]. Fine et al [47] reported the incidence of malignancy to be 2.3-fold greater than expected in a follow-up study of infants exposed in utero to VZV or CMV.
VZV vaccine A live attenuated vaccine is available in some countries (e.g. USA, Germany). This vaccine, when more widely available, may have a role for VZV IgG negative women during early adolescence [27]. Immunization of this important target population may greatly reduce the incidence of maternal, fetal and neonatal varicella infection.
J. Royle
Enteroviruses The enteroviruses (echovirus, coxsackievirus, and polioviruses) are RNA viruses which can cause devastating infection in the newbom. Poliovirus is now exceedingly rare in developed countries and becoming less common in developing countries due to immunization. Echoviruses (of various serotypes) can cause fulminant neonatal infection characteristically associated with hepatic necrosis and a bleeding diathesis. Type B coxsackieviruses may cause myocarditis, which is frequently fatal in the newborn period.
Epidemiology Enterovirus infections can occur any time of year, although in temperate climates are more common in the summer and autumn [48, 49]. Irregular epidemics may occur. Enterovirus infections commonly occur during community outbreaks in infants of mothers who have acquired infection near term. Disease in the newborn is uncommon but reflects the frequency of infections in the population. Estimating the incidence is difficult since many cases are asymptomatic and many symptomatic infants may not be diagnosed if the appropriate viral cultures are not performed. Neonatal echovirus and coxsackievirus infections have been described world-wide, coxsackie infections have been reported extensively from South Africa due to their frequent epidemics [50].
Transmission Enteroviruses spread rapidly by the faecal-oral route although respiratory transmission can occur [51]. Vertical transmission from the mother appears to occur at the time of delivery. The mode of infection is almost certainly contact with infected cervical secretions or maternal blood during delivery. Infection following caesarean section, even with intact membranes has been reported, suggesting that infection has occurred from maternal blood or that the virus can cross intact membranes [12]. Enteroviruses can also spread horizontally via secretions carried on hands. When there is no clear index case, infection presumably has started from a staff or family member. Horizontal infections are usually less severe [49, 52]. presumably due to a
Perinatal viral infections
smaller initial viral load and possibly due to the presence of passively acquired maternal antibodies
[12]. Enteroviruses enter the body by attaching to receptors on respiratory or gastrointestinal epithelial cells. Following oral or pharyngeal acquisition, local spread occurs to the submucosal (regional) lymph nodes where the virus replicates. Primary (minor) viraemia occurs within 24 hours. This causes viral dissemination but is usually asymptomatic. The virus then multiplies at many sites and at about 4-5 days the major symptomatic (high level) viraemia commences.
Clinical manifestations Symptoms in children and adults
The common clinical features of enterovirus infection are fever and upper respiratory tract infection. Aseptic (viral) meningitis, often with a rash, is relatively common and can be caused by many of the enterovirus serotypes. There are some less common but well described clinical syndromes usually caused by particular groups of enteroviruses: pleurodynia and myocarditis (coxsackie B virus), hand foot and mouth disease (coxsackie A virus 16 and enterovirus 71), paralysis (polioviruses and occasionally coxsackieviruses) and haemorrhagic conjunctivitis (enterovirus 70). The severity of infection and clinical picture depends on the enterovirus serotype, age, sex, immune competence and previous exposure of the host [53]. Despite the relatively benign clinical manifestations of non-polio enterovirus infections in other age groups, the neonate is uniquely susceptible to severe and potentially fatal infections. The timing of infection in relation to delivery may be very important. Symptomatic and particularly fatal disease is most. likely in infants of women infected within a few days of delivery, before protective antibodies can be transferred to the infant [54]. Generally in half to two-thirds of cases of vertical infection there is a history of peripartum maternal illness, usually mild fever and coryza or gastroenteritis [48, 49]. A characteristic syndrome is described with echovirus 11 infection (and sometimes other serotypes), where there is an acute onset of fever in the pregnant mother associated with severe lower abdominal pain which can masquerade as placental abruption or acute appendicitis [54, 55].
