TORCH Infections

Natalie Neu, MD, MPHa,*, Jennifer Duchon, b

MDCM, MPH ,
Philip Zachariah, MDb

KEYWORDS
 TORCH  Toxoplasmosis  Treponema pallidum  Rubella  Parvovirus  HIV
 Hepatitis B  Hepatitis C

KEY POINTS
 The TORCH pneumonic typically comprises toxoplasmosis, Treponema pallidum, rubella,
cytomegalovirus, herpesvirus, hepatitis B virus, hepatitis C virus, human immunodefi-
ciency virus and other viruses, including varicella, parvovirus B19.
 These infections are well-described causes of stillbirth and may account for up to half of all
perinatal deaths globally.
 The burden is especially great in developing countries.
 Stigmata of disease may be seen at birth, in the early neonatal period, or later.
 Treatment strategies are available for many of the TORCH infections.
 Early recognition, including maternal prenatal screening and treatment when available, are
key aspects in management of TORCH infections.

INTRODUCTION

Congenital infection is a well-described cause of stillbirths, as well as perinatal

morbidity. TORCH infections classically comprise toxoplasmosis, Treponema pal-
lidum, rubella, cytomegalovirus (CMV), herpes simplex virus (HSV), hepatitis viruses,
human immunodeficiency virus (HIV), and other infections, such as varicella and
parvovirus B19. The epidemiology of these infections varies, and in low-income and
middle-income countries, where the burden of disease is greatest, TORCH infections
are major contributors to prenatal and infant morbidity and mortality (Table 1).1–14
Transmission of the pathogens may occur prenatally, perinatally, and postnatally,
through, respectively, transplacental passage of organisms, from contact with blood
and vaginal secretions, or from exposure to breast milk for CMV, HIV, and HSV. Evi-
dence of infection may be seen at birth, in infancy, or not even until years later,

Disclosure statement: the authors have nothing to disclose.

a
Division of Pediatric Infectious Disease, Columbia University Medical Center, 622 West 168th
Street, PH-468, New York, NY 10032, USA; b Division of Pediatric Infectious Disease, New
York-Presbyterian Morgan Stanley Children’s Hospital, 622 West 168th Street, PH-471, New
York, NY 10032, USA
* Corresponding author.
E-mail address: nn45@columbia.edu

Clin Perinatol - (2015) -–-

http://dx.doi.org/10.1016/j.clp.2014.11.001 perinatology.theclinics.com
0095-5108/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
2 Neu et al

Table 1
Worldwide prevalence estimates of selected TORCH infections

US Prevalence of Seropositivity in Women of Childbearing

Congenitally Agea
Worldwide Acquired Disease in
Prevalence the United States Low Prevalence (%) High Prevalence (%)
Toxoplasmosis 201,000b 10–33/100,000 live 11 (Europe) 77 (South America)
births
Treponema 36.4 million 7.8/100,000 live 0.67 (North America) 10 (Central Africa)
pallidum births
CMV Unavailable 800/1000,000 live 30–50 (United States) >90 (South America)
births
Hepatitis B 240 million <0.1/1000,000 US 1.3 (North America) 8.7 (west sub-Saharan
population Africa)
Hepatitis C 130–150 <0.1/100,000 US 1.2 (North America) >10 (Middle East,
million population Eastern Asia)
HIV 35.3 million 162 infants/y, 2010 0.1 (North America, 12 (Southern Africa)
Western Europe)
a
Women aged 15–49 y.
b
Congenital toxoplasmosis.

because the fetal origins of adult disease are now increasingly recognized. The
infected newborn infant may show abnormal growth, developmental anomalies, or
multiple clinical and laboratory abnormalities. Many of the clinical syndromes for those
viruses that present in the immediate neonatal period overlap, as shown in Table 2.15
Some have classic physical stigmata, as shown in Figs. 1 and 2.16,17 For many of
these pathogens, treatment or prevention strategies are available; early recognition,
including prenatal screening, is key, and recognized national and international stan-
dards and protocols are available to the provider. This article covers toxoplasmosis,
parvovirus B19, syphilis, rubella, hepatitis B virus (HBV), hepatitis C virus (HCV),
HIV; other sections are dedicated to HSV, CMV, and varicella zoster virus.

TOXOPLASMOSIS
Disease Description
The protozoa Toxoplasma gondii is an obligate intracellular parasite, which is ubiquitous
in the environment, and whose only definitive hosts are members of the feline family. The
forms of the parasite are oocysts, which contain sporozoites; these sporozoites divide
and become tachyzoites; tachyzoites localize in neural and muscle tissue and develop
under the pressure of the host immune system into bradyzoites, which congregate
into tissue cysts. These cysts remain in skeletal and heart muscle, brain and retinal tissue,
and lymph nodes. Cats acquire the infection either by consuming tissue cysts from their
prey or ingesting oocysts in soil. Replication occurs in the intestine of the cat, and oocysts
are formed, excreted, and sporulate to become infectious in as little as 24 hours.18–21

Transmission/Pathogenesis
Both animals in the wild and animals bred for human consumption may become
infected from oocysts in the environment. Human infection (other than congenital) oc-
curs by ingestion of the tissue cysts from undercooked or raw meat or oocysts from
contact with cat feces or contaminated food or soil, or from transfusion of blood prod-
ucts or organ transplantation. Three genotypes (I, II, III) of T gondii have been isolated.
 Table 2
Clinical findings associated with selected TORCH infections

Intracranial Hearing
Hepatosplenomegaly Cardiac Lesions Skin Lesions Hydrocephalus Microcephaly Calcifications Ocular Disease Deficits
Toxoplasmosis 1 ( ) Petechiae/purpura, 11 1 Diffuse Chorioretinitis ( )
maculopapular intracranial
rash calcifications
Treponema 1 ( ) Petechiae/purpura, ( ) ( ) ( ) Chorioretinitis, ( )
pallidum maculopapular glaucoma
rash
Rubella 1 Patent ductus Petechiae/purpura 1 ( ) ( ) Chorioretinitis, 11
arteriosus, cataracts,
pulmonary microphthalmia
artery stenosis,
myocarditis
CMV 1 1 Petechiae/purpura ( ) 11 Periventricular Chorioretinitis 11
calcifications
HSV 1 Myocarditis Petechiae/purpura, 1 1 ( ) Chorioretinitis, 1
vesicles cataracts
Parvovirus 1 Myocarditis Subcutaneous ( ) ( ) ( ) Microphthalmia, ( )
B19 edema, petechiae retinal and
corneal

TORCH Infections
abnormalities

Adapted from Remington J, Klein J, Wilson C, et al, editors. Infectious diseases of the fetus and newborn infant. 7th edition. Philadelphia: Elsevier Saunders, 2011;
with permission.

