Walter Channing, Professor of Obstetrics and Dean of the School of Medicine at Harvard, described one of the first reports of the effects of anesthesia on the neonate in 1847. Based upon his inability to smell ether at the cut ends of the umbilical cord, Dr. Channing suggested that anesthesia had negligible effects on the fetus (1). Sir John Snow, one of the founders of anesthesia, eventually brought this opinion into question. Sir Snow detected ether on exhalation of infants whose mothers had been exposed to ether. It was not until the 1850s that experimental evidence was generated to prove that drugs are able to cross the placenta (1). This quest for knowledge has continued to this day.

The placenta provides a vital link between the mother and the fetus. It plays the fundamental role of transferring nutrients and oxygen from the mother to the developing fetus. It also allows waste products and carbon dioxide to be removed from the fetus and returned to the mother. In addition, it plays a role in the synthesis of hormones that are important in maintaining a successful pregnancy.

The placenta was at one time considered to provide an impenetrable barrier of protection to the fetus against drugs administered to the mother. However, it has been shown that the majority of drugs given to the mother during pregnancy will enter the fetal circulation to some degree. Studies have used many different models in an effort to better understand the function and mechanism of nutrient and drug transport across the placenta. The mammalian organ exhibits the greatest variation in placental structure among species. Mammalian placentas may be classified based upon the number of layers between the maternal and fetal circulations: (i) Hemochorial, (ii) endotheliochorial, and (iii) epitheliochorial (2). The placentas of guinea pigs and rabbits are frequently selected for studies due to the similarity of their hemochorial placenta to the human placenta (3). The sheep placenta has also been used in multiple studies. Although fewer parallels exist between the epitheliochorial sheep placenta and the hemochorial human placenta, the sheep placenta has been utilized because it allows for the performance of intricate surgery and the collection of large samples for chemical analysis (3). The effects in the human placenta must be extrapolated from these studies. For both ethical and technical reasons, in vivo studies on human placental drug transfer are limited to drug administration near the time of delivery and collection of maternal venous samples and fetal umbilical samples at delivery (4). Comparison of the drug concentration in the fetus to the drug concentration in maternal plasma at a given time provides an idea of the amount of drug administered to the mother that may eventually reach the fetus. The need for a more accurate model of human placental drug transfer has led to the development of models using perfused human placentas including the ex vivo dually perfused placental cotyledon model (5).

Drugs cross the placenta by one of the four possible mechanisms: (1) Simple diffusion, (2) facilitated diffusion, (3) active transport, and (4) pinocytosis.

The F/M ratio provides a quantitative measurement that helps delineate the degree of fetal exposure to drugs administered to the mother during pregnancy. The following section profiles some of the pharmacologic agents used by obstetric anesthesia providers. Specifically, F/M ratios are presented in conjunction with other pertinent pharmacodynamic and pharmacokinetic information to aid in one’s better understanding of transplacental drug transfer (Table 3-1).

Thiopental—The rapid transfer of thiopental across the placenta is attributed to the drug’s high lipid solubility. Despite this characteristic, the newborn of the mother who has received thiopental is often vigorous and cries spontaneously following its use in cesarean deliveries. This inconsistency has been attributed to the extensive uptake of thiopental into the fetal liver with decreased plasma levels reaching the fetal brain (14). The highly lipid soluble nature of this drug has been demonstrated in studies with an F/M ratio of approximately 1 (15) while other studies have found an F/M ratio of 0.43 (16). The wide range of values is likely due to the short dose delivery time and rapid redistribution in the maternal circulation. Thiopental is also highly bound to albumin—a factor that influences the pharmacokinetics of the drug (6).

Ketamine—Ketamine is a weak base that readily crosses the placenta. Less than half of the drug is bound to plasma proteins. An F/M ratio of 1.26 was observed following intravenous bolus dosing for cesarean delivery (17). It has also been demonstrated that the umbilical cord gasses were similar when small doses of ketamine were used for vaginal delivery compared to spinal anesthesia for vaginal delivery (18). In their study, Houlton et al. observed similarly comparable blood gasses although thiopentone showed better fetal oxygenation when compared to ketamine for induction of anesthesia for cesarean delivery (19).

Propofol—A broad range of F/M ratios following bolus doses of propofol given for cesarean delivery has been noted in many studies varying as much as 0.74 to 1.13 depending on the albumin concentration in the fetal perfusate (20,21,22). Another study found that increasing uterine blood flow rates resulted in increased maternal venous concentrations. This finding was attributed to decreased extraction of propofol from the maternal circulation possibly due to either shortened contact time with placental tissues or to saturation of placental binding sites with propofol (21). In contrast, increased propofol placental transfer was noted during increased umbilical blood flow rates—likely due to increased clearance of propofol (21). It could then be presumed that the amount of propofol received by a fit fetus with adequate umbilical blood flow rates would be higher than the amount received by a distressed fetus with poor umbilical blood flow. Another proposed reason for the wide variation of F/M ratios observed following a bolus dose of propofol is the wide spectrum of time taken to deliver the fetus following administration of an induction dose (22).

Etomidate—In a study that compared etomidate to thiopentone for induction of anesthesia for cesarean delivery, similarities were observed in Apgar scores as well as in F/M ratios (etomidate F/M ratio ∼0.5 and thiopentone F/M ratio 0.6). Despite these similarities, the clinical status of the newborns in the etomidate group was deemed superior by the investigators (23,24,25).

Inhalational agents are usually administered to the mother under steady-state conditions during general anesthesia while bolus dosing is utilized in administration of induction agents; hence, the F/M ratios of inhalational agents tend to have less erratic values (6). These agents have been shown to readily cross the placenta and have equal solubility in fetal and maternal blood; therefore, longer maternal exposure to an inhalational agent corresponds to a higher fetal exposure to the agent (26).

Halothane—Dwyer et al. studied the uptake of halothane by mother and infant during cesarean delivery. With an induction-to-delivery time averaging 10.8 minutes, an F/M ratio for halothane of 0.71 was reported after exposure to 0.5% halothane (27). There was a correlation of the duration of exposure to halothane and the measured F/M ratio (28). However, it appears that the volatile anesthetic received by the newborn

is quickly eliminated since the blood–gas partition coefficient has been found to be less in the newborn versus adult subjects. Consequently, as soon as respiration has been established, the elimination of the volatile anesthetic is rapid (29).

Isoflurane—Isoflurane 0.8% rapidly crosses the placenta resulting in an F/M ratio of 0.71 (27). As isoflurane is less soluble in blood than halothane, the elimination should be even faster.

Enflurane—It was found that enflurane has an F/M ratio of approximately 0.6 (30).

Sevoflurane—In a study by Okutomi et al., sevoflurane and isoflurane were given to gravid sheep to determine the hemodynamic effects of these volatile agents as well as their effect on the blood gasses. Although the blood gasses showed little change from exposure to the volatile anesthetics, the agents produced decreases in maternal and fetal arterial pressure (31). In another study in which sevoflurane was compared to other inhalational anesthetics (including halothane, enflurane, and isoflurane), there were no differences in any of the following: Blood pressure, heart rate, Apgar score, blood loss, uterine contractility, maternal arterial blood gas, umbilical venous gas, anesthetic recovery time, and intraoperative awareness (32). This study deemed sevoflurane to be as safe as the other volatile anesthetic agents used for cesarean delivery.