Vertical Transplacental Infections

Etiology

Maternal infection with the pathogen precludes fetal acquisition of a transplacental infection. Various transmission routes can result in maternal infection, including sexual contact, consumption of contaminated food, or vectors such as insects or ticks. However, the mechanisms by which pathogens traverse the placental barrier to affect the developing fetus are not fully understood and differ among pathogens. Specific placental cell types play a crucial role in this process, including cytotrophoblasts and syncytiotrophoblasts, which act as the primary barrier between the maternal and fetal blood. Extravillous trophoblasts invade maternal tissues, establishing a connection with the maternal immune system.[1] For a more comprehensive discussion of the immunological mechanisms at the maternal-fetal placental interface, please see StatPearls' companion reference entitled "Immunology at the Maternal-Fetal Interface." Generally, after a pregnant individual acquires a primary infection, the pathogen will circulate in the maternal bloodstream and establish a route to traverse the placenta by infecting several of these cell types. Alternatively, in the presence of multiple infectious agents or placental trauma, weakening of the placental barrier may permit maternal and fetal blood interaction that leads to fetal infection.

Sexually Transmitted Infections

Syphilis is the clinical manifestation of infection with the spirochete Treponema pallidum, and maternal infection can result in fetal infection.[2] Previously, experts believed that congenital syphilis could only be acquired after the first trimester of pregnancy.[3] However, it is now widely accepted that maternal syphilis at any stage (primary, secondary, latent, tertiary) carries the potential for congenital syphilis infection throughout the pregnancy. Congenital infection is typically more severe when acquired later in gestation.[3][4][2][5] For a more comprehensive discussion of syphilis in nonpregnant individuals, please see StatPearls' companion reference "Syphilis." For a more detailed discussion of syphilis in pregnancy, please see "Congenital and Maternal Syphilis."

Human herpesvirus 1 (HHV-1) and Human herpesvirus 2 (HHV-2) are also sexually transmitted. Approximately 5% of cases of herpetic infections are transmitted transplacentally. Although transplacental infection typically results in more severe fetal infections, perinatal acquisition is much more common (85%). Fetal outcomes are thought to be better when infections with alphaherpesvirinae are acquired at an earlier gestational age.[6][7][8] For a more detailed discussion of congenital herpes simplex, please see StatPearl's companion reference "Congenital Herpes Simplex."

HIV, Hepatitis B virus (HBV), and Hepatitis C virus (HCV) can be maternally acquired via sexual contact, intravenous drug use, or other blood or body fluid exposures. Vertical transmission of HIV is thought to occur primarily in the intrapartum period.[9] Throughout pregnancy, the risk of fetal acquisition of HIV is correlated with the maternal HIV viral load. A recent study demonstrated no vertical transmission of HIV when the viral load was undetectable at the time of delivery.[10] The mechanism of in utero HIV transmission is incompletely understood but estimated to account for 5% to 10% of cases, with suspected mechanisms involving infection of the trophoblasts and transcytosis with HIV in the third trimester.[9] Please see StatPearl's companion reference "HIV in Pregnancy" for more detail.

A minority of cases of HBV are vertically transmitted by the transplacental route (3.7%).[11] According to one study, the suspected pathophysiologic mechanisms of viral transmission center around maternal hepatitis B e antigen (HBeAg) positivity, threatened preterm labor, and HBV in the villous capillary endothelial cells of the placenta.[11] This study also confirmed that transplacental leakage of maternal blood can cause intrauterine infection.[11] Emerging evidence also demonstrates that HBV infection of maternal peripheral blood mononuclear cells plays a critical role in intrauterine infection.[12] 

These peripheral mononuclear cells are also involved in the transmission of HCV to the fetus; transmission is also affected by maternal HCV viremia and coinfection with HIV.[13][14] HCV is unique because intrauterine infection is thought to make up the majority of vertical rather than perinatal transmissions. Furthermore, fetal infection is primarily established in the second or third trimester, though transmission can rarely occur in the first trimester.[15] Additional discussion of the transmission of the hepatidites can be found in StatPearl's companion reference, "Pregnancy and Viral Hepatitis."