3
4 Neu et al

Fig. 1. Ophthalmologic and cerebral findings of congenital toxoplasmosis. (A) Diffuse intra-
cerebral calcifications and hydrocephalus. (B) Acute retinitis.

Type II is the predominate lineage responsible for up to 80% of congenital infections in

Europe and in the United States. During active parasitemia, the tachyzoite replicates
rapidly and destroys infected cells, causing necrosis, which may then transform into
tissue calcification.18,22,23
Congenital infection results most commonly from the transplacental transmission of T
gondii after maternal primary infection during pregnancy, during a time of high parasite
burden with tachyzoites. However, women infected shortly (3 months) before concep-
tion may also transmit T gondii as a result of persistent parasitemia, which continues into
the pregnancy. In addition, reactivation of toxoplasmosis in immunocompromised
women (ie, women with HIV) may also lead to congenital toxoplasmosis. Infection
with T gondii leads to lifelong immunity; however, it has also been posited that women
may be infected with a different genotype of T gondii during pregnancy.18,20,22–24
As shown in Fig. 3,25 the risk of transmission increases with the date of maternal
infection, from less than 15% at 13 weeks of gestation to greater than 70% at 36 weeks.

Epidemiology
Seroprevalence in pregnant women varies greatly among countries; the highest
prevalence is noted in regions with tropical climates, where the oocysts can survive

Fig. 2. Cutaneous and ophthalmologic findings of congenital rubell. (A) Purpuric “blueberry
muffin rash and (B) Cataracts. (Courtesy of CDC Public Health Image Library.)
 TORCH Infections 5

Fig. 3. Risk of MTCT of T gondii by gestational age at maternal seroconversion (n 5 1721).

Dotted lines are bounds of 95% confidence interval. (From SYROCOT (Systematic Review
on Congenital Toxoplasmosis) study group, Thiébaut R, Leproust S, et al. Effectiveness of
prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients’
data. Lancet 2007;369(9556):118; with permission.)

in soil, as well as countries with dietary customs of raw meat consumption. Seropre-
valence among Brazilian, French women, and women in the United States at child-
bearing age is approximately 77%, 44%, and 11%, respectively. Prevalence of
congenital infection ranges from 0.1 to 0.01 per 1000 live births, with concomitant
decrease in both maternal prevalence and congenital infection as a result of aggres-
sive screening approaches in certain countries.8,18,23,26,27
Clinical Correlation
Most (70%–90%) infants infected with T gondii are asymptomatic at birth; the classic
diagnostic triad of symptoms (chorioretinitis, hydrocephalus, and intracranial calcifi-
cations) is rare but still remains highly suggestive. More common manifestations
include18,22:
 Anemia
 Seizures
 Jaundice
 Splenomegaly
 Hepatomegaly
 Thrombocytopenia
The signs and symptoms of T gondii overlap other TORCH infections; more severe
manifestations usually indicate infection earlier in gestation, whereas fetal infections
occurring in the third trimester are usually subclinical at birth. Newborns who show
mild or no signs and symptoms are still at high risk for development of late manifes-
tations and sequelae of the disease.28,29 These manifestations and sequelae
include:
 Chorioretinitis
 Approximately 20% of infants are noted to have retinal lesions at birth, but up
to 90% of untreated congenitally infected infants develop chorioretinitis, into
and including early adulthood30
 Motor and cerebellar dysfunction
6 Neu et al

 Microcephaly
 Seizures
 Intellectual disability (mental retardation)
 Sensorineural hearing loss

Discussion
Diagnosis and treatment
Prenatal There is no 1 universally endorsed screening protocol for T gondii in pregnant
women: most providers take a risk factor–based approach,8,25 and screen based on
suspicious findings (ie, hydrocephalus, cerebral, hepatic, or splenic calcifications) on
ultrasonography. Maternal screening comprises31,32:
 T gondii IgM
 This test has a high false-positive rate and may persist for up to 2 years after
acute infection
 T gondii IgG
 More sensitive techniques such as IgG avidity testing allow for more accurate
timing of maternal infection
 Polymerase chain reaction (PCR)
 Amniotic fluid PCR at 18 weeks’ gestation can determine fetal infection and
guide medical therapy

Maternal treatment
 For maternal infection diagnosed before 18 weeks’ gestation, treatment begins
with spiramycin until PCR and ultrasonography results are available25,28
 If fetal infection is confirmed, treatment switches to pyramethamine sulfadiazine
and folinic acid, and spiramycin
 No trial data exist on the efficacy of either of these therapies to reduce transmis-
sion to the fetus or reduce disease burden in congenitally infected infants; how-
ever, observational data29 do suggest both decreased fetal infection and
incidence of serious neurologic sequelae

Postnatal Infant with stigmata of congenital toxoplasmosis:

 IgG, IgM, and IgA, which is more sensitive than IgM, as well as serum (and cere-
brospinal fluid [CSF], if indicated); PCR should be obtained.
 Testing should be performed at experienced reference laboratories.
 Ophthalmologic, auditory, and neurologic examinations
 Computed tomography of the head is the preferred method of visualization of
intracranial calcifications.
For infants diagnosed prenatally with toxoplasmosis, either symptomatic or asymp-
tomatic, as well as infants diagnosed postnatally, treatment of 12 months with pyri-
methamine and sulfadiazine is indicated. Folinic acid is also given to minimize
pyrimethamine-associated hematologic toxicity.8,18,28–32 Repeat testing is recom-
mended 1 month after discontinuation of therapy. Close and sequential follow-up
with serial ophthalmologic as well as auditory and neurologic examinations is the
key to recognizing sequelae from this disease.

TREPONEMA PALLIDUM
Disease Description
Syphilis is a sexually transmitted infection caused by the spirochete Treponema pal-
lidum. Unlike many other congenital infections, syphilis is treatable, and thus,
 TORCH Infections 7

preventing infection of the infant is possible. Infection may occur in the newborn as a
result of transmission of spirochetes across the placenta during pregnancy.

