Viral Infections of the Fetus and Newborn — Questions

• 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.

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.

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.

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.

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.

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.

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.

• 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.

• 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.