It is suspected that CMV is also transmitted via sexual contact in addition to other body fluids like saliva; CMV can be acquired when in close contact with children.[16] CMV is very common; the seropositivity of women of childbearing age is estimated to be 86% globally.[17] Thus, primary CMV infection during pregnancy is less common, but when it occurs, fetal outcomes are significantly worse compared to secondary maternal infection.[18] Fetal outcomes are also worse when CMV is acquired early in the pregnancy.[19] Though CMV is known to infect villous cytotrophoblasts and blood vessels in the villous core, even without actual fetal transmission, this damage to the placenta can also cause intrauterine growth restriction.[20] Further discussion may be found in StatPearls' companion reference, "Congenital Cytomegalovirus Infection."

Foodborne Illness

The consumption of contaminated food by the pregnant individual is a well-known route for acquiring toxoplasmosis, caused by the parasitic protozoan Toxoplasma gondii, and listeriosis, caused by the gram-positive facultative intracellular bacillus, Listeria monocytogenes. Pregnant individuals can acquire toxoplasmosis by consuming T gondii oocysts in contaminated food, water, or soil (eg, cat litter) or by ingestion of tissue cysts in infected meat.[21] Oocysts and tachyzoites are other forms of T gondii, the latter of which is the mobile form known to infect a fetus transplacentally.[22] Other sources of congenital T gondii infection include reactivation of latent disease in a pregnant individual or reinfection with a different, more virulent strain.[21] Please see StatPearl's companion references "Toxoplasmosis" and "Congenital Toxoplasmosis" for further discussion.

Listeriosis can be contracted from eating foods made with unpasteurized milk, deli meats, and ready-to-eat food that has not been properly cooked or is contaminated after cooking.[23][24] L monocytogenes has proven to have a specific tropism for the placenta, with significantly increased fetal death occurring when infection is established before 29 weeks of gestation.[23][25] 

Illness Acquired Via Airborne Transmission

Human parvovirus B19 (B19V) is the etiologic agent of the common childhood disease erythema infectiosum and is spread via respiratory droplets. Infection with B19V most frequently occurs among those with repeated contact with school-aged children.[26][27] Although often asymptomatic, once a pregnant individual is infected, it is suspected that parvovirus B19 infection of endothelial cells within placental villi, rather than syncytial and cytotrophoblast, plays the primary role in transplacental infection of the fetus.[28] When parvovirus B19 fetal infection occurs before 20 weeks of gestation, it has been shown to disproportionally result in the most severe complications, including fetal death.[27] 

The rubella virus is also spread via respiratory droplets. The overall incidence of rubella is low due to widespread vaccination. Due to the rarity of fetal rubella infection, the pathophysiologic mechanism is unclear; emboli of necrotized endothelial cells from the infected chorion are suspected.[29] If rubella is acquired by a pregnant individual within the first 12 weeks of gestation, there can be severe consequences for the developing fetus. Maternal infection in the second and third trimesters carries significantly less risk to the fetus.[30] Further discussion of the fetal implications of maternal rubella infection can be found in StatPearls' companion reference, "Congenital Rubella Syndrome."

Varicella-zoster virus (VZV), or Human herpesvirus 3, is the etiologic agent of chickenpox; reactivation of VZV causes shingles. VZV primarily spreads through respiratory droplets or direct contact with blister fluid. Primary infection with VZV during pregnancy is now rare secondary to vaccination; individuals of childbearing age have a high seroprevalence, especially in the United States.[31][7] It is believed that primary VZV infection during pregnancy leads to congenital varicella syndrome rather than secondary infection or reactivation.[32] Vertical transmission of VZV is thought to be transplacental; the mechanism is unknown. Primary acquisition of VZV by pregnant individuals before 20 weeks estimated gestational age poses the highest risk of subsequent congenital varicella syndrome (0.91%). Congenital varicella syndrome has been reported following maternal primary varicella infection between 20 and 28 weeks estimated gestational age, and recently as late as 36 weeks estimated gestational age.[33][34] A more comprehensive discussion of congenital varicella syndrome may be found in StatPearls' companion reference, "Congenital Varicella Syndrome."

Vector-Borne Disease

Zika virus (ZIKV) is a vector-borne disease with maternal-fetal relevance. ZIKV is transmitted primarily through bites from infected Aedes mosquitoes and through sexual contact with infected individuals, blood transfusions, and contact with bodily fluids. It is suspected that once a pregnant individual is infected, ZIKV infects trophoblasts, crosses the placental and blood-brain barriers, and infects brain endothelial cells.[35] In addition, ZIKV appears to disrupt the permeability of tight junctions, permitting paracellular transplacental but not blood-brain barrier transmission.[35]

Epidemiology

Not all epidemiologic studies separate infections acquired transplacentally from infections that may be acquired perinatally. The following discussion focuses on the epidemiology of vertically transmitted infectious agents thought to be acquired primarily by the transplacental route.