Transmission/Pathogenesis
Characteristic features of congenital infection are detectable after 18 to 22 weeks’
gestation, when the fetal immune response occurs. It has been postulated33,34 that
congestion of the placenta as a result of infection may cause constricted blood flow
and result in severe adverse pregnancy outcomes, such as miscarriage and stillbirth.
Diagnosis and treatment of syphilis in the mother during antepartum visits is critical for
prevention of maternal to child transmission (MTCT) of syphilis. Recognizing the
stages of maternal infection is important. The primary stage (3–6 weeks) presents
as a painless, spontaneously resolving papule. The secondary stage occurs 6 to
8 weeks later, with diffuse inflammation and a disseminated rash (often on the palms
and soles). The latent stage then occurs, in which women are characteristically
asymptomatic. If untreated, maternal syphilis may then progress to the final or tertiary
stage of the disease, which is characterized by granulomas affecting the bones and
joints as well as the cardiovascular and neurologic systems. Infection of the neonate
occurs when maternal infection is active, inadequately treated, or untreated.
Risk for congenital syphilis is dependent on the stage of maternal infection and the
stage of infection at the time of exposure during pregnancy. One of the most important
risk factors for neonatal infection is lack of maternal prenatal care, including antenatal
clinic visits, screening, and treatment of syphilis.35 Other factors that increase the risk
of transmission of congenital syphilis include high nontreponemal test titers, early
stages of syphilis during pregnancy, late treatment of infection (eg, short time between
treatment and delivery), and lack of complete treatment.36

Epidemiology
MTCT of syphilis is declining but is still prevalent in the United States. The US Centers
for Disease Control and Prevention (CDC) estimates that the annual rate of primary or
secondary syphilis among women was 0.9 cases per 100,000, representing approxi-
mately 1500 cases in 2012.37 The incidence of congenital syphilis was 7.8 cases per
100,000 live births for a total of 322 congenital cases reported in 2012.38 Southern
states in the United States have the highest incidence of MTCT of syphilis.39 Global es-
timates of pregnant women with syphilis indicate that approximately 2 million women
were infected in 2003 and 1.4 million cases in 2008.35,40 World Health Organization
(WHO) data are based on voluntary reporting by countries, which is incomplete and var-
iable. However, from reported data, it can be concluded that maternal syphilis is a sig-
nificant problem in African countries as well as countries in the Americas.
In addition, recent increases in seroprevalence have also been documented in
China.37 In 2007, WHO launched a program for the global elimination of syphilis
with the goal of 50 or fewer cases of congenital syphilis per 100,000 live births. These
goals were to be achieved by structured service delivery interventions, including
increasing the number of women having at least 1 antenatal care visit (95% compli-
ance), increased testing of pregnant women (95% compliance), and early treatment
of syphilis in pregnancy (95% compliance).40,41

Clinical Correlation
A recent literature review and meta-analysis on adverse outcomes of maternal syphilis
infection from 1917 to 200042 showed that the range of adverse pregnancy outcomes
ranged from 53% to 82% in untreated women versus 10% to 20% in women without syph-
ilis. A study to estimate global impact of adverse outcomes in pregnancy based on antenatal
8 Neu et al

surveillance found that 520,905 adverse outcomes occurred because of maternal syphilis.
These estimates included 212,327 stillbirths, 92,764 neonatal deaths, 65,267 preterm or low
birth weight infants, and 151,547 infected newborns.35 Approximately 66% of the adverse
outcomes occurred in antenatal clinic attendees who were not screened or treated.
Clinical evidence of congenital syphilis may be characterized as early manifestations
(within 2 years) and late. Early findings may include hepatosplenomegaly, snuffles (nasal
secretions), lymphadenopathy, mucous membrane lesions, pneumonia, osteochondritis
and pseudoparalysis, maculopapular rash, edema, Coombs negative hemolytic anemia,
and thrombocytopenia. Untreated infants, even those without early evidence of infection,
may present with manifestations involving the central nervous system, bone and joint,
teeth, eyes, and skin. Table 3 shows both early and late sequelae of congenital syphilis.43

Discussion
Diagnosis and treatment
Prenatal Maternal screening
 All pregnant women should be screened for syphilis at the first prenatal visit;
many advocate repeat screening at the time of delivery44
Maternal treatment comprises:
 Intramuscular (IM) benzathine penicillin; pregnant women with syphilis who are
allergic to penicillin should be desensitized

Postnatal
 Diagnosis of congenital syphilis may be made by examination of the placenta
(dark field microscopy to detect spirochetes, which is clinically and practically
not available in most settings)

Table 3
Selected early and late sequelae of congenital syphilis

Percent of Cases and Approximate

Organ System Signs and Symptoms Time of Presentation
Reticuloendothelial Lymphadenopathy 4–8 wk
Anemia
Leukopenia or leukocytosis
Thrombocytopenia 30%
Hepatosplenomegaly 50%–90%
Mucocutaneous Rhinitis <5%; within first week of life
Maculopapular rash on palms and 1–2 wk of life and lasts 3 mo of age
soles
Mucous patches
Skeletal Symmetric long bone lesions 50%–95%; 6 wk–6 mo (resolve
(upper extremity>lower spontaneously)
extremity)
Metaphyseal and osteochondritis
Ostitis and dactylitis
Neurologic Meningitis 40%–60% abnormal CSF parameters
Infarction and hydrocephalus 10–40 y
Cranial nerve deafness
Ocular Chorioretinitis 5–20 y
Glaucoma

Adapted from Follett T, Clarke D. Resurgence of congenital syphilis: diagnosis and treatment.
Neonatal Netw 2011;30(5):320–8.
 TORCH Infections 9

 After evaluation of maternal testing, the infant should be tested using standard
nontreponemal serologic tests, including:
 The Venereal Disease Research Laboratory test or
 The rapid plasma regain test
 Nontreponemal tests detect antibodies to the cardiolipin
 False-negative results may occur in congenital syphilis as a result of high titers
(called the prozone effect), and thus, diluting the sample before testing is
recommended
 Reactive nontreponemal tests should be confirmed with a Treponema-specific
test, such as:
 Fluorescent antibody absorption, microhemagglutination tests for antibodies
to T pallidum, T pallidum enzyme immunoassay, or T pallidum particle agglu-
tination tests.
Guidance on interpretation of maternal and infant testing, as well as the treatment
guidelines endorsed by the American Academy of Pediatrics (AAP) are provided on
page 695 of the AAP 2012 Report of the Committee on Infectious Diseases.45

