Viral Infections in Pregnancy

Sangeeta  Gupta; Sutopa  Banerjee

Viral Infections in PregnancyCHAPTER 1

Sangeeta Gupta

Sutopa Banerjee

INTRODUCTION

Viral infections in pregnancy are major causes of morbidity and mortality for both mother and foetus. The viral infections of concern during pregnancy are those caused by cytomegalovirus, rubella virus, herpes simplex virus, varicella-zoster virus, parvovirus, coxsackievirus, measles virus, enterovirus, adenovirus and human immunodeficiency virus.

This chapter will focus on some of these viral infections, except human immunodeficiency virus infection, which is described in another chapter of this book.

CYTOMEGALOVIRUS (CMV)

INTRODUCTION

Human cytomegalovirus infection is the most common cause of intrauterine infection resulting in congenital disease and hence, is of particular concern to the obstetrician.

Causative Agent

CMV infection is caused by a double stranded DNA virus of the herpes family.

Pathogenesis

CMV has special affinity for nuclei of infected cells and multiplies in them to form intranuclear inclusions in the affected tissues and therefore, is also known as cytomegalic inclusion disease. It has the ability to become latent following an acute attack and reactivate at a later time.¹ It also exhibits persistency of viral shedding; infected children shed the virus in saliva and urine till almost two years of age and adolescents for almost few months after infection. Incubation period is 28 to 60 days.

Epidemiology

Primary maternal infection occurs in 0.7 to 4 per cent of pregnancies, with 30 to 40 per cent of them resulting in congenital infection.² 40-60 per cent women of childbearing age of mid-high socio-economic status and 80 per cent of low socio-economic status are already seropositive.^2,3 But, preexisting maternal antibodies do not prevent reactivation or recurrent infection in pregnancy and is essentially not protective against intrauterine CMV infection with around 0.2 to 2 per cent risk of delivering a congenitally infected infant.²

Table 1.1 Foetal affection in CMV infection

	Primary maternal infection	Recurrent/Reactivation
Incidence	0.7-4% of pregnancies. (less frequent)	1-14% (more frequent)
Risk to foetus:
Congenital infection	30-40% (much more)	Only 0.2-2% (much less)
Symptomatic at birth	10% (much more)	< 1% (much less)
Long-term sequel	10-15% (much more)	5-10% (much less)

The above table deduces that in pregnancy, though recurrent/reactivation of CMV infection is more common than primary infection, risk of foetal transmission, congenital infection and affection are much more and severe with primary maternal infection. Almost all cases of infants symptomatic at birth are due to primary maternal infection.

CMV infection affects approximately 1 per cent of all births and is the most common infectious cause of childhood deafness.

CMV is not highly contagious. Horizontal spread occurs through close contact with saliva, urine, body secretions, contaminated fomites, sexual contact or receipt of infected organs or blood. The most common mode of infection is from a 2 to 3 year-old child attending a day care centre, who usually shed the virus in around 50 per cent cases. Vertical transmission occurs by haematogenous spread to the placenta with placental infection and subsequent foetal infection. The virus replicates in the foetal renal tubular epithelium and is excreted into the amniotic fluid. CMV can spread at perinatal period (10-15%) following exposure to infected genital tract secretions during passage through birth canal or from breastfeeding of infected mother's milk. Recurrent or reactivated infection transmits by migration of infected leukocytes across the placenta, reactivation of infection locally within the endometrium, ascending infection via the cervical canal due to lower genital tract virus shedding and re-infection with a different strain of CMV.

Clinical Features

In 90 per cent cases CMV infection in the mother is asymptomatic. Sometimes it may present as a febrile illness mimicking mononucleosis with malaise, fatigue, myalgia, sore throat, lymphadenopathy and hepatosplenomegaly. Rarely, serious complications may occur like interstitial pneumonitis, hepatitis, meningoencephalitis, myocarditis, thrombocytopenia and haemolytic anaemia.⁴ Recurrent infection is always asymptomatic.

Effect of Pregnancy on CMV

Course of disease is not altered or severed due to pregnancy.

Effect of CMV on Pregnancy

There is no evidence of increase in spontaneous abortions or late pregnancy losses in CMV infection but, it is associated with an increased incidence of premature rupture of membranes and pre-term delivery.

Foetal Transmission and Prognosis

Transmission of CMV infection to the foetus occurs with equal frequency in all the trimesters (40%), but the infection is more virulent when occurs in early pregnancy (< 20 weeks of gestation) and hence severe sequel occur. Neonates are usually asymptomatic if infection occurred in the third trimester or intrapartum, unless in low birth weight babies. These babies shed the virus for about 2 years in childhood, but, the development is normal with no permanent sequel. Hence, caesarean section in order to avoid intrapartum foetal exposure is not justified.

The mechanisms of development of congenital anomalies due to CMV infection are cell death, resultant ischaemia from vasculitis and immune system mechanisms.

It is the primary maternal infection in early pregnancy which is of greatest concern because 10 per cent neonates born to these mothers are symptomatic at birth and have poor prognosis with 25 per cent mortality rate; the survivors develop permanent sequel like mental retardation, neurological symptoms, sensorineural hearing loss and visual impairment. Out of the rest 90 per cent asymptomatic neonates, 10 to 15 per cent develop significant long-term sequel usually within the first 2 years of life; most commonly sensorineural hearing loss^5,6 followed by developmental delay and mental retardation. So, with primary CMV infection at early gestation, there is 92.7 per cent chance of having a normal infant while 7.3 per cent chance of neonatal death or sequel. With recurrent/reactivated infection < 1 per cent neonates are symptomatic and only 5 to 10 per cent of the asymptomatic neonates develop long-term sequel: suggesting some but, not all protection by pre-existing maternal antibodies.