115
Symptoms in the neonate
Vertical (maternally acquired) neonatal infection usually presents at 3-5 days of age. It may occasionally present at birth or as late as 7 days. Horizontal infection with echovirus generally has a much milder clinical course than vertical infection [49, 52]. Coxsackievirus does not share this distinction and can cause fulminant infection horizontally, making nursery outbreaks potentially devastating
[50]. Echovirus
Echovirus infection produces three groups of clinical illness in the neonate, of increasing rarity and severity [51]. The first group is of fever, gastrointestinal upset (manifest by anorexia and vomiting) and mild respiratory symptoms often with an associated rash. The second group is aseptic (viral) meningitis, which is usually mild and characterized by temporary irritability, lethargy, fever and feeding difficulties [48]. Overwhelming meningoencephalitis with focal neurological signs can occur, albeit rarely [53]. The third group is that of severe infection which can lead to fulminant hepatitis, DIC and death [49]. Clinically the initial picture in this third group is a non-specific febrile illness perhaps with a rash, which rapidly progresses to pallor, collapse, apnoea, metabolic acidosis, severe jaundice, hepatospIenomegaly and ascites. A severe bleeding disorder secondary to DIC ensues which may become generalized with bloody ascites and haemopericardium. Bleeding can be catastrophic. Hypotension may not respond to fluid and inotropic support. Accompanying the fulminant hepatitis may be meningoencephalitis, pneumonitis, myocarditis and gastroenteritis. Mortality is about 80% [12]. Liver autopsy reveals centrilobular necrosis suggestive of ischaemia rather than hepatitis, the primary effect on the liver may be infection or ischaemia or both [I2]. Any serotype probably can cause severe infection though the most common reported serotypes have been 11, 6 and 7. Horizontal echovirus infection is usually mild, even in premature babies [49, 52], and does not cause the fulminant clinical picture. Over half the cases are symptom flee. Presentation is later, after 7 days, and often after I4 days. The non-specific illness comprises fever, irritability and apnoeic episodes. Meningitis may develop with a presentation similar to that of bacterial meningitis. Deaths have been reported following horizontal outbreaks though the mortality rate is very low [49].
J. Royle
116
Coxsackievirus
Treatment
The severity of neonatal infection with coxsackievirus does not have the clear distinction between horizontal and vertical infection. Neonatal outbreaks have been reported in which horizontal infection has developed into fatal myocarditis [49,
The treatment of severe enterovirus infection is supportive: blood transfusions, fresh frozen plasma, vitamin K, inotropic support and antiarrhythmic agents as individually required. Babies may have an increased sensitivity to digoxin during enterovirus infection and it should be used with caution and initially at low doses [12]. Use of immunoglobulin has been attempted in severe infection though it appears its use is unlikely to modify the disease once established [12].
50]. Most neonatal coxsackievirus reports are of type B rather than A. Clinically three patterns of severe disease occur: a biphasic illness, an abrupt illness with rapid death, or a progressive illness [56]. The biphasic illness commences with an initial episode of fever, mild anorexia, coryza or diarrhoea lasting 1-3 days. A macular rash (occasionally petechial) is a common accompaniment of the initial phase. A period of apparent recovery occurs, lasting 1-7 days. Abrupt recurrence of fever is seen, with associated tachycardia, cyanosis and circulatory collapse. This myocarditis, when onset occurs more slowly, may cause poor feeding, tachycardia and listlessness. Cardiomegaly is present and there may be a cardiac murmur. An abnormal ECG and echocardiogram assist with confirming the diagnosis [48]. In some cases there is no prodrome or it is so mild as to have been missed. Sudden collapse can occur without warning. In others, no biphasic illness occurs, there is a progressive course over 1-2 weeks with relentless deterioration despite intensive support [56]. Coxsackievirus myocarditis has a high mortality. The illness can also be complicated by encephalitis, hepatitis or coagulopathy [56].