Syphilis

Incidence rates of congenital syphilis are highest in low- and middle-income countries, while in high-income countries, cases have resurged over the past decade.[36] Between 2012 and 2016, 1120 cases of congenital syphilis per 100,000 live births were diagnosed in Africa, 19 cases per 100,000 were diagnosed in Europe, 339 per 100,000 were diagnosed in the Americas, and 640 per 100,000 were identified in the Eastern Mediterranean region.[36] In 2016, the global incidence of congenital syphilis was estimated to be 473 cases per 100,000 live births; this was nearly unchanged in 2020, estimated at 425 cases per 100,000.[37][36] In the United States, the absolute number of congenital syphilis cases increased from 941 in 2017 to 2677 in 2021. All of this data likely underestimates the true disease burden due to unrecognized or asymptomatic infection, among other reasons.[36] The reasons behind increasing case numbers are multifactorial, but decreased testing during the COVID-19 pandemic plays a key role.[38]

Hepatitis C Virus

Geographically, the burden of HCV infection is similar to syphilis, with a pooled prevalence of HCV among pregnant women in low-income countries (2.7%) higher than that of lower–middle-income countries (2.3%); both are higher than the global prevalence of 1.0%. However, unlike syphilis, the prevalence of HCV is decreasing over time, with a prevalence of 0.8% reported for 2001 to 2010 and 0.5% from 2011 to 2020. Of children born to HCV antibody-positive and RNA-positive women, about 5.8% go on to develop HCV infection, while about 10.8% develop HCV when they are born to mothers who are HCV- and HIV-positive.[14]

Toxoplasmosis

The most robust epidemiologic data for congenital toxoplasmosis comes from France and Brazil, where surveillance programs exist for pregnant individuals. In France, it is estimated that 2 to 3 infants per 10,000 live births were infected, while in Brazil, this number is between 1 in 622 to 1 in 770 live births.[39] In the United States, the prevalence of T gondii in women of childbearing age has decreased from 15% from 1988 to 1994 to 9% from 2009 to 2010.[21] Approximately 91% of these women in the United States are at risk of primary infection with T gondii; in France, this number approximates 70%.[21][40] Not all primary infections result in congenital toxoplasmosis. The risk of transmission increases significantly with infections later in pregnancy, estimated at 15%, 44%, and 71% for seroconversion occurring at 13, 26, and 37 weeks of gestation, respectively.[21]

Listeriosis

The incidence of listeriosis is less well-defined, and many cases likely go unreported due to a lack of severe symptoms or testing. However, a recent epidemiologic study in the United States demonstrated that the average incidence rate of pregnancy-associated listeriosis between 2004 and 2009 was 4.5 cases per 100,000.[41] In this study, the consumption of Mexican-style soft cheeses emerged as a significant risk factor. Subsequently, Hispanic ethnicity was also identified as a notable risk factor. This same United States-based study estimated 1 listeriosis infection in every 8000 pregnancies within the Hispanic population, and nearly 1 in 3 of these cases resulted in neonatal death or fetal loss.[41]

Cytomegalovirus

Respiratory-acquired illnesses are common, and the epidemiology of congenital CMV infection reflects this. A 2007 meta-analysis reviewing the epidemiology of CMV estimated the combined birth prevalence of congenital CMV to be 0.64% when assessed in all live-born infants.[16]

Parvovirus B19

Infection with B19V occurs globally, and the susceptibility of women of childbearing age ranges from 26% to 44%, with the risk of acquiring B19V during pregnancy estimated to be 1% to 2% during endemic periods and 10% during epidemic periods.[42] Seronegative pregnant patients who are initially exposed to the virus are estimated to transmit the infection to the fetus in approximately 17% to 35% of cases.[42]

