Viral Infections in Pregnancy & Neonate: Questions

a. Oral valganciclovir for 6 months (intravenous ganciclovir if oral therapy is not tolerated). Treating central-nervous-system-involved symptomatic disease improves hearing and neurodevelopmental outcomes.

b. Neutropenia; the full blood count is monitored through the course.

c. Asymptomatic infants, and those with isolated hearing loss without other disease, are generally not treated, because the benefit does not outweigh the toxicity; the decision is specialist-led.

• Maternal first-episode (primary) genital infection near delivery: the single biggest factor, with transmission of ~30 to 50% against ~3% for recurrent disease.
• Absence of protective maternal antibody: a primary infection means little or no transplacental antibody to protect the infant.
• Viral shedding or active genital lesions at the time of vaginal delivery.
• Prolonged rupture of membranes (beyond about 4 to 6 hours).
• Breaches of the infant’s skin barrier, notably the use of fetal scalp electrodes or instrumental delivery.
• Prematurity, which compounds the newborn’s vulnerability.

A complete answer contrasts vaccine availability, the window of risk and the maternal infections that transmit, then draws the preventive implication.

Congenital rubella. Rubella is vaccine-preventable and near-eliminated wherever coverage is high. Fetal damage follows maternal primary infection in the first trimester, so prevention is achieved by immunising women before pregnancy.

Congenital CMV. CMV has no licensed vaccine, transmits throughout gestation, and follows both primary and non-primary maternal infection. Where rubella is controlled, CMV is now the commonest congenital viral infection.

Implication. Without a vaccine, CMV prevention rests on hygiene counselling of seronegative pregnant women rather than on the pre-pregnancy immunisation that controls rubella.

Differential diagnosis. The absent rash does not exclude neonatal herpes: up to a third of central nervous system disease never shows vesicles, and a second-week onset with seizures and hepatitis fits central nervous system or disseminated herpes. Bacterial sepsis and meningitis must be covered. Neonatal enteroviral and parechoviral infection produces an almost indistinguishable sepsis-like picture with hepatitis and coagulopathy. Disseminated cytomegalovirus and an inborn error of metabolism complete the list.

Investigations. Herpes simplex virus polymerase chain reaction on blood and cerebrospinal fluid, and on surface swabs (mouth, conjunctivae, nasopharynx, rectum) and any lesion; a lumbar puncture is mandatory, and a negative cerebrospinal fluid result does not exclude the diagnosis. Enterovirus and parechovirus polymerase chain reaction on cerebrospinal fluid, sent even without pleocytosis. Blood culture and the standard sepsis screen. Liver transaminases and coagulation studies to define disseminated disease. Cytomegalovirus urine polymerase chain reaction. Neuroimaging for central nervous system involvement. Empirical intravenous aciclovir is started while the results are awaited.

A complete answer describes the clinical association, the biological mechanism and the determinants of risk.

The association

The 2015 to 2016 American epidemic was accompanied by a marked rise in infants born with microcephaly, first recognised in north-east Brazil, which drew the link between maternal Zika infection and congenital brain injury and prompted a WHO public health emergency in 2016.

Congenital Zika syndrome

Microcephaly is the hallmark of a broader congenital Zika syndrome that also includes intracranial calcification, ventriculomegaly, ocular lesions such as macular scarring, congenital contractures and sensorineural hearing loss, with later neurodevelopmental impairment; infection can also cause miscarriage and stillbirth.

Mechanism

Zika virus has a tropism for fetal neural progenitor cells, in which it impairs proliferation and causes cell death, interrupting cortical development; the placenta and fetal tissues sustain the infection that seeds the fetal brain.

Determinants of risk

The risk is greatest with infection in the first trimester, though injury can follow later infection. Because about 80% of maternal infections are asymptomatic, exposure is often unrecognised, which is why maternal serology and fetal ultrasound surveillance are central to management.

A complete answer marshals the epidemiological, virological and biological lines of evidence that together establish causation rather than mere association.

Epidemiological evidence

The temporal and geographic coincidence of the microcephaly surge with the wave of Zika transmission, the sharp rise above expected baseline rates, and the reproduction of the association across affected regions and in later outbreaks support a causal link. The greatest risk with first-trimester infection provides a biological gradient consistent with a teratogen.

Direct virological evidence

Zika viral RNA and antigen have been detected in the amniotic fluid, fetal brain tissue and placenta of affected pregnancies, and virus has been recovered from the brains of infants with microcephaly, placing the virus at the site of injury.

