COVID-19 and Congenital Cleft Lip and Palate: A Systematic Review Focusing on Nonsyndromic Neonatal Outcomes

Craniofacial anomalies (CFAs), such as cleft lip and palate, are among the most frequent birth defects, often necessitating multidisciplinary care. The COVID-19 pandemic raised concerns that maternal SARS-CoV-2 infection and associated factors, such as fever, inflammation, and psychosocial stress, might elevate teratogenic risk. This systematic review aims to synthesize the evidence on the association between maternal COVID-19 exposure and nonsyndromic CFAs in neonates. We conducted a systematic review in accordance with the PRISMA 2020 guidelines. Major electronic databases (PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, and the WHO COVID-19 Database) were searched from their inception until February 2025. We included studies examining the association between documented maternal COVID-19 infection (before or during pregnancy) and the incidence, type, or severity of CFAs, with a focus on nonsyndromic orofacial clefts (NSOFC). Risk of bias of the studies was assessed using the ROBINS-I tool. Findings were synthesized narratively, and bibliometric analyses, including geo-mapping and conceptual structure mapping, were performed. Eleven studies met the inclusion criteria. The evidence was mixed: smaller regional studies suggested a possible link, particularly with first-trimester infection, which aligns with the critical timing of craniofacial development. However, large-scale, robust epidemiological and registry-based studies from the USA and Nordic countries consistently found no significant association between maternal COVID-19 infection and congenital anomalies. A meta-analysis could not be performed due to study heterogeneity. Maternal stress and fear of COVID-19 were repeatedly highlighted as potential factors, in some cases showing stronger or even paradoxical associations than the infection itself. Research activity was concentrated primarily in Saudi Arabia and the United States. Robust population-level evidence does not currently support a direct, major causal link between maternal SARS-CoV-2 infection and NSOFC. While a modest or context-specific association cannot be entirely excluded, the effects of maternal psychosocial stressors and restricted healthcare access during the pandemic appear to be important explanatory factors that warrant further investigation, independent of the viral infection itself.