Diagnosis The diagnosis of enteroviral infections is confirmed by culture. The virus is readily cultured from a throat swab, nasopharyngeal aspirate (NPA) and stool in an infected infant. In addition, CSF or ascitic fluid can be cultured for enteroviruses. Importantly, if a mother has a suspicious periparturn illness, maternal stool and throat swabs should be collected for culture and cultures from the infant should include NPA, throat and stool. Viral cytopathic effect in the tissue culture monolayer can sometimes be seen within a few days. PCR for enteroviruses is available in a few centres. Serology should be sent although unless specific enteroviral [gM is present, it may not be immediately helpful.
Prognosis Vertically transmitted echovirus infection has a mortality of greater than 60%, and if hepatic necrosis develops the mortality is greater than 80% [49]. Horizontal echovirus infections have occasionally been fatal in neonates, as they have in infants, older children and adults. However, death from horizontal infections is extremely rare. Estimates of the incidence of residual neurological sequence following echovirus meningitis range from 0% [57] to 15% [58-60]. Echovirus myocarditis usually responds to medical management, whereas coxsackievirus myocarditis has a high mortality
[56].
Prevention Prevention requires the reduction of horizontal cross-infection. Scrupulous handwashing is the most important technique in reducing nursery cross-infection [50, 52]. Whenever possible, infants with known or suspected enterovirus infection should be isolated. In relation to echovirus, the cross-infection cases are usually milder and no active preventative treatment for contacts is recommended other than cohorting and improved handwashing [52]. Coxsackievirus cross-infection is of greater concern and outbreaks should be managed more actively. Use of immunoglobulin has been advocated for use in all neonatal coxsackievirus contacts, especially if more than one case of myocarditis has occurred in the nursery [12]. When prenatal enterovirus infection is strongly suspected on clinical grounds, or if the virus has been isolated from the mother, immunoglobulin should be given to the infant, dosage
Perinatal viral infections
300-400 mg k g - i by infusion [12], and the infant should be isolated.
References 1 Hall S, Glickman B. The British paediatric surveillance unit. N Engl ] Med 1991; 63: 344-346. 2 Nahmias AJ, Keyserling HL, Kerrick CM. Herpes simplex. In: Remington JS, Klein JO, eds. hlfectious Diseases of the Fetus and Newborn Infant, 2nd edn. Philadelphia: WB Saunders, 1983; 636-678. *3 Mclntosh D, Isaacs D. Herpes simplex virus infection in pregnancy. Arch Dis Child 1992; 67: 1137-1138. 4 Light IJ. Postnatal acquisition of herpes simplex virus by the newborn infant: a review of the literature. Pediatrics 1979; 63: 480-482. 5 Whitley RJ. Herpes simplex virus infection. In: Remington JS, Klein JO, eds. hlfectious Diseases of the Fetus and Newborn Infant. 3rd edn. Philadelphia: WB Saunders, 1990; 282-305. 6 Prober CG, Sullender WM, Yasukawa BS et al. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl ] Med 1987; 316: 240--244. 7 Brown ZA, Benedetti J, Ashley R et al. Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labour. N Engl ] Med 1991; 324: 1247-1252. 8 Nahmias AJ, Josey WE, Naib ZM et al. Perinatal risk factors associated with maternal genital herpes simplex virus infection. Am ]Obstet Gynecol 1971; 110: 825833. 9 Brown ZA, Vontver LA, Benedetti J et aI. Effects on infants of a first episode of genital herpes during pregnancy. N Engl ] Med 1987; 317: 1246-1251. * 10 Whitley RJ, Nahmias AJ, Visintine AM et al. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics 1980; 66: 489-494. 11 Yeager AS, Arvin AM. Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus. Pediatrics 1984; 7.3: 188-193. "12 Isaacs D, Moxon ER. Neonatal Infectiolts. Oxford: Butterworth Heinemann, 1991; 149-166. 13 Nahmias AJ, Whitley RJ, Visitine AM et al. Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. ] Infect Dis 1982; 145: 829-836. 14 Kahlon J, Whitley RJ. Antibody response of the newborn after herpes simplex virus infection. ] Infect Dis 1988; 158: 925-933. * 15 Whitley R, Arvin A, Prober C et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex viral infection. N Engl ] Med 1991; 324: 444-449. 16 Whitley RJ, Nahmias AJ, Seng-Jaw Song et al. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics 1980; 66: 495-501. 17 Whitley RJ, Hutto C. Neonatal herpes simplex virus infections. Pediatricsin Review 1985; 7: 119-126.
