Introduction

Teratology is the study of congenital abnormalities, their causes, and the treatment options available for those affected.[1] These abnormalities are principally the result of infections, physical agents, metabolic conditions or chemicals and can cause death as well as physical, behavioral, and intellectual deficits.[2] The most widely accepted infectious teratogens are known as TORCH infections. If a woman is infected prenatally, perinatally, peripartum, or even postnatally, these pathogens are known to cause congenital birth defects. 

TORCH infections classically include:

• Toxoplasmosis
• Other Infections (Varicella, syphilis and Parvovirus B19)
• Rubella
• Cytomegalovirus (CMV)
• Herpes simplex virus (HSV)

TORCH infections have also been known to include Treponema pallidum, Hepatitis viruses, and human immunodeficiency virus (HIV).[3]

Development

In addition to passing horizontally (from person to person), TORCH infections can also transmit vertically (from mother to infant). When a pregnant woman becomes infected, the infection can spread to her unborn fetus. Generally, the earlier the exposure to the teratogen, the more deleterious its effects. Infection during the first trimester is likely to cause a more severe version of the congenital defects in the growing embryo. The later in pregnancy that an infection occurs, the more likely that the fetus will develop a neonatal infection rather than develop congenital abnormalities.[3]

Cellular

Transmission of viral or bacterial agents from mother to fetus is often transplacental, but the means by which these particles can cross the placenta and affect the fetus is not fully understood.[4][5]

Mechanism

Toxoplasmosis:

Toxoplasmosis results from infection with the parasite Toxoplasma gondii. This parasite goes through its reproductive stages in the intestines of the Felidae family and then gets expelled as an oocyst into the environment. Then, these oocysts cause toxoplasmosis through inhalation of fecal particles or by the ingestion of infected tissue. After infection of the mother, there is a transplacental transmission of the parasite to the fetus causing congenital toxoplasmosis. The likelihood of infection is the highest in the third trimester but the earlier in the pregnancy that the infection occurs, the more severe the manifestation of the congenital birth defects.[6][7]

Other:

Varicella-zoster virus (VZV) is an airborne DNA virus of the herpesvirus group that spreads by sneezing, coughing, or contact with active lesions.[8] It also passes from mother to fetus transplacentally.[9] There is an estimated 2% chance that an infant will develop congenital varicella syndrome if the mother contracts VZV during the first two trimesters.[10]

Syphilis is an infection of the spirochete Treponema pallidum and spreads by sexual exposure or vertical transmission. Vertical transmission most commonly occurs transplacentally but can also occur due to peripartum exposure to vaginal fluid. In women recently infected with syphilis, the probability of transmission is more than 80%.[11]

Parvovirus B19, a single-stranded DNA virus, is the only member of the Parvoviridae family that is pathogenic in humans. It passes through respiratory droplets, blood exposure, or vertically transmitted through the placenta.[12][13]

Rubella:

Rubella is a single-stranded, positive-sense RNA virus that gets transmitted from infected individuals through aerosols. It also passes from the infected mother to the fetus transplacentally.[14]

CMV:

CMV is a human-specific double-stranded DNA virus of the Herpesviridae family. Horizontal transmission is via the mucous membrane, blood transfusions or, organ transplants. It can pass from mother to fetus transplacentally but also from contact with cervical or vaginal secretions during the birthing process or by breastmilk postnatally. Though rarer, a woman with a latent CMV infection can infect her fetus if she becomes infected with an additional strain during pregnancy.[15]

HSV:

HSV-1 and HSV-2 are large, enveloped double-stranded DNA viruses. These viruses are passed from direct contact with mucous membranes, saliva or sores and can occur despite a lack of active infection. Once acquired, the virus often is asymptomatic or non-specific, which leads to the spread of the infection due to a lack of proper precautions. HSV-1 is more commonly found orally, while HSV-2 is more often a genital infection, but infection of either virus can occur anywhere on the body. This virus is primarily passed to the infant during delivery when the mother has an active infection with sores but has been known to occur during latent infections. While episodes of active HSV can be relatively rare after initial infection, pregnancy often triggers active infection in approximately 75% of HSV positive women. Infants born to mothers initially infected with HSV in the third trimester of pregnancy are at the highest risk for contracting neonatal HSV.[16][17]

