Section 4: Subspecialty Management
Chapter 57: Anesthesia for Obstetrics

PLACENTAL TRANSFER OF ANESTHETICS

Medications administered to the mother enter the fetal circulation primarily by passive diffusion. The Fick law of diffusion determines the rate of transfer across the placenta, which is represented by

where Q/t is the rate of diffusion, K is the diffusion constant of the drug, A is the membrane surface area, Cm is the maternal drug concentration, Cf is the fetal drug concentration, and D is the membrane thickness.

Passive diffusion is the primary means of placental transfer of drugs. As such, the maternal-fetal concentration gradient, the uterine and umbilical blood flow, and the various factors that determine the diffusion constant of the drug are important in determining fetal exposure to maternally administered anesthetics. Factors producing a high diffusion constant (i.e., rapid diffusion) include low molecular weight (<500 d), low protein binding, high lipid solubility, and low degree of ionization. Almost all drugs used to produce anesthesia, analgesia, or sedation have a molecular weight of less than 500 d, are partially not ionized at physiologic pH, have a relatively high lipid solubility, and are incompletely protein bound in maternal blood and rapidly cross the placenta. Neuromuscular blocking drugs, because of their low lipid solubility and high degree of ionization, are not transferred across the placenta in clinically significant amounts. Factors tending to increase maternal drug concentration are high total doses, use of slowly metabolized drugs, low protein binding, and administration of drugs into highly vascular areas. Once the drug crosses the placenta, fetal pH and protein binding 60  affect the drug disposition. Circumstances of fetal acidosis and low pH favor “trapping” of potentially ionized drugs (e.g., local anesthetics) in the fetal circulation. 61 

The fetal circulation is unique in several ways and greatly modifies drug distribution (Fig. 57–11). Drugs cross the placenta and enter the fetal circulation via the umbilical vein. Umbilical venous blood returning from the placenta either perfuses the liver (40–60%) or bypasses the liver via the ductus venosus. 62  Hepatic drug uptake in the fetus may protect against the occurrence of high drug levels in the fetal heart and central nervous system (CNS). 63, 64  Dilution of umbilical venous blood in the fetal right atrium and shunting of blood across the foramen ovale and ductus arteriosus also modify fetal drug distribution.

Click thumbnail to see full size image
FIGURE 57–11 Diagram of the fetal circulation. Numbers indicate mean percent oxygen saturation. (From Born et al430 )

Hepatic enzyme activity in the fetus is generally less than that in adults. However, liver microsomes of human fetuses have significant levels of cytochrome P-450 and nicotinamide adenine dinucleotide phosphate–cytochrome C reductase as early as week 14 of gestation. 65, 66  This enzyme activity, even though less than that in adults, suggests that even the premature human fetus has the capacity to metabolize numerous drugs, including most local anesthetics.