Alterations in drug absorption, distribution, metabolism, and excretion during pregnancy

Maternal responses to drugs during pregnancy are influenced by both maternal physiology and the presence of the placental-fetal unit.⁸¹ Variations in handling of specific drugs by the pregnant woman may occur due to effects of the normal physiologic changes of pregnancy on drug absorption, distribution, metabolism, and excretion (Table 7-2). The presence of the placental-fetal compartment can also alter maternal kinetics.⁸¹ For example, many antibiotics are lipid-soluble and may readily cross the placenta and become sequestered in the fetal compartment and thus be unavailable to the mother. This can lead to lower maternal levels.

Evidence regarding effects, effectiveness, and safety of most pharmacologic agents during pregnancy is limited.^69,80,87 Pharmacokinetic data on specific drugs during pregnancy is often minimal because pregnant women are excluded from drug trials. As a result, many drugs are not labeled for use in pregnancy, because the effects of the drug on the fetus are unknown.^70,131 This is protective for the fetus but may also limit benefits to the pregnant women from these drugs. The net result of changes in drug handling during pregnancy depends on the individual drug, with both increases in levels (with need for a lower dose or less frequent dosing) and decrease in levels (with a need for a higher dose or more frequent dosing) seen.⁷⁸ In general, both peak and steady-state serum concentrations are lower or unchanged in the pregnant woman.²⁰ Although changes may not be clinically significant the efficacy and toxicity of drugs can be harder to predict, because of the physiologic changes during pregnancy that have the potential to alter pharmacokinetics.^20,57

Little analyzed data on pharmacokinetics of drugs in pregnancy and found that across all agents (1) drug oral bioavailability decreased during pregnancy in 47% of studies of different agents; (2) Vd increased in 39%, with no change in 48%; (3) peak plasma levels decreased in 33%, with no change in 57%; (4) steady-state plasma levels decreased in 45%, with no change in 45%; (5) half-life decreased in 41%, with no change in 44%; (6) clearance increased in 55%, with no change in 34%; and (7) protein binding decreased in 86%.⁷⁸ Therefore during pregnancy, there are considerable variations in the direction of pharmacokinetic changes among different drugs. This increases the complexity for the practitioner in choosing a specific pharmacologic agent and monitoring its effects. Many studies have significant methodologic problems, for example, sample sizes may be small, the composition of the control group may vary (e.g., the group may include nonpregnant women, adult males, or the same subjects postpartum), women of various gestational ages may be grouped together, and dosing methods may vary.^36,78 Pregnancy drug registries have been established to collect experiences with specific drugs or groups of drugs (such as antiepileptic agents) during pregnancy and fetal and neonatal outcomes (see Box 7-2). Three types of drug registries have been established: individual academic sites; pharmaceutical drug company sites; and population-based sites (from individual countries or a group of countries).^24,128

Alterations in drug absorption, distribution, metabolism, and excretion during the intrapartum and postpartum periods

Drug handling is further altered during the intrapartum period. GI absorption may decrease to a greater extent than seen in pregnancy. Gastric emptying is reported to decrease during labor (see Chapter 12), although this may be secondary to use of opiate agents such as meperidine and pentazocine. Administration of antacids to decrease the risk of acid aspiration with anesthesia can alter ionization by altering gastric pH, prolonging gastric emptying, or complexing with drugs, reducing their absorption. Cardiac output increases in the intrapartum period further increase the Vd and may transiently alter hepatic and renal blood flow.¹⁰¹ Blood flow to the lower extremities may be reduced, especially if the woman is in a supine position. This may result in a slower and more unpredictable rate of absorption of drugs given intramuscularly in the buttock or thigh.¹⁰¹ Plasma nonesterified fatty acids rise during labor and may compete for albumin binding sites, with an increase in free drug levels.¹⁰¹ Both supine positioning and oxytocin may reduce renal blood flow and delay renal excretion of drugs and drug metabolites during labor. Most analgesics and anesthetics used in labor, especially opioids, tend to be low-molecular-weight, lipid-soluble, weak bases that enhance movement across the placenta to the fetus once they enter maternal circulation. The clinical effects depend on the timing of the dose, half-life, drug physicochemical characteristics, placental blood flow, and maternal and fetal drug metabolism and excretion.⁷⁹

During the immediate postpartum period, the pattern of pharmacokinetics and drug distribution is similar to that of late pregnancy and remains so until the pregnancy-induced physiologic alterations of each system return to nonpregnant status.⁴² During this transition, drug handling by the woman may remain altered to some extent for some drugs. Transfer of drugs to nursing infants is discussed later in this chapter in “Drugs and Lactation.”

