The placenta is a complex structure composed of both maternal and fetal tissues. In order for a substance to reach the fetal circulation, it must cross the endometrial arteries, intervillous spaces, syncytiotrophoblast, fetal connective tissue, and the endothelium of fetal capillaries. Nevertheless, it is basically a semi-permeable biological membrane and as such obeys the laws that govern transport across such membranes.
Most transfer of drugs across the placenta occurs by simple diffusion. In addition, some drugs will reach the fetal circulation through facilitated diffusion, whereby a carrier molecule aids transfer down the concentration gradient (e.g. glucocorticoids), or through active transport (e.g., noradrenaline). All drugs administered to the mother will reach the fetus, albeit to a variable extent depending on the factors discussed below.
Factors determining placental transfer
Molecular weight and lipid solubility
The molecular weight of the drug, its degree of ionisation, its lipid solubility and the degree to which it is protein-bound will all affect the readiness with which it crosses the placenta. The majority of anaesthetic drugs are small (molecular weights < 500 Da) and lipid-soluble; thus they cross the placenta readily. The main exceptions are the neuromuscular blocking drugs, which are less lipid-soluble, more highly ionised quaternary ammonium compounds, and in the doses used in normal clinical anaesthesia do not cross the placenta to any significant extent. However, if used in large doses or over a prolonged period of time (e.g. to facilitate artificial ventilation in the intensive care unit) they do reach the fetal circulation in doses that may have a clinical effect necessitating ventilatory support. Opioids also cross the placenta, fentanyl being highly lipid-soluble, and morphine being only 35% protein-bound.
Changes in maternal or fetal pH may alter the degree of ionisation and protein binding of a drug, and thus alter its availability for transfer. This is most likely to occur if the pKa of a drug is close to physiological pH, and becomes clinically relevant in the acidotic fetus. Once drug transfer to the fetus has occurred, acidosis results in increased ionisation of the drug, which is then unable to equilibrate with the maternal circulation by diffusion back across the placenta. This results in drug accumulation in the fetus (‘ion trapping’), and is particularly relevant for local anaesthetics, which all have a pKa greater than 7.4.
Maternal drug concentration
Drug transfer occurs down a concentration gradient (which is usually from mother to fetus but can also occur from fetus to mother). The drug concentration on the maternal side depends on the route of administration, total maternal dose, volume of distribution and drug clearance and metabolism. The highest maternal blood concentration of a drug will be achieved following intravenous administration; epidural and intramuscular administration result in similar maternal blood concentrations. Systemic drug absorption will be greater from more vascular tissues, such as the paracervical region. The increase in blood volume and cardiac output that accompanies normal pregnancy has an effect on maternal drug concentration; the volume of distribution and plasma clearance of drugs such as thiopental is increased.
Placental factors
The area of placenta available for transfer is important. Physiological shunting occurs in the placenta, and in maternal disease such as pre-eclampsia the placenta itself may present an increased barrier to transfer. Although there is evidence that some drug metabolism occurs within the placenta itself, this is not clinically significant.
Fetal drug concentration
Once a drug has reached the fetus it is subject to redistribution, metabolism and excretion. The fetus has less plasma protein-binding capacity and less mature enzyme systems than the mother, and will therefore eliminate drugs less effectively. Some transfer of drugs occurs back across the placenta to the mother if the maternal concentration falls below that in the fetus (unless ion trapping occurs - see above).
Uteroplacental blood flow
This is the other major factor influencing placental transfer. Any reduction in blood flow to the placenta will inevitably reduce transfer of drugs (and nutrients) to the fetus. Reduction in uteroplacental flow may occur as a result of generally reduced maternal blood flow (hypotension, reduced cardiac output states, aortocaval compression, generalised vasoconstriction) or direct obstruction of flow (aortocaval compression, uterine contraction, umbilical cord compression).
Problems and special considerations
All general anaesthetic agents cross the placenta readily, and in normal clinical practice their effects on the fetus are only of significance immediately after delivery. The compromised fetus, or one in whom the interval between uterine incision and delivery has been prolonged, may be depressed at birth, but rarely requires more than simple resuscitative measures.
Pethidine (and all other opioids) crosses the placenta readily. It has maximal effect in the fetus 3-4 hours after maternal administration and minimal effect if given to the mother within an hour of delivery. (This is contrary to traditional midwifery teaching, which recommends that pethidine is not given if delivery is expected within 2-3 hours.) Both pethidine and its active metabolite norpethidine have prolonged half-lives in the fetus and cause respiratory depression and reduced sucking ability. While remifentanil rapidly crosses the placenta, it is also rapidly metabolised by the neonate, reducing the likelihood of side effects. Opioid side effects are reversed by naloxone.
Local anaesthetics cross the placenta by simple diffusion, but the extent of placental transfer is also dependent on maternal plasma protein binding (bupivacaine and ropivacaine are highly protein-bound, and therefore cross less readily than lidocaine, which is less protein-bound).
Key points
• The major determinants of transfer by simple diffusion are the maternal-fetal drug concentration gradient, molecular weight of the drug, lipid solubility, degree of drug ionisation and extent of protein binding.
• Uteroplacental blood flow is also important.
• Opioids given to the mother for labour analgesia cross the placenta freely and may cause fetal respiratory and neurobehavioural depression, which are reversible with naloxone.
Further reading
Griffiths SK, Campbell JP. Placental structure, function and drug transfer. Contin Educ Anaesth Crit Care Pain 2015; 15: 84-89.
Littleford J. Effects on the fetus and newborn of maternal analgesia and anesthesia: a review. Can J Anesth 2004; 51: 586-609.