Rubella and Varicella

The epidemiology of congenital rubella syndrome and congenital varicella syndrome has changed dramatically with widespread vaccine availability. Prior to the introduction of rubella vaccines, congenital rubella syndrome incidence ranged between 0.1 to 0.2 cases per 1000 live births and 0.8 to 4.0 cases per 1000 during epidemic periods.[43] Since the vaccine's introduction, the incidence has decreased to less than 1 case per 100,000 live births.[44] However, as of 2020, the rubella vaccine has reached only 70% of the global population, and the incidence in vaccine-limited areas remains elevated at approximately 64 per 100,000 live births.[44][45] Congenital varicella syndrome appears to be rare overall; a recent review of the literature found 130 cases of congenital varicella syndrome reported from 1947 to 2013.[34] The authors estimated the incidence of congenital varicella syndrome to be 0.59% and 0.84% for women infected with varicella virus throughout pregnancy and in the first 20 weeks of gestation, respectively.[34]

Zika Virus

ZIKV stands out epidemiologically from other infectious agents because its reach is geographically bound. Before 2007, ZIKV cases were reported in Africa and Southeast Asia. In 2007, a ZIKV outbreak was reported in Yap State, Federated States of Micronesia, followed by a 2013 outbreak in French Polynesia. The virus subsequently spread to other Pacific islands and, in 2015, Brazil and the Americas.[46] Each of these outbreaks had varying incidence rates, and vertical transmission was suspected to occur in approximately 20% to 30% of cases, irrespective of the trimester when maternal infection occurred.[47] A report of the 2015 Brazil outbreak had 5909 suspected cases of congenital ZIKV syndrome; of these, only 1501 underwent complete investigation, and 76 were definite.[48]

History and Physical

Vertical transplacental infections may cause symptoms or signs in pregnant individuals, a fetus, or a neonate. Fetal signs and symptoms are typically identified via antenatal ultrasonography. The most crucial components of the medical history for all of these situations require a comprehensive interview of the pregnant or recently postpartum individual. Inquiries should focus on the aforementioned risk factors for each etiologic agent, including a thorough sexual, occupational, dietary, travel, and substance use history.

If the pregnant individual is symptomatic, then a thorough physical examination should be performed in conjunction with fetal ultrasonography. Nonspecific ultrasonographic findings that may raise concern for vertical transplacental infections include but are not limited to intracranial, abdominal, and liver calcifications, microcephaly, cardiac malformations, limb deformities, hepatosplenomegaly, echogenic bowel or kidneys, ascites, cerebral ventriculomegaly, hydrops fetalis, and growth restriction.[49][7] Nonspecific physical findings in neonates that may raise concern for vertical transplacental infections include but are not limited to fever, sepsis, low birth weight, microcephaly, cataracts, maculopapular rash, purpuric skin lesions classically described as "blueberry muffin" lesions, petechiae, jaundice, hepatosplenomegaly, and lymphadenopathy.

Some fetal and neonatal findings are more characteristic of specific infections. Early-onset sepsis is more typical of listeriosis.[50] Microcephaly should prompt suspicion of congenital rubella syndrome or infection with CMV, Human herpesvirus 1 or 2, T gondii, and ZIKV.[51] Ocular abnormalities such as cataracts may be indicative of congenital rubella or varicella syndromes or infection with CMV or T gondii.[7] Microphthalmos and certain limb abnormalities, such as hypoplastic lower extremities, are commonly seen in congenital varicella syndrome.[52] Low birth weight or being small for gestational age are commonly associated with transplacental infections and are nonspecific.[7] Hepatosplenomegaly is also common with transplacental infections and is nonspecific.[51] 

Neonates with CMV are most likely to have several abnormal findings (91%); an isolated finding is seen in only 8% of infants.[53] In one study, the most common finding for infants with CMV was petechiae (74%), but hydrocephalus and intracranial calcifications are classically described.[53] The blueberry muffin rash classically raises concern for most TORCH infections; however, a true blueberry muffin-appearing rash is thought to be due to extramedullary erythropoiesis occurring in the skin, and rubella and CMV are the only infectious agents that have dermal erythropoiesis documented by skin biopsy.[54]

Evaluation

Diagnosing a vertical transplacental infection may require evaluating a pregnant person, neonate, or both. Standard prenatal protocols in the United States recommend routine screening for many infections capable of transplacental infection, including HIV, HBV, HCV, and syphilis, in addition to rubella and varicella immune status. In high-risk areas, T gondii serology is also recommended.[55][56][57][49] These evaluations should be repeated if new risk factors develop during pregnancy. Interestingly, beyond this screening, the use of the ToRCHes screening panel is falling out of favor.[58][59] Risk factors primarily drive maternal and neonatal evaluation.

