Congenital Viral Infections

An Overview

Congenital Infection
There are a number of organisms that can cause congenital neonatal illness Congenital infection can occur during pregnancy or the peri-partum period Primary infection in the mother, generally, results in greater risk of consequences to the developing fetus compared with 're-activation' The timing of infection is important in regards to the severity of neonatal illness and in relation to the organism involved

Congenital, Perinatal, and Neonatal Viral Infections

Intrauterine Viral Infections
Rubella Cytomegalovirus (CMV) Parvovirus B19 Varicella-Zoster (VZV) Enteroviruses HIV HTLV-1 Hepatitis C Hepatitis B Lassa Fever Japanese Encephalitis West Nile Virus Measles

Perinatal and Neonatal Infections

Human Herpes Simplex VZV Enteroviruses HIV Hepatitis B Hepatitis C HTLV-1

Infection with High Mortality Rate in Pregnant Women HEV (20%) Pandemic Influenza A (H1 1) 2009 (50%)

Diagnosis of Congenital disease

Maternal history History of recent exposure to ill individual Maternal immunization history Physical findings in the newborn Appropriate laboratory testing

Rubella
History
1881 Rubella accepted as a distinct disease 1941 Associated with congenital disease (Gregg) 1961 Rubella virus first isolated 1967 Serological tests available 1969 Rubella vaccines available

Characteristics of Rubella
RNA enveloped virus, member of the togavirus family Spread by respiratory droplets. In the prevaccination era, 80% of women were already infected by childbearing age. IP: 2-3 weeks

Clinical Features
maculopapular rash lymphadenopathy fever arthropathy (up to 60% of cases)

Rash of Rubella

Risks of rubella infection during pregnancy

Onset of maternal infection <12 weeks 12-18 weeks >18 weeks Fetal Complications Congenital rubella syndrome (>90%) Sensorineural deafness (20%) Rare

Congenital Rubella Syndrome

Classical triad consists of cataracts, heart defects, and sensorineural deafness. Many other abnormalities had been described and these are divided into transient, permanent and developmental. Transient
low birth weight, hepatosplenomegaly, thrombocytopenic purpura bone lesions, meningoencephalitis, hepatitis, haemolytic anemia pneumonitis, lymphadenopathy Sensorineural deafness, Heart Defects (peripheral pulmonary stenosis, pulmonary valvular stenosis, patent ductus arteriosus, ventricular septal defect) Eye Defects (retinopathy, cataract, microopthalmia, glaucoma, severe myopia) Other Defects (microcephaly, diabetes mellitis, thyroid disorders, dermatoglyptic abnormalities

Permanent

Developmental Sensorineural deafness, Mental retardation, Diabetes Mellitus,

thyroid disorder

Outcome
1/3 rd will lead normal independent lives 1/3 rd will live with parents 1/3rd will be institutionalised The only effective way to prevent CRS is to terminate the pregnancy

Prevention (1)
Antenatal screening
All pregnant women attending antenatal clinics are tested for immune status against rubella. Non-immune women are offered rubella vaccination in the immediate post partum period.

Prevention (2)
Since 1968, a highly effective live attenuated vaccine has been available with 95% efficacy Universal vaccination is now offered to all infants as part of the MMR regimen in the USA, UK and a number of other countries. Some countries such as the Czech Republic continue to selectively vaccinate schoolgirls before they reach childbearing age. Both universal and selective vaccination policies will work provided that the coverage is high enough.

Laboratory Diagnosis
Diagnosis of acute infection Rising titres of antibody (mainly IgG) - HI, EIA Presence of rubella-specific IgM - EIA Immune Status Screen HI is too insensitive for immune status screening SRH, EIA and latex agglutination are routinely used 15 IU/ml is regarded as the cut-off for immunity

Typical Serological Events following acute rubella infection

Note that in reinfection, IgM is usually absent or only present transiently at a low level

RUBELLA SEROLOGY

SRH Ab Specific IgG (RIA/EIA) Specific IgM (RIA/EIA) eutralization & HI Abs 14 16 18 20 22 24 26 28 30

Days after Exposure

VIRUS ISOLATIO

Pharynx Blood Stool Urine 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Days after exposure

Following information required: Date and duration of exposure Date of onset of illness Presence and distribution of rash Lymphadenopathy and arthralgia H/O rubella vaccination Result of previous rubella screening test and technique used

A.