Testing

Toxoplasmosis:

Diagnosing a patient with congenital toxoplasmosis requires proving the presence of either the parasite itself, through PCR, microscopy or inoculation, or by identifying the toxoplasma gondii specific IgG, IgM or IgA humoral response. Brain imaging (calcifications, hydrocephaly, and microcephaly) and retinal exams (chorioretinitis) can be used to determine the severity of symptoms but are not considered diagnostic.[3][18]

Other:

The mother’s history of chickenpox clinically confirms congenital varicella syndrome (CVS) during the pregnancy and the presence of congenital skin lesions following dermatomes in the infant. It is also diagnosable by detecting VZV DNA in either amniotic fluid or fetal blood.[19]

Congenital syphilis diagnosis is by a combination of serology and the presence of clinical symptoms. Often this diagnosis is presumptive, and an infant will need to be periodically checked by a physician if it is at risk for congenital syphilis.[20]

Congenital parvovirus B19 is most accurately diagnosed using a PCR assay to isolate parvovirus B19 DNA in the amniotic fluid or fetal blood. Clinicians can measure it with IgM antibody serology.[21]

Rubella:

To diagnose a patient with congenital rubella, the virus itself can be isolated, through PCR or culture, or the virus’ RNA can be isolated through reverse transcriptase PCR of bodily fluids. The presence of rubella specific IgM and IgG is also enough to base a diagnosis of congenital rubella.[3]

CMV:

Despite the high disease burden, there are still no screening programs for mothers or infants to detect CMV infections. In infants, clinical symptoms can go absent or can be ambiguous enough not to suspect congenital CMV. In the past, testing for congenital cytomegalovirus involved using urine or saliva samples to isolate the virus in tissue cultures.[22] More recently, real-time PCR, which gets repeated if positive, is being used to detect the virus, which is less resource-intensive and could potentially support more widespread screening in the future.[23] In pregnant women, CMV diagnosis can also be through CMV specific IgM and IgG serology.[24]

HSV:

Congenital HSV is detected by either HSV isolation on culture or by PCR. Today, PCR is becoming a more common test due to its more accurate and precise ability to diagnose an HSV infection. Screening for HSV antibodies is problematic as it is not type-specific, and oral HSV-1 infections are prevalent and do not pose the same risk as a genital HSV-2 infection.[25] 

TORCH IgG or IgM Panel Testing:

There are lab panels collectively performed to look for specific IgM or rising IgG titers in fetal, cord, or infant blood. The panel will include antibody testing for Toxoplasmosis, Rubella, CMV, HSV 1/2, and VZV. Positive tests will indicate congenital infection by one of these agents. These are more straightforward and easier tests to be performed collectively for any neonate suspected clinically to be suffering from the above named congenital infections.

Clinical Significance

Toxoplasmosis:

A perinatal, or more rarely prenatal, initial infection of Toxoplasma gondii classically causes a baby to be born with retinal lesions, hydrocephalus, and intracranial calcifications but is also associated with anemia, jaundice, hepatosplenomegaly, and thrombocytopenia. Approximately 75% of those infected in utero will be asymptomatic at birth, but as they grow, they will be at significant risk for developing motor dysfunction, cerebellar dysfunction, microcephaly, seizures, chorioretinitis, intellectual disabilities, and sensorineural hearing loss.[26] Toxoplasmosis in healthy adults is typically asymptomatic.[3] The prevalence of congenital toxoplasmosis is approximately 0.1 to 0.01 per 1000 live births and is attributable to pregnant women eating undercooked meat and cleaning cat litter boxes.[3]

