Each drug has a threshold concentration above which fetal abnormalities can occur and below which no effects are discernible. Whether a drug reaches the threshold concentration in the fetus depends on determinants (i.e., the drug’s molecular weight, lipid solubility, pKa, and plasma protein binding) that affect a drug’s ability to translocate across biological membranes and in this case that includes the placental barrier as well.
The genetic determinants of both the mother and the fetus will influence the extent to which an agent will affect the developing fetus. If threshold concentration occurs, major malformations are usually the result of fetal exposure to a drug during organogenesis (first trimester), while exposure during the second and third trimesters primarily affects organ function. However, it is paramount to recognize that human teratogenicity is not predictable.
In 2014, the FDA amended its regulations governing the content and format of labeling for human prescription drugs and biological products.2 The amendment, which became effective on June 30, 2015, requires the removal of the old pregnancy categories A, B, C, D, and X from all drug product labeling and the inclusion of a new “Pregnancy” subsection that provides consistent information about risks to the fetus (Box A).3