RUBELLA
Disease Description
Congenital rubella is infection with a single-stranded positive-sense RNA virus. Trans-
mission and infection of the mother occurs by inhalation of aerosolized particles from
an infected individual.
Transmission/Pathogenesis
Congenital rubella occurs primarily after maternal infection in the first trimester (80%–
100%), with decreasing risk to the fetus of congenital infection in the second
trimester (10%–20%), but higher risk again at term (up to 60%). Infection with the
rubella virus causes cellular damage as well as having an effect on dividing cells.
The pathologic effects result in progressive necrotizing vasculitis and focal inflamma-
tory response.46 Infection may also result in miscarriage, stillbirth, or congenital
rubella syndrome (CRS). There is a higher risk of vertical transmission (80%–90%)
from a nonimmune mother with primary rubella infection in the first trimester of preg-
nancy, and infection during this period is associated with the most severe manifes-
tations at birth.
Epidemiology
Indigenous rubella transmission and CRS were declared eliminated in the United
States in 2004.47 However, worldwide, it is estimated that around 110,000 infants
are born with CRS every year, and WHO has targeted regional elimination of CRS
by 2015.48
Clinical Correlation
The classic picture of CRS is a small for age infant with a constellation of anomalies,
including:
 Sensorineural deafness (66%)
 Cataracts (78%)
 Cardiac defects (58%)49:
 Patent ductus arteriosus
 Pulmonary artery stenosis
 Coarctation of aorta
10 Neu et al

 Other ocular findings:

 Microphthalmia
 Corneal opacity
 Glaucoma
Features common to other perinatal infections such as the blueberry muffin rash,
hepatosplenomegaly, and thrombocytopenia may also be present.
Delayed manifestations include a higher incidence of:
 Diabetes mellitus
 Hypertension
 Panencephalitis
 Behavioral disorders

Discussion
Diagnosis, prevention, and treatment
Prenatal Prevention of congenital rubella is achieved by providing rubella vaccination
to all children and adolescents. Women who are of childbearing age should have ev-
idence of immunity to rubella. If they are fond to be nonimmune, the Advisory Commit-
tee on Immunization Practices (ACIP) recommendation is for vaccination with 1 dose
of measles-mumps-rubella (MMR) vaccine. Pregnant women should have serologic
screening with rubella IgG if they lack evidence of rubella immunity; those who are
not immune should be vaccinated with 1 dose of the MMR vaccine on completion
of their pregnancies and be counseled to avoid becoming pregnant for 28 days after
administration of MMR vaccine.50

Postnatal Case definitions and testing recommendations for suspected and probable
CRS were published by the CDC in 2009.48 Diagnosis can be based on:
 Isolation of the virus by PCR or culture
 Rubella-specific IgM, which is usually positive at birth to 3 months for congenital
infection
 This diagnosis is confirmed by stable or increasing serum concentrations of
rubella-specific IgG over the first 7 to 11 months of life
 False-positive IgM can occur
- Avidity testing of IgG can help diagnose recent infection

 Rubella virus RNA can be also be detected by reverse transcriptase PCR in naso-
pharyngeal swabs, urine, CSF, and blood at birth48
Specific treatment of infected children is not available. All suspected cases of CRS
should be reported to the CDC. All infants with CRS are considered contagious until at
least 1 year of age, unless 2 cultures of clinical specimens obtained 1 month apart are
negative for rubella virus after 3 months of age.51

PARVOVIRUS B19
Disease Description
Human parvovirus B19 is a single-stranded DNA virus in the family Parvoviridae.
Parvovirus B19 is primarily transmitted by respiratory droplets, but infection from
blood products as well as prenatal vertical transmission can occur.
Transmission/Pathogenesis
Approximately 35% to 55% women of childbearing age are not immune to parvovirus.
The incidence of parvovirus infection in pregnancy is approximately 1% to 2%, with
 TORCH Infections 11

differential incidence occurring seasonally or during outbreak conditions. The vertical

transmission rate is approximately 35%. Fetal parvovirus infection takes place via
transplacental transmission 1 to 3 weeks after maternal infection, during peak
maternal viremia.52–55 Occupational exposures (ie, health care workers, childcare
workers, or teachers) have historically been described as having increased risk of
parvovirus seroconversion between early pregnancy and birth. However, the CDC
does not recommend that pregnant women refrain from employment in these areas.56
Clinical Correlation
Infection with parvovirus B19 is characterized by a distinctive facial rash, described as
slapped cheek, with a pruritic, laticiform macular rash on the trunk, which spreads to
the extremities and may be accompanied by a polyarthritis. The rash is often preceded
by a mild, nonspecific illness consisting of fever, malaise, myalgia, and headache
1 week before the exanthem. However, many women are asymptomatic during pri-
mary infection. Fetal infection may resolve spontaneously or lead to severe conse-
quences such as nonimmune hydrops fetalis and miscarriage.
Parvovirus shows a high affinity toward erythroid progenitor cells. Cellular receptors,
including the receptor of blood group P antigen are present in erythroid precursor cells.
In addition, some antigenic receptors are present in endothelial cells and myocardial
cells and may therefore be infected with parvovirus. Both direct toxic cell injury by
the viral proteins and the induction of apoptosis contribute to cell death and the man-
ifestations as fetal anemia and myocarditis. The risk of fetal complications is believed to
be highest when infection occurs before the end of the first trimester of pregnancy. Fetal
anomalies are typically evident on prenatal sonograms at 1 to 33 weeks of gestation,
regardless of the gestational age at time of maternal infection.52,53,57–59

Fetal parvovirus infection may lead to:

 Fetal demise
 Severe anemia
 Nonimmune hydrops fetalis caused by fetal heart failure
 High-output cardiac failure from anemia
 Myocardial failure attributable directly to parvovirus infection
 Thrombocytopenia
 Maternal mirror syndrome
 Meningoencephalitis is rare but described60
Many of these conditions necessitate premature delivery. In the infant, persistent
viremia with anemia caused by red cell aplasia after perinatal infection with parvovirus
has been well described.59,61,62