Syphilis

Infants born to mothers with a positive rapid plasma reagin (RPR) at any point during pregnancy should also undergo RPR testing at birth. Infants are subsequently risk-stratified by physical examination findings, neonatal and maternal RPR titers, and maternal treatment history to determine if further evaluation is indicated. Further fetal evaluation may include a complete blood count, lumbar puncture, or bone radiographs to evaluate for osteolytic lesions.[60]

Hepatitis C Virus

Infant HCV evaluation should include an HCV antibody test at approximately 18 months of age or an HCV RNA polymerase chain reaction (PCR) test between 1 and 2 months of age.[61] If HCV infection is suspected, serial monitoring of liver function with transaminases and coagulation studies is reasonable.

Toxoplasmosis

The evaluation for T gondii infection in a pregnant individual should include IgG and IgM serology, followed by IgG avidity testing if appropriate.[49] Fetal T gondii infection can be confirmed by PCR of amniotic fluid after 18 weeks gestation, and the fetus should subsequently be followed by ultrasound at least monthly for the remainder of gestation.[49][21] Newborn T gondii infection can be confirmed via T gondii IgG, IgM, and IgA titers, and if the suspicion is high, blood, urine, or cerebral spinal fluid PCR should also be obtained.[21] Further investigation for end-organ damage and to ensure treatment tolerance may include blood counts, liver and kidney function testing, screening for glucose-6-phosphatase dehydrogenase deficiency, head ultrasonography or computed tomography, eye examination, and hearing evaluation.[21]

Listeriosis

Fever in a pregnant individual or early-onset sepsis in an infant should prompt evaluation for listeriosis with studies including blood culture, placental culture, or cerebrospinal fluid evaluation.[50][62]

Cytomegalovirus

Abnormal findings on fetal ultrasound usually prompt CMV evaluation using IgG avidity assays combined with IgM titers or serial serologic assays.[49] These assays are considered positive if seroconversion or a ≥4-fold increase in anti-CMV IgG titers is identified.[49] Congenital CMV can be detected in amniotic fluid by culture or PCR at least 6 weeks after maternal infection and after 21 weeks of gestation.[49][63] The diagnosis of congenital cytomegalovirus in newborns includes PCR of preferably, saliva; urine can also be tested up to age 21 days.[63] Further investigation for end-organ damage includes blood counts, liver, kidney, and coagulation testing, head ultrasonography, eye examination, and, most importantly, hearing evaluation.

Parvovirus B19

Pregnant individuals exposed to B19V should have serologic IgG and IgM evaluations performed immediately after exposure.[49] Those who are IgG positive and IgM negative likely have immunity from previous exposure and are not at risk of transplacental transmission.[49] Meanwhile, those who are IgM positive, regardless of IgG status, should be monitored for fetal infection.[49] Those who are negative for IgG and IgM are susceptible to infection, and testing should be repeated in 4 weeks.[49] If repeat testing demonstrates positive IgG or IgM, these individuals should be monitored for potential fetal infection and anemia by serial ultrasonography with Doppler of the middle cerebral artery or B19V PCR in amniotic fluid.[49] After birth, serum B19V PCR can be obtained in neonates to confirm the diagnosis.

Rubella Virus

All pregnant individuals should undergo a rubella IgG test at the earliest prenatal visit.[64] Positive rubella IgG antibody testing indicates immunity.[64] Pregnant individuals who are IgG-negative and therefore susceptible to rubella infection should be monitored for signs or symptoms of rubella infection and vaccinated postpartum.[64] A rubella IgM antibody titer can be used to diagnose acute or recent rubella infection in pregnant individuals.[64] The laboratory evaluation for congenital rubella syndrome in a neonate can comprise rubella-specific IgM antibodies performed within 2 months of birth, rubella-specific IgG antibodies persisting at a high concentration or long duration after birth, defined as the titer not decreasing to a 2-fold dilution per month, or isolation of rubella by viral culture or detection of viral RNA from the nasopharynx, urine, CSF, or serum or cord blood.[65] A further investigation of the possible complications or diagnostic confirmation of congenital rubella syndrome includes reviewing documentation of maternal rubella immunity, physical examination assessing for the aforementioned features, blood counts, liver function and bilirubin testing, CSF evaluation, echocardiography, radiography of long bones, ophthalmologic evaluation, audiology evaluation, and neuroimaging by ultrasound or computed tomography.[64][65]

