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

Box A. Elements of the “Pregnancy” subsection of the FDA’s new labeling requirements for drugs.
  • A summary of the risks of using the drug during pregnancy.
    • If data demonstrate that the drug is not absorbed systemically, the risk summary contains a specified statement regarding this fact.
    • If data demonstrate that the drug is absorbed systemically, the risk summary is based on data from all relevant sources (human, animal, and/or pharmacologic) that describe the risk of adverse developmental outcomes.
  • Relevant information, if it is available, to help healthcare providers make prescribing decisions and counsel women about the use of the drug during pregnancy.
    • This includes information on disease-associated maternal and/or embryo/fetal risk, dose adjustments during pregnancy and the postpartum period, maternal adverse reactions, fetal/neonatal adverse reactions, and/or the effect of the drug on labor or delivery.
  • A specific statement about the existence of a pregnancy exposure registry for the drug.
    • When such a registry exists for the drug, the telephone number and/or information needed to enroll in the registry or to obtain information about the registry is included at the beginning of the “Pregnancy” subsection.