Discussion
Diagnosis and treatment
Prenatal There is no endorsed routine screening protocol for parvovirus in pregnant
women. Diagnosis of infection is made whether caused by maternal symptoms with
the classic clinical presentation, suspicious finding (ie, hydrops fetalis) on screening
ultrasonography, or known maternal exposure.52,55,58,59
Diagnosis of maternal infection57:
 Parvovirus IgM
 Becomes detectable in serum 7 to 10 days after infection, peaks at 10 to 14 days
 The sensitivity of IgM antibody detection between 8 and 12 weeks after
maternal infection is reported as 60% to 70%
12 Neu et al

 Parvovirus B19 DNA PCR

 Sensitivity reported up to 96%
 B19V DNA levels may persist for longer periods after acute infection
Fetal infection
 Amniotic fluid PCR can determine fetal infection
 Monitoring for fetal hydrops and anemia is recommended for at least 12 and up to
20 weeks after exposure
Treatment
 There is no treatment of maternal infection
 Fetal treatment is targeted toward anemia and subsequent fetal hydrops, with a
goal of reduction in fetal demise
 In utero fetal transfusion has become the mainstay of treatment

Postnatal Treatment of the hydropic neonate is primarily supportive.

Persistent congenital infection manifested as red cell aplasia has increasingly been
reported, because supportive care has improved and prenatal transfusion therapy is
now widely used. The use of intravenous g globulin has been extrapolated from its
use in persistent symptomatic parvovirus infection in immunocompromised hosts.
Case studies in infants have shown that this therapy may be adventitious in improving
the need for red blood cell transfusion but that repeated infusions are often required
for weeks to months after birth.61,62
Case series only are available to evaluate the long-term outcomes of infants with
congenital parvovirus infection; it has been posited that survivors of the neonatal period
may have an increased risk of neurodevelopmental impairment when compared with
healthy population standards, but these finding may be confounded63; in general, sur-
vivors of the neonatal period have a good prognosis and neurologic outcomes.64,65

PERINATAL HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Disease Description
HIV-1 and HIV-2 are lentiviruses that belong to the family Retroviridae. There are 3
distinct groups of the virus worldwide: M (major), O (outlier), and N (new). HIV infection
is transmitted by exposure to infected body fluids, including through sexual contact,
percutaneous blood exposure, mucous membrane exposure, and MTCT during preg-
nancy, labor, and delivery, or through breastfeeding. The pathogenesis of infection is
complex and not completely understood. HIV infects dendritic cells; active replication
occurs at the lymphoid tissues, with resultant primary viremia. This stage is followed
by a massive loss of gut-associated lymphoid tissues, downregulation of CD8 cells,
and the production of neutralizing antibodies. There are usually no clinical manifesta-
tions of HIV infection at birth.

Epidemiology
Perinatally acquired HIV-1 infection is less common in the United States as a result of
earlier identification of maternal HIV infection, access to comprehensive HIV treatment
programs, including combination antiretroviral therapy (cART) for pregnant women,
and the avoidance of breastfeeding. The perinatal transmission rate has been reduced
from 18% to 32% in the preantiretroviral era to 1% to 2% in the United States as a
result of these interventions.66 In 2011, it was estimated that there were 192 children
younger than 13 years who were diagnosed with HIV in the United States.67 Globally,
WHO estimates that there are 3.2 million children younger than 15 years living with
HIV. Most (>90%) of these children live in sub-Saharan Africa. Interventions instituted
in resource-limited settings have reduced the estimated number of children newly
 TORCH Infections 13

infected with HIV from greater than 400,000 in 2009 to approximately 200,000 in
2013.68 HIV-2 is endemic in some West African countries but rare in the United States
and is not discussed further in this article. Table 4, from the Global Update on Health
Sector Response to HIV, describes the impact of efforts to prevent MTCT of HIV.

Transmission/Pathogenesis
There are several factors that increase the risk of perinatal HIV transmission. These
factors include maternal plasma viral load, maternal CD4 count, more advanced
WHO clinical disease stage, breastfeeding and mastitis, and acute maternal infec-
tion.69,70 A recent meta-analysis71 reported that incident HIV during pregnancy and
postpartum was associated with a significantly higher risk of MTCT of HIV. Table 5
shows the timing of HIV transmission and some possible mechanisms for
transmission.72,73

Discussion
Diagnosis and treatment
In the United States, recommendations for HIV testing in early pregnancy have been
promoted by many prominent medical service groups, including the Panel on

Table 4
The global impact of prevention of MTCT

Estimated
Cumulative
Number of
Infections
Estimated Averted by
Estimated Number of Mother-to-Child Estimated Number of Prevention
Pregnant Women Living Transmission Rate Children Newly Infected of MTCT
Year with HIV (Range) of HIV (Range) (%) with HIV (Range) (Range)a
2005 1,410,000 33 (31–36) 470,000 (430,000–510,000) 41,000
(1,320,000–1,520,000)
2006 1,390,000 32 (30–35) 450,000 (420,000–490,000) 73,000
(1,290,000–1,490,000)
2007 1,370,000 31 (29–33) 420,000 (390,000–460,000) 130,000
(1,270,000–1,470,000)
2008 1,360,000 29 (27–31) 400,000 (360,000–430,000) 200,000
(1,260,000–1,450,000)
2009b 1,340,000 26 (24–28) 350,000 (310,000–380,000) 320,000
(1,250,000–1,430,000)
2010 1,330,000 23 (21–25) 300,000 (280,000–330,000) 480,000
(1,230,000–1,420,000)
2011 1,310,000 21 (20–23) 280,000 (250,000–300,000) 660,000
(1,210,000–1,400,000)
2012 1,290,000 17 (16–19) 220,000 (200,000–250,000) 880,000
(1,190,000–1,380,000)
2013 1,260,000 16 (15–17) 200,000 (170,000–230,000) 1,120,000
(1,170,000–1,360,000)
a
Compared with the counterfactual scenario in which no ARVs are provided for MTCT.
b
Baseline year for the Global Plan.
From WHO. Global update on the health sector response to HIV, 2014. Geneva: World Health
Organization, 2014; with permission.
14 Neu et al

