This chapter examines the potential of natural estrogens, particularly estradiol and estetrol, in combined hormonal contraceptive pills as alternatives to the widely used synthetic ethinyl estradiol. Current evidence highlights the promise of these natural estrogens in providing effective contraception with improved safety profiles and maintained tolerability. What we knowEstradiol and estetrol exhibit favorable safety and efficacy profiles compared to ethinyl estradiol. What we think we knowInitial studies suggest that estetrol combined with drosperinone provide effective contraception with a predictable bleeding patternand reduced risk for venous thromboembolism compared to ethinyl estradiol containing pills. Such risk may also be further mitigated by non-oral administration of estradiol. What we do not knowLong-term efficacy and safety data are needed to confirm the benefits of natural estrogens and their impact on diverse populations and comorbid conditions. By addressing these gaps, future research can enhance our understanding of natural estrogens in hormonal contraception, ultimately refining their use in clinical practice.

Advances in ultrasound and prenatal diagnosis are leading an expansion in the options for parents whose fetus is identified with a congenital disease. Obstetric diseases such as pre-eclampsia and fetal growth restriction may also be amenable to intervention to improve maternal and neonatal outcomes. Advanced Medicinal Therapeutic Products such as stem cell, gene, enzyme and protein therapies are most commonly being investigated as the trajectory of treatment for severe genetic diseases moves toward earlier intervention. Theoretical benefits include prevention of in utero damage, smaller treatment doses compared to postnatal intervention, use of fetal circulatory shunts and induction of immune tolerance. New systematic terminology can capture adverse maternal and fetal adverse events to improve safe trial conduct. First-in-human clinical trials are now beginning to generate results with a focus on safety first and efficacy second. If successful, these trials will transform the care of fetuses with severe early-onset congenital disease.