Fetal exposure to drugs is determined primarily by maternal pharmacokinetics, route and timing of drug administration, changes in uterine blood flow, and placental permeability. Drugs that are rapidly metabolized by the mother, such as chloroprocaine, are unlikely to appear in the fetal circulation in significant amounts. The route of administration (e.g., oral, intravenous, intrathecal, epidural) dictates fetal exposure just as it determines maternal blood concentration. The dose and timing of administration is also important, as even drugs with low placental permeability may accumulate in the fetus if they are given in large doses or continually administered (e.g., as an intravenous infusion) over a longer period of time. A drug given during periods of minimized uterine blood flow, such as during a uterine contraction, is unlikely to reach the fetus, regardless of its placental permeability. Finally, there are multiple factors inherent to the drug itself that determine its likelihood of passing through the placenta (Table 156-1).
TABLE 156-1Factors Affecting Placental Transfer of Drug (Maternal to Fetal) ||Download (.pdf) TABLE 156-1 Factors Affecting Placental Transfer of Drug (Maternal to Fetal)
| ||Increased Transfer ||Decreased Transfer |
|Molecular weight (Da) ||<500 ||>1000 |
|Charge ||Uncharged ||Charged |
|Lipid solubility ||Lipophilic ||Hydrophilic |
|Blood pH vs. drug pKa ||Higher proportion of un-ionized drug in maternal plasma ||Higher proportion of ionized drug in maternal plasma |
|Placental efflux transporter proteins ||Absent ||Present |
|Binding protein type ||Albumin (lower binding affinity) ||Alpha-1-acid glycoprotein (AAG) (higher bindery affinity) |
|Free (unbound) drug fraction ||High ||Low |
PLACENTAL TRANSFER OF DRUGS
Though the implications are still being investigated, the placenta is known to have various drug transporters and metabolic enzymes. Efflux of drugs via these transporters is likely to play an important role in fetal drug exposure. Drugs that are passively transferred across the placenta diffuse at rates determined in large part by uterine blood flow. Finally, there are several factors inherent to the drug itself that plays a role in its disposition: molecular weight, degree of protein binding, lipophilicity, and charge.
Drugs with molecular weights <500 Da tend to cross the placenta, while most drugs with molecular weights of >1000 Da are unable to cross. Heparin, low molecular weight heparin, protamine, insulin, and nondepolarizing neuromuscular blockers are all too large to cross the placenta.
Drugs that are highly protein-bound (e.g., bupivacaine and ropivacaine) usually do not appear in great quantities in the fetal circulation, as only the free, unbound portion is able to cross the placenta. Some drugs (e.g., diazepam) are bound to albumin while others (e.g., sulfentanil, cocaine) are bound to alpha-1-acid glycoprotein (AAG). Albumin has a lower binding affinity than AAG, so drugs bound by albumin tend to have higher rates of transfer than those bound by AAG.