Table 1.

Infectious agents with known teratogenic potential.

Organism	Mechanism of Infection	Histologic Findings in the Human Placenta	References
Toxoplasma gondii	Transplacental infection occurs with primary infection of the mother; while transmission to the fetus is more common later in gestation, it is more severe in early gestation.	Early spontaneous abortion villous tissues: delayed villous maturation with Hofbauer cell hyperplasia. Later placental tissues: in addition to delayed villous maturation with Hofbauer cell hyperplasia, lymphohistiocytic chronic villitis, which may also be granulomatous and necrotizing. Pseudocysts and true cysts can be seen in the stroma of the cord and chorionic plate. Free tachyzoites may be identified in areas of active inflammation.	[37,51,52]
Treponema pallidum	Transplacental infection is most common in untreated secondary syphilis. Penicillin treatment is thought to be able to prevent 98% of vertical transmission in deliveries >20 weeks.	Classical triad: (1) delayed villous maturation with Hofbauer and stromal cell hyperplasia; (2) thickened fetal vasculature with prominent endo- and perivascular connective tissue; and (3) acute and/or chronic villitis, variably associated with necrosis. Other findings may include necrotizing funisitis, acute chorioamnionitis, and plasma cell deciduitis.	[41,51,53]
Human immunodeficiency virus	Vertical transmission occurs mostly during delivery; however, up to 30% of congenital HIV may be transplacental.	Early therapeutic abortion villous tissues with detection of HIV in fetal tissues: acute chorioamnionitis, plasma cell deciduitis, and necrotizing deciduitis. No specific findings in later placental tissues.	[51,54]
Zika virus	Transplacental infection occurs with primary infection of the mother.	Reports consistently mention Hofbauer cell hyperplasia. Placental infarcts, villous stromal calcifications, and plasma cell deciduitis with leukocytoclastic/lymphocytic vasculitis have been described in rhesus macaques.	[24,27,43,45,51,55,56,57,58]
Varicella zoster virus	Transplacental infection is rare (believed to be <1%) but may occur with primary infection of the mother.	Not well established, but the literature includes a case report describing diffuse, necrotizing chronic villitis with granulomatous inflammation.	[51,59]
Coxsackievirus	Transplacental infection.	Massive perivillous fibrin deposition with trophoblast necrosis and mixed acute and chronic inflammation within the fibrinoid has been described in placentas from stillbirths due to Coxsackievirus A.	[38,51]
Parvovirus B19	Transplacental infection.	The placenta is notable erythroblastosis fetalis in the villous circulation. Characteristic nuclear enlargement and ground-glass inclusions may be striking.	[51]
SARS-CoV-2	Transplacental infection is rare.	Placental pathology may vary depending on whether there is maternal infection only (nonspecific findings reported include maternal and fetal vascular malperfusion) vs. infection of both the mother–baby dyad (chronic histiocytic intervillositis and massive perivillous fibrin deposition, which may co-occur).	[60,61]
Rubella virus	Transplacental infection <16 weeks leads to congenital rubella syndrome (deafness, eye abnormalities, and congenital heart disease).	Fetal vasculitis with necrotizing acute and chronic villitis. Intranuclear and cytoplasmic nuclear inclusions can be seen in various compartments (amnion, endothelial cells, extravillous trophoblast, and decidua).	[39,51]
Cytomegalovirus	Transplacental infection earlier in gestation may lead to fetal hydrops and demise. Congenital cytomegalovirus infection is one of the most common causes of microcephaly and sensorineural hearing loss.	Chronic villitis, characteristically lymphoplasmacytic. Villous stromal hemosiderin deposition is also associated with CMV placentitis.	[40,51]
Herpes simplex virus	Both transplacental and ascending infections involving the amniotic fluid are documented.	Transplacental infection: plasma cell villitis and necrotizing deciduitis. Ascending infection: acute and chronic chorioamnionitis and necrotizing funisitis, with plasma cells in the membranes and cord. HSV viral cytopathic effect may be present.	[51,62]