Varicella Virus

Acute varicella viral skin infection, or chickenpox, in an individual of any age, pregnant or otherwise, is usually diagnosed clinically based on the finding of a classic pruritic, vesicular rash. However, if laboratory diagnosis is desired, a sample may be taken from an unroofed lesion for qualitative varicella PCR. Subsequently, fetal varicella infection can be evaluated by ultrasonography after documented acute maternal infection.[49] Congenital varicella syndrome criteria include the appearance of chickenpox during pregnancy, the presence of congenital skin lesions in a dermatomal distribution or neurologic defects, eye disease, limb hypoplasia, proof of intrauterine VZV infection by detection of viral DNA in the fetus, the presence of VZV-specific IgM or IgG beyond 7 months of age, and the appearance of zoster during early infancy.[66][34]

Zika Virus

In pregnant individuals with suspected ZKIV infection or suspicious fetal ultrasound findings, specific IgM and nucleic acid testing is recommended as soon as possible, up to 12 weeks after symptom onset.[67] If ZKIV infection is confirmed, serial fetal ultrasonographic evaluations should be obtained to monitor for the effects on the fetus.[67] Amniocentesis is not considered beneficial for diagnostic confirmation.[67][68][69] PCR and IgM enzyme-linked immunosorbent assay testing can be performed on serum and urine for neonatal testing at birth.[70] PCR testing for ZKIV RNA and IgM can also be performed on CSF.[70] Cord blood studies are not recommended.[70] If the diagnosis is highly suspicious, further infant evaluation should include a head ultrasound, thorough eye examination, and hearing screen.[70]

Treatment / Management

The management of transplacental infections depends on the timing of the diagnosis (eg, antenatal or postpartum). Additionally, the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States recommendations are available at https://clinicalinfo.hiv.gov/en/guidelines.[56][71][72][73](A1)

Syphilis

Penicillin G is the mainstay of treatment for syphilis in all persons, including pregnant individuals, neonates, and infants.[74] For pregnant individuals, the recommended penicillin G regimen is based on the stage of the disease.[74] Intramuscular (IM) penicillin G is recommended in all cases except for neurosyphilis, where intravenous (IV) treatment is needed.[74] For primary, secondary, and early latent syphilis, a single IM dose of 2.4 million units of penicillin G is recommended.[74] For late latent and tertiary syphilis, 7.2 million units total, administered in 3 divided doses of 2.4 million units IM weekly, is recommended.[74] Finally, for neurosyphilis, including ocular and otic, 18 to 24 million units daily, administered as 3 to 4 million units IV every 4 hours or a continuous infusion for 10 to 14 days, is recommended.[74] 

For infants, IV penicillin G with age-based dosing for 10 days is preferred. The standard dose according to age is 50,000 units/kg every 12 hours for neonates aged 0 to 7 days, followed by 50,000 units/kg every 8 hours starting at 8 days of age, and another adjustment after 1 month.[74] If treatment is missed for a day, the course should be restarted, and previously administered antibiotics should not count toward the total course duration.[74]

Hepatitis C Virus

No treatment options currently exist for HCV diagnosed during pregnancy.[56] However, after birth, if the infant is also diagnosed with HCV based on the screening recommendations, treatment should be delayed until the child is 3 years or older. The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America HCV recommendations are available at https://www.hcvguidelines.org.(A1)

Toxoplasmosis

In pregnant patients diagnosed with toxoplasmosis before 18 weeks gestation, treatment with spiramycin is recommended.[21] If the fetus has signs of congenital toxoplasmosis, either by amniotic fluid PCR or ultrasonographic findings, treatment should be changed from spiramycin to pyrimethamine, sulfadiazine, and folinic acid for the remainder of the pregnancy.[21] For fetuses without toxoplasmosis signs, spiramycin should be continued throughout gestation. For pregnant individuals diagnosed with toxoplasmosis after 18 weeks gestation, pyrimethamine, sulfadiazine, and folinic acid are preferred initially.[21] If the fetus does not develop congenital toxoplasmosis as determined by amniotic fluid PCR or ultrasound findings, the pregnant individual can either continue the regimen for the remainder of pregnancy or be switched to spiramycin.[21] 

Treatment for neonatal toxoplasmosis is more ill-defined. Some treatment protocols for neonates include pyrimethamine, sulfadiazine, and folinic acid treatment for the first 3 weeks of life, followed by a change to spiramycin until 2 months of age, and then returning to the pyrimethamine, sulfadiazine, and folinic acid regimen until 12 months of age.[21] Conversely, some treatment protocols continue the same regimens until 24 months of age, and others forgo spiramycin.[21]

