Pitfalls of Maternal Physiology and Placental Transfer
Substantial changes in maternal physiology complicate the extrapolation of the safety profile and dosing of drugs. Changes in the cardiovascular, renal, and gastrointestinal systems affect the absorption, distribution and excretion of certain drugs given to the pregnant woman during pregnancy [13]. There is no doubt that drug pharmacokinetics are different in pregnancy and non-pregnant state and, ideally, drug properties should be studied in every trimester and in the postpartum period. However, these trials are challenging to conduct, and the information is scarce, which is why researchers often rely on opportunistic studies in which patient are already receiving the therapeutic agent in question [14, 15]. In addition to that, the placenta was thought to be an impenetrable barrier that protected the fetus from harmful agents including medication. However, after the thalidomide incident, challenges have been unearthed to explore mechanisms of transfer of compounds across the lipid membrane [16]. Several mechanisms have been proposed to explain the drug transfer across the placenta including simple diffusion, facilitated diffusion, pinocytosis, and active transport. Ongoing research is crucial in identifying potential drugs that follow the trajectory of maternal to fetal transfer, and the molecular characteristics of compounds. Uncharged lipophilic drugs tend to transfer readily [17], whereas size does not usually limit transfer as most drugs have a molecular weight of less than 500 Daltons [18].Insulin and enoxaparin are two examples of drug transfers that are limited due to size [19, 20]. Human placental drug transfer studies are often limited to drugs given near time of delivery. This limitation to study design led to development of ex vivo perfused human placental models which represented a non-invasive and effective method of studying transplacental transfer [21].