What is the relationship between gestational diabetes (GD) and cholestasis of pregnancy (COP)?

The Relationship Between Gestational Diabetes and Cholestasis of Pregnancy

Gestational diabetes mellitus (GDM) is approximately twice as common in women with intrahepatic cholestasis of pregnancy (ICP), with a prevalence of 13.9% in women with ICP compared to the general pregnant population. 1

Pathophysiological Connection

• Bile acid metabolism link: The connection between these conditions stems from the modulating role of serum bile acids, which affect glucose and lipid homeostasis through regulation of:

  • Farnesoid X receptor (FXR)
  • Takeda G protein-coupled receptor 5 (TGR5) 2

• Severity correlation: GDM is more than twice as common in women with severe cholestasis compared to those with mild cholestasis (OR 2.168; 95% CI 1.429-3.289) 1

• Temporal relationship: ICP may be a predisposing factor to late-onset GDM, suggesting a potential causal relationship 2

Clinical Implications

Increased Maternal Risks

• Women with ICP have significantly higher odds of developing:
  • Gestational diabetes (aOR 2.81; 95% CI 2.32-3.41)
  • Pre-eclampsia (aOR 2.62; 95% CI 2.32-2.78) 3

Increased Fetal and Neonatal Risks

• The co-occurrence of GDM and ICP increases risk for:
  • Preterm delivery (both spontaneous and iatrogenic)
  • Low 5-minute Apgar scores (aOR 1.45; 95% CI 1.14-1.85)
  • Large for gestational age infants (aOR 2.27; 95% CI 2.02-2.55) 3
  • Respiratory distress syndrome 2

Long-term Offspring Risks

• Children born to mothers with both conditions face increased risks of:
  • Obesity
  • Type 2 diabetes
  • Metabolic syndrome 4
  • Altered body composition with increased adiposity even in non-macrosomic infants 4

Management Considerations

Screening Recommendations

• Women diagnosed with ICP should be screened for GDM if not already done
• Conversely, women with GDM should be monitored for symptoms of ICP, particularly pruritus without rash 5

Treatment Implications

• Ursodeoxycholic acid remains the first-line treatment for ICP maternal symptoms 5
• Emerging evidence suggests metformin (used for GDM) may have a beneficial effect on bile acids and liver enzymes in women with recurrent ICP 6

Delivery Timing

• For women with ICP and total bile acid levels ≥100 μmol/L, delivery at 36 0/7 weeks is recommended due to increased stillbirth risk 5
• For women with ICP and bile acids <100 μmol/L, delivery between 36 0/7 and 39 0/7 weeks is recommended 5
• The presence of GDM may influence this decision-making, requiring individualized assessment

Monitoring Recommendations

• Close fetal surveillance is recommended for women with both conditions
• Postpartum glucose tolerance testing at 4-12 weeks after delivery 4
• Long-term follow-up of both mother and child due to increased risks of:
  • Type 2 diabetes (50-60% lifetime risk for women with GDM) 4
  • Cardiovascular disease 4

Common Pitfalls to Avoid

• Misdiagnosis: Not all pruritus in pregnancy indicates ICP; laboratory confirmation with elevated bile acids is essential before initiating treatment or early delivery 5, 7
• Overlooking comorbidity: Failing to screen for GDM in women with ICP and vice versa
• Premature delivery: Delivery before 37 weeks should not be performed without laboratory confirmation of elevated bile acids 5
• Inadequate follow-up: Both conditions require postpartum monitoring for long-term health implications

The association between GDM and ICP highlights the importance of comprehensive screening and management strategies to optimize both maternal and fetal outcomes in affected pregnancies.