**Background:** SARS-CoV-2 infection during pregnancy has been associated with placental damage, including syncytiotrophoblast necrosis, histiocytic intervillositis, and increased perivillous fibrin deposition, which can lead to placental malperfusion and adverse pregnancy outcomes such as fetal growth restriction and stillbirth. However, the molecular and cellular mechanisms underlying this placental pathology remain poorly understood. This scoping review aimed to synthesize the emerging evidence on these mechanisms and identify gaps in the literature.
**Methods:** The review followed PRISMA-ScR guidelines and was preregistered with Open Science Framework. Five databases (MEDLINE, EMBASE, Scopus, CINAHL, PubMed) were searched for studies published between September 2019 and April 2022. Primary observational studies assessing placental outcomes (histopathology, molecular, or cellular analysis) with respect to SARS-CoV-2 diagnosis in pregnancy were eligible. Three reviewers independently screened and extracted data using the Joanna Briggs Institute method. Risk of bias was assessed using the Newcastle-Ottawa Scale. Of 1366 records after deduplication, 88 met inclusion criteria; 27 studies reporting molecular and/or cellular mechanisms were included in the final synthesis.
**Key Results:** The 27 included studies comprised 15 case-control, 7 cohort, 2 case studies, and 3 systematic reviews/meta-analyses, spanning 14 countries (most from the USA, 14/27). Most infections were detected in the third trimester (only 15/27 reported trimester), and severity classification varied widely. Quality scores ranged from 3–10/10 for case-control studies and 5–7/7 for cohort studies.
Three main mechanistic pathways were identified:
1. **ACE2/RAS pathway:** ACE2 protein and mRNA expression were reduced in infected placentas from third-trimester infections, but not second-trimester. ACE2 levels were lower in asymptomatic/mild vs. severe infections. ADAM17 (involved in ACE2 shedding) was increased. TMPRSS2 showed no differences. Furin levels were decreased in one study but unchanged in another. Endocytosis-related proteins RAB5 increased and RAB7 decreased.
2. **Mitochondrial dysfunction:** Infected placentas showed increased TBARS (lipid peroxidation), HIF-1α, catalase, SOD, and glutathione synthetase. Respiratory chain subunit genes NDUFA9, SDHA, and COX4I1 were decreased in symptomatic cases. mtDNA was decreased in one study but elevated in another. Aberrant mitochondrial fission over fusion was observed, with decreased DNM1L and FIS1.
3. **Immune/inflammatory mediators:** Infection was associated with increased subchorionic neutrophil infiltration, intervillous macrophage and T-cell infiltration, and increased CD14+ macrophages. Inflammatory cytokines including IFI6, OAS1, CCL3, IFNa, IFNy, CCL4, IL-10, CXCL10, TNFα, CXCL8, IP-10, CCL3, CCL5, IL-6, IL-1β, IFNa, and IFNβ were elevated, while IL-4 and MIF decreased. Antiviral effector genes MX1, IFITM1, IFITM3, CH25H, TLR3, and DDX58 were upregulated. However, some studies found no significant differences in IL-1β, IL-6, TNFα, or CXCL8, and one found pro-inflammatory cytokines were downregulated. scRNAseq revealed CD8 T-cell activation and macrophage overactivation.
Additional findings included increased von Willebrand factor and decreased claudin-5 and VE-cadherin in endothelium, increased VEGF, and impaired trophoblast differentiation with decreased PSG3 and CGB3.
**Clinical Implications:** The review suggests that SARS-CoV-2 may cause placental damage through ACE2 depletion disrupting the RAS balance (shifting toward vasoconstriction), mitochondrial oxidative stress, and dysregulated immune responses. These pathways may link to adverse outcomes including preeclampsia, fetal growth restriction, and preterm birth. However, the evidence is preliminary and limited by small sample sizes, lack of adequate controls, inconsistent severity classification, and predominant focus on third-trimester infections. Critical gaps include: (1) need for studies with well-defined pregnant controls, (2) investigation of first- and second-trimester infections on placentation, (3) data on viral variants, (4) assessment of social determinants of health, and (5) longitudinal studies linking placental mechanisms to maternal and neonatal outcomes.