Table 5
Mechanisms and timing of MTCT of HIV

Timing of
Transmission Rate (%) Mechanism Prevention
In utero Approximately 30 Placental breakdown and Early maternal diagnosis
microtransfusions; Maternal cART
chorioamnionitis
Intrapartum Approximately 50 Contact with infant mucous cART
membranes and >4 h rupture Cesarean section
of amniotic membranes Neonatal ART
Breastfeeding Approximately 20 Contact with infant mucous No breastfeeding
membranes

Antiretroviral Therapy and Medical Management of HIV-Infected Children, the US Pub-

lic Health Service, the AAP, the American College of Obstetricians and Gynecologists,
and the US Preventive Services Task Force. These testing algorithms have made a
significant impact on perinatal HIV as a result of early identification of maternal
infection.74–80

Prenatal: maternal testing Opportunities for testing include:

 Early in pregnancy
 Third trimester of pregnancy
 At the time of labor or delivery
 Immediately post partum

Postnatal testing of HIV-exposed infants Diagnosis of HIV infection in infants requires the
use of nucleic acid tests (NATs), including HIV DNA or HIV RNA assays. For high-risk
exposures, such as maternal HIV, or when maternal HIV status is unknown, testing of the
infant at birth is recommended.75 In general, testing for the HIV-exposed infant should be:
 Within 48 hours of birth
 At 2 weeks of life
 At 4 to 6 weeks of life
 At 4 to 6 months of life
Both HIV DNA PCR and qualitative HIV RNA are sensitive for the diagnosis of peri-
natally acquired infection, although HIV DNA PCR may be less affected by cART.
Therefore, infants who receive cART at birth should be retested with an HIV NAT to
4 weeks after cessation of cART. HIV RNA testing of infants does have the advantage
of being more sensitive than HIV DNA PCR for nonsubtype B viruses, which are found
around the world. An HIV-exposed infant is generally considered to be HIV-1 negative
if the HIV NAT is negative at up to 4 months of age. Any infant with a positive HIV NAT
should have the test repeated immediately to confirm the result.75

Treatment Early cART for HIV-infected infants is associated with reduced mortality
and attainment of normal developmental milestones and gross motor skills when
compared with infants who have cART delayed.81,82 The reported functional cure in
an HIV-infected child in Mississippi led many experts to consider early cART initiation
for HIV-exposed infants. This child was treated at 30 hours of life to 18 months of age
and maintained HIV viral suppression for a period.83 However, current data now show
HIV viral rebound in this child off therapy. Therefore, empirical treatment at birth and
interruption of therapy after early initiation cannot be recommended.84
 TORCH Infections 15

The latest guideline recommendations for infant antiretroviral (ARV) prophylaxis are
shown in Table 6 and include85:
 Six-week zidovudine regimen or 4-week regimen if maternal cART was given with
consistent viral suppression and no concerns for lack of maternal adherence
 Zidovudine regimen started as close to birth as possible and within 6 to 12 hours
of delivery
 Infants born to women who did not receive cART should receive 6 weeks of zido-
vudine combined with 3 doses of nevirapine in the first week of life (first dose
given from birth to 8 hours, second dose given 48 hours after the first dose,
and third dose given 96 hours after the second dose)

Table 6
Recommendation for prophylaxis of newborns exposed to HIV

All HIV-Exposed Infants (Initiated as Soon After Delivery as Possible)

ZDV Dosing Duration
ZDV 35 wk gestation at birth: 4 mg/kg/dose PO twice Birth to 4–6 wka
daily, started as soon after birth as possible and
preferably within 6–12 h of delivery (or, if unable
to tolerate oral agents, 3 mg/kg/dose IV,
beginning within 6–12 h of delivery, then every
12 h)
ZDV 30 to <35 wk gestation at birth: 2 mg/kg/dose PO Birth to 6 wk
(or 1.5 mg/kg/dose IV), started as soon after birth
as possible, preferably within 6–12 h of delivery,
then every 12 h, advanced to 3 mg/kg/dose PO
(or 2.3 mg/kg/dose IV) every 12 h at age 15 d
ZDV <30 wk gestation at birth: 2 mg/kg body weight/ Birth to 6 wk
dose PO (or 1.5 mg/kg/dose IV) started as soon
after birth as possible, preferably within 6–12 h
of delivery, then every 12 h, advanced to
3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) every
12 h after age 4 wk
Additional ARV Prophylaxis Agents for HIV-Exposed Infants of Women who Received No
Antepartum ARV Prophylaxis (initiated as soon after delivery as possible)
In addition to ZDV Birth weight 1.5–2 kg: 8 mg/dose PO 3 doses in the first
as shown above, Birth weight >2 kg: 12 mg/dose PO week of life
administer NVP  First dose within
48 h of birth
(birth–48 h)
 Second dose 48 h
after first
 Third dose 96 h
after second

Abbreviations: IV, intravenously; NVP, nevirapine; PO, orally; ZDV, zidovudine.

a
A 6-week course of neonatal zidovudine is generally recommended. A 4-week neonatal zido-
vudine chemoprophylaxis regimen may be considered when the mother has received standard ART
during pregnancy with consistent viral suppression and there are no concerns related to maternal
adherence.
From Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Trans-
mission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for
maternal health and interventions to reduce perinatal HIV transmission in the United States. Avail-
able at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed October 29,
2014.
16 Neu et al

 Consult pediatric infectious diseases specialist about options for 3-drug ARV
prophylaxis regimens for extremely high-risk infants (eg, mother with high viral
load, known resistant virus) (discussions before delivery are recommended)
 Infants born to mother of unknown status
 Expedited HIV testing of mother or infant (rapid HIV test) should be performed,
followed by:
 Immediate initiation of infant ARV prophylaxis if initial test positive
 If confirmatory testing of the infant’s mother is negative, infant ARV prophylaxis
can be discontinued
 In the United States, HIV ARV drugs other than zidovudine and nevirapine cannot be
recommended in premature infants, because dosing and safety data are lacking
 Free consultation is available at the National Perinatal HIV Hotline (1-888-488-8765)