The classical tetrad of CMV affection is mental retardation, cerebral calcifications, microcephaly and chorioretinitis. Neonates with severe congenital infections present with thrombocytopenia with petechiae, hepatitis with jaundice, hepatosplenomegaly, microcephaly, pneumonitis, chorioretinitis, optic atrophy, micro-phthalmia, aplasia of various parts of the brain, intrauterine growth retardation and dentine defects. Intracranial calcifications are an indication that the infant will have at least moderate to severe mental retardation.

Structural foetal sequels are common in primary maternal infection in the first trimester (e.g. microcephaly and intracranial calcifications), whereas functional abnormalities are more common in primary maternal infections closer to delivery (e.g. hepatitis, thrombocytopenia and pneumonia).³

Diagnosis

Diagnosis of CMV infection in antenatal women clinically is difficult because mostly it is asymptomatic or has non-specific symptoms. Routine antenatal screening of CMV infection is not recommen-ded because neither it influences the management nor it is cost effective. In primary infection IgM antibodies become positive but, may persist for 6 to 9 months and even upto 18 months. Therefore it is difficult to say if the infection has been acquired during the pregnancy or before. A four-fold rise in IgG antibody titres at 4 to 6 weeks interval is suggestive of a recent or recurrent infection. CMV IgG antibody avidity test is useful in diagnosing primary infection when the IgG antibodies produced have low affinity for the CMV antigens whereas on reactivation or re-infection the antibodies 4have high avidity. Viral culture or PCR (polymerase chain reaction) will diagnose CMV infection but, they do not differentiate between primary and recurrent/reactivated infection.

Prenatal diagnosis of CMV infection of foetus is best done by analysis of amniotic fluid by PCR after 21 weeks of gestation when it is 100 per cent sensitive. Hence, amniocentesis should be done after 21 weeks of gestation and atleast 4 weeks after maternal serological diagnosis. A positive amniotic fluid test suggests foetal infection (excreting virus into urine) but, not the degree of fetal affection or its prognosis. A single negative amniotic fluid test does not exclude intrauterine infection and a repeat test should be done 4 to 8 weeks later. Viral culture of amniotic fluid can also be used. Ultrasound is also useful in prenatal diagnosis but positive findings like microcephaly, ventriculomegaly, intracerebral calcifications, hydrops, IUGR and oligohydramnios are limited to those foetuses with severe symptoms.

Foetal blood culture has low sensitivity and hence, is not recommended. IgM antibodies in foetal blood are not present until after 20 weeks of gestation and may not appear even in later gestation despite long infection. Therefore, cordocentesis is not justified.

Diagnosis of congenital CMV infection in neonates is best done by PCR or viral culture from urine, saliva or cord blood in first 2 weeks of life. A positive test on cerebrospinal fluid suggests high risk for abnormal neurological development.

Management

Preconceptional counselling is required in women with unknown serostatus who come in contact with CMV infected individuals more often like health care personnel or day care workers. They should be advised to prevent infection by maintaining proper hygiene, frequent hand washing and taking universal precautions or change occupation. Counselling may also be sought by a lady who has delivered a CMV affected infant previously. She should be told that there is no increased risk of vertical transmission. Chances of delivering an infected infant is small (about 2%) and the neonate is usually asymptomatic with very low risk of developing long term sequel. Usually the risk of clinically symptomatic neonate is 0.2 per cent. No prophylactic measures to prevent transmission are required and prenatal diagnosis is impractical. There is no data to indicate how long conception should be delayed after a primary infection.

Routine maternal screening of primary CMV infection is not recommended because in seronegative women, serial samples have to be taken to exclude seroconversion and is not cost effective; hygiene and sanitation instructions can be given to all women irrespective of knowledge of her serostatus; no vaccine is available; less than 25 per cent of infected foetus will be affected and hence it is difficult to advice how to proceed in the pregnancy, above all there is no therapy available to prevent the fetal damage and pregnancy termination is the only alternative to expectant management.

The management options for women with presumed primary CMV infection are as follows:

Treatment of an affected neonate with ganciclovir or forscarnet has considerable haematotoxicity and is recommended only in CMV retinitis in immunocompromised host. Acyclovir is not useful in CMV infection because the virus does not induce its own thymidine kinase enzyme. There is no data to indicate how congenital compilations can be delayed. 5

Prevention

Prevention of CMV infection in pregnancy is through health education regarding maintaining hygiene. There are no controlled trials till date to support the use of passive immunization with hyperimmune plasma or globulin after a primary infection. Vaccination trials using CMV 6surface glycoprotein rather than live attenuated virus are currently being conducted. These will avoid the possibility of re-activation of vaccine virus during pregnancy. Blood transfusion in pregnancy if required should be done with seronegative blood for seronegative lady or for unknown serostatus especially in the first two trimesters.

RUBELLA (GERMAN MEASLES OR LITTLE RED)

INTRODUCTION

Rubella infection is important in pregnancy due to its devastating teratogenic effects on the foetus.

Causative Agent

Rubella is caused by a single-stranded RNA virus of family togovirus⁷ and genus rubivirus.

Epidemiology

Incidence of rubella has decreased over the past years due to the advent of rubella vaccine; still 5 to 25 per cent of women in the child bearing age lack protective antibodies and are susceptible to primary infection.

It is primarily a disease of young children and adolescents where it is inconsequential; usually occurring in spring. Transmission is through respiratory droplets. Vertical transmission occurs during maternal viraemia when there is haematogenous spread to the placenta and the foetus. Incubation period is about 14 to 21 days. The virus replicates in the nasopharynx and regional lymphnodes. Viraemia occurs about 7 days after the exposure and 7 days before the onset of rash. The period of infectivity is 7 days before to 7 days after the onset of rash. Infants with congenital rubella syndrome may shed the virus for about 2 years. The rash of rubella is immunologically mediated and its development coincides with the development of antibodies. Acquired immunity is usually life long.

Clinical Features

Rubella usually presents with mild constitutional symptoms like malaise, headache, myalgias, arthralgias, low grade fever and conjunctivitis. Postauricular lymphadenopathy may occur in the second week. The principal clinical manifestation is a widely disseminated, non-pruritic, erythematous maculopapular rash around 2 weeks after the exposure, which affects centrifugally with initial involvement of the face followed by spread to the trunk and extremities. These signs and symptoms are usually short lived and self-limiting. As such pregnant women are not at a greater risk of complications. Rarely complications like encephalitis, myelitis, optic and peripheral neuritis, myocarditis, pericarditis, hepatitis, thrombocytopenia and Guillain-Barré syndrome may occur.

Effect of Pregnancy on Rubella

Disease course is not altered or severed. As such pregnant women are not at a greater risk of complications.

Effect of Rubella on Pregnancy

Rubella may lead to spontaneous abortions and congenital rubella syndrome (CRS) in early pregnancy and stillbirths in late pregnancy.

Foetal Transmission and Prognosis

Many a times the foetus may escape the infection with or without placental infection and may show no clinically detectable lesion.

The various mechanisms of teratogenecity of rubella are direct cellular destruction causing altered formation or function of developing tissues, blood vessel obliteration with hypoxic damage, chromosomal injury, immunopathologic damage to tissues, formation of antigen-antibody complexes with deposition into certain tissues and interference with cell mitosis. Rubella virtually affects every organ.⁸ The foetal consequences relate directly to the gestational age at the time of maternal infection:

Table 1.2 Foetal consequences in Rubella

Period of gestation	Risk of infection	Consequence
0-12 weeks	40-50%	100% risk of major congenital abnormalities
13-16 weeks	30-35%	Deafness and retinopathy in 15%. Spontaneous abortion in 20%.
After 16 weeks	10%	Usually normal development with slight risk of deafness and retinopathy.

The clinical manifestations of CRS are:

Table 1.3 Clinical manifestations of CRS

Classical triad	Cataract, heart defects, sensorineural deafness.
Others
a. Transient (Present at birth but resolve spontaneously)	Low birth weight, hepatosplenomegaly, thrombocytopenic purpura, meningoencephalitis, hepatitis, haemolytic anaemia, pneumonitis, myocarditis lymphadenopathy, blue berry muffin spots.
b. Permanent	Sensorineural deafness (most common manifestation; 80% CRS children are affected). Eye defects like salt and pepper retinopathy, cataract, microphthalmia, glaucoma and severe myopia-(10-30%). CNS anomalies like microcephaly and mental retardation -(10-25%). CVS defects like patent ductus arteriosus (most common cardiac defect), pulmonary artery and valve stenosis (most pathognomonic of rubella) and VSD- (10-20%).
c. Developmental (appear and progress with age)	Sensorineural deafness, mental retardation, IDDM (autoimmune mechanism), thyroid disorders and hypertension.

Diagnosis

Diagnosis of rubella in mother is done by serology; ELISA for IgG and IgM antibodies. Demonstration of serocoversion is suggestive of recent infection, i.e. a four-fold or greater rise in IgG titres in paired acute and convalescent sera samples taken at 3 to 4 weeks 8interval. IgG antibody appears within 7 to 10 days of exposure and persists for life. IgM antibody usually peaks within 7 to 10 days after the onset of illness and then declines over a period of 4 weeks. Presence of rubella specific IgM also suggests recent infection. But, false positive and false negative results may occur. Moreover it may persist for many months and may not suggest a recent infection. It may also be present with re-infection. IgG avidity testing may help to differentiate recent from long ago infection. Viral culture 9 is time consuming, costly and difficult.

Prenatal diagnosis of congenital rubella is investigational. Foetal infection can be diagnosed by PCR of amniotic fluid for rubella antigen or culture for rubella virus. Cordocentesis for PCR and to detect rubella specific IgM is not useful since before 22 weeks the foetus is not immunocompetent and even after that appropriate immune response may not occur. Prenatal diagnosis on USG is not reported but, cerebral ventriculomegaly, intracranial calcifications, cardiac malformations, and foetal growth retardation can be looked for in suspected first trimester exposure.

Diagnosis of CRS is by PCR in nasal secretions, urine or CSF. IgM in serum and postnatal persistence of IgG supports the diagnosis of CRS. Imaging studies for periventricular calcifications, leukomalacia or subependymal cystic lesions can be done.

Management Options of Rubella in Pregnancy

Women coming for preconceptional counselling should be tested for susceptibility to rubella by IgG testing:
All women in their first antenatal visit should undergo rubella testing

Test for primary infection in pregnant women exposed to rubella with demonstration of seroconversion or presence of IgM antibody (see Flow chart on next page).

Postexposure prophylaxis with immunoglobulins does not prevent infection or viremia; therefore, not routinely recommended. But, it may be considered for women exposed to rubella in the first 16 weeks of gestation who, under no circumstances would terminate their pregnancy. Suggested dose is 20 ml.

