What are the risk factors for cleft lip?

Risk Factors for Cleft Lip

Maternal tobacco use during pregnancy is a significant risk factor for cleft lip, with the 2014 Surgeon General's Report concluding that tobacco smoking in early pregnancy causes orofacial clefts. 1

Genetic Risk Factors

• Family history of cleft lip/palate significantly increases risk, suggesting strong genetic components in the etiology 2, 3
• Genetic mutations in specific genes have been associated with cleft lip development, including:
  • T-box transcription factor-22 (TBX22)
  • Interferon regulatory factor-6 (IRF6)
  • Poliovirus receptor-like-1 (PVRL1) 2
• Chromosomal abnormalities and monogenic diseases are particularly associated with syndromic forms of cleft lip/palate 2
• 22q11.2 deletion syndrome is associated with cleft palate abnormalities, including submucous cleft palate and overt cleft palate 1

Maternal Nutritional Factors

• Insufficient folic acid intake during pregnancy is one of the strongest risk factors for cleft lip development 4, 5
  • Not taking folic acid during pregnancy increases risk significantly (OR 3.27,95% CI 1.32-8.09) 4
  • Folic acid supplementation has been shown to reduce the occurrence of orofacial anomalies 1
• Lack of multivitamin supplementation during pregnancy (OR 2.6,95% CI 1.19-7.27) 4

Maternal Substance Use

• Maternal smoking during pregnancy significantly increases risk (OR 1.55,95% CI 1.34-1.79) 6
  • Active smoking during pregnancy (OR 2.05,95% CI 1.23-3.41) 4
  • Passive smoking exposure may be even more damaging than active smoking 6
• Alcohol consumption during pregnancy (OR 1.90,95% CI 1.17-3.08) 4
  • However, some recent research suggests alcohol may not be a significant risk factor 6

Maternal Health Conditions

• Maternal obesity significantly increases risk of clefting (OR 1.28, CI:1.08-1.51) 6
• Maternal underweight also increases risk (OR 1.21 CI:1.06-1.38) 6
• Type 1 diabetes in mothers elevates odds of cleft development (OR 1.75, CI:1.45-2.12) 6
• Essential hypertension is associated with higher odds of developing clefts (OR 1.55, CI:1.18-2.03) 6
• Maternal fever exceeding 39°C, particularly during the first trimester 5

Medication Exposure

• Certain medications taken during pregnancy can increase risk:
  • Corticosteroids: Older data suggested an association between first-trimester use of oral corticosteroids and cleft lip/palate abnormalities, though more recent studies have not supported this link 1
  • Mycophenolate mofetil (MMF): Associated with increased risk of cleft lip/palate abnormalities when used during pregnancy 1
  • Antihistamines: Some studies have reported associations between specific H1-antihistamines in early pregnancy and certain birth defects, though the general risk is not significantly elevated 1

Maternal Age

• Advanced maternal age (over 35 years) increases risk of cleft lip/palate 5

Prevention Strategies

• Folic acid supplementation at a dose of 0.4 to 0.8 mg during the initial trimester of pregnancy is recommended for prevention 5
• Avoidance of tobacco smoke exposure (both active and passive) during pregnancy 1, 6
• Maintaining healthy maternal weight before and during pregnancy 6
• Proper management of maternal diabetes and hypertension during pregnancy 6
• Avoiding teratogenic medications during pregnancy, particularly during the first trimester 1

Understanding these risk factors is crucial for prevention strategies and for identifying high-risk pregnancies that may benefit from enhanced monitoring and intervention.