Congenital TORCH infections

Congenital infections are caused by pathogens transmitted from mother to child during pregnancy (transplacentally) or delivery (peripartum). They can have a substantial negative impact on fetal and neonatal health. The acronym TORCH stands for the causative pathogens of congenital infections: Toxoplasma gondii, others (including Treponema pallidum, Listeria, varicella zoster virus, and parvovirus B19), rubella virus, cytomegalovirus (CMV), and herpes simplex virus (HSV). TORCH infections can cause spontaneous abortion, premature birth, and intrauterine growth restriction (IUGR). These infections can also cause abnormalities in the CNS, the skeletal and endocrine systems, and the complex organs (e.g., cardiac defects, vision and hearing loss). Prophylaxis is of great importance during pregnancy. Primary prevention includes vaccination for varicella and rubella (prior to pregnancy), hygiene measures (washing hands and avoiding certain foods), and screening for syphilis during pregnancy. Affected infants require regular follow-ups to monitor for hearing loss, ophthalmological abnormalities, and developmental delays.

Several other pathogens can also be vertically transmitted during pregnancy and have detrimental effects on the fetus and/or newborn. These include HIV in pregnancy, perinatal hepatitis B, group B streptococci, E. coli, gonococcal infections and chlamydial infections, West Nile virus, Zika virus, measles virus, enterovirus, and adenovirus. The pathogens are discussed in more detail in their respective articles.

Description

Congenital TORCH infections are vertically transmitted infections (acquired directly from the mother and transmitted to the embryo, fetus, or newborn through the placenta or birth canal) that are capable of significantly influencing fetal and neonatal morbidity and mortality

• Toxoplasmosis
• Others (e.g., syphilis, varicella, parvovirus B19 infection, listeriosis)
• Rubella
• Cytomegaly (CMV)
• Herpes simplex virus (HSV) infection

Common findings

• During pregnancy: may cause intrauterine fetal demise and miscarriage
• In neonates
  • Hepatosplenomegaly
  • Jaundice
  • Lethargy
  • Growth retardation
  • Thrombocytopenia

Transplacental transmission occurs following primary infection of a seronegative mother during pregnancy. Maternal IgM antibodies, which are unable to cross the placenta, form first. Protective IgG antibodies, which are able to cross the placenta, have not yet been formed, so the infant is not protected from infection via the placenta.

In general, the earlier in pregnancy a TORCH infection occurs, the more severe the complications.

Attenuated live vaccines (measles, mumps, rubella, and varicella) are contraindicated in pregnancy. Conception should be avoided for 1 month after immunization with live vaccines.

Epidemiology

∼ 0.5–1:10,000 live births per year in the US ^[2]

Pathogen

Toxoplasma gondii

Transmission

• Mother
  • Cat feces
  • Raw or insufficiently cooked meat
  • Unpasteurized milk (especially goat milk)
  • See “Etiology” in “Toxoplasmosis.”
• Fetus
  • Transplacental transmission
    • First trimester: ∼ 15%
    • Third trimester: ∼ 70%

Clinical features ^[3]

• First trimester
  • Increased risk of premature birth and spontaneous abortion
  • Classic triad of toxoplasmosis
    • Chorioretinitis (a form of posterior uveitis)
    • Diffuse intracranial calcifications
    • Hydrocephalus
  • Possible other nonspecific clinical features
    • Petechiae and purpura (blueberry muffin rash)
    • Fever
    • Jaundice
    • Hepatosplenomegaly
    • Lymphadenopathy
    • Pneumonitis
    • Seizures
    • Macrocephaly or microcephaly ^[4]
    • Thrombocytopenia
• Second or third trimester: subclinical or mild toxoplasmosis
• Sequelae of congenital toxoplasmosis
  • Epilepsy
  • Intellectual disability
  • Visual disabilities; (chorioretinitis → increased risk of chorioretinal scars , cataracts, and glaucoma)
  • Sensorineural hearing loss

Diagnostics ^[5]

• Mother: See “Diagnostics” in “Toxoplasmosis.”
• Fetus: PCR for T. gondii DNA in amniotic fluid
• Newborn
  • CT/MRI: intracranial calcifications, hydrocephalus, ring-enhancing lesions
  • T. gondii-specific IgM antibodies (CSF, serum)
  • PCR forT. gondii DNA (CSF, serum)
  • Ophthalmological evaluation: chorioretinitis

Treatment ^[5]

• Mother: immediate administration of spiramycin to prevent fetal toxoplasmosis ^[6]
• Fetus: : When confirmed or highly suspected, switch to pyrimethamine, sulfadiazine, and folinic acid.
• Newborn: pyrimethamine, sulfadiazine, and folinic acid

Prevention ^[3]

• Avoid raw, undercooked, and cured meats.
• Wash hands frequently, especially after touching soil (e.g., during gardening).
• Avoid contact with cat litter.

The 4 Cs of congenital toxoplasmosis: Cerebral calcifications, Chorioretinitis, hydroCephalus, and Convulsions.

Epidemiology

∼ 23:100,000 live births per year in the US ^[7]

Pathogen

Treponema pallidum

Transmission ^[7]

• Mother
  • Sexual contact (contact with infectious lesion)
  • See “Etiology” in “Syphilis.”
• Fetus: transplacental transmission from infected mother
  • Increased risk of transmission with recent syphilis infection
  • Risk of transmission increases with gestational age
• Neonate: perinatal transmission during birth

Clinical features of congenital syphilis ^[8]

• In utero syphilis
  • Miscarriage
  • Stillbirth
  • Hydrops fetalis
• Early congenital syphilis (onset < 2 years of age)
  • Hepatomegaly and jaundice
  • Rhinorrhea; with white or bloody nasal discharge (also called “snuffles”)
  • Maculopapular rash on palms and soles; a bullous form of the rash called pemphigus syphiliticus may be present at birth.
  • Skeletal abnormalities (e.g., metaphyseal dystrophy, periostitis)
  • Generalized lymphadenopathy (nontender)
• Late congenital syphilis (onset > 2 years of age)
  • Typical facial features: saddle nose, frontal bossing, short maxilla
  • Dental findings: Hutchinson's teeth (notched, widely spaced teeth); mulberry molars (poorly developed first molars)
  • Eyes and ears ^[9]
    • Syphilitic keratitis: nonulcerative, interstitial keratitis that develops as a late complication of syphilis
      • More common in patients with congenital syphilis than acquired syphilis
      • Causes stromal inflammation
    • Sensorineural hearing loss
  • Skin: rhagades (perioral fissures, cracks, and/or scars, particularly near the corners of the mouth and nose)
  • Skeletal
    • Saber shins
      • An anterior bowing of the tibia, causing it to resemble a saber
      • Other causes include rickets and Paget disease of bone.
    • Painless arthritis in knees and other joints
  • Neurological: cranial nerve palsies (e.g., CN VIII defect causing deafness), intellectual disability, hydrocephalus

Diagnosis ^[10]

• Mother: See “Diagnostics of syphilis in pregnancy.”
• Fetus: repeated ultrasound examinations (placentomegaly, hepatomegaly, ascites, and/or hydrops fetalis)
• Neonate
  • RPR or VDRL (serum)
  • Dark-field microscopy or PCR of CSF
  • CBC and differential
  • Radiographs of the long bones
  • Further studies depend on clinical features of congenital syphilis

Treatment

• Neonates: 10 days of IV penicillin G ^[10]
• Mothers
  • Treatment depends on whether diagnosed prenatally or postnatally
  • See “Treatment of syphilis in pregnancy” and Treatment of syphilis.”

Prevention ^[7]

• Prenatal screening for syphilis and, if positive, antibiotic treatment: should take place in early pregnancy because placental transmission is most likely to occur after the first trimester.
• Nationally notifiable condition: Congenital syphilis and syphilitic childbirth must be reported to the local or state health department.

Hutchinson triad: interstitial keratitis, sensorineural hearing loss, Hutchinson teeth

Epidemiology

∼ 3:100,000 live births per year in the US ^[11]

Pathogen

Listeria monocytogenes

Transmission ^[12]

• Mother
  • Contaminated food: especially raw milk products
  • Other possible sources: fish, meat, and industrially processed vegetables (e.g., ready-made salads)
  • See “Etiology” in “Listeriosis.”
• Fetus
  • Transplacental transmission from an infected mother
  • Direct contact with infected vaginal secretions and/or blood during delivery

Clinical features ^[13]

• Listeriosis of pregnancy
  • Increased risk of premature birth and spontaneous abortion
  • Early-onset syndrome: granulomatosis infantiseptica
    • Severe systemic infection characterized by disseminated abscesses (may develop in any organ system)
    • Most common findings: respiratory distress and skin lesions
    • Signs of meningitis may already develop.
• Neonatal listeriosis
  • Late-onset syndrome (5 days to 3 weeks after birth): Listeria meningitis/encephalitis
  • See “Neonatal infection.”

Diagnosis

Culture from blood or CSF samples (pleocytosis) ^[14]

Treatment

IV ampicillin and gentamicin (for both mother and newborn) ^[14]

Prevention ^[12]

• Avoidance of soft cheeses
• Avoidance of potentially contaminated water and food
• Nationally notifiable condition: Listeriosis must be reported to the local or state health department.
• See “Food and water safety.”

Epidemiology

• Seroprevalence in the general population is ∼ 95%. ^[15]
• Most mothers have been vaccinated, so congenital infection is rare (< 2%). ^[15]

Pathogen

Varicella-zoster virus (VZV)

Transmission ^[16]

• Mother
  • Primary infection
    • Airborne droplets
    • Direct skin contact with vesicle fluid
  • Reactivation: usually in immunocompromised individuals
  • See “Chickenpox” and “Shingles.”
• Fetus: transplacental transmission from an infected mother

Clinical features ^[16]

• Congenital varicella syndrome (infection during first and second trimester) ^[17]
  • Hypertrophic scars (cicatricial skin lesions)
  • Limb defects (e.g., hypoplasia)
  • Ocular defects (e.g., chorioretinitis, cataracts, microphthalmia)
  • CNS defects (e.g., cortical atrophy, seizures, intellectual disability), hydrocephalus
• Neonatal varicella
  • Mild infection (maternal exanthem > 5 days before birth)
  • Severe infection (maternal exanthem < 5 days before birth): hemorrhagic exanthem; , encephalitis, pneumonia, or congenital varicella syndrome (mortality rate of up to 30%)

Diagnosis ^[16]

• Newborn and mother
  • Usually clinical diagnosis is confirmed by appearance of skin lesions
  • DFA or PCR of fluid collected from blisters or cerebrospinal fluid (CSF)
  • Serology
• Fetus: PCR for VZV DNA (in fetal blood, amniotic fluid) and ultrasound to detect fetal abnormalities

Treatment ^[16]

• For pregnant women or newborns with (severe) infection: acyclovir
• Administer postexposure prophylaxis in newborns if mother displays symptoms of varicella < 5 days before delivery: IgG antibodies (varicella-zoster immune globulin, VZIG) ^[18]
• For other indications for varicella postexposure prophylaxis, see “Prevention” in “Varicella.”
• Cesarean delivery if lesions are present at the delivery
• Breastfeeding is encouraged because of the possible protective effect of antibodies in breast milk.

Prevention

• Immunization of seronegative women before pregnancy
• VZIG in pregnant women without immunity within 10 days of exposure
• Nationally notifiable condition: Varicella must be reported to the local or state health department.

Epidemiology ^[19]

• ∼ 5% incidence in pregnant women per year in the US
• Higher prevalence in daycare workers and elementary school teachers

Pathogen

• Parvovirus B19
• Mechanism of action: infection of erythrocyte progenitor cells in bone marrow and endothelial cells by attaching to their P antigen → cell destruction → hydrops fetalis in neonates and pure RBC aplasia in adults

Transmission

• Mother
  • Mainly via aerosols
  • Rarely hematogenous transmission
  • See “Fifth disease.”
• Fetus: transplacental transmission from infected mother

Clinical features ^[19]

• Severe anemia and possibly fetal hydrops
• Fetal demise and miscarriage/stillbirth in approximately 10% of cases (Risk is highest in the first and second trimesters.)
• Most intrauterine infections do not result in fetal developmental defects.

Diagnosis

• Mother: serologic assays for IgG and IgM against parvovirus B19

• Fetus ^[19]
  • PCR for parvovirus B19 DNA (amniotic fluid or blood)
  • Periodic ultrasound of fetal vessels for anemia and hydrops fetalis (every 1–2 weeks)
  • In cases of suspected anemia according to Doppler ultrasound, fetal hemoglobin levels are determined via the umbilical vein.

Treatment

• Intrauterine fetal blood transfusion in cases of severe fetal anemia
• Additional platelet transfusion if thrombocytopenia is also present

Prevention

• Hand hygiene (frequent hand washing)
• Pregnant women with risk factors for TORCH infection should avoid potentially contaminated workplaces (e.g., schools, pediatric clinics).

Epidemiology

Most mothers have been vaccinated, so congenital infection is very rare. ^[20]

Pathogen

Rubella virus

Transmission

• Mother
  • Mainly via airborne droplets
  • See “Rubella.”
• Fetus
  • Transplacental from infected mother
  • Risk of fetal infection is high in the first trimester, decreased in the second trimester and then increased again in the third trimester. ^[21]
  • Risk of congenital rubella syndrome ^[22]
    • 1–12 weeks gestation (period of organogenesis): highest risk
    • 12–20 weeks gestation: very low
    • > 20 weeks gestation: no documented cases

Clinical features ^[22]

• Intrauterine rubella infection: miscarriage, preterm birth, fetal growth restriction (especially likely if infection occurs during the first trimester)
• Congenital rubella syndrome
  • Triad of congenital rubella syndrome
    • Cardiac defect; : most common defect (e.g., patent ductus arteriosus, pulmonary artery stenosis)
    • Cataracts: Other eye manifestations may also occur later in life, including glaucoma and salt and pepper retinopathy (abnormal retinal pigmentation)
    • Cochlear defect: bilateral sensorineural hearing loss
  • Early features
    • Hepatosplenomegaly, jaundice
    • Hemolytic anemia, thrombocytopenia
    • Petechiae and purpura, i.e., blueberry muffin rash (due to extramedullary hematopoiesis in the skin)
    • Transient meningitis and/or encephalitis
    • Pneumonia
  • Late features
    • CNS defects: microcephaly, intellectual disability, panencephalitis
    • Skeletal abnormalities
    • Endocrine disorders (e.g., diabetes, thyroid dysfunction)
    • Vascular disease
    • Immune defects

Diagnosis ^[23]

• Newborn and mother
  • PCR for rubella RNA (throat swab, CSF)
  • Serology (abnormally high or persistent concentrations of IgM and/or IgG antibodies)
  • Viral culture (nasopharynx, blood)
• Fetus
  • IgM antibody serology (chorionic villi, amniotic fluid)
  • PCR for rubella RNA (chorionic villi, amniotic fluid)

Treatment

• Intrauterine rubella infection ^[23]
  • < 16 weeks: Counsel about potential maternal-fetal transmission and the possibility of terminating the pregnancy.
  • > 16 weeks: reassurance and symptomatic therapy (e.g., acetaminophen)
• Congenital rubella syndrome: supportive care (based on individual disease manifestations) and surveillance (including monitoring for late-term complications)

Prevention ^[24]

• Immunization of seronegative women before pregnancy
• Nationally notifiable condition: Suspected congenital rubella syndrome must be reported to the local or state health department.

CCC-Triad of congenital rubella syndrome: Cataracts, Cochlear defects, Cardiac abnormality

Overview

Epidemiology

∼ 0.5–1% of live births per year in the US ^[25]

Pathogen

Cytomegalovirus

Transmission

• Mother: via CMV-contaminated blood, urine, saliva, and genital secretions
  • Blood transfusions
  • Sexual transmission
  • Droplet transmission
  • Transplant-transmitted infection (e.g., bone marrow, lungs, kidneys)
  • See “Cytomegalovirus infection.”
• Fetus: : transplacental transmission from an infected mother
• Newborn: : during birth or postnatal via breastmilk from infected mother

Clinical features ^[26]

• Fetal infection
  • Increased risk of fetal demise
  • IUGR
  • Oligohydramnios or polyhydramnios, placental abnormalities
• Newborn infection
  • Severity
    • Subclinical infection (∼ 90%): ∼ 10% go on to develop a late complication (most commonly hearing loss) ^[26]
    • Symptomatic infection at birth (∼ 10%): ∼ 70–80% go on to develop a late complication.
  • CNS findings
    • Hydrocephalus
    • Microcephaly .
  • Sensorineural hearing loss (∼ 30%) ^[27]
  • Chorioretinitis (∼ 10%)
  • Nonspecific findings (similar to other TORCH infections)
    • Petechiae, purpura (blueberry muffin rash)
    • Hepatosplenomegaly, jaundice
    • Small for gestational age (SGA)
    • Seizures, lethargy, poor suck
    • Hemolytic anemia, thrombocytopenia
    • Pneumonia
  • Late complications
    • Hearing loss, vision impairment
    • Psychomotor retardation, intellectual disability
    • Dental abnormalities

Diagnosis ^[28][29]

• Fetus and newborn
  • CNS imaging: hydrocephalus, periventricular calcifications, or intraventricular hemorrhage
  • Ultrasound: periventricular calcifications, hyperechogenic foci (bowel and liver, ascites), and hydrops fetalis
• Newborn and mother
  • CMV IgM antibodies (blood)
  • Viral culture or PCR for CMV DNA (urine, saliva)
• Fetus
  • Viral culture or PCR for CMV DNA (amniotic fluid)
  • CMV IgM antibodies (fetal blood)

Differential diagnosis ^[28]

• Congenital toxoplasmosis
  • Causes chorioretinitis, hydrocephalus, and intracranial calcifications
  • Intracranial calcifications in congenital toxoplasmosis typically show ring-enhancement.

Treatment

• Fetus
  • Severe anemia: intrauterine blood transfusions
  • Thrombocytopenia: platelet transfusions
• Newborn
  • Supportive therapy of symptoms (e.g., fluid and electrolyte imbalances, anemia, thrombocytopenia, seizures, secondary infections)
  • Ganciclovir, valganciclovir, or foscarnet
• Mother: valacyclovir is the only therapy approved during pregnancy ^[30]

Prevention

• Frequent hand washing, especially after contact with bodily secretions of small children (e.g., diaper changing)
• Avoidance of food sharing with children
• Avoidance of kissing small children on the mouth

Congenital toxoplasmosis may manifest with symptoms resembling congenital CMV infection.

Epidemiology

∼ 1:3,000–10,000 live births per year ^[31]

Pathogen

Mainly herpes simplex virus 2 (HSV-2); in rare cases HSV-1

Transmission ^[31]

• Mother
  • Primary infection: contact with contaminated oral secretions via small skin lesions
  • Reactivation: usually in immunocompromised individuals
  • See “Herpes simplex virus infections.”
• Fetus: transplacental transmission from an infected mother (rare)
• Newborn: : perinatal transmission during birth (∼ 30% transmission rate if mother has not yet undergone seroconversion at time of delivery)

Clinical features ^[32]

• Intrauterine HSV infection (∼ 5% of cases)
  • Fetal demise, preterm birth, very low birth weight
  • Microcephaly, hydrocephalus, and other CNS defects
  • Microphthalmia and chorioretinitis
  • Vesicular skin lesions
• Perinatal and postnatal transmission
  • Skin, eye, and mouth disease
    • Vesicular skin lesions
    • Keratoconjunctivitis leading to cataracts, chorioretinitis
    • Vesicular lesions of oropharynx
  • CNS disease
    • Meningoencephalitis (manifesting with fever, lethargy, irritability, poor feeding, seizures, bulging fontanelle)
    • Possibly vesicular skin lesions
  • Disseminated disease
    • Features similar to those of sepsis, with organ involvement (e.g., liver, CNS, lungs, heart, adrenal glands, kidneys, GI tract)
    • Vesicular skin lesions (may not appear until late in disease course)

Diagnosis

• Mother: typically a clinical diagnosis
• Fetus: The ultrasound may show CNS abnormalities.
• Newborn: Perform neonatal HSV testing.
  • Standard: viral culture of HSV from skin lesions, conjunctiva, oro/nasopharynx, or rectum
  • Alternative: PCR for HSV DNA (CSF, blood)

Treatment ^[33]

• Newborn and mother: IV acyclovir or valacyclovir
• Additionally in newborns: supportive therapy of fluid/electrolyte imbalances, SIRS, septic shock, seizures, secondary infections, etc.

Prevention of neonatal HSV infection ^[34]

• Antiviral therapy (acyclovir) beginning at 36 weeks of gestation for individuals with a known history of HSV lesions
• Cesarean delivery in women with active genital lesions or prodromal symptoms (e.g., burning pain)

HSV should be considered in infants up to 6 weeks of age with vesicular skin lesions, persistent fever with negative cultures, and/or symptoms of meningitis, encephalitis or sepsis.

Skin, eye, and mouth disease caused by HSV has a good prognosis if detected and treated early.