Serological Assessment of Women Exposed to or Developing Rubella-like Illness in Pregnancy Rubella IgM Sensitive techniques can detect low level of IgM in reinfection cases *Has been shown to persists at low levels from few months to 4 years following vacc -> 4 fold rise in Ab titre in paired sera -Single sample HI Ab present in absent of SRH, CF, IgG (ELISA) Possibilities of false positive/negative Should follow with Rubella IgM HI:

1.

2.

B.

Congenital Rubella

(1) Fetal diagnosis is possible from cord blood IgM rubella PCR of amniotic fluid (2) Postnatal diagnosis is by IgM isolation of rubella virus (possible form many sites including NPA, eye, throat, CSF, stool and urine for up to 12 months) PCR

Other test include: FBE Renal function and electrolytes Liver function tests Cranial ultrasound (looking for discrete calcification) Echocardiography (looking particularly for Pulmonary Stenosis and PDA) Renal ultrasound LP (pleocytosis with elevated protein) CXR (indicated if the baby has respiratory symptoms) Long Bone Xrays Hearing assessment is mandatory, even in babies with no overt disease at birth. Deafness may be progressive, and therefore serial hearing assessments over the 1st few years of life are essential. Ophthalmological assessment is also essential and progressive retinal damage can be seen. Endocrine problems can occur in the long term including diabetes mellitus and hypothyroidism

C.

Rubella Antibody Screening

Single Radial Haemolysis (SRH) Latex Agglutination (LA) ELISA (IgG) Passive Haemagglutination (PHA) Immunofluorescence (IF)

D.

Serological Techniques used for diagnosis

1.

Techniques used to demonstrate a significant rise in antibody titre. ELISA IgG HI Rubella specific IgM

2.

Reporting Result of SRH Tests for Rubella Antibody Screening Test Zone Size Test zone larger than that of 15 IU/ml standard serum and that produced on the control plate Test zone smaller than that of 15 IU/ml standard serum, but larger than that produced on the control plate No test zone, or a test zone equal to or similar to that on on the control plate Report Rubella antibody detected (> 15 IU/ml)

Low level of rubella antibody (< 15 IU/ml): regard as susceptible

Rubella antibody not detected: non-immune

Cytomegalovirus
member of the herpesvirus Primary infection usually asymptomatic. Virus then becomes latent and is reactivated from time to time. transmitted by infected saliva, breast milk, sexually and through infected blood 60% of the population eventually become infected. In some developing countries, the figure is up to 95%.

Congenital CMV Infection

Defined as the isolation of CMV from the saliva or urine within 3 weeks of birth. Commonest congenital viral infection, affects 0.3 - 1% of all live births. The second most common cause of mental handicap after Down's syndrome and is responsible for more cases of congenital damage than rubella. Transmission to the fetus may occur following primary or recurrent CMV infection. 40% chance of transmission to the fetus following a primary infection. 5-10% transmission in recurrent infection. 10% of congenital CMV infection result in signs and symptoms May be transmitted to the fetus during all stages of pregnancy. No evidence of teratogenicity, damage to the fetus results from destruction of target cells once they are formed.

Congenital CMV Infection

More than 30% infants with severe CMV infection die; among the survivor >50% develop neurological sequelae CNS abnormalities - microcephaly, mental retardation, spasticity, epilepsy, periventricular calcification. Eye - choroidoretinitis and optic atrophy Ear - sensorineural deafness (most common sequelae of recurrent CMV) Liver - hepatosplenomegaly and jaundice which is due to hepatitis. Lung - pneumonitis Heart - myocarditis Thrombocytopenic purpura, Haemolytic anaemia Late sequelae in individuals asymptomatic at birth - hearing defects and reduced intelligence.