Other:

Despite there being 60 million new cases of varicella infection each year, CVS is rather rare, only 130 cases reported since 1947, but mortality rates are 30% in the first few months. CVS often causes skin lesions, limb hypoplasia, neurological abnormalities, and developmental delay. There is no evidence that infants born asymptomatic will develop symptoms in the future.[27][28]

Syphilis infects 5.6 million people per year.[11] Pregnancies where the woman contracts syphilis and is not treated result in stillbirth 25% of the time, neonatal death 14% of the time and in 41% of cases the infant is born with congenital syphilis. Congenital syphilis can result in neurodevelopmental deficits, musculoskeletal deformities as well as renal and gastrointestinal issues. The classical Hutchinson triad described in infants with congenital syphilis consists of Hutchinson teeth (small, peg-shaped, notched upper incisors), interstitial keratitis and sensorineural hearing loss. There is only a 20% chance that an untreated affected mother will have a healthy infant. The longer the fetus is exposed to T. pallidum in utero the bleaker the outcome. Pregnant women can be treated with benzathine penicillin G to diminish the bacterial load and decrease the likelihood of complications during pregnancy.[20]

Parvovirus B19 only affects 1 to 5% of pregnant women, but the consequences can be devastating. This infection can lead to spontaneous abortion, severe neurodevelopmental deficits, and hydrops fetalis but 67 to 76% of infants are born to mothers infected with parvovirus B19 are unaffected.[21][12]

Rubella:

Infants perinatally infected with rubella are often asymptomatic but may later develop hearing loss, blindness, heart defects, encephalitis, endocrinopathies as well as behavioral and intellectual deficits. Children suspected of having congenital rubella must be surveilled carefully for the onset of new symptoms. The prevalence of congenital rubella is as high as approximately 175 per 100000 live births in the developing Americas.[29][30][31] In general, the earlier the fetus is infected with rubella during pregnancy, the more severe the congenital deficits are. Up to 85% of babies born to mothers infected with rubella during the first trimester may develop the congenital rubella syndrome which consists of sensorineural deafness, cataracts, congenital heart problems, central nervous system deficits, impaired mental development, bone defects, and hepatosplenomegaly. 

CMV:

Though commonly asymptomatic in healthy adults, CMV affects an estimated 60% of people in the United States (age-adjusted).[32] Additionally, CMV is the number one cause of infection-induced birth defects. Congenital CMV affects one in every 150 live births globally.[33] CMV is also the leading cause of nongenetic congenital hearing loss. Approximately 7 to 10% of infants with congenital CMV develop clinical manifestations. These include petechiae, jaundice, hepatosplenomegaly, chorioretinitis as well as neurological deficits, which consists of physical and mental retardation, deafness, and even death in about 10% of patients. Many of these infants are born asymptomatic and lack proper screening for congenital CMV. They are likely to develop these issues later in life. It is common practice to treat symptomatic CMV positive infants with six months of valganciclovir. Asymptomatic infants customarily receive no treatment.[34][23][15][22] 

HSV:

Approximately 50 to 70% of people in developed countries and nearly 100% of those in developing countries are seropositive for oral herpes simplex virus (HSV-1). Genital herpes simplex virus (HSV-2) is present in approximately 10 to 40% of the population and about 22% of pregnant women.[16][25] These viruses affect a huge percentage of the population and are incurable and require lifetime management. Neonatal herpes is uncommon, but symptoms are severe and can be deadly. Symptoms include viral sepsis, organ failure (lung, liver), disseminated intravascular coagulation, encephalitis, vesicular rash, seizures, bulging fontanelle, and death. Acyclovir, an anti-viral treatment, is available for affected infants but must be administered promptly to afford the most protection to the infant. If an HSV infection is suspected, a cesarean delivery is the recommended approach as 85% of neonatal HSV infection is peripartum.[16]