Protection for fetal infection is also not guaranteed.

Women with known immunity when exposed to natural rubella or vaccination may develop asymptomatic re-infection with viremia.

They generally do not have congenital infection in their foetus and risk of CRS is too low to justify pregnancy termination. For the same reason, serological testing for all women exposed to rubella to exclude re-infection is not recommended.

Prevention

Prevention is the key to rubella management in pregnancy. It can be done by universal MMR (mumps-measles-rubella) vaccination of children and selective vaccination of women in childbearing age.

HERPES GENITALIS

INTRODUCTION

Herpes simplex virus (HSV) is important to the obstetrician because it causes neonatal herpes which is a severe viral infection with significant morbidity and mortality.

Causative Agent

HSV is a double stranded DNA virus of the herpes family. In humans there are two serotypes: HSV-1 and HSV-2. HSV-1 primarily causes oropharyngeal infection whereas HSV-2 primarily causes genital herpes; but, both can cause genital herpes with equal severity. 3/4 cases of neonatal herpes infection is caused by HSV-2 while ¼ cases by HSV-1.

Epidemiology

0.5 to 1 per cent of reproductive age group women have clinically evident disease and 25 to 30 per cent have sub-clinical disease with the rate of asymptomatic shedding during pregnancy 11between 0.2 to 7.4 per cent and at the time of delivery 0.1 to 4 per cent. Asymptomatic shedding is episodic and lasts for approximately 1.5 days with less viral load.

Transmission of herpes genitalis virus is via sexual contact or through fomites. Vertical transmission is maximum during intrapartum period via direct contact of the infant with virus infected maternal secretions while passing through the birth canal. The virus gains entry into the foetus through the eyes, upper respiratory tract, scalp and cord. Vertical transmission can also occur rarely by haematogenous dissemination or ascending infection from the cervix. Infection may be transmitted post delivery from contact with infected caregivers.

Clinical Features

Pregnant women may present with any of the three types of presentations as given in the table.

Table 1.4 Clinical presentations of genital herpes

Classification	Criteria
Primary genital herpes	First clinical infection. No pre-existing antibody.
Non-primary first episode	No history of genital tract infection.Positive antibody for the other strain of the virus (HSV-1 or HSV-2)
Recurrent	Prior history of clinical infection. Positive antibody for the same strain of virus causing the present infection.

Primary genital herpes presents with multiple painful vesicles on the vulva, vagina, cervix and urethra between 2 to 14 days of exposure which rupture to form shallow eroded ulcers with erythematous bases resolving in 4 to 6 weeks without scarring. It is accompanied by constitutional symptoms, regional lymphadeno-pathy, dysuria, haematuria, and vaginal discharge; very rarely viral meningitis, encephalitis and hepatitis may occur.

First episode of non-primary infection is characterized by fewer systemic manifestations, lesser pain, briefer duration of viral shedding and more rapid resolution of clinical lesion.

Recurrent genital herpes occurs due to reactivation of the virus lying dormant in the neuronal ganglia. The infection is much milder and shorter with viral shedding lasting an average of only 3 to 5 days.

Many of the times, the maternal infection is asymptomatic or unrecognised, and it may be difficult to distinguish clinically between recurrent and primary genital HSV infections.

Effect of Pregnancy on HSV

Disease course is not altered or severed. As such pregnant women are not at a greater risk of complications.

Effect of HSV on Pregnancy

Primary herpes simplex infection but, not recurrent genital herpes in early pregnancy is associated with an increased rate of spontaneous abortions (50%)⁹, whereas in later pregnancy it manifests as stillbirth, pre-maturity and IUGR.

Foetal Transmission and Prognosis

The transmission rates, and incidence of neonatal herpes depend on the type of infection, e.g. with primary genital herpes it is greatest upto 50 per cent, with non-primary first episode infection it is 33 per cent, with recurrent HSV infection it is 0 to 3 per cent due to pre-existing protective antibodies and with asymptomatic shedding it is only 0.94 per cent. Risk factors for increased intrapartum transmission of HSV are maternal first episode infection with HSV, multiple genital lesions, maternal infection acquired at or just before onset of labour, pre-term delivery, premature rupture of membranes, rupture of membranes for more than 4 hours,⁹ placement of foetal scalp electrodes, prolonged second stage of labour and instrumental vaginal delivery. Infection in utero by haematogenous transmission is rare and may cause skin vesicles or scarring, retinitis or keratoconjunctivitis, microcephaly or hydranencephaly.¹⁰ Routine termination of pregnancy is not recommended if genital herpes occurs during first or second trimester of pregnancy.

Neonatal herpes is a severe viral infection with significant morbidity and mortality especially without antiviral treatment. It is most commonly acquired during intrapartum period with active genital lesions in the mother. It presents within the first 1-2 weeks of life with three distinct syndromes.

Involving mainly the skin, eyes and mouth (45% cases)
CNS symptoms with or without mucocutaneous involvement (35% cases)
Disseminated infections where multiple organs are involved like visceral infection, meningitis, encephalitis with high mortality rates (20% cases).

Infants with topical disease show 100 per cent survival with antiviral treatment; 5 per cent survivors have long-term complications. 85 per cent infants with CNS disease survive; but, 85 per cent of these survivors suffer serious sequel like mental retardation, chorioretinitis and seizures. The risk of serious sequel is more if treatment is delayed, severely affected CNS or multiple recurrences in first six months of life. Disseminated disease results in 20 per cent survival rates; 40 per cent out of them have serious morbidity.