Transfer of drugs across the placenta

Dancis suggested that in thinking of placental transfer one should “Ask not whether a maternal [substance] crosses the placenta. Ask rather, how, how much, and how fast. Ask also as to fetal need.”³⁵ There are few compounds, endogenous or exogenous, that are unable to cross the placenta in detectable amounts given sufficient time and sensitivity of detection.^{20,23,35,87,91} Drugs with similar physiodynamic properties can differ in placental transfer.^87,105 Plonait and Nau suggest that if no other information is available and a group of drugs is not known to have teratogenic effects, then a comparison of lipid solubility, molecular weight (MW), ionization, and degree of protein binding might assist the clinical selection of an appropriate drug for more efficient transfer (fetal drug therapy) or least efficient transfer (limited fetal exposure).¹⁰⁵ For example, drugs that are lipid soluble have an extremely low (50 daltons) or low (51 to 599 daltons) MW, and are nonionized with low protein binding in maternal plasma cross the placenta more rapidly and in higher concentrations than drugs that are water soluble (polar), have a high MW (greater than 600 daltons), and are ionized and highly bound to protein in maternal plasma. Transfer of drugs across the placenta varies with developmental changes in the placental, and thus gestational age.¹²¹

Patterns of transfer kinetics

Three major patterns of transfer pharmacokinetics are seen: (1) complete transfer (drugs rapidly equilibrate between mother and fetus, with blood flow being the rate limiting step); (2) exceeding transfer (levels are higher in the fetus than in the mother); and (3) incomplete transfer (levels are higher in the mother than the fetus).⁹⁹ These patterns are illustrated in Figure 7-2. Examples of drugs with each pattern are listed in Table 7-3.

Table 7-3

Examples of Drugs with Transplacental Kinetics^*

MODEL A OR B	MODEL C	MODEL D	MODEL E	MODEL F
Some barbiturates:  Thiopental  Pentobarbital  Secobarbital Antipyrine Promethazine Ritodrine Magnesium sulfate Digoxin	Some benzodiazepines:  Diazepam  Lorazepam  Desmethyl-diazepam  Oxazepam Valproate Salicylate Nalidixic acid Nicotine Urea Some penicillins:  Ampicillin  Penicillin G  Methicillin	Ascorbate Colistimethate† Furosemide Meperidine Some cephalosporins:  Cephalothin  Cefazolin  Cephapirin  Cephalexin Some aminoglycosides:  Gentamycin  Kanamycin	Amide-type local anesthetic agents:  Lidocaine  Bupivacaine Some β-adrenoceptor blockers:  Propranolol  Sotalol  Labetalol Dexamethasone Cimetidine Ranitidine Methadone Some sulfonamides‡	Heparin Quaternary ammonium compounds:  Tubocurarine  Succinylcholine  Vecuronium  Pancuronium Elementary ions:  Chlorthalidone  Dicloxacillin  Erythromycin  Nitrofurantoin

^*According to models A through F in Figure 7-2. Differentiation between models A and B, C and D, and E and F is often uncertain because of incomplete data on the initial phase of drug distribution across the placenta. Model B is rarely applied.

^†Polypeptide antibiotic, with a molecular weight of 1200 daltons.

^‡First and second trimester.

Modified from Plonait, S.L. & Nau, H. (2012). Physiochemical and structural properties regulating placental drug transfer. In R.A. Polin, W.W. Fox, & S.H. Abman (Eds.). Fetal and neonatal physiology (4th ed.). Philadelphia: Saunders.

There is a great deal of variability even among drugs with similar pharmacokinetic characteristics. However, in general, complete transfer tends to be seen with drugs that have a high pKa and MW less than 600 daltons, whereas incomplete transfer is seen with drugs that have a high pKa and MW greater than 600 daltons. Strongly ionized drugs generally have incomplete transfer, although exceptions occur. For example, ampicillin and methicillin are strongly ionized but have lipophilic side groups, so they have a complete transfer pattern.^98,101 Valproate and salicylates are ionized at the normal (physiologic) pH level but rapidly cross the placenta.⁸¹

Factors influencing placental transfer

Most drugs cross the placenta by diffusion. Diffusion of a substance across the placenta can be expressed as follows:

< ?xml:namespace prefix = "mml" />Diffusion=Substance characteristics× Surface area× Concentration gradientDistance

Placental transfer is influenced by the following: (1) maternal and fetal drug handling; (2) surface area of the placenta; (3) diffusing distance between maternal and fetal blood; (4) physicochemical characteristics of the drug; (5) gradients (drug concentration, electropotential [normally 20 mV], and pH) between mother and fetus; (6) degree of binding of a substance to proteins in maternal and fetal circulations; (7) concentrations of binding proteins and protein binding gradients between mother and fetus; (8) permeability of the placental barrier (primarily the syncytiotrophoblast); (9) rates of maternal and fetal blood flow through the intervillous space and villi; and (10) placental influx and efflux transporters (Table 7-4).^{58,68,86,98,99,102,126}

