Congenital and Perinatal Infections: Throwing

New Light with an Old TORCH

Gupta Ashutosh
DM – Medical Genetics (SGPGI)
• Congenital infections in the neonate can lead to significant morbidity and mortality.
• “ToRCH,” first described in 1971
• Perinatal infections Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and
herpes simplex virus (HSV) (Nahmias 1971).
• “O” in “TORCH” has expanded to “Other” and includes hepatitis B virus (HBV),
varicella zoster virus, and HIV, among others.
• Recognition of these congenital infections must be diagnosed early to provide
prevention and treatment strategies that improve the newborn’s prognosis.
• Transmission of congenital infections may occur in utero, peripartum, or after
delivery, and clinical manifestations of the infection may vary depending on the time
of transmission
CMV Demographics
• Most common congenital infection worldwide – ~ 1% of live births (0.3-2.4%
worldwide)
• Congenital CMV is most common infectious cause of intellectual impairment,
sensorineural deafness, and visual impairment
• II gravida; Autoinoculation
• Incidence of primary infection in pregnancy up to 2.2%
• 40% vertical (transplacental) transmission rate to fetus
• 75-80% transmission rate if primary infection in 3rd trimester
• Nonprimary infection rate in pregnancy (Reactivation of previous infection) 5%
• Vertical transmission rate of 5-10%
• Affected infants generally asymptomatic at birth but at risk for developing mild visual,
auditory, developmental deficits
 Ultrasonographic Findings
• Ventriculomegaly (moderate to severe in 45%)
• Abnormal periventricular echogenicity ; Intraventricular adhesions
• Calcifications (Nonshadowing) – Echogenic intraparenchymal foci; periventricular, cortical, in basal ganglia
• Intraparenchymal cysts – Periventricular, anterior temporal, occipital, frontoparietal – In children, anterior
temporal cysts with associated white matter disease is particularly suggestive of CMV infection
• Microcephaly (27% of infants with congenital infection)
• Cortical dysplasia
• Cerebellar/cisterna magna abnormalities (cerebellar volume loss in 67% of infants with congenital
infection)
• Signs of lenticulostriate vasculopathy – Uni-/bilateral curvilinear echogenic streaks within basal ganglia,
thalami
• Hepatosplenomegaly
• Cardiomyopathy, nonimmune hydrops
• Foetal growth restriction (FGR)
Congenital CMV infection
shows macular "blueberry
muffin" spots consistent
with extramedullary
hematopoiesis.
CMV infection is
associated with abnormal
erythropoiesis and
hemolytic anemia. (Right)
PSV MCA - 112 cm/sec.

Fetus with
hepatosplenomegaly from
CMV infection shows a
large liver & spleen.
Extramedullary
hematopoiesis secondary
to fetal anemia.
Liver markedly enlarged
with numerous white
areas from hepatic
necrosis
Periventricular; basal ganglia
calcifications; cortical dysplasia
regions of edema,
demyelination, gliosis.
Congenital CMV infection -
periventricular calcifications;
Multiple linear calcifications
along lenticulostriate vessels.

Irregularly shaped
parenchymal cyst In the right
temporal lobe;
ventriculomegaly and
multiple periventricular and
intraparenchymal
calcifications
• Diagnosis of primary maternal CMV infection
• Initial serology for CMV often difficult to interpret
• IgM may remain positive for up to 1 year after acute infection
• IgM may become positive in face of reactivation infection
• If suspected maternal infection,
• Test for CMV-specific IgM, IgG and IgG avidity
• IgG avidity is low in setting of acute infection
• IgG avidity is high in setting of recurrent or reactivated infection
• Development of CMV-specific IgG in previously seronegative woman or detection of specific CMV
IgM antibody associated with low avidity CMV IgG
• Diagnosis of secondary maternal CMV infection
• Should be based on significant rise of IgG antibody titer ± presence of IgM and high IgG
avidity
Amniocentesis for diagnosis of fetal infection
• Takes 5-7 weeks following fetal infection for detectable quantity of virus to
be secreted into amniotic fluid
• If ultrasound is suggestive of fetal CMV infection, offer amniocentesis even
if maternal serology does not support recent seroconversion
• PCR; Viral load in maternal blood, amniotic fluid, and fetal blood important
prognostic factors
• Risk-benefit ratio of amniocentesis with secondary maternal infection
different because of lower vertical transmission rate (5-10%)
• Treatment with hyperimmune globulin is under investigation
• Absence of sonographic findings does not guarantee normal outcome
• CMV vaccine research
• Phase II trials for vaccinations have shown almost 50% efficacy for preventing maternal
seroconversion; however, immunization waned over time (Bernstein 2016; Pass 2009). Additional
vaccination trials are ongoing (ClinicalTrials.gov trial registry NCT02594566, NCT02396134,
NCT02506933, and NCT01877655).
• IV ganciclovir 6 mg/kg/dose every 12 hours with enteral valganciclovir 16 mg/kg/dose every 12
hours. A recent randomized trial showed that neonates of at least 32 weeks’ gestation and
weighing at least 1800 g receiving 6 months of enteral valganciclovir had a 2- to 6-fold increased
likelihood of improved total hearing at 24 months of age compared with those who received only
6 weeks of enteral valganciclovir followed by placebo (Kimberlin 2015)
• Preterm infants with congenital CMV infection can have symptomatic, end-organ disease such as
pneumonitis, hepatitis, or thrombocytopenia. Antiviral treatments have not been studied in this
population; thus, recommendations are limited.
DIFFERENTIAL DIAGNOSIS
• Parvovirus - Ascites common presenting finding in fetus ; Fetal hydrops secondary to
anemia
• Toxoplasmosis - Intracranial calcifications ; Liver calcifications and hepatosplenomegaly
• Varicella - Calcifications (liver, heart, renal), skin lesions
• Herpes simplex - Echogenic bowel, ventriculomegaly
• Syphilis - Hepatosplenomegaly, dilated bowel, bowing of long bones, abnormal epiphyses
• HIV - FGR, intrauterine death in severe cases
• Rubella - Cardiac defects, microcephaly, microphthalmia, FGR
• Nonimmune Hydrops - Aneuploidy, anemia, tachydysrhythmia
• Echogenic Bowel - Aneuploidy, gastrointestinal anomalies including bowel obstructions,
cystic fibrosis
Toxoplasmosis General Features
• 3 principal routes of infection in humans
• – Ingestion of inadequately cooked (infected) uncooked meat
• – Ingestion of oocytes from contaminated soil or water / Gardening
• – Transplacental
• Detection of IgM not sufficient to prove recent infection; high titer IgM often detectable for years
• Maternal infection most often asymptomatic; symptoms occur in 10-20% of infected adults
• If immunocompromised, including HIV, may be fatal
• Transplacental passage in HIV-infected women enhanced and may result in higher risk of
congenital infection
• Congenital infection causes classic triad of hydrocephalus, intracranial calcifications,
chorioretinitis
• Fetal death, abortion common
Periventricular;
intraparenchymal calcifications.
Calcifications are nonspecific
NECT - punctate calcifications in
an infant with congenital
toxoplasmosis; periventricular
scattered throughout the
parenchyma; Ventriculomegaly