Five per cent of neonatal herpes is acquired in utero by haematogenous transmission which presents at birth or within 24 to 48 hours of life.

Diagnosis

Diagnosis is clinical and confirmed best by PCR of HSV DNA or viral culture from vulva, cervix and anal canal.

Serology is of limited value because of often poor and slow antibody response, pre-existing antibodies and cross-reacting antibodies to both HSV-1 and HSV-2. In primary infection, seroconversion from negative to positive serology in noted in 2 to 3 weeks. Presence of antibody titre in the initial specimen is suggestive of non-primary first episode infection or recurrent infection.

Cytology for demonstration of intranuclear inclusion bodies and multinucleated giant cells in scrapings from base of lesions in Tzanck smear, Wright's staining or Papanicolaou's staining can be done with 20 to 25 per cent false positive rates.

Electron microscopy can demonstrate herpes virus in vesicular fluid and scrapings from the base of an active lesion by negative contrast.

Management

The management options for herpes genitalis mainly aim at prevention of neonatal herpes which is a serious infection with great morbidity and mortality and is as follows:

Management of women presenting with first episode of genital herpes in pregnancy:
- The woman should be managed in association with a genitourinary physician. Screen for other sexually trans-mitted diseases. Treatment with acyclovir is recommended for all women who develop a first episode of genital herpes in pregnancy in doses of 400 mg TDS or 200 mg five times a day for five days. In cases of severe infection the duration of treatment is 7 to 14 days. Life threatening herpes genitalis or herpes encephalitis require intravenous acyclovir 10 mg/kg over 1 hour every 8 hourly for 14-21 days. Acyclovir reduces the duration and severity of symptoms and decreases the duration of viral shedding. Acyclovir is well tolerated in late pregnancy and there are no clinical or laboratory evidence of maternal or foetal toxicity.^11,12
- Consider daily suppressive therapy with oral acyclovir 200 mg QID in the last four weeks of pregnancy (36 weeks of gestation to term) which may prevent genital herpes recurrences at term and the potential of continuous viral shedding to prevent neonatal herpes and reduce the need for caesarean sections. However, there is insufficient evidence to recommend this practice routinely. Moreover, in recurrent genital herpes, transmission to foetus is very low and women may be delivered vaginally.
- Caesarean section is recommended for all women presenting with first episode genital herpes lesions at the time of delivery to reduce intrapartum transmission of infection to the foetus but, is not indicated for women who develop first episode genital herpes lesions during the first or second trimester. Even in the presence of rupture of membranes for more than 4 hours, caesarean section should be done because it significantly decreases the size of viral inoculation to the foetus. For women who present with first episode genital herpes lesions within 6 weeks of the expected date of delivery or onset of pre-term labour, elective caesarean section may be considered at term, or as indicated, and the paediatricians should be informed. For women like this, who opt for a vaginal delivery, invasive procedures like fetal scalp electrode monitoring , foetal blood sampling and instrumental deliveries should be avoided. In these women, intravenous acyclovir given intrapartum to the mother and subsequently to the neonate may reduce the risk of neonatal herpes by minimising maternal viraemia and reducing exposure of the foetus to HSV.
- Earlier it was said that weekly viral cultures should be taken in the last six weeks of pregnancy in women with a history of genital herpes to detect recurrent herpes episodes, both symptomatic and asymptomatic and positive cultures near term were an indication for caesarean section. However, this practice is no longer recommended because antenatal swabbing did not predict the shedding of virus at the onset of labour.¹³
Management of women presenting with a recurrent episode of genital herpes during pregnancy.

For women presenting with recurrent genital herpes lesions at the onset of labour, the risk to the baby of neonatal herpes during vaginal delivery is small (only 0-3%), ^14,15 and should be set against the risks to the mother of caesarean section. Caesarean section to 14prevent this small per centage of neonatal transmission is not cost effective.¹⁶ A recurrent episode of genital herpes occurring at any other time during pregnancy is not an indication for delivery by caesarean section.

Neonates born to mothers with herpes genitalis infection should be observed for the development of neonatal herpes. Cultures should be obtained from the conjunctiva, skin and pharynx at birth and repeated after 24 hours.

Women with prior history of genital herpes can be reassured that in the event of HSV recurrence during pregnancy, the risk of transmission to the neonate is very small, even if genital lesions are present at delivery.^9,11,14,15

Type specific antibody testing to identify women susceptible to acquiring genital herpes in pregnancy as a routine screening has not been found to be cost effective.

Prevention

All women should be asked in their first antenatal visit if they or their male partners have ever had genital herpes. Prevention of herpes genitals in pregnancy in women with no prior history of genital herpes can be attempted by avoiding sexual intercourse at times when their partner with previous history of genital herpes has an HSV recurrence. However, the impact of this intervention is limited because sexual transmission of HSV commonly results from sexual contact during periods of asymptomatic viral shedding.¹⁷ Use of condoms throughout pregnancy has also been proposed.

For prevention of postnatal HSV transmission to the neonate, mothers with symptomatic infection do not need to be isolated from their babies. She should wash her hands carefully before handling the infant and shield the baby from any contact with the vesicular lesions. Breastfeeding is permissible as long as no skin lesions are present on the breasts. Health care workers and family members with active HSV infection, such as orolabial herpes or herpetic whitlow should avoid direct contact between lesions and the neonate.