Listeriosis

If listeriosis is suspected or confirmed in a pregnant individual, the preferred treatment is a minimum of 14 days of high-dose intravenous ampicillin, with or without gentamicin.[62] For patients with a penicillin allergy, trimethoprim with sulfamethoxazole is preferred.[62] Similar regimens are recommended for infants.(B3)

Cytomegalovirus

Currently, no treatment is consistently advised for suspected or confirmed CMV infection in a pregnant individual or their fetus.[49] Valacyclovir does have mounting evidence supporting its use in this circumstance, but it is only currently used in research settings.[63][75][76] However, the use of valacyclovir is routinely recommended for moderate to severe illness in the postpartum period.[63] Typically, treatment is recommended for at least 6 months, and antiviral therapy is not routinely recommended for asymptomatic or mild disease or neonates with isolated sensorineural hearing loss.[63](B3)

Parvovirus B19

Monitoring for hydrops fetalis and fetal anemia is recommended when managing suspected or confirmed maternal or fetal B19V infection. Fetal hematocrit obtained by blood sampling is used to monitor and determine the need for fetal transfusion.[49] Outside of these interventions, no B19V-specific antivirals or supportive measures are recommended.

Rubella Virus

No specific antiviral treatments are available to treat rubella infection at any age.[45] The management of congenital rubella syndrome targets prevention with rubella vaccination and managing complications.

Varicella Virus

If varicella infection is suspected or confirmed in a pregnant individual or their fetus, oral acyclovir, when started within 24 hours of developing the varicella rash, can decrease the duration of symptoms and the number of lesions that may develop.[49] Intravenous acyclovir may also reduce maternal complications associated with varicella pneumonia. However, neither route of acyclovir seems to have a significant effect on reducing the fetal effects of congenital varicella syndrome.[49] Pregnant patients exposed to varicella infection without evidence of immunity should be offered varicella immunoglobulin (VZIG) within 10 days of exposure.[49][77] Despite sparse evidence, VZIG is believed to reduce the incidence of congenital varicella syndrome.[49] After birth, acyclovir and VZIG can be used to reduce perinatal transmission opportunities.

Zika Virus

No specific antiviral treatments are available for ZIKV infection at any age.[78] The management of congenital ZIKV infection focuses on preventing exposures and managing infection complications.

Differential Diagnosis

The differential diagnosis of a pregnant individual, fetus, or neonate with the signs and symptoms consistent with a transplacental infection is broad. Transplacental infections have a vast array of presentations and may mimic many other conditions. Diagnoses to consider include:

• Autoimmune diseases leading to placental insufficiency and other complications
• Chromosomal abnormalities, such as Trisomy 21, Trisomy 18, and Trisomy 13, with growth restriction and structural anomalies
• Genetic syndromes
• Environmental or teratogenic exposures 
• Langerhans cell histiocytosis or other hematologic or oncologic conditions [79]
• Nontransplacentally acquired infections

Prognosis

The prognosis of transplacental infections is dictated by the timing of the diagnosis and treatment and the infection severity, which can be highly variable, making studies difficult. Additionally, prognostic studies typically focus on fetal and infant outcomes; the importance of research regarding maternal outcomes following antenatal infections should not be overlooked. 

Syphilis

A recent study conducted in the United States demonstrated a case fatality rate of congenital syphilis of 31%, primarily due to fetal demise in the third trimester.[80] Beyond fetal fatality, weight-for-age was lower in patients during follow-up for congenital syphilis. However, 102/120 were healthy by the last follow-up visit.[81]

Hepatitis C Virus

The most concerning complication of HCV infection is the development of chronic HCV, leading to liver inflammation and cirrhosis, which in turn may cause other health concerns such as hepatocellular carcinoma. Fortunately, the development of chronic infection in children with HCV infection is suspected to be much lower than in adults, with 50% to 60% of infected children developing chronic disease.[82] Similarly, the long-term prognosis is generally good, though interstudy variability is high. Some studies following patients after acquiring HCV at birth showed 5% to 10% of individuals with significant fibrosis and less than 5% with cirrhosis.[82] 

