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Fetal Clinical Pharmacology: A New Frontier of Drug Safety and Therapeutics

Fetal therapy is not new. In 1963, A.W. Liley described a case of intrauterine blood transfusion in New Zealand that undoubtedly saved the life of the baby with erythroblastosis fetalis.1 Dr. Liley cited prior work on intraperitoneal transfusions in neonates and infants as the basis for this remarkable accomplishment. This procedure was all themore remarkable when considering that it was done before the introduction of obstetrical ultrasound. The current state of fetal therapy is represented by the 55 chapters in the book titled Fetal Therapy published in 2020.2 How, then, can the exposure of the fetus to drugs be labeled as “one of the most neglected areas of drug development and clinical pharmacology” by staff from the National Institutes of Health?3 The answer to this question is clear; no investigator or pharmaceutical company wants to be liable for adverse effects of drugs in the pregnant individual or the fetus. The tragedy of thalidomide is described by the US Food and Drug Administration in a story in recognition of Dr. Frances Oldham Kelsey.4 Dr Kelsey was the medical reviewer for thalidomide and persisted in refusing approval of thalidomide despite constant pressure from the company.While thalidomide did notmake it into theUnited States, its widespread use in Europe, Australia, and Japan led to over 10 000 children being born with phocomelia, a rare birth defect associated with severe malformation of the extremities.5 While the outcome of the thalidomide tragedy is most commonly described as leading to the 1962Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act in the United States, an equally important consequence was the complete suppression of any drug research in pregnant people. Considering that >90% of pregnant individuals in the United States take at least 1 drug during pregnancy,6 this dearth of drug information in pregnancy is remarkable. The administration of drugs to pregnant people in the absence of critical information on drug concentrations in both the pregnant individual and fetus is a significant risk. We now know that multiple changes occur during pregnancy that alter the pharmacokinetics (PK) of drugs.7 When drug administration is critical for the health of the pregnant person, blood sampling of the pregnant individual to determine drug concentrations is viewed as minimal risk. Armed with drug concentrations in the pregnant individual at various times during pregnancy, the changes in drug PK during pregnancy is now easily accomplished through the use of PK modeling techniques.8 But in addition, the possibility for using PK modeling to predict the drug concentrations in the fetus for both therapeutic and toxicologic purposes has opened up a new frontier of therapeutics! The new era of fetal clinical pharmacology including understanding drug disposition and effect in the fetus will come in several stages. The first stage is to understand drug concentrations and disposition in the fetus through PK sampling of the pregnant individual and the neonate at the time of birth. Physiologically based PK (PBPK) models have been established for many drugs in pregnancy,9 and these models will facilitate an understanding of drug concentrations in the