Covid 19 and Congenital Cleft Lip/ Palate: A systematic review focusing on Non Syndromic neonatal outcomes

1. Background and Rationale Congenital cleft lip and/or palate (CL/P) are among the most common craniofacial birth defects worldwide, with an estimated incidence of 1 in 700 live births. The etiology of non-syndromic cleft lip and/or palate (NSCL/P) is multifactorial, involving complex interactions between genetic susceptibility and environmental exposures during early pregnancy, particularly during the first trimester when craniofacial development occurs. The emergence of the COVID-19 pandemic in late 2019 raised concerns regarding the potential teratogenic effects of maternal SARS-CoV-2 infection. Maternal viral infections are known to influence fetal development through mechanisms such as systemic inflammation, fever, hypoxia, cytokine dysregulation, placental dysfunction, and immune-mediated effects. In addition, indirect pandemic-related factors—including maternal stress, altered antenatal care, medication exposure, and nutritional changes—could contribute to adverse neonatal outcomes. Since 2020, several case reports, case series, cohort studies, and registry-based studies have described a variety of congenital anomalies in neonates born to mothers infected with SARS-CoV-2 during pregnancy. However, findings related to orofacial clefts remain scattered, inconsistent, and often embedded within broader congenital anomaly datasets without focused analysis. Furthermore, many studies include syndromic cases or chromosomal anomalies, limiting inference regarding non-syndromic outcomes. To date, no systematic review has specifically evaluated the association between maternal COVID-19 infection and non-syndromic cleft lip and/or palate in neonates. A focused and methodologically robust synthesis is therefore warranted to collate existing evidence, identify knowledge gaps, and guide future research and surveillance strategies. 2. Research Question Is maternal SARS-CoV-2 infection during pregnancy associated with an increased risk of non-syndromic cleft lip and/or palate in neonates? 3. Objectives Primary Objective • To systematically review and synthesize available evidence on the association between maternal COVID-19 infection during pregnancy and the occurrence of non-syndromic cleft lip and/or palate in neonates. Secondary Objectives • To determine the timing of maternal COVID-19 infection (trimester-specific exposure) in reported NSCL/P cases. • To assess the severity and clinical characteristics of maternal COVID-19 in reported cases. • To describe neonatal outcomes associated with NSCL/P following maternal COVID-19 exposure. • To evaluate the quality and certainty of existing evidence. • To identify research gaps and methodological limitations in current literature. 4. Methods 4.1 Study Design This protocol describes a systematic review conducted in accordance with: • PRISMA 2020 guidelines The protocol will be prospectively registered on the Open Science Framework (OSF). 4.2 Eligibility Criteria (PICOS Framework) Population • Neonates, infants, or fetuses with non-syndromic cleft lip, cleft palate, or cleft lip with palate • Born to mothers with confirmed or suspected SARS-CoV-2 infection during pregnancy Exposure • Maternal COVID-19 infection diagnosed by: o RT-PCR o Antigen testing o Serology o Clinically diagnosed COVID-19 (as defined by authors) Comparator • Pregnancies without maternal COVID-19 infection (where applicable) • General population baseline data (in descriptive studies) Outcomes • Primary outcome: o Occurrence of non-syndromic cleft lip and/or palate • Secondary outcomes: o Laterality and type of cleft o Associated but non-syndromic anomalies o Birth outcomes (gestational age, birth weight) Study Designs • Cohort studies • Case-control studies • Cross-sectional studies • Case series and case reports • Population-based surveillance studies Exclusion Criteria • Syndromic cleft cases (e.g., chromosomal abnormalities, known genetic syndromes) • Studies without clear maternal COVID-19 exposure data • Animal studies • Review articles, editorials, opinions (reference lists will be screened) 4.3 Information Sources The following electronic databases will be searched: • PubMed/MEDLINE • Embase • Scopus • Web of Science • Cochrane Library • WHO COVID-19 Database Additional sources: • Preprint servers (medRxiv, bioRxiv) • Grey literature (conference abstracts, registries) • Manual reference list screening of eligible articles 4.4 Search Strategy A comprehensive search strategy will be developed using controlled vocabulary (MeSH/Emtree terms) and free-text keywords. Sample PubMed search strategy: (COVID-19 OR SARS-CoV-2 OR coronavirus) AND (pregnancy OR maternal OR antenatal) AND (cleft lip OR cleft palate OR orofacial cleft) AND (non-syndromic OR isolated) Searches will be limited to studies published from December 2019 onwards. No language restrictions will be applied; non-English articles will be translated where feasible. 4.5 Study Selection • All records will be imported into a reference management software (e.g., Zotero/EndNote). • Duplicate records will be removed. • Two independent reviewers will: o Screen titles and abstracts o Perform full-text review of eligible articles • Disagreements will be resolved by discussion or third-reviewer arbitration. • A PRISMA flow diagram will document the study selection process. 4.6 Data Extraction A standardized data extraction form will be used, capturing: • Study characteristics (author, year, country, design) • Maternal characteristics (age, COVID-19 severity, trimester) • Diagnostic method for COVID-19 • Neonatal characteristics: o Type of cleft (CL, CP, CLP) o Laterality o Syndromic exclusion criteria • Key findings and conclusions • Confounders adjusted for (if applicable) 4.7 Risk of Bias Assessment Risk of bias will be assessed independently by two reviewers using appropriate tools: • Newcastle-Ottawa Scale (NOS) for observational studies 4.8 Data Synthesis • A narrative synthesis will be performed due to expected heterogeneity. 5. Ethics and Dissemination Ethical approval is not required, as this study uses published data only. Findings will be disseminated through: • Peer-reviewed journal publication • Conference presentations • Open access data sharing via OSF 6. Expected Outcomes and Impact This systematic review will: • Provide the first focused synthesis of evidence on COVID-19 and non-syndromic cleft lip/palate • Inform clinicians, genetic counselors, and public health authorities • Highlight gaps for future epidemiological and mechanistic studies • Support evidence-based counseling of pregnant women exposed to COVID-19

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