Biological plausibility

Zika virus infects and kills neural progenitor cells in cell and animal models, and infection of pregnant animals reproduces fetal brain injury, providing an experimental mechanism.

Judgement

Applying causal criteria of strength, consistency, temporality, biological gradient, plausibility and experimental support, the evidence is judged sufficient to conclude that Zika virus infection causes congenital microcephaly and the wider congenital Zika syndrome.

A complete answer names the responsible genotypes, quantifies the maternal and fetal risk, and gives the leading explanations for the severity.

The clinical problem

The waterborne genotypes 1 and 2 acquired in the third trimester can progress to fulminant hepatic failure. Genotype 1 is the most common and best-documented cause, but genotype 2 also poses a severe threat, with high maternal mortality and miscarriage rates reported during outbreaks. Maternal case-fatality in outbreak settings is high, in the order of 20 to 30%, far exceeding the mortality of hepatitis E in non-pregnant adults or of other acute viral hepatitides in pregnancy. Fetal and neonatal outcomes are also poor, with high rates of miscarriage, stillbirth, premature delivery and vertical transmission. This severity is a feature of the genotype 1 and 2 epidemics of Asia and Africa; the zoonotic genotype 3 of high-income settings does not show the same risk in pregnancy.

Proposed mechanisms

The reason for the exaggerated severity is not fully settled, but several contributing factors are recognised:

• Higher viral replication: pregnant women with hepatitis E tend to have higher HEV viral loads.
• Hormonal influence: the high oestrogen and progesterone levels of pregnancy modulate viral replication and the immune response.
• Immune adaptation of pregnancy: the shift away from a T-helper-1 response that protects the fetus may blunt antiviral immunity, allowing more severe hepatic injury.

Hepatitis E is therefore an important cause of maternal mortality during outbreaks, and supportive care with prompt recognition of acute liver failure is essential, since ribavirin is contraindicated in pregnancy.

Parvovirus B19 uses the blood group P antigen to infect erythroid progenitor cells, halting fetal red-cell production. The resulting severe anaemia causes high-output cardiac failure and non-immune hydrops. The fetus is monitored with serial ultrasound and middle cerebral artery Doppler, which detects the anaemia before hydrops is established; intrauterine red-cell transfusion takes survival in severe hydrops from near zero to over 80%. Post-exposure immunoglobulin is not recommended, because the maternal viraemia has usually passed by diagnosis.

Every infant of an HBsAg-positive mother receives both the hepatitis B vaccine and hepatitis B immunoglobulin within 12 hours of birth, combining active and passive immunisation, with the vaccine course then completed on schedule. Hepatitis B is transmitted predominantly at delivery: an HBeAg-positive mother transmits to 80 to 90% of infants without prophylaxis, and infection at birth becomes chronic in about ~90% of cases. Caesarean section is not indicated to prevent transmission.

Treatment is decided by phenotype. Any central nervous system involvement, defined broadly to include abnormal neuroimaging, microcephaly, chorioretinitis or hearing loss, is treated for six months; symptomatic disease without central nervous system involvement is treated for six weeks. The drug of choice is oral valganciclovir at 16 mg/kg per dose twice daily, started before four weeks of age. A randomised trial established that six months preserves hearing and neurodevelopment better than six weeks. Asymptomatic infants with normal hearing are not treated.

Saliva is easy to collect but prone to a false positive from cytomegalovirus in breast milk retained in the mouth, so a positive saliva result is confirmed on urine, which is the specimen of choice, and saliva is collected at least one to two hours after a feed. Virus must be detected within the first three weeks of life to prove congenital infection, because after three weeks acquisition through the birth canal or breast milk can no longer be excluded.

A first (primary) genital infection acquired late in pregnancy leaves no time for the mother to make and transfer protective antibody, so the infant attack rate is ~30 to 50%. A recurrence in a woman with established antibody carries a rate of only ~3%. Around ~85% of neonatal herpes is acquired from the maternal genital tract at delivery, and about ~90% of mothers who transmit have no recognised history of genital herpes, so a reassuring history does not exclude the risk.

Varicella-zoster immunoglobulin, given as soon as possible and ideally within 96 hours of exposure, is the mainstay for high-risk susceptible contacts: susceptible pregnant women, the immunocompromised, and neonates whose mothers develop varicella around delivery.

The live vaccine is contraindicated in pregnancy, and immunoglobulin attenuates rather than always prevents disease.

Oral valaciclovir, 8 g a day, started before 16 weeks for a first-trimester or periconceptional primary infection, reduces transmission to the fetus (odds ratio ~0.37) and shifts the balance towards milder, asymptomatic infection. It is continued until a negative amniotic-fluid result. Cytomegalovirus hyperimmune globulin, by contrast, does not work: two randomised trials found no benefit and it has been abandoned. Ganciclovir and valganciclovir are neonatal, not maternal, treatments.