HEPATITIS B
Disease Description
HBV is a partially double-stranded circular DNA enveloped hepadnavirus. It is
composed of an outer lipoprotein envelope containing the hepatitis B surface antigen
(HBsAg) and an inner nucleocapsid consisting of hepatitis B core antigen (HBcAg).
The genome contains 4 partially overlapping open reading frames, coding for viral sur-
face proteins, which correspond to HBsAg, the core antigen, and the soluble antigen e
(HBeAg), the viral polymerase that possesses a DNA polymerase and reverse tran-
scriptase, a regulatory X protein essential for virus replication and activating the
expression of numerous cellular and viral genes.86–88
The virus itself is not directly cytotoxic to hepatocytes or other cells; instead, the
cellular injury seen in the disease is related to the host immune response, most
commonly with HBV directed cytotoxic T cells. After infection occurs, HBV DNA
and HBsAg increase exponentially in the serum. The peak of HBV DNA and HBsAg
is reached before the acute disease, and both decrease after the onset of clinical
symptoms. HBsAg disappears, unless a chronic carrier state is present.88 It is now
known that HBV genome may also become integrated into hepatocytes, and produce
an occult HBV infection, in which the carrier is HBsAg negative, but the integrated virus
is able to reactivate and replicate under certain conditions.89

Transmission/Pathogenesis
Most MTCT of HBV occurs at the time of delivery, with less than 2% to 4% of all trans-
mission occurring in utero. Hypothesized prenatal modes of transmission include
transplacental or inhalation or chronic ingestion of infected amniotic fluid. HBV infec-
tion caused by fetal contamination with maternal blood during procedures such as
amniocentesis has been posited but not proved to occur.90
Perinatal transmission of HBV usually occurs from exposure to blood during labor
and delivery; HBV has also been isolated in vaginal secretions. The highest rate of viral
transmission occurs from mothers who are HBsAg and HBeAg positive; of women
who are acutely infected during pregnancy, the risk of neonatal infection is greatest
when maternal infection occurs during the third trimester. Historically, of infants
who do not receive appropriate prophylaxis, only 5% to 20% who are born to
HBsAg-positive but HBeAg-negative mothers become infected, as opposed to up
to 90% of infants born to women who are both HBsAg and HBeAg positive.1,86,90,91
The biological basis for this finding is that HBeAg is produced during active viral
replication and is associated with high HBV DNA levels. Maternal HBeAg can pass
through the placenta because of its small size. This factor induces T-cell intolerance
 TORCH Infections 17

in the fetus to both HBeAg and HBeAg as a result of cross-reactivity between HBeAg
and HBcAg. After birth, cytotoxic T-helper cell recognition and response may be
shown to HBeAg and HBcAg, but not to HBsAg; this enables both acute infection
with HBV and persistent HBV infection after delivery.86,88,92

Epidemiology
HBV is estimated to affect approximately 360 million people globally. The preva-
lence of HBV infections varies throughout different regions of the world, but up
to half of the world’s population live in regions where the prevalence of chronic
HBV infection (CHB) is greater than 8%. Transmission during pregnancy or delivery
is responsible for more than one-third of CHBs worldwide. Table 1, adapted for the
Red Book, shows the prevalence of HBV as indicated by HBsAg positivity and the
major source of new infections.88,93 In these regions, most new infections occurred
in early childhood or perinatally. In regions of intermediate HBV endemicity, where
the prevalence of HBV infection is 2% to 7%, multiple modes of transmission (ie,
perinatal, household horizontal transmission, sexual transmission, injection drug
use) contribute to the burden of infection. In countries of low endemicity, such
as the United States, where CHB prevalence is less than 2% and immunization
readily available, the peak age of new infections is among the unimmunized in older
age groups.93

Clinical Correlation
The risk of progressing to CHB is primarily determined by the age at the time of acute
infection. Approximately 90% of infants infected perinatally or in the first year of life
develop CHB. Between 25% and 50% of children infected between 1 and 5 years of
age develop CHB, whereas 5% to 10% of acutely infected older children and adults
develop CHB. Infants infected with HBV rarely show signs of disease at birth or in the
neonatal period, and the natural history of perinatally acquired chronic HBV may be
classified into the immune tolerant, immune active/clearance, inactive carrier state,
and reactivation stages. Children who are infected perinatally develop mildly
increased alanine aminotransferase concentrations, with detectable HBeAg and
high HBV DNA concentrations (20,000 IU/mL), with minimal or mild liver histologic
abnormalities, defining the immune-tolerant phase, starting at approximately 2 to
6 months of age. Spontaneous loss of HBeAg in this stage is low, which typically
lasts for many years, and children are contagious as a result of their high viral
burden.87–89
A few infants develop clinical hepatitis within a few months of age and present with
jaundice, poor feeding, and vomiting.
Infection of an infant with HBV caused by vertical transmission from an HBV-infected
mother is most commonly diagnosed by the presence of HBsAg by 1 to 2 months of age.

Discussion
Diagnosis and treatment
Prenatal In the past, women were screened for HBsAg if they fell into a high-risk group
based on such data as immunization status, history of exposure to blood products,
intravenous drug use, and so forth. However, less than 60% of HBsAg carriers were
captured using these screening criteria, and thus, it is recommended that all pregnant
women be screened for HBsAg at the first prenatal visit. Additional screening at the
time of delivery is recommended if any of the maternal risk factors outlined earlier
are present.94,95
18 Neu et al

Postnatal Newborns of HBsAg-positive mothers should receive:

 Hepatitis B immunoglobulin (HBIG) and
 Single-antigen hepatitis B vaccine within 12 hours of birth
 The vaccine series should then be completed according to the standard ACIP/
AAP schedule96–99
Follow-up:
 Testing after the hepatitis B vaccine series of infants born to HBsAg-positive
mothers should then be performed at 9 to 18 months of age
 Postvaccination testing is not recommended before 9 months of age, to minimize
the likelihood of detecting passively transferred anti-HBs from HBIG and to maxi-
mize the likelihood of detecting HBV disease that presents with late HBsAg
positivity14
 Although breast milk is theoretically capable of transmitting HBV, the risk for
transmission in HBsAg-positive mothers whose infants have received timely
HBIG and hepatitis B vaccine is not increased by breastfeeding