Table 7-4

Factors Influencing the Distribution of Drugs and Other Substances in the Fetus

FACTOR	POSSIBLE INFLUENCES
Type of drug	Factors that increase transfer include lipid solubility, low molecular weight (less than 500 to 600 daltons for lipid soluble and less than 100 daltons for polar substances), nonioinized, and unbound.
Amount of drug	Transfer is increased by greater maternal-to-fetal gradient, especially for drugs transferred by diffusion.
Membrane permeability	Diffusion of substances increases with increasing gestation and greater placental efficiency. Some drugs have greater affinity for specific fetal tissues (e.g., tetracycline in teeth, warfarin in bones, phenytoin in the fetal heart [because this is a highly lipid organ in the fetus, whereas in adults the central nervous system has a high lipid content owing to myelin sheaths], streptomycin in the optic nerve).
Fetal body water compartment	Drug distribution and dilution change as the total body water compartment decreases with increasing gestation. With an increased volume of distribution, peak volumes of drugs are reduced and excretion may be delayed.
Fetal circulation	Maternal and fetal blood flow rates will influence transfer. Upon reaching the fetal circulation, drugs may be shunted by the ductus venosus past the liver (thus missing an opportunity for detoxification), with highest concentrations of these substances in blood going to the heart and upper body.
Serum protein binding	Protein binding of a drug in the maternal system limits the amount of free drug available for transfer to the fetus. Binding of drugs to macromolecules in the fetal circulation may increase the maternal-to-fetal transfer by maintaining a concentration gradient from the mother to the fetus.
Receptor function	Functional ability of receptors on cell membranes increases with gestation, leading to increased specificity to respond to or exclude certain drugs.
Placental enzymes	Enzymes produced by the placenta (e.g., insulinase) may detoxify drugs and reduce transfer to the fetus.
Gestational age	Many of the factors identified above are altered with advancing gestation and maturity of the fetus and placenta. The size and efficiency of the placental exchange area increase with increasing gestational age.
Fetal pH during labor	The fetal pH is usually 0.1 to 0.15 units below that of the mother. A decrease in the fetal pH may increase the transfer of acidophilic agents from the mother to fetus. Hypoxia alters blood flow and thus drug distribution, metabolism, and excretion. For example, with hypoxia, blood flow to the liver and kidneys may be reduced with preferential flow to the brain. Albumin binding of drugs may also be reduced, resulting in more free drug in the fetal circulation.

Diffusing distance and surface area.

Increased surface area for exchange, increased concentration gradient, and decreased diffusing distance enhance transfer across the placenta. With increasing gestation and placental growth, efficiency of the placental transfer increases as a result of the increased surface area. As the placenta matures, the distance between maternal and fetal blood decreases due to thinning of the syncytiotrophoblast and connective tissue and increases in the size and number of capillaries in the villi (see Chapter 3). Thus more drug passes to the fetus in the third trimester than in the first trimester. Transfer may be reduced with decreased surface area (small placenta, placental infarcts) or increased diffusing distance (placental edema, infection). Edema with fetal hydrops increases the diffusing distance and decreases transfer so drugs such as digoxin may be less effective in treating arrhythmias in the fetus with hydrops.⁷¹

Physiochemical characteristics and concentration gradients.

Physiochemical characteristics that influence movement across the placenta include lipid solubility, MW, degree of ionization, and protein binding. These characteristics can increase, decrease, or deter movement of potentially harmful drugs and other substances from the maternal to the fetal circulation.¹⁰⁵ For example, placental transfer may be increased or enhanced if a substance is lipid soluble (e.g., diazepam, lipoproteins, most sedatives) or nonionized (e.g., phenobarbital), has a low MW (e.g., alcohol), or has a lower albumin binding (e.g., ampicillin). A substance will have reduced, slower, or no transport across the placenta if it has a certain charge or molecular configuration (e.g., heparin) or certain size (e.g., heparin, IgM), is altered or bound by enzymes within the placenta (e.g., amines, insulin), or is firmly and highly bound to the maternal red blood cell (e.g., carbon monoxide) or plasma proteins (e.g., dicloxacillin).

Lipid-soluble substances cross the placenta more readily than water-soluble substances, because cell membranes are made primarily of lipids that enhance diffusion. Lipid-soluble substances dissolve in the lipid membranes of the tissues separating maternal and fetal blood, primarily the syncytiotrophoblast. Polar substances cross slowly unless they have low MW and can move through pores. If the syncytiotrophoblast has a high lipid affinity for a drug (e.g., buprenorