Harm and benefit of second and third generation beta1-blockers on placental vascular function, fetal growth and fetal cardiovascular function.

Pregnant mums with heart and blood vessel disease (~4% of pregnancies), take medications known as beta1-blockers. These drugs ameliorate the function of mum's heart to pump sufficient blood to vital organs. In the UK, bisoprolol is the beta1-blocker often given for this purpose. These drugs are used with no knowledge of their side effects on the placenta and with limited information on their potential effects on baby's growth and development. Blood vessels in the placenta supply nutrients to enable baby's growth in the womb. Bisoprolol crosses the placenta into the fetal blood and when pregnant women take bisoprolol, fetal blood flow through the placenta is diminished, thus limiting nutrients and oxygen needed for normal baby's growth. Being born small may have detrimental consequences in the adulthood, as these babies have increased risk of developing high blood pressure and diabetes. Thus, compromised health of the baby in the womb is responsible for a significant emotional and financial burden on families and the NHS, before and after birth. Nebivolol is a different beta1-blocker which appears to cause little disturbance to fetal blood flow through the placenta during pregnancy. My studies aim to demonstrate whether maternal bisoprolol reduces the growth and compromises the health of the baby by altering the function of placental blood vessels, and whether nebivolol may suggest a better medication for pregnant mums with heart disease to improve placental blood flow, baby's growth and baby's health. To meet the aims of my studies, evidence of the effects of bisoprolol and nebivolol will be proven on the baby during pregnancy using pregnant sheep. These animals will be treated with bisoprolol or nebivolol to check placental blood flow to the unborn lamb, its growth and the function of its heart and major blood vessels in pregnancy. I will test how much of these drugs crosses the placenta from mum's side of the organ to the baby's side, using human placentas in the laboratory that have been donated to research. To determine effects of nebivolol and whether bisoprolol causes placental blood vessels to fail to work properly, cutting-edge technologies will be used to identify important signals mediated by bisoprolol and nebivolol. This will involve growing placental blood vessel cells in tiny plastic chambers that recreate the natural blood vessel: endothelial cells that line the inside of blood vessels, and smooth muscle cells that contract or relax, which work together in the placenta to control blood flow supply to the baby in the womb. Whether other beta1-blockers currently available may provide a better option than bisoprolol with respect to the baby, to then improve maternal prospective clinical practice, will need to be proven. These studies will shed a light on how bisoprolol and nebivolol may affect the function of the placenta to nourish the baby, and the consequences of these effects on the growth and the health of the baby. The experiments performed in these studies will provide the first evidence base of harm and benefit of different beta1-blockers taken by mums during pregnancy with the ultimate aim of preserving baby's growth. This work will be hosted at the Maternal and Fetal Health Research Centre (MFHRC) at the University of Manchester. The MFHRC is one of the largest pregnancy-based research group in Europe and is acknowledged as a world-class research facility for obstetric research. The centre consists of scientists, clinicians and midwives, all of whom work together with a combined aim of making pregnancy safer for both mum and baby. In addition, considering the deserved reputation in their specific field, the expertise of pharmacologist at the University of Buenos Aires will be essential to understand the effects of beta1-blockers; the animal work will be undertaken at the University of Cambridge, and studies using cell approach will involve the collaborations with the Universities of Leeds and Catania.