Heavy calcifications around the

ventricle; generalized
CMV - Only in the ependyma &
periventricular area
Multiple punctate
nonshadowing calcifications in
liver.
• Overall risk of congenital infection without maternal treatment - 20-50%
• I Trimester - 10-15%; Severe / Abortion
• II Trimester - 25%
• III trimester - 60+%
• Host immune response protective but Inflammatory damage
• Sequelae of congenital infection - blindness, epilepsy, intellectual impairment
• Most infected infants asymptomatic at birth; up to 90% develop sequelae
• Effect of prenatal therapy variable – May decrease fetal infection rate or
ameliorate severity of neurologic sequelae
 Fetal varicella syndrome/embryopathy
• Maternal pruritic pustular rash
• Most mild and resolve in 5-10 days
• Elevated MSAFP & AF α-fetoprotein; acetylcholinesterase
• Correlate with fetal skin, muscle, and nerve damage from VZV
• Neonate with fetal varicella syndrome with multiple abnormalities
• Cutaneous lesions in dermatomal distribution, limb hypoplasia/ atrophy,
chorioretinitis, segmental intestinal atresia, varying degrees of neurologic
dysfunction
 Demographics
• Majority of reproductive-aged women (> 90%) immune
• Immunization <13 yrs; Up to 90% effective in preventing chickenpox
• Maternal varicella infection < 20 ~ 6% fetal transmission
• 1/3 of infected fetuses have clinical manifestations, usually cutaneous
• 1-2% of infected fetuses congenital varicella syndrome
• Peripartum - 25% risk of life-threatening neonatal infection
• Imaging
• Intrahepatic and intracranial calcifications
• Polyhydramnios due to neurologic impairment of swallowing
• Limb hypoplasia, contractures
• Paradoxical diaphragmatic motion on real-time sonography due to unilateral
paralysis
 Preterm infant; Polyhydramnios.
Zoster lesion; Ipsilateral
diaphragmatic paralysis; elevated
hemidiaphragm

Multiple nonshadowing
hepatic calcifications;
polyhydramnios.
Terminal transverse limb defect.
The arm was mildly atrophic.
Tiny digital "nubbins"
 Parvovirus
• Adults (maternal)
• Transient, migratory maculopapular rash
• Polyarthritis, polyarthralgia occurs in 60% of symptomatic adults
• Aplastic crisis in immunocompromised, chronic hemolytic anemia
• Children
• "Slapped cheek" rash in children
• Mild febrile illness, upper respiratory symptoms
• Epidemiology
• 30-50% of adult women are nonimmune to parvovirus
• Main reservoir: School-aged children, day care facilities
• Mostly self-limiting
• Immunocompromised - severely ill; Fatal in sickle cell anemia
• Transplacental transmission - 17-33%
• Risk of fetal loss
• 8-17% (< 20-wk); 2-6% (> 20-wk)
• Stillbirth may occur from 1 to 11 wk after maternal seroconversion
• Reports of spontaneous recovery without transfusion in less severe hydrops
• Normal developmental outcome in most children who survive intrauterine
infection with parvovirus,
• Increased risk of neurodevelopmental delays in survivors that required
transfusion
PSV MCA - 90 cm/sec;
Pleural effusion, ascites,
and mildly echogenic
bowel, Parvovirus B19.

Moderate pleural effusion

and cardiomegaly
Fetal blood - hematocrit of 7
and PLT of 10,000.
Histology shows intranuclear
inclusions
IMAGING
• Maternal seroconversion – Fetus at risk for Hydrops
• Ascites most common
• Progression to hydrops in severe cases
• Cardiac failure secondary to severe fetal anemia, myocarditis
• Placentomegaly, polyhydramnios
• PSV MCA - Fetal anemia and predicts potential need for intrauterine
transfusion
Congenital Rubella Syndrome - CRS
• I trimester – 80-100%
• II trimester – 10-20%
• Cellular damage; Progressive necrotizing vasculitis
• Sensorineural deafness- 66%
• Cataracts – 78%
• Cardiac defects – Patent Ductus arteriosus; Pulmonary artery
stenosis; Coarcataion of aorta
Cutaneous and ophthalmologic findings of congenital rubella.
(A) Purpuric “blueberry muffin” rash and (B) Cataracts
Clinical findings associated with selected TORCH infections
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THANK YOU