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Challenges of involving pregnant individuals in clinical research

• Historical Factors 
  Legacy of catastrophic events such as the Thalidomide tragedy created a long-lasting culture of caution in research involving pregnancy. This historical context still influences regulatory and ethical frameworks today. 
  (Ref: Bencheva V et al., 2024; https://doi.org/10.1016/j.cct.2022.106806) 

• Ethical Factors 
  Fear of teratogenic or fetal harm from experimental drugs, difficulty predicting risk/benefit ratios for both mother and fetus, and medical-legal liability concerns in case of adverse outcomes (e.g., malformations, preterm birth). Consent issues are particularly complex: newborns cannot provide consent, and proxy consent raises ethical debates. 
  (Ref: Moayad L et al., The Lancet, 2024; ACOG Committee Statement, 2024) 

• Regulatory Factors 
  Restrictive interpretation of “minimal risk” and “direct benefit” requirements often limits trial design. Approval processes for vulnerable populations are complex and time-consuming, discouraging sponsors from pursuing these studies. 
  (Ref: Moayad L et al., The Lancet, 2024) 

• Economic Factors 
  Low perceived profitability due to smaller population size compared to adults. Trials are more expensive because of intensive monitoring and safety requirements. Pharmaceutical companies are often reluctant to invest in specialized formulations for neonates, adding further cost barriers. 
  (Ref: Shankar M et al., PLoS Med, 2024) 

• Scientific & Methodological Factors 
  Pregnancy alters pharmacokinetics and pharmacodynamics (blood volume, metabolism, renal clearance), requiring different dosages and complex modeling. Variability across trimesters means larger and more stratified sample sizes. For infants, hepatic and renal immaturity complicates dose definition, and customized formulations (e.g., syrups, drops) increase costs and complexity. 
  (Ref: Shaikh H et al., JAMA Netw Open, 2024; Bencheva V et al., Syst Rev, 2024) 

• Sociocultural Factors 
  Reluctance of women and families to participate due to fear, mistrust, and cultural norms influencing decision-making and autonomy. These factors often intersect with socioeconomic barriers, further reducing enrollment rates. 
  (Ref: Shankar M et al., PLoS Med, 2024)