, , , , , , ,

by Raman Venkataramanan

Raman Venkataramanan
Approximately two-thirds of pregnant women in the United States are prescribed medications (4.2 medications per subject on an average) during pregnancy for acute or chronic conditions such as urinary tract infections, nausea, depression, hypertension, diabetes, asthma, seizures, HIV, or organ transplantation. Given the physiological changes that occur in pregnancy, dosing based on non-pregnant subjects is expected to lead to inadequate therapeutic response in pregnant mothers due to use of lower doses, or it can lead to excessive side effects due to use of higher doses. However, limited studies have systematically evaluated the pharmacokinetics, pharmacodynamics, placental transfer, fetal exposure in utero, and exposure of the baby to the drug through breast milk. To enhance our understanding of obstetrical pharmacology and to rationally use medications during pregnancy, the Obstetric-Fetal Pharmacology Research Unit Network, which is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, has embarked on several projects to characterize the clinical pharmacology of drugs used in pregnancy.

Drug therapy during pregnancy should take into consideration the potential benefits of the therapeutic option versus the potential risks of adverse events to the woman, fetus, and newborn. Attention must be paid to the maintenance of the therapeutic concentration to achieve optimal response with minimal side effects. More frequent therapeutic monitoring should be considered to guide therapy of drugs in pregnant women such as immunosuppressives, anticonvulsants, antidepressants, and antiretroviral drugs. In an ideal condition, dosing changes should be performed based on the pharmacologically active unbound drug rather than total drug concentrations.

Appropriate selection of a drug in a given patient should also be based on placental transfer of the drug. While it may be ideal to minimize drug exposure to developing fetuses in general, in certain cases it may be necessary to deliver drugs (e.g., drugs to treat HIV) to the fetus as well. A thorough knowledge of the placental transporters and their modulation during pregnancy will help us guide in the selection of the proper drug and dosing regimen.

It is well known that breastfeeding improves outcomes for infants as it promotes bonding between mother and infant and provides immunity to the infant. Benefits of breastfeeding may outweigh the risk of drug exposure through breast milk in a newborn. The mere presence of a drug in breast milk itself should not be a contradiction for breastfeeding. Exposure of a drug to the newborn is a function of the concentration of the drug in the breast milk and the volume of milk consumed. Several drugs can be administered to women without concern for breastfeeding the newborns. However, greater precaution may need to be exercised when premature babies are breastfed.

Pregnancy appears to increase the elimination of certain drugs such as glyburide, indinivir, emtricitabine, lamivudine, doxorubicin, paclitaxel, sulfadoxine-pyrimethamine, lopinavir, lamotrigine, clonidine, nelfinavir, Tamiflu and methadone necessitating an increase in dose during pregnancy. Drugs such as amphetamines, atenolol, benzodiazepines, cocaine, doxepin, fluoxetine, ergotamine, heroin, lithium, marijuana, methamphetamine, phencyclidine, phenobarbital, salicylate, theophylline have been shown to exert adverse effects in infants and should be avoided while breastfeeding.

However, the optimal dosing and safety of several drugs in pregnant women are unknown at this time and efforts must be directed at improving our knowledge base in this area. The safe use of medication during pregnancy and lactation deserves more attention as it affects every human being. Preventing use of medications that cause fetal malformations (e.g., thalidomide) has been a long term goal of drug developers, but now we need to focus on proper dosing of drugs given large pregnancy related changes in all aspects of drug behavior. We should challenge the pharmaceutical community to invest time and effort and pay more attention to optimally treat pregnant women and their babies. They deserve this!

Raman Venkataramanan, Ph.D., is a professor of pharmaceutical sciences at the University of Pittsburgh School of Pharmacy, and recently served as member-at-large on the American Association of Pharmaceutical Scientists Executive Council.