Cytomegalic CMV Infection

Incidence of Cytomegalic Disease

U.S.A.
o. of live births p.a. Rate of congenital CMV o. of infected infants Symptomatic at birth (5 - 10% ) Fatal disease (~ 20% ) o. with sequelae (90% of survivors) Asymptomatic (90 - 95% ) o. with late sequelae 3,000,000 1% 30,000 1,500-3,000 300-600 1080-2160 27000 1350-4550

U.K.
700,000 0.3% 2100 105 22 83 1995 315

Diagnosis
Isolation of CMV from the urine or saliva of the neonate. Presence of CMV IgM from the blood of the neonate. PCR T/S, Saliva, NPA Detection of Cytomegalic Inclusion Bodies from affected tissue (rarely used)
Culture and PCR should be performed as soon as possible in the first 2 weeks of life as CMV detected after this time can indicate peri/post natal infection

Management
Primary Infection - consider termination of pregnancy. 40% chance of the fetus being infected. 10% chance that congenitally infected baby will be symptomatic at birth or develop sequelae later in life. Therefore in case of primary infection, there is a 4% chance (1 in 25) of giving birth to an infant with CMV problems. Recurrent Infection - termination not recommended as risk of transmission to the fetus is much lower. Antenatal Screening impractical. Vaccination - may become available in the near future.

Neonatal Herpes Simplex

Neonatal herpetic infection is defined as infection within 28 days of birth Incidence of neonatal HSV infection varies inexplicably from country to country e.g. from 1 in 4000 live births in the U.S. to 1 in 10000 live births in the UK. The baby is usually infected perinatally (85%) during passage through the birth canal, ~10% acquired intrauterine and ~10% postnatally. Premature rupturing of the membranes is a well recognized risk factor. The risk of perinatal transmission is greatest when there is a florid primary infection in the mother. There is an appreciably smaller risk from recurrent lesions in the mother, probably because of the lower viral load and the presence of specific antibody. The baby may also be infected from other sources such as oral lesions from the mother or a herpetic whitlow in a nurse.

Neonatal Herpes Simplex

The spectrum of neonatal HSV infection varies : -mild disease localized to the skin/eyes/mouth (45%) -CNS disease: meningitis/encephalitis (30%) -to a fatal disseminated infection (25%) Infection is particularly dangerous in premature infants. Where dissemination occurs, the organs most commonly involved are the liver, adrenals and the brain. Where the brain is involved, the prognosis is particularly severe. The encephalitis is global and of such severity that the brain may be liquefied. A large proportion of survivors of neonatal HSV infection have residual disabilities. Acyclovir should be promptly given in all suspected cases of neonatal HSV infection (65% mortality rate if untreated , 25% in treated cases). The only means of prevention is to offer caesarean section to mothers with florid genital HSV lesions.

Neonatal Herpes Simplex

HSV-1 HSV-2 (70%) Transmission rate: 25-50% primary infection 1% recurrent infection

Varicella-Zoster Virus
90% of pregnant women already immune, therefore primary infection is rare during pregnancy Primary infection during pregnancy carries a greater risk of severe disease, in particular pneumonia First 20 weeks of Pregnancy up to 3% chance of transmission to the fetus, recognised congenital varicella syndrome; Scarring of skin Hypoplasia of limbs CNS and eye defects Death in infancy normal (especially 5 days prior to delivery/ 2 days after delivery)

Neonatal Varicella
VZV can cross the placenta in the late stages of pregnancy to infect the fetus congenitally. Neonatal varicella may vary from a mild disease to a fatal disseminated infection. If rash in mother occurs more than 1 week before delivery, then sufficient immunity would have been transferred to the fetus. Zoster immunoglobulin should be given to susceptible pregnant women who had contact with suspected cases of varicella. Zoster immunoglobulin should also be given to infants whose mothers develop varicella during the last 7 days of pregnancy or the first 14 days after delivery.

Parvovirus
Causative agent of Fifth disease (erythema infectiosum), clinically difficult to distinguish from rubella. Also causes aplastic crisis in individuals with haemolytic anaemias as erythrocyte progenitors are targeted. Spread by the respiratory route, 60-70% of the population is eventually infected. 50% of women of childbearing age are susceptible to infection.

Congenital Parvovirus Infection

Known to cause fetal loss through hydrops fetalis; severe anaemia, congestive heart failure, generalized oedema and fetal death No evidence of teratogenicity. Risk of fetal death: 17% < 20 weeks of pregnancy and 6% >20wks. Minimal risk to the fetus if infection occurred during the first or third trimesters of pregnancy. Maternal infection during pregnancy does not warrant termination of pregnancy. Cases of diagnosed hydrops fetalis had been successfully treated in utero by intrauterine transfusions and administration of digoxin to the fetus.

Parvovirus:Serological profile,haematological and clinical events