Delineating the placental mechanisms underpinning poor pregnancy outcomes in advanced maternal age and exploring the therapeutic potential of melatoni

In the UK, 20% of all births occur to women over the age of 35 (defined as advanced maternal age, AMA) whilst 4% of pregnant women are over the age of 40. Women of AMA are more likely to have a baby that is growth restricted (fetal growth restriction, FGR) and to have a stillbirth than women aged 20-30. Both FGR and stillbirth have profound consequences for families and place a significant burden on maternity services.

An important reason for the increased risk of FGR/stillbirth in AMA is abnormalities in placental function. The placenta is crucial for a healthy pregnancy and one of its key roles is to transfer nutrients to the developing baby. When the placenta fails to function appropriately, termed placental dysfunction, nutrient transfer is inadequate for normal growth of the baby and FGR is the result. We have demonstrated that placental structure and some aspects of placental function are altered in women over 40 years of age. Similar observations have been made in a mouse model of AMA developed by our research group. We do not fully understand the reasons behind these placental changes in AMA. However, this understanding is vital to reducing the number of FGR babies and stillbirths in older mothers.

This project will compare placental function in AMA women compared with women aged between 20-30 (ideal age range), and will also compare normal pregnancies and pregnancies resulting in FGR/stillbirth within each age group. Specifically we will assess placental nutrient transfer and mitochondrial function. In our mouse model of AMA, preliminary experiments show evidence of oxidative stress and mitochondrial dysfunction in older mice and that treating them with melatonin, a naturally occurring antioxidant hormone, reduces the incidence of stillbirth. We plan to assess the mechanisms by which melatonin reduces stillbirth in this model and also to assess the timing of placental dysfunction in AMA mice; this will help to guide us as to when therapies should be timed during pregnancy in order to prevent FGR/stillbirth.

This project will provide understanding of the increased risk of FGR and stillbirth in older mothers and the mechanisms by which melatonin improves outcomes in our mouse model of AMA. Following completion of this PhD, the candidate will have received thorough training in whole animal physiology, together with functional physiological studies on human tissue. This combination will thus equip the student with a desirable skill set post-award.