117
* 18 Whitley RJ, Arvin A, Prober C et al. Predictors of morbidity and mortality in neonates with herpes simplex virus infections. N Engl ] Med 1991; 324: 450--454. 19 Gutman LT, Wilfert CM, Eppes S. Herpes simplex virus encephalitis in children: analysis of cerebrospinal fluid and progressive neurodevelopmental deterioration. ] hlfect Dis 1986; 154: 415-421. 20 Greffe BS, Dooles SL, Deddish RB et al. Transplacental passage of acyclovir. ] Pediatr 1986; 108: 1020-1021. 21 Overall JC, Whitley RJ, Yeager AS et al. Prophylactic or anticipatory antiviral therapy for newborns exposed to herpes simplex infection. Pediatr Infect Dis 1984; 3: 193-195. * 22 McIntosh D, Isaacs D. Varicella zoster virus infection in pregnancy. Arch Dis CMd 1993; 68: 1-2. 23 Sever JA, White LR. Intrauterine viral infections. Ann Rev Med 1969; 19: 471-486. 24 Gershon AA, Raker R, Steinberg S e t al. Antibody to varicella-zoster virus in parturient women and their offspring during the first year of life. Pediatrics1976; 58: 692-696. 25 Weller TH. Varicella and herpes zoster: changing concepts of the natural history, control, and importance of a not-so-benign virus. N Engl ] Med 1983; 309: 1362-1368, 1434-1440. 26 Gershon AA. Chickenpox, measles and mumps. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fehts and Newborn Infant. 3rd edn. Philadelphia: WB Saunders, 1990; 395-445. 27 Paryani SG, Arvin AM. Intrauterine infection with varicella-zoster virus after maternal varicella. N Engl ] Med 1986; 314: 1542-1546. 28 La Foret, Lynch LL. Multiple congenital defects following maternal variceIla. N Engl ] Med 1947; 236: 534-537. * 29 Alkalay AL, Pomerance JJ, Rimoin DL. Fetal varicella syndrome. ] Pediatr 1987; 111: 320-323. 30 Preblud JR, Cochi SL, Orenstein WA. Varicella-zoster infection in pregnancy. N Engl ] Med 1986; 315: 1416--1417. 31 Siegel M. Congenital malformations following chickenpox, measles, mumps and hepatitis, lAMA 1973; 226: 1521-1524. 32 Enders G. Varicella-zoster virus infection in pregnancy. Prog Med Virol 1984; 29: 166-196. 33 Manson MM, Logan WPD, Loy RM. Rubella and other virus infections during pregnancy. In: Reports o l l Public Health and Medical Nibjects (no. 101). London: Her Majesty's Stationery Office, 1960. 34 Brice JEH. Congenital varicella resulting from infection during second trimester of pregnancy. Arch Dis Child 1976; 51: 474-476. 35 Bai PVA, John TJ. Congenital skin ulcers following varicella in late pregnancy. ] Pediatr 1979; 94: 65-67. 36 Webster MH, Smith CS. Congenital abnormalities and maternal herpes zoster. Br Med ] 1977; ii: 1193. 37 Chapman S, Duff P. Varicella in pregnancy. Semin Perinatol 1993; 6: 403-409. 38 De Nicola LK, Hanshaw JB. Congenital and neonatal varicella. ] Pediatr 1979; 94: 175-176.
118
39 Miller E, Cradock-Watson JE, Ridehalgh MKS. Outcome of newborn babies given anti-varicella-zoster immunoglobulin after perinatal maternal infection with varicellazoster virus. Lancet 1989; ii: 371-373. 40 Hanngren K, Grandier M, Granstrom G. Effect of zoster immunoglobulin for varicella prophylaxis in the newborn. Scand] Infect Dis 1985; 17: 343-347. 41 Holland P, Isaacs D, Moxon ER. Fatal neonatal varicella infection. Lancet 1986; ii: 1156. 42 Preblud SR, Orenstein WA, Bart KJ. Varicella: clinical manifestations, epidemiology and health impact in children. Pediatr Infect Dis J 1984; 3: 505-509. 43 Preblud SR, Bregman DJ, Vernon LL. Deaths from varicella in infants. Pediatr h~fect Dis ] 1985; 4: 503-507. 44 Rubin L, Leggiadro R, Elie MT et al. Disseminated varicella in a neonate: implications for immunoprophylaxis of neonates exposed to varicella. Pediatr h~fect Dis ] 1986; 5: I00--102. 45 Prober CG, Gershon AA, Grose C et al. Consensus: varicella-zoster infections in pregnancy and the perinatal period. Pediatr Infect Dis ] 1990; 9: 865-869. 46 Adelstein AM, Donovan JW. Malignant disease in children whose mothers had chickenpox, mumps or rubella in pregnancy. Br Med ] 1972; 4: 629-63I. 47 Fine PEM, Adelstein AM, Snowman J e t al. Long term effects of exposure to viral infection in utero. Br Med ] 1985; 290: 509-511. 48 Krajden S, Middleton PJ. Enterovirus infections in the neonate. Clin Pediatrics 1983; 22: 87-92. * 49 Modlin JF. Perinatal echovirus infection: insights from a literature review of 61 cases of serious infection and 16 outbreaks in nurseries. Rev Infect Dis 1986; 8: 918-925.
J. Royle
50 Editorial. Avoiding the danger of enteroviruses in newborn babies. Lancet I986; i: 194-I96. 51 Nagington J, Wreghitt TG, Gandy G e t al. Fatal echovirus 11 infections in outbreak in special-care baby unit. Lancet 1978; ii: 725-728. 52 Isaacs D, Dobson SRM, Wilkinson AR et al. Conservative management of an echovirus I I outbreak in a neonatal unit. Lancet 1989; h 543-545. * 53 Gilbert GL. hlfectious Disease in Pregnancy and the Newborn hzfant. Vol. 2. Chur: Harwood Academic, 1991; 381-391. 54 Modlin JF. Fatal echovirus 11 disease in premature neonates. Pediatrics 1980; 66: 775-780. 55 Kurnetz R, Cacciarelli A, Egerer R et al. ] Pediatr 198I; 99: 822-826. *56 Kaplan MH, Klein SW, McPhee J et al. Group B coxsackievirus infections in infants younger than three months of age: a serious childhood illness. Rev h~fect Dis 1983; 5: I019-1032. 57 Bergman I, Painter MJ, Wald ER et al. Outcome in children with enteroviral meningitis during the first year of life. ] Pediatr 1987; 110: 705-709. 58 Farmer K, MacArthur BA, Clay MM. A follow-up study of 15 cases of neonatal meningoencephalitis due to coxsackie B5. ] Pediatr I975; 87: 558-571. 59 Sells CJ, Carpenter RL, Ray CG. Sequelae of central nervous system enterovirus infections. N Engl ] Med 1975; 293: I-4. 60 Wilfert CM, Thompson RJ JR, Sunder TRO et al. Longitudinal assessment of children with enterovirus meningitis during the first three months of life. Pediatrics 1981; 67: 811-815.