VARICELLA-ZOSTER VIRUS

INTRODUCTION

Primary infection with Varicella zoster virus (VZV) causes chickenpox and reactivation of latent virus causes shingles (Zoster).

Causative Agent

VZV is a double stranded DNA virus of herpes family.

Epidemiology

Primary VZV infection in pregnancy is uncommon (3/10,000 pregnancies)¹⁸ because 90 per cent of antenatal population is seropositive for VZV IgG antibodies due to infection acquired in childhood.¹⁹

15It is a highly contagious infection transmitted by respiratory droplets, direct personal contact with vesicle fluid, fomites and vertical transmission by haematogenous dissemination of virus across the placenta. Incubation period is 10 to 21 days. The disease is infectious 48 hours before the rash appears and continues until the vesicles crust over 6 to 10 days later. Once infection is acquired, antibodies to VZV develops within 2 weeks and persist for life offering lifelong immunity. Presence of IgG antibody within a week of exposure reflects prior immunity.

Clinical Features

Primary infection of a pregnant women is characterised by fever, malaise and pruritic rash that develops into crops of maculopapules which become vesicular and crust over before healing; first on the trunk and then centripetally to the extremities.

Reactivation of latent virus in the sensory nerve root ganglia after a primary infection causes a vesicular erythematous skin rash in a dermatomal distribution known as herpes zoster or shingles. Shingles in pregnancy does not pose major risk either to the mother or to the baby. It is usually mild and viraemia is uncommon unless immunocompromised. There are no foetal or neonatal risks due to transplacentally acquired maternal antibodies.

Effect of Pregnancy on Chickenpox

In pregnancy chickenpox is associated with greater maternal morbidity and mortality due to varicella pneumonia (10% incidence) whose severity increase in later gestation,²⁰ hepatitis and encephalitis (< 1%). Delivery during the viraemic period is extremely hazardous and maternal risks are bleeding, thrombocytopenia, DIC and hepatitis.

Effect of Chickenpox on Pregnancy

There are no increased risks of spontaneous miscarriages if infection occurs in the first trimester. It is the primary infection which poses risk to the foetus and the newborn.

Foetal Transmission and Prognosis

Presentations in the foetus and newborn vary according to the time when maternal primary infection occurred, and is as follows:

Before 20 weeks of gestation:

Only 1 to 2 per cent of primary maternal VZV infection occurring before 20 weeks of gestation present with foetal varicella syndrome (FVS)^21,22 (previously called congenital varicella syndrome) characterised by one or more of the following: skin scarring in dermatomal distribution; eye defects like microphthalmia chorioretinitis, cataracts; hypoplasia of the limbs distal to the skin involvement; neurological abnormalities like microcephaly, cortical atrophy, mental retardation and dysfunction of bowel and bladder sphincter. FVS doesn't occur at the time of initial foetal infection but results from a subsequent herpes zoster reactivation in utero. It also does not occur if infection occurs 16after 20 weeks of gestation. FVS can be diagnosed prenatally by detailed ultrasound revealing limb deformity, microcephaly or hydrocephalus, soft tissue calcifications and IUGR. VZV DNA can be detected by PCR in amniotic fluid but, only 3.7 per cent of those having VZV infection develop FVS.
After 20 weeks of gestation and before 36 weeks:
1. Primary infection during this period is not associated with adverse foetal effect but, may present as shingles in the first few years of infant life due to reactivation of primary infection in utero.
2. There may be an increased incidence of pre-term labour and delivery due to production of inflammatory mediators.
After 36 week of gestation and immediate postpartum:

Primary maternal infection during this period leads to varicella infection of the newborn which occurs within 10 days of birth. Upto 50 per cent babies are infected and approximately 23 per cent of these develop clinical varicella despite high titres of passively acquired maternal antibodies. Most severe neonatal infection occurs when onset of maternal rash happens 5 days before and 2 days after delivery, resulting in significant morbidity and mortality (30%) of neonates.^23,24 This is because it takes atleast 5 days after the onset of maternal disease for the antibodies to be transferred to the foetus and the disease is infectious from 2 days prior to the onset of rashes.

Prevention

Prevention of primary infection of mother is done as follows:

In a non-immune lady who plans to become pregnant, e.g. a seronegative lady undergoing infertility treatment or coming for preconceptional counselling may be offered vaccination (two doses) with live attenuated varicella vaccine at 4 to 8 weeks interval followed by avoidance of pregnancy for one month after receiving each vaccine with appropriate contraceptive method. Otherwise, they may be advised to avoid contact with chickenpox.
In a pregnant lady who has come for her first antenatal visit, inquire about previous history of chickenpox. If no such history is present, advise to avoid contact and report immediately if exposure occurs.
In a pregnant lady with a history of contact with chickenpox, a careful history should be taken to confirm (i) the certainty of infection and infectiousness, e.g. a vesicular rash or rash within 48 hours of contact. (ii) the significance of contact or the degree of exposure, e.g. household or face to face contact for atleast five minutes or indoor contact for more than fifteen minutes or for that matter, any close contact during the period of infectiousness. (iii) the susceptibility of the patient e.g. she is immune if past history of chickenpox is present or if no such definite history is present but, her serum is positive for VZV IgG antibodies.