Best Practice

 Universal screening for HBV in pregnant women (HBsAg) at first prenatal visit, regardless of
risk stratification
 Repeat screening for women at high risk for HBV at delivery
 Prophylaxis of infant
- Maternal HBsAg positive
 HBIG 0.5 mL IM and single-antigen hepatitis B vaccine IM within 12 hours of delivery
 Complete vaccine series by 6 months of life
 Follow-up testing at 9 to 18 months
- Maternal HBsAg negative
 Single-antigen hepatitis B vaccine IM soon after birth, before hospital discharge
 Complete vaccine series by 6 to 18 months of life months of life99

HEPATITIS C
Disease Description
HCV is an enveloped, single-stranded RNA with 6 main genotypes. A hypervariable re-
gion within the structural protein E2 also leads to subtypes, or quasispecies, that show
varying clinical presentation and degrees of resistance to antiviral therapy. The virus
infects hepatocytes or other cells, but like HBV virus, may not be directly cytotoxic
to the cells. Signs and symptoms of this disease often parallel the host immune
response with HCV-directed CD81 and then CD41 T cells.100–102

Transmission/Pathogenesis
MTCT of HCV in the absence of maternal viremia is rare; however, studies of perinatal
transmission of HCV have yielded conflicting results, and the timing and mechanisms
of transmission from mother to infant are unclear. Infants may have positive cord or
serum HCV PCR tests soon after delivery, suggesting in utero transmission. However,
after 18 months of age, some of these children have negative PCR testing, recom-
mending against using early PCR as a diagnostic tool.101 Hypothesized mechanisms
 TORCH Infections 19

of transmission include prenatal or perinatal exposure to maternal peripheral blood

mononuclear cells (PBMCs) infected with HCV and release of virus into fetal or infant
circulation. Fetal and maternal HLA type, as well as HCV quasispecies, has been impli-
cated in transmission.103–107 Research into differential predilection for PBMCs by qua-
sispecies may help elucidate the risk of MTCT of HCV. Other risk factors described by
epidemiologic studies include female gender and coinfection with HIV, mediated
through viral load and immunologic status. Mode of delivery and exposure to breast
milk do not seem to be associated with infection.103–109

Epidemiology
HCV is one of the most common causes of chronic liver disease worldwide, with global
prevalence estimated at 130 to 150 million and maternal seroprevalence at approxi-
mately 1% to 2% in developed countries. MTCT has been estimated from 4% to
8% historically, and a recent meta-analysis showed that in children born to HIV-
negative women, the pooled risk of vertical HCV infection was 5.8% as opposed to
a 10.8% risk of HCV vertical transmission in children born to HIV-positive women. Inci-
dence in infants and children remains low, with a prevalence of less than 0.1 per
100,000 in the United States.12,108,110

Clinical Correlation
Infants infected perinatally are generally asymptomatic; although up to 80% of infants
infected perinatally develop chronic HCV, most are still asymptomatic at age 5 years.

Discussion
There are no known prenatal or perinatal interventions to prevent congenital HCV.
Although observational studies have suggested that invasive instrumentation or pro-
longed rupture of membranes may confer a higher risk of transmission, no experi-
mental data exist to confirm these finding. Elective cesarean section is not
recommended in the case of maternal HCV infection, nor is breastfeeding prohibited,
although mothers with cracked or bleeding nipples are advised to abstain.

Diagnosis and treatment

Prenatal
 Routine screening of pregnant women is not advocated. However, targeted
screening in high-risk women (ie, HIV positive, history of intravenous drug abuse)
is recommended.102,111
Postnatal follow-up
 Anti-HCV IgG:
 Persistence of maternal antibodies can be as long as 18 months, and there-
fore, testing is after the age of 18 months
 HCV Nucleic acid amplification test (RNA PCR):
 May be performed at 1 to 2 months of life
 Should be repeated after 12 months of age, because up to 30% of infants may
clear their infection
Although interferon-based therapy combined with ribavirin is approved for children
aged 3 years and older, neither this nor therapy with intravenous g globulin is indicated
in infancy.102,110,111 There now exist direct acting antiviral agents, both first and sec-
ond generation, which have proved efficacious in the treatment of chronic HCV in
adults. Therapy in pregnant women is not indicated to prevent perinatal transmission,
but this may change as these drugs become more widely used.102,112
20 Neu et al

SUMMARY

Infants with a suspected congenital infection should undergo a judicious review of

both the maternal and perinatal history to appropriately guide the next steps in eval-
uation and therapy. As sensitive and specific diagnostic tools become widely avail-
able, prevalence estimates of maternal, fetal, and perinatal infection will likely
increase as the burden and spectrum of these diseases become more apparent.
We hope that this situation will allow for the development of more sophisticated pre-
natal therapeutic and preventive strategies, targeted at key moments in the disease
process, with the intent of mitigating sequelae of these diseases.

Best practices

What is the current practice?

 Toxoplasmosis
 Treponema pallidum
 Rubella
 Parvovirus B19
 HIV
 Hepatitis B
 Hepatitis C
Best practice/guideline/care path objective(s)
What changes in current practice are likely to improve outcomes?
 Universal screening for T pallidum, HIV, and HBV, as well as for immunity to rubella in
pregnant women at first prenatal visit, regardless of risk stratification
 Targeted screening for toxoplasmosis, parvovirus B19, and HCV in pregnant women
Major Recommendations
Toxoplasmosis: CDC recommendations for prevention of toxoplasmosis in pregnant women can
be found at: http://www.cdc.gov/parasites/toxoplasmosis/prevent.html.113
HBV: Recommendations for screening for HBV infection in pregnancy can be found at: US
Preventive Services Task Force reaffirmation recommendation statement95
HCV: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
practice guidelines for the diagnosis and management of hepatitis C infection in infants,
children, and adolescents can be found at J Pediatr Gastroenterol Nutr 2012; 54:838–55111
Clinical Algorithm(s)
T pallidum: Testing and treatment algorithm endorsed by the AAP are provided on page 695 of
the AAP 2012 Report of the Committee on Infectious Diseases45
HIV: Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal
Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected
Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the
United States. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
Accessed October 31 201485
HBV: American Academy of Pediatrics. Hepatitis B. In: Red Book: 2012 Report of the Committee
on Infectious Disease (29th edition), Pickering, LK. (Ed), American Academy of Pediatrics, Elk
Grove Village, IL 2012. p. 384, Table 3.2.
 TORCH Infections 21

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