Toxoplasmosis

The prospective studies that evaluated the prognosis of congenital T gondii infection are quite dated, and the case fatality rate is difficult to determine. However, many studies have shown that congenital toxoplasmosis in neonates may be asymptomatic, but as many as 90% of untreated patients or 30% of treated patients may develop eye lesions that impair vision.[83][84][85] Those treated may still develop long-term ocular or other complications; available antiparasitic drugs are only active against the tachyzoite of T gondii and not the bradyzoite that can remain latent in the eye and nervous systems. Only 2% of those treated were suspected to have long-term neurologic sequelae.[85]

Listeriosis

The prognosis for pregnant individuals with listeriosis is generally good, with a study revealing no deaths among 107 pregnant individuals.[25] However, the fetal and neonatal outcomes are much worse. A study including more than 200 pregnant individuals with listeriosis revealed that 1 in 5 pregnancies end in spontaneous abortion or stillbirth, and approximately two-thirds of surviving infants develop neonatal listeriosis.[86] Of the 94 surviving infants, 62.8% recovered completely, 24.5% died, and 12.7% had long-term neurologic sequelae or other complications.[86]

Cytomegalovirus

Neonatal CMV infections have variable symptomatology, which appears predictive of outcomes. In one study, symptoms were noted in 11% of 176 CMV-infected neonates with no deaths.[87] At follow-up, 7% had mild, 5% moderate, and 6% severe neurological sequelae. Sequelae were more frequently noted in those symptomatic at birth (42%) than asymptomatic (14%); all moderate-to-severe outcomes included in the study were identified by age 1 year. Mild sequelae comprised mild hearing loss or language developmental delay; moderate sequelae included moderate hearing loss, cerebral palsy, and moderate learning difficulties. Severe sequelae were characterized by severe disability or multiple problems. Studies have demonstrated some evidence that treatment with ganciclovir improves audiological outcomes in congenital CMV infection. However, the optimal duration of treatment and its long-term impact is not entirely clear.[88][89]

Parvovirus B19

Parvovirus B19 infection is estimated to contribute 0.1% to 0.8% of the overall fetal loss burden during B19V epidemics.[90] Pregnant individuals with B19V infection have been found to have a 2.68 times higher risk of fetal loss, a 2.42 times higher risk of spontaneous abortion, and a 3.53 times higher risk of stillbirth compared with uninfected pregnant individuals.[91] Hydrops fetalis is the leading cause of fetal morbidity and mortality in B19V infections. In a study of fetal hydrops survivors, abnormal neurodevelopment was present in 9.5% compared to 0% of the control group.[92]

Rubella Virus

The long-term outcomes for individuals with congenital rubella syndrome are best described by a cohort of 50 patients identified by an Australian ophthalmologist in the 1930s and 1940s.[93][94] In this cohort, 96% were deaf, and approximately 50% had typical rubella cataracts or chorioretinopathy. Other findings included mild aortic valve sclerosis (68%), diabetes (22%), thyroid disorders (19%), early menopause (73%), and osteoporosis (12.5%), all of which had a higher prevalence than the general population. Interestingly, 25% of the patients studied were found to have elevated HLA-A1, -B8, or -DR3 antigens associated with autoimmune conditions.

Varicella Virus

Congenital varicella syndrome is suspected to have a mortality rate up to 30% months after birth and a 15% risk of developing zoster in the first 2 years of life. However, a good long-term outcome can occur after this initial poor prognosis stage.[32][95]

Zika Virus

In a Brazilian study, the mortality rate among infants with confirmed or probable congenital ZIKV infection ranged from 4% to 6%.[48] Another study evaluated a cohort of children presumed to have congenital ZIKV infection and found neurodevelopment or abnormal vision or hearing assessments that were below average in 31.5% aged between 7 and 32 months.[96] Furthermore, the authors found that 12% scored greater than 2 standard deviations below average developmental scores in at least 1 domain, and 28% scored between 1 and 2 standard deviations below the mean in any neurodevelopmental domain assessed. Language function was most affected, with 35% below average. Predictors of improved neurodevelopmental outcomes were female sex, term delivery, normal findings on eye exams, and maternal infection at later gestational ages.

Complications

The complications arising from transplacental infections can be wide-ranging and severe, impacting both the pregnant or postpartum individual and the fetus or infant. However, the complications that develop depend on the timing and severity of the specific infection, making the timely screening and management of these infections pivotal. (Please refer to the Evaluation and Prognosis sections for more information on infection-specific complications).