Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs. In this review drugs are classified according to their type of transfer across the placenta. Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed ‘complete’. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in fetal than maternal plasma. It is said that these drugs have an ‘exceeding’ transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent transfer varies considerably. The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.

Placental Transfer of Drugs Administered to the Mother

Maternal and fetal plasma differ in their concentrations of the important drug binding plasma proteins, albumin and alpha 1-acid glycoprotein, with albumin being slightly more concentrated in fetal plasma, and alpha 1-acid glycoprotein being only 37% of the maternal concentration at term. In general, these differences relate linearly to the bound to free concentration ratio of drugs associated with these proteins. Although only the free concentration is generally considered to be the pharmacologically active form, these differences can dramatically affect the total concentration and relative distribution of drugs between maternal and fetal plasma. In order to test our hypothesis that plasma protein binding is the major determinant of fetal/maternal drug distribution at steady-state, we examined whether fetal binding could be predicted from adult binding information. Data from studies of maternal plasma protein binding were used to predict fetal plasma protein binding based solely on the differences in protein concentrations. These predictions were compared with observed fetal binding data. This analysis showed a slope near unity and a high correlation (r2 = 0.900) which implies that there are no significant differences between the binding affinities of these proteins. A similar analysis performed using data on drug binding in non-pregnant adults gave an r2 or 0.971. Having established that fetal plasma proteins bind drugs similarly to their maternal counterparts, fetal/maternal plasma drug concentration ratios (F/M) were predicted for various drugs using information from literature on the drug's adult plasma protein binding, the protein to which it binds, and the fetal and maternal plasma concentrations of that binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

The significance of plasma protein binding on the fetal/maternal distribution of drugs at steady-state.

Clinical significance of fetal heart rate patterns during labor. V. Variable decelerations.

Administration of local-regional anesthesia during norgnal deliveries was correlated significantly with newborn behaviors as evaluated by the Brazelton neonatal assessment scale. Three days after birth, infants whose mothers received local-regional anesthesia were more irritable and motorically less mature than those infants whose mothers were not medicated.

https://science.sciencemag.org/content/sci/186/4164/634.full.pdf

Local-Regional Anesthesia during Childbirth: Effect on Newborn Behaviors

The primary pharmacological action of local anesthetic agents is the inhibition of the excitation conduction process in peripheral nerves. However, the ability of these agents to stabilize membranes is not limited to peripheral nerves. Any excitable membranes such as exist in heart, brain, neuromuscular junction will be altered by local anesthetic agents if they achieve a sufficient tissue concentration. Regional anesthesia which is properly performed usually does not result in blood levels of local anesthetics which are sufficient to cause systemic effects. However, the accidental intravascular injection or the use of an excessive extravascular amount of local anesthetics can result in blood and tissue levels which will cause profound systemic effects. Most of the systemic effects of local anesthetic agents are considered to be undesirable and toxic in nature. However, some actions have proven to be of therapeutic value. For example, the effect of lidocaine on cardiac membranes is responsible for the efficacy of this agent in the treatment of ventricular dysrhythmias (Rosen et al. 1975). The effect of various local anesthetics on membrane structures in the brain have also proven to be of therapeutic value in the treatment of epilepsy (Bernard and Bohn1965). In general, the primary systemic effects of local anesthetic agents are manifest in the central nervous system and the cardiovascular system.

Toxicity and Systemic Effects of Local Anesthetic Agents

Determinations of levels of a local anesthetic (mepivacaine) during labor after paracervical block indicated a rapid absorption of the drug into the maternal blood, with peak concentrations achieved by 10 to 20 minutes, followed by prompt placental passage to the fetus. The fetal bradycardia frequently encountered with this form of anesthesia appears to be related to high concentrations of the drug in fetal blood, 12.8 to 15 μg per milliliter. Although such levels might cause neonatal depression they do not appear to be high enough to cause death of a healthy fetus. Fetal bradycardia as a result of drug toxicity should be distinguished from that due to fetal asphyxia. Paracervical block is contraindicated when placental insufficiency is anticipated.

Howard R. Gordon

Papers

Fetal bradycardia after paracervical block. Correlation with fetal and maternal blood levels of local anesthetic (mepivacaine).