The classic congenital rubella triad is sensorineural deafness, cataracts and congenital heart disease (typically patent ductus arteriosus or branch pulmonary artery stenosis). The risk falls steeply through gestation: maternal rubella with rash in the first 12 weeks transmits in 70 to 85% and causes the full syndrome, while the teratogenic risk is negligible after 17 weeks. Deafness is the commonest isolated defect. Rubella is vaccine-preventable, the key contrast with cytomegalovirus.

First-trimester infection carries the highest risk, and microcephaly is the hallmark, accompanied by intracranial calcification, ventriculomegaly, ocular lesions, contractures and hearing loss; infection can also cause miscarriage and stillbirth.

The other combinations misstate the timing or the pattern of injury.

Transmission to the fetus rises steadily through gestation, from ~9% for a periconceptional infection to ~40% in the third trimester, while the severity of damage moves the opposite way: severe neurological injury follows almost only first-trimester infection, and after the first trimester the risk falls sharply and is largely limited to hearing loss. A virus acquired late is therefore more likely to reach the fetus but far less likely to harm it seriously.

Detecting the virus by polymerase chain reaction (PCR) on urine or saliva within the first 21 days of life confirms congenital infection. After 21 days a positive result cannot be separated from the common, benign infection acquired around birth, so the timing of the sample is what makes the diagnosis. A retrospective dried blood spot, the stored newborn screening card, is the fallback when a child presents late.

Neonatal IgG reflects transplacental maternal antibody; maternal IgM does not confirm fetal infection; cord blood is prone to maternal contamination; and culture is slower and less sensitive than PCR.

A primary infection in a seronegative woman carries the highest per-event risk of transmission, but pre-existing immunity does not fully protect, because a seropositive woman can transmit through reactivation or reinfection with a new strain. Because the seroimmune population is so large, about two-thirds of congenital cytomegalovirus arises in already-immune mothers, each pregnancy carrying a low individual risk. Once the fetus is infected, primary versus non-primary infection no longer predicts severity.

In a Gauteng cohort, congenital cytomegalovirus was commoner in HIV-exposed than HIV-unexposed neonates (~5.2% against ~1.4%), and a congenitally infected HIV-exposed neonate carried roughly a twentyfold higher risk of acquiring HIV in utero, independent of maternal CD4 count or treatment duration. A positive cytomegalovirus result in this setting therefore flags a pregnancy at high risk of vertical HIV transmission, rather than confirming infant HIV in itself.

When the maternal rash appears from five days before to two days after delivery, the infant is exposed to virus without transferred maternal antibody, and neonatal varicella then carries a mortality of 23 to 30%. A rash more than five days before delivery allows antibody to transfer and the illness is usually mild. First-trimester infection causes congenital varicella syndrome, a different disease. Varicella-zoster immunoglobulin is given to the newborn whose mother develops chickenpox in this peripartum window.

Sensorineural hearing loss is the commonest long-term consequence of congenital CMV and the leading non-genetic cause of childhood hearing loss. It may be present at birth or have delayed, progressive onset over the first few years, so infected infants need audiological follow-up even when they appear normal at birth and even when the infection was asymptomatic.

Cataract and patent ductus arteriosus point to congenital rubella; limb reduction defects suggest varicella; cleft palate is not a CMV sequela.

Amniotic-fluid polymerase chain reaction works because the infected fetus excretes virus in its urine into the amniotic fluid, so two intervals must both be met: at least 6 to 8 weeks after the maternal infection, and from about 17 weeks of gestation, by which time placental transfer and fetal renal excretion have occurred. Under those conditions sensitivity is 90 to 95%; the residual false-negative rate of ~8% falls mainly on fetuses without injury.

Congenital varicella syndrome follows maternal chickenpox in the first or, less often, second trimester, and is thought to represent a zoster-like reactivation in the infected fetus, which explains its dermatomal pattern. Its signature is cicatricial scarring of the skin in a dermatomal distribution with hypoplasia of the underlying limb, accompanied by eye and brain defects and, in 15 to 23%, gastrointestinal malformations. Periventricular calcification with deafness suggests cytomegalovirus, and cataracts with heart disease suggest rubella.

Neonatal herpes takes three forms: skin, eye and mouth (~45%); central nervous system (~30%); and disseminated (~25%). The absence of a rash is treacherous, because up to a third of babies with herpes encephalitis never develop skin vesicles, and vesicles may also be absent in disseminated disease. Disease in the first 72 hours points away from herpes; central nervous system disease typically appears in the second to third week. The diagnosis must therefore be considered in any neonate with seizures, unexplained sepsis or hepatitis even when the skin is clear.

Diagnosis in the infant is virological, not serological. Maternal IgG crosses the placenta, so a positive IgG in a newborn usually reflects the mother’s past exposure rather than the baby’s own infection, and finding it is neither diagnostic nor reassuring. Neonatal diagnosis therefore rests on detecting the virus itself by polymerase chain reaction on the right specimen, urine and saliva for cytomegalovirus, within the first three weeks of life.

a. Zika virus infection. The mild febrile illness with rash, arthralgia and non-purulent conjunctivitis after travel to an endemic region is characteristic (dengue and chikungunya are the main differentials).

b. Reverse-transcriptase PCR on blood and urine (urine has a longer detection window), with serology if presentation is later; the key pitfall is strong flavivirus cross-reactivity, so a positive IgM needs confirmation by plaque-reduction neutralisation and interpretation is harder with prior flavivirus exposure.

c. The concern is congenital Zika syndrome, particularly microcephaly, greatest after first-trimester infection; monitoring is by serial fetal ultrasound, with amniotic-fluid testing where indicated and paediatric assessment of the neonate.

d. Because Zika persists in semen and is sexually transmitted, the partner should use condoms or abstain for the recommended period to avoid re-exposing her during the pregnancy.

A complete answer contrasts the two on transmission rate, on severity once the fetus is infected, and on their relative contribution to the overall burden.

Primary maternal infection. A first infection in pregnancy carries the highest vertical transmission, around 30 to 40% across the trimesters, because the mother has no pre-existing immunity to limit viraemia.

Non-primary infection. Reactivation or reinfection in an already-immune woman transmits far less often, of the order of 1%, because pre-existing maternal immunity is substantially protective.

Severity and the absolute burden. Once the fetus is infected, the type of maternal infection no longer reliably predicts the outcome: symptomatic disease at birth and long-term sequelae are broadly similar either way, and about 10 to 15% of infected infants are symptomatic at birth. Because seropositive women so greatly outnumber those having a first infection, most congenitally infected infants are born to immune mothers despite the low per-pregnancy risk, so non-primary infection contributes a large share of the absolute caseload where seroprevalence is high.

• Keep a high index of suspicion, even without skin vesicles: around a third of central-nervous-system and disseminated cases have no rash, so the diagnosis must be considered in any septic-looking neonate.
• Surface swabs from the conjunctivae, mouth, nasopharynx and rectum for HSV polymerase chain reaction (PCR) and culture.
• Swab or scraping of any skin or mucosal lesion for HSV PCR (and culture); direct immunofluorescence is faster but less sensitive.
• Cerebrospinal fluid HSV PCR in every suspected case (lumbar puncture even when disease looks confined to skin, eye and mouth), as PCR is the test of choice for central-nervous-system involvement.
• Whole blood or plasma HSV PCR to detect viraemia. Serology is not helpful at presentation, and a persistently positive cerebrospinal-fluid PCR at the end of treatment guides extending therapy.

A complete answer explains what avidity measures, how it changes after primary infection, and how that dates the infection.

What avidity measures. Avidity is the strength with which IgG binds its antigen. Antibody from a recent primary infection binds weakly (low avidity) and matures to high avidity over about the following six months as germinal-centre affinity maturation proceeds.

How it dates the infection. Low-avidity CMV IgG in early pregnancy indicates a primary infection within roughly the preceding three to four months, the window of highest risk for fetal transmission. High-avidity IgG indicates a past infection and a much lower risk to the fetus.

Why it matters. Avidity resolves the ambiguity of a positive CMV IgM, which can persist for months or be falsely positive, and so helps avoid unnecessary intervention when the infection is in fact long-standing.

• First-episode genital herpes: treat the episode with oral aciclovir or valaciclovir, or intravenous aciclovir if disease is severe.
• Suppressive aciclovir or valaciclovir from 36 weeks of gestation, which reduces recurrences and viral shedding at term and so lowers the need for caesarean section and the risk of neonatal transmission.
• Mode of delivery: caesarean section if there are active genital lesions or prodromal symptoms at the onset of labour, particularly with a first episode near term; vaginal delivery is acceptable when no lesions are present.
• Severe or disseminated maternal disease (for example HSV hepatitis) is a medical emergency treated with intravenous aciclovir. Aciclovir is regarded as safe in pregnancy.