Congenital Infections

Congenital infections are a group of prenatal and perinatally acquired infections of the newborn with similar characteristics that are associated with significant morbidity and mortality.

Transmission

Pre-natal Infections:

• Acquired transplacentally
• The most frequent
• Developmental anomalies – More common
• Intrauterine growth restriction

Perinatal Infections:

• Acquired shortly before or during delivery.
• May be asymptomatic at birth
• Symptoms appear after the incubation period

An acronym used for congenital infections of the newborn – TORCH:

• Toxoplasmosis.
• Others (syphilis, HIV, coxsackie virus, hepatitis B, varicella-zoster).
• Rubella.
• Cytomegalovirus disease
• Herpes simplex disease.

The overall incidence of these infections is about 2.5% in live newborns. The diagnosis from birth of these infections is very important because the long-term prognosis is affected.

Intrauterine infections can lead to:

• Abortion
• Stillbirth
• Prematurity
• IUGR (Intrauterine Growth Restriction)
• Congenital malformations

The severity or the clinical manifestation of these infections at fetus or newborn depends on:

• Gestational age – Abortions and stillbirth in early infection.
• Virulence of the pathogen
• Primary or recurrent infections of the mother;
• If the fetus or newborn received transfer of antibodies from the mother

• Premature delivery;
• IUGR (Intrauterine Growth Restriction) or intrauterine death;
• Jaundice, petechia, or purpura;
• Hepatosplenomegaly, anemia, thrombocytopenia;
• Hydrocephaly, microcephaly, intracranial calcification;
• Chorioretinitis, cataracts, microphthalmia;
• Pneumonitis, hepatitis;
• Myocarditis and cardiac abnormalities.

Caused by a DNA herpes virus called Cytomegalovirus (CMV).

It is the most common congenital infection.

The majority of congenital CMV infections are asymptomatic.

Both primary infection in the mother and reactivation of latent infection can cause disease in the infant.

The severity of the disease in the infant is worse if the infection is acquired earlier in pregnancy.

Pathogenesis

Neonatal

1. Antenatal (in utero) – 80-96% of cases
   • Primary Maternal Infection
   • Recurrent Maternal Infection
2. Perinatal
3. Postnatal

Childhood

1. Horizontal Transmission
   • CMV excreted in saliva, urine, stool, tears
2. Organ Transplantation
   • Kidney, marrow, heart, liver, blood (leukocytes)

Clinical Features

Asymptomatic in 90% of cases

• Low birth weight for gestational age
• Thrombocytopenia – purpura, petechiae
• Anemia
• Pneumonitis
• Jaundice and hepato-splenomegaly
• Hepatitis
• Blueberry muffin rash
• Chorioretinitis
• Intellectual impairment
• Sensorineural hearing loss
• Seizures
• Microcephaly
• Intracerebral periventricular calcifications
• Generally with no symptoms of encephalitis

Investigations

• Diagnostic
• Virology
• Gold standard
• Testing of urine, saliva, blood, CSF, nasopharynx
• Serology
• ELISA - CMV-specific IgM
• Testing of neonatal blood specimens, cord sampling
• Others
• PCR
• Serum
• CBC - anemia, thrombocytopenia
• Conjugated, unconjugated hyperbilirubinemia
• Elevated hepatic transaminases
• CSF
• Elevated protein content
• Imaging Studies
• CT (Head)
• Periventricular calcifications
• Can be identified in 25-50% of symptomatic infants

Therapy

Ganciclovir

• May halt the progression of hearing loss

Causative Agent: Protozoan infection caused by Toxoplasma gondii.

Transmission: Acquired through:

• Ingestion of raw or undercooked meat, particularly from cattle.
• Ingestion of infectious oocysts found in cat or bird feces.

Impact During Pregnancy: The severity of the disease depends on the timing of infection:

• In the 1st trimester, there's a 17% chance of spontaneous abortion.
• In the 2nd trimester, a 25% chance of spontaneous abortion or severe disease.
• In the 3rd trimester, 65% may have subclinical disease.

Fetal Risks:

• Early infections are more likely to result in fetal death.
• The severity of fetal symptoms is directly related to the timing of infection.

High-Risk Period: Occurs between the 10th and 24th gestational weeks.

• During this time, the placental blood flow develops, and the fetus is particularly vulnerable.

Transmission Rate: Overall transmission rate is approximately 30-40%.

Increased Risk in Later Pregnancies: Risk of transmission is higher in later pregnancies due to increased blood flow.

Transmission Route: Toxoplasmosis is only acquired through transplacental transmission to the fetus.

Clinical Manifestations of Congenital Toxoplasmosis

Transmission: Toxoplasmosis is typically acquired during a primary infection in the mother. This maternal infection can be asymptomatic or present with non-specific symptoms.

Neonatal Presentation:

• Most cases (70-90%) are asymptomatic at birth.
• The classic triad of symptoms includes:

• Chorioretinitis (inflammation of the retina).
• Hydrocephalus (accumulation of cerebrospinal fluid in the brain).
• Intracranial calcifications (abnormal calcium deposits in the brain).

Other Possible Symptoms:

• Fever, rash, hepatosplenomegaly (enlarged liver and spleen), and microcephaly (abnormally small head).
• Seizures, jaundice (yellowing of the skin and eyes), thrombocytopenia (low platelet count), and lymphadenopathy (enlarged lymph nodes).

CNS Manifestations:

• Hydrocephalus can lead to increased intracranial pressure.
• Motor and intellectual retardation may develop due to brain damage.
• Seizures can occur as a result of brain involvement.
• Sensorineural hearing loss may be present.

Clinical Features of Congenital Toxoplasmosis

Ocular Manifestations:

• Chorioretinitis: Inflammation and damage to the choroid and retina, which can affect vision.
• Optic Nerve Atrophy: Degeneration of the optic nerve, leading to vision problems.
• Microphthalmia: Abnormally small eyes.
• Blindness: Severe cases of chorioretinitis can result in blindness.

It's important to note that initially asymptomatic infants are still at a high risk of developing ocular abnormalities, especially chorioretinitis.

Furthermore, some patients who appear normal at birth may later develop symptoms of the disease, potentially leading to hearing loss or intellectual disability.

Diagnosis of Congenital Toxoplasmosis

Serologically:

• IgM Specific Antibodies to Toxoplasma: Detection of specific IgM antibodies in the blood, indicating recent infection.

Other Diagnostic Methods:

• PCR (Polymerase Chain Reaction): Molecular technique used to detect Toxoplasma DNA in clinical samples.
• Histological Examination of the Placenta: Microscopic analysis of placental tissue to identify Toxoplasma infection.
• Skull X-ray or CT Scan: Imaging studies to identify diffuse intracranial calcifications, a characteristic sign of congenital Toxoplasmosis.
• CSF Analysis (Cerebrospinal Fluid): Examination of CSF for eosinophilia (an increase in eosinophils) and pleocytosis (an abnormal increase in cells), which can be indicative of the disease.
• Ophthalmologic Examination: Comprehensive eye examination to detect ocular manifestations, such as chorioretinitis.
• Auditory Tests: Evaluation of hearing function using auditory evoked potentials, as hearing loss is a potential complication of congenital Toxoplasmosis.

Treatment of Congenital Toxoplasmosis

Medical Therapy:

• Pyrimethamine + Sulfadiazine: Combination therapy administered for a duration of 12 months to treat the infection.
• Folinic Acid: Supplementation with folinic acid may be provided alongside the treatment regimen.
• It's important to note that while treatment can eradicate the Toxoplasma organism, it does not reverse neurologic damage that may have occurred.

Prevention of Congenital Toxoplasmosis

Preventing Infection in Pregnant Women:

• Proper Cooking of Food: Ensuring that meat and vegetables are thoroughly cooked to kill the Toxoplasma cysts, reducing the risk of infection.
• Thorough Hand Hygiene:
• After Preparing Raw Meat and Vegetables: Preventing potential contamination from handling raw food.
• After Contact with Cats: Reducing the risk of infection from contact with cat litter or soil contaminated with cat feces, which can contain Toxoplasma oocysts.

After gestational week 20:

• Congenital Defects Do Not Appear:
• During this later stage of pregnancy, congenital defects typically do not manifest in the fetus even if the mother contracts Rubella.
• Chronic Infection (Inflammation) Is Possible:
• However, chronic infection with Rubella can occur, which may lead to persistent inflammation and affect various organs in the developing fetus.
• Affected Organs May Include:
• Eyes
• Hearing
• Central Nervous System (CNS)

Clinical Features of Congenital Rubella Infection

General Presentation:

• Congenital Malformations:
• Rubella infection during pregnancy can lead to congenital malformations in the newborn.
• At birth, these infants may present with a generalized disease.
• Some infants may appear "asymptomatic" at birth, but the infection can have hidden consequences.

Congenital Malformations May Include:

• Cardiovascular Abnormalities:
• Examples include patent ductus arteriosus, pulmonary artery stenosis, and ventricular and atrial septal defects.
• Ocular Manifestations:
• These may involve cataracts, chorioretinitis, and glaucoma.
• Hearing Loss (Sensorineural):
• Infants with congenital Rubella infection are at risk of sensorineural hearing loss (SNHL).
• Central Nervous System (CNS) Damage:
• This can result in conditions such as microcephaly, mental retardation, and spastic paralysis.

Symptomatic Infection at Birth: Generalized Newborn Disease

• Low Birth Weight: Infants born with congenital Rubella infection may have a lower birth weight.
• Jaundice and Hepatosplenomegaly: Clinical signs often include jaundice (yellowing of the skin) and hepatosplenomegaly (enlargement of the liver and spleen).
• Thrombocytopenia: These newborns may have low platelet counts, increasing the risk of bleeding.
• Purpuric (Blueberry Muffin) Rash: A distinctive rash, resembling blueberry muffin spots, can be observed.
• Pneumonitis: Some infants may develop pneumonia, leading to respiratory symptoms.
• Meningoencephalitis: Severe cases can involve inflammation of the meninges (meningitis) and the brain (encephalitis).

"Asymptomatic" Infection at Birth

Infants with congenital Rubella infection may initially appear asymptomatic at birth, but later, they may manifest various health issues:

• Lower Birth Weight: Even in "asymptomatic" cases, affected infants may have a lower birth weight compared to uninfected newborns.
• Late-Onset Symptoms: Some complications become apparent over time, including:
• Sensorineural Hearing Loss (SNHL): Gradual hearing loss may develop, affecting the infant's auditory abilities.
• Eye Problems: These can encompass conditions like glaucoma and cataracts.
• CNS Damage: Central Nervous System damage may lead to behavioral disorders and mental retardation.

Diagnosis

Postnatally:

1. Serology - Detection of Antibodies: Serological testing involves the detection of antibodies. It includes:
• IgM: Presence of IgM antibodies indicates evidence of fetal infection. IgM antibodies are produced solely by the child.
• IgG: Initially, IgG antibodies can be of maternal origin, but later, only the child's IgG antibodies remain.
2. Viral Culture: Specimens from various sources such as throat, urine, blood, and cerebrospinal fluid (CSF) can be cultured to detect the virus.

Prenatally:

1. Viral Culture of Amniotic Fluid: Amniotic fluid can be collected and tested for the presence of the virus.
2. RNA Hybridization from Biopsied Chorionic Villi: Invasive procedures like chorionic villus sampling can provide tissue samples for RNA hybridization testing.

Prevention

MMR Vaccine (Live Attenuated): Rubella can be prevented through vaccination with the MMR (Measles, Mumps, and Rubella) vaccine. This vaccine is administered:

1. during the child's second year of life
2. at the beginning of elementary school

Pregnant Women - Not to Vaccinate: Pregnant women should not receive the MMR vaccine because viremia (presence of virus in the bloodstream) and fetal infection can occur. It is recommended to avoid pregnancy for at least 3 months after vaccination to minimize potential risks.

Herpes Simplex Virus Types 1 and 2 (HSV-1 and HSV-2)

• HSV-1: This type is commonly associated with oral herpes (cold sores) and can also cause genital herpes. HSV-1 is primarily transmitted through oral-to-oral contact or via contact with oral secretions.
• HSV-2: HSV-2 is predominantly responsible for genital herpes, although it can also lead to oral herpes. Genital herpes is typically transmitted through sexual contact, and it is a major sexually transmitted infection (STI).
• Neonatal Herpes: Neonatal herpes can occur when an infant is exposed to HSV during childbirth. The risk of transmission to the neonate depends on various factors, including the mother's HSV infection status.

Epidemiology

• Transmission During Delivery: Approximately 90% of HSV infections in neonates occur during the process of childbirth.
• Prevalence of HSV-2: HSV-2 is responsible for around 80% of neonatal herpes cases.
• Genital Herpes Symptoms: It's important to note that most often, symptoms of genital herpes are absent in newborns. However, the risk of transmission to the neonate varies based on the mother's herpes infection status:
• Mother's Primary Infection: Neonates born to mothers with a primary HSV infection during pregnancy have a higher risk of transmission.
• Recurrent Genital Herpes: Neonates born to mothers with recurrent genital herpes have a lower risk of transmission.

Pathogenesis of Neonatal Herpes

Neonatal herpes can result from herpes simplex virus (HSV) infection in newborns and is classified into two primary modes of transmission:

1. Intrauterine Infection (Rare):
   • Transmission occurs via transplacental transfer of the virus from a viremic mother to the fetus.
   • The virus can disseminate to multiple organs within the fetus, with the central nervous system (CNS) being the most frequently affected.
2. Intrapartum Infection:
   • The source of infection is typically maternal vaginal secretions during childbirth.
   • Entry points for the virus include the conjunctiva, leading to localized infection, and the respiratory mucosa.
   • The virus can then disseminate via hematogenous spread to various organs.
   • Retrograde axonal transport to the CNS is another possible route of dissemination.
   • Symptoms of neonatal herpes usually develop within the first seven postnatal days following exposure.

Clinical Spectrum of Neonatal Herpes Infection

Neonatal herpes infection can manifest across a spectrum of severity, ranging from mild symptoms to severe and potentially life-threatening conditions:

• Mild Disease:
  • Vesicles (blisters) or scarring may appear on the skin or mucous membranes.
• Severe Disease:
  • Generalized (disseminated) infection affecting multiple organ systems.
  • Encephalitis as the sole clinical manifestation, involving the brain.
  • Pneumonia as the sole clinical manifestation, affecting the respiratory system.
• Disseminated Disease:
  • May involve various organs, such as the liver (hepatitis), heart (myocarditis), lungs (pneumonia), and brain (encephalitis).
  • Other potential manifestations include chorioretinitis, keratoconjunctivitis, and a rash characterized by vesicles or bullae (fluid-filled lesions), which can aid in the diagnostic process.

Diagnosis of Neonatal Herpes Infection

Diagnosing neonatal herpes infection involves obtaining various specimens from the affected infant and utilizing diagnostic methods to confirm the presence of the virus:

• Specimens:
  • Swabs and aspirates from vesicles (blisters), conjunctiva (eye), nasopharynx (nose and throat), and rectum.
  • Collection of blood, cerebrospinal fluid (CSF), urine, and stool samples for analysis.
• Diagnostic Methods:
  • Viral culture to grow and identify the virus in collected samples.
  • PCR (Polymerase Chain Reaction) to detect evidence of viral DNA, providing a highly sensitive diagnostic tool.

Treatment

The primary treatment for neonatal herpes infection is intravenous Aciclovir administration.

Prevention of Neonatal Herpes Infection

Preventing neonatal herpes infection depends on the circumstances of the infection:

• Primary Infection of Mother:
  • If the mother experiences a primary herpes infection during pregnancy, the risk for the child is approximately 50%.
  • Immediate introduction of acyclovir therapy for the mother is crucial to manage the infection and reduce the risk to the child.
• Recurrent Genital Herpes:
  • When a mother has recurrent genital herpes, certain steps should be taken:
  • Obtain swabs for viral diagnosis.
  • If symptoms are present in the child, introduce acyclovir therapy.
  • If no symptoms are present in the child, follow up with appropriate monitoring.

Transmission

• Hematogenous (Transplacental): The most common mode of transmission.
• Contact with Mother's Chancre During Birth: A rare mode of transmission.

Timing of Symptomatic Disease

• Symptomatic at Birth
• Late Neonatal Onset: Within 5 weeks postpartum.
• Late Onset: After 2 years of age.

Symptomatic Infection at Birth

• Stillbirth
• Generalized Neonatal Disease:
  • Low birth weight
  • Hepato-splenomegaly
  • Nonimmune hydrops + hemolytic anemia
  • Neutropenia and thrombocytopenia

Late Neonatal Onset

• Osteohondritis (metaphysitis), periostitis (new bone)
• Rash: maculopapular desquamative
• Syphilitic rhinitis (hemorrhagic)
• Hepatitis, lymphocytosis
• Keratitis
• CSF: pleocytosis + proteinorachia

Late Onset (≥2 years after birth)

Hutchinson triad:

• Interstitial keratitis
• 8th nerve damage (deafness)
• Hutchinson teeth

Diagnosis

For the diagnosis of congenital syphilis, the following serological tests are commonly used:

• Non-treponemal Antibodies: VDRL (Venereal Disease Research Laboratory), RPR (Rapid Plasma Reagin)
• Treponemal Antibodies: TPHA (Treponema pallidum hemagglutination assay)

Testing is recommended for:

• All pregnant women
• All newborns born to mothers with positive syphilis test results

Further evaluation of the child is warranted if:

• The mother's titers increase by ≥4-fold during pregnancy
• The child's titers are ≥4-fold higher than the mother's titers
• A child born to a positive mother is asymptomatic

In cases where a diagnosis of congenital syphilis is established, a lumbar puncture (LP) and cerebrospinal fluid (CSF) serology should be performed.

Therapy

The treatment for congenital syphilis typically involves intravenous administration of Penicillin G for a duration of 2 weeks.

Documenting the cure of congenital syphilis involves monitoring:

• Falling antibody titers at month 3, 6, and 12 following treatment
• In cases of neurosyphilis, cerebrospinal fluid antibody titers should be checked every 6 months for 3 years.

Epidemiology

• Source: Mother with genital infection
• Infection occurs during childbirth with the following risks:
• Up to 20% risk for pneumonia
• Up to 50% risk for conjunctivitis

Symptoms

• Conjunctivitis:
• Usually appears between days 5-14 of life
• Manifests as conjunctival redness and eyelid edema
• Discharge: Initially watery, then becomes purulent
• Duration: Typically around 2 weeks
• Scarring (pannus) is rare
• Pneumonia:
• Occurs between 2-19 weeks of age
• No fever
• Symptoms include dyspnea and attacks of "staccato" cough
• Chest X-ray findings consist of diffuse interstitial infiltrations and hyperinflations

Diagnosis

• Laboratory findings are nonspecific
• Slightly higher percentage of eosinophils

Pneumonia

• Serologic evidence

Conjunctivitis: Conjunctival Scraping

• Detection of antigens (DF, ELISA) is usually performed
• Direct microscopy or culture
• PCR (Polymerase Chain Reaction)

Differential Diagnosis

Neisseria gonorrhoeae Conjunctivitis

• Earlier onset: within the first 5 days postpartum
• More serious disease with corneal ulceration

Therapy of Chlamydia trachomatis

• Erythromycin PO (Oral) for 14 days for conjunctivitis and pneumonia
• Topical prophylaxis is useless