Placental pathology: Cracks in the feto-maternal bridge

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), designated as coronavirus disease 2019 (COVID-19), had swept the world as a dreaded pandemic. It had been shown to affect almost every organ of the body, and the placenta was no exception. The involvement of the placenta is significant as it can impact the course of pregnancy, affecting the growth and further development of the fetus. The placenta is a large disk, and the responses of placental tissue to various diseases are limited. Thus, several maternal conditions can produce similar effects to a lesser or greater extent. Besides, if lesions are small and peripheral, they are devoid of significant maternal or fetal outcomes. Though the placenta was initially thought to be a barrier against COVID-19, few studies have suggested vertical transmission of the virus through the placenta.[1] The placenta can be involved either directly due to the virus, or indirectly by modifying the maternal environment (inflammation or defective oxygenation).[2] As COVID-19 was a relatively new disease, there were hardly any past experiences and many articles (from few to large numbers to meta-analysis) have been published on placental histopathology in mothers infected by COVID-19 with variable results.

All variants of the virus interact with acetylcholine 2 receptors that are located on the trophoblasts, endothelial cells, and vascular smooth muscle.[1] The spectrum of lesions that have been described in the placentae of COVID-19-infected mothers can be grouped as maternal malperfusion-related alterations (increased peri-villous fibrin deposition, increased syncytial knots, infarction, calcification, or hemorrhage), fetal malperfusion-related changes (chorangiosis or delayed villous maturation), placentitis (chronic villitis, deciduitis, or chorioamnionitis), and increased intervillous thrombosis.[3] The most common lesions observed were maternal or fetal malperfusion-related lesions. Among the maternal malperfusion-related lesions, increased peri-villous fibrin deposition (a sign of trophoblastic damage) is the most common, followed by intervillous thrombosis that is related to hypercoagulability of the intervillous space.[4]

In the article published in this issue, Lad et al.[5] have performed a prospective case–control study on the placental histopathology of 100 COVID-19-positive mothers and an equal number of gestational age-matched controls. All patients with obstetric complications, pregnancy-related disorders, and associated conditions such as diabetes mellitus were rightly excluded as they could have given rise to confounding results. They have compared changes between asymptomatic and symptomatic patients. They did not find any histologic correlation between the asymptomatic cases and the symptomatic cases. Furthermore, in the symptomatic patients, the severity of the disease also did not seem to affect the placental changes. The authors have found peri-villous fibrin deposition, fibrinoid necrosis of villi, infarction, intervillous thrombosis, and calcification, which were comparable in both groups (statistically not significant). Acute intervillositis was the only finding that appeared significant, but was comparable in both groups.

Overall, most studies have shown an increased incidence of inflammatory and ischemic pathology in the infected placentae.[1,4,6,7] However, the studies have not specified the extent of involvement. An occasional study has reported massive peri-villous fibrin deposition seen in 82% of cases, and in the majority of cases, it was reported as “diffuse” or specified as involving more than 50% of the parenchyma.[6] Excessive peri-villous fibrin deposition is believed to be a pathological immune reaction and has been described in response to varied causes, such as preeclampsia, hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, and rarely viral infections in pregnancy.[4] Another prospective analytical study from India[8] describing placental pathology in 174 cases concluded that abnormal placental histopathology can be seen in almost 50% of cases and maternal vascular malperfusion was the most common finding; when seen, it was associated with poor pregnancy outcome. However, they did not compare their findings with non-COVID-19 controls.

Though the virus has been demonstrated within the placenta by various tests, the incidence of vertical transmission is very low and has been described by very few researchers, such as Vivanti et al.[1] The pregnancy outcome can range from preterm delivery, low birth weight, and growth retardation, to stillbirths.[9] Lad et al.[5] have reported in their study that there was no adverse pregnancy outcome in the form of growth restriction or fetal deaths.

Many studies that described placental changes in COVID-19-positive mothers claimed that these were significant.[1,4,7] In contrast, some studies showed that there were no relevant differences in placental histopathologic patterns between SARS-CoV-2-infected pregnant women and noninfected controls with similar maternal characteristics.[2,3,10] These conclusions were like those derived by the authors of the current article. Hence, though a spectrum of pathologies has been observed in the placenta of COVID-19-affected mothers, it should be noted that, with a large sample size and adequate control group, there have been no characteristic findings that are exclusive to COVID-19.