Prevention of chickenpox in a pregnant lady with history of contact with chickenpox is as follows:

Management Options for Chickenpox in Pregnancy

Management for mother:
- Initial management on OPD basis.
  - –Report to the doctor immediately because varicella in pregnancy is associated with serious complications like pneumonia, hepatitis and encephalitis.
  - –Avoid contact with other pregnant ladies and neonates until 5 days of onset of rash or until the lesions have encrusted.
  - –Symptomatic treatment with antipruritic, analgesics and hygiene to prevent secondary bacterial infection of the lesions.
  - –Oral acyclovir, (800 mg orally five times a day for 5 to 7 days) after an informed consent is started within 24 hours of onset rash if pregnancy is of > 20 weeks of gestation. It reduces the duration of fever and symptoms of VZV infection.25 Data to support its role on serious complications like pneumonia is insufficient. No adverse foetal or neonatal effect of oral acyclovir in pregnancy has been reported.
  - –VZIG has no therapeutic benefit once chickenpox has developed.²⁶
- 18Hospital referral is required if the lady develops chest symptoms, neurological symptoms, haemorrhagic rashes, significant immunosuppression, patient is a smoker, has chronic lung disease, taking steroids or is in the latter half of her pregnancy even in the absence of complications.²⁶ In the above conditions and delivery during the viraemic period, the patient may be given supportive treatment with mechanical ventilation and intravenous acyclovir (500 mg/m² or 10-/kg 8 hourly for 7 days) or vidarabine (Ara-A 10 ml/kg over 15 m to 12 hrly for 5 days) to prevent maternal and foetal morbidity and mortality.
Management for foetus or neonate:
- If maternal primary infection occurs before 20 weeks of gestation:
  - –Inform mother of 1 to 2 per cent risk of FVS and its implications.
  - –There is no conclusive evidence that VZIG given within 24 hours of contact prevents intrauterine infection in pregnant lady who has developed varicella despite VZIG.
  - –Detailed USG for evidence of FVS at 16 to 20 weeks of gestation or at 5 weeks after infection is done. If abnormality is detected on USG, choice of termination of pregnancy may be offered, but this cannot be routinely advised as all abnormal sonographic findings may not preclude a favourable outcome. However, presence of a limb abnormality is associated with poor prognosis (50% are brain damaged) and some patients choose MTP.
  - –Neonatal ophthalmic examination after birth.
  - Neonatal blood examination for IgM antibodies and follow up after 7 months for VZV IgG antibodies.
- If maternal primary infection occurs at term:
  - –If possible delay delivery until 5 days after the onset of maternal rash with tocolytics to allow passive transfer of antibodies.
  - –If delivery occurs within 5 days of maternal infection or the mother develops chickenpox within 2 days of giving birth, administer VZIG 125 U to the newborn and observe for the signs of infection for 14 to 16 days. VZIG does not prevent neonatal infection but decreases its severity.
  - –Isolate the infant from the mother until all vesicles are encrusted.
  - –Breastfeeding is permissible in the absence of vesicles on the nipples.
  - –If neonatal infection occurs, treat with acyclovir. VZIG is of no benefit once neonatal chickenpox has developed.²⁶

Herpes zoster requires no specific treatment in pregnancy. It is not associated with adverse foetal or maternal outcomes, which would justify the routine use of acyclovir except, for patients with zoster involving the ophthalmic branch of the trigeminal nerve to reduce the risks of serious ocular and central nervous system complications.

Prevention of Spread of Infection

If a neonate is exposed within the first 7 days of life; no due to passively acquired maternal antibodies; administer VZIG to the neonate if the mother is non-immune or if the baby is premature or very low-birth weight. The mother does not require VZIG 19because she is no longer a high-risk for complications of chickenpox once she has delivered; acyclovir prophylaxis may be considered for her as it provides some protection from the infection with an associated reduction in the chance of transmission to the newborn.

Non-immune health workers who are exposed to the infection should be warned that they may develop chickenpox and therefore minimise patient contact from day 8 to 21 post contact. VZIG is not recommended for exposed non-immune health workers.

HUMAN PARVOVIRUS B19 INFECTION

CAUSATIVE AGENT

Human parvovirus B19 is a small (20-25 nm diameter with 5.5 kilo base genome) single stranded DNA virus of genus parvoviridae.

Epidemiology

Parvovirus infection is usually a disease of children of elementary school age. Outbreaks are usually in spring. Fifty per cent of women by the childbearing age are already seropositive and therefore immune to the infection.²⁷ Rest 50 per cent are susceptible, especially those who work at day care centres or primary schools.

Parvovirus infection is transmitted through respiratory droplets and infected blood components and fomites. Incubation period is 4 to 20 days. Serum and respiratory secretions are infective several days prior to onset of clinical symptoms. Once symptoms appear, respiratory secretions and serum are free of virus, as antibodies have already formed. Symptoms occur due to immune complex formation.

Clinical Features

Parvovirus infection in 25 per cent pregnant women is asymptomatic. Others may present with erythema infectiosum or fifth disease; most commonly low grade fever, malaise, adenopathy, polyarthritis and arthralgia of hands, wrists and knees²⁸ and occasionally characteristic pruritic erythematous “slapped cheek” rash on the face and finely reticulated erythematous rash on the trunk and extremities. It is usually self limiting with no serious long-term sequel. Patients with chronic haemolytic anaemias such as thalassaemia or sickle cell disease may present with a transient aplastic crisis due to destruction of the red cell precursors. Overall risk of parvovirus infection in pregnancy is 1 to 5 in 1000 pregnancies. The probability of infection is based on the prevalence of seronegativity in reproductive age population (50%), occupational risk of infection (20% for teachers, 30% for day care personnel), and the risk of foetal infection if the mother develops the disease (10%).

Pathogenesis

Parvovirus B19 has a predilection for the haematopoietic system by binding to a specific cellular receptor, erythrocyte P antigen, thus destroying the erythroid progenitor cells. It also infects the endothelial cells and the myocardium.

Foetal Transmission and Prognosis

Parvovirus B19 infection in foetus present as non-immune hydrops with ascites, pleural and pericardial effusions and subcutaneous oedema due to destruction of the foetal erythroid stem cells, resulting in aplastic anaemia and high output congestive heart failure. Also infection of myocardium results in myocarditis and congestive heart failure.²⁹ Non-immune hydrops may lead to intrauterine death especially when the foetal affection is severe and in early gestation; before 20 weeks.

Risk of foetal infection is greatest if the maternal illness occurs in the first trimester (19%). Between 13 to 20 weeks gestation 15 per cent foetus are infected and in more than 20 weeks gestation around 6 per cent. Affection of foetus is most common between 16 to 28 weeks gestation because this is a period of very active erythropoiesis causing red cell aplasia; foetal immune system is relatively immature before 22 weeks of gestation with inability to produce significant foetal IgM response; maternal IgG antibodies cross the placenta most readily in the third trimester; during the third trimester red cells begin to contain more adult type haemoglobin and less of foetal haemoglobin thus, red cell life span is longer. Teratogenecity of parvovirus infection has not been clearly established but, has rarely caused ocular abnormalities detected in abortus. The risk of foetal growth restriction may be slightly increased.

Neonates born to parvovirus B19 infected mothers rarely present with hepatic disease, transfusion dependent anaemia, myocarditis, CNS abnormalities like arthrogryposis, ventriculomegaly, periventricular calcifications and cerebral atrophy. Long-term prognosis of neonate is usually excellent.

Diagnosis

Serological testing is recommended in pregnant women with nonspecific flue like syndrome with rashes or joint pains, those with foetal hydrops with no other obvious cause, who had contact with children with erythema infectiosum or have abnormally raised maternal serum alpha-fetoprotein in absence of other causes (marker of hydrops foetalis associated with parvovirus infection). Maternal serum IgG and IgM should be done. IgM appears by the third day of symptoms and typically disappears by 30 to 60 days, but, may persist upto 120 days. IgG antibodies appear by day seven of illness and persist for life, offering life long immunity. Immuno-compromised women may not mount an antibody response to the virus and PCR testing may be necessary to determine infection.

Diagnosis of foetal affection is by ultrasound examination for the development of hydrops. Since the incubation period may be longer in the foetus and most IUDs occur within 6 to 8 weeks of infection, serial weekly ultrasounds for 8 to 10 weeks after acute illness in mother should be done to see the development of hydrops. On development of hydrops, cordocentesis is to be done to detect foetal anaemia. PCR on foetal blood can be done to detect parvovirus antigens or characteristic nuclear clearing and inclusions in nucleated RBCs can be seen. Cordocentesis to detect IgM antibodies is not useful because it may not be positive before 22 weeks of pregnancy after which, foetus becomes immunocompetent or even after that immune response may not be mounted.

21It is routinely not required to determine foetal infection with invasive testing like cordocentesis or amniocentesis for PCR testing of parvovirus DNA because, only infection without hydrops has no adverse sequel on the foetus.

Management Options for Parvovirus B19 Infection in Pregnancy

Intrauterine blood transfusion with packed red blood cells in hydrops foetus with anaemia and low reticulocyte count prevents intrauterine death and mostly causes resolution of foetal 22hydrops.³⁰ A single transfusion to raise the foetal haematocrit to 45 per cent may suffice because foetal red blood cell aplasia is transient and related to the period of viraemia. The foetus should further be followed up with biophysical profile. Hydrops with anaemia and high reticulocyte count suggests resolution stage of transient marrow aplasia and hydrops may resolve without transfusion. Current status of digitalisation to counteract myocarditis induced hydrops is unknown. Maternal administration of intravenous immunoglobulin has been proposed as an alternative to foetal transfusion but no guidelines have been set yet.

Parvovirus infection in the mother is usually self limiting without serious sequel. They may not require anything more than supportive care. No antiviral drug is available till date.

Prevention

Recombinant vaccine is being currently developed for all children, susceptible adult women before or during pregnancy and patients with chronic haemolytic anaemias. Passive immunity with immunoglobulin has not been used to prevent or treat perinatal infection. It could be considered for susceptible pregnant women who have been exposed to parvovirus infection.

Isolation for newborn has no role in reducing transmission because, spread of respiratory droplets has already occurred by the time the patient has clinical symptoms.

Universal antenatal screening for parvovirus B19 is not recommended. Avoiding exposure to infected individuals is desirable but, quitting or changing occupation from daycare centres or schools is not justified because, infection in a women of unknown serologic status is very low and during epidemic period, exposure is likely to have occurred before realisation.

Indian Scenario of Viral Infections in Pregnancy

In a survey of 380 serum samples collected from pregnant women having bad obstetric history from Mumbai demonstrated IgM positivity in 26.8 per cent for rubella, 8.42 per cent for CMV and 3.6 per cent for HVS- 2.³¹

In a study on 1026 asymptomatic healthy pregnant women and 892 women with obstetric complications, it was found that 13.93 per cent of asymptomatic pregnant women, while 18.27 per cent of women with obstetric complications were positive for CMV specific IgM antibodies. These seropositive women presented with inevitable abortion in 16.83 per cent, IUD in 28.85 per cent, premature delivery in 10 per cent and IUGR in 7.14 per cent.³²

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Chapter Notes

Viral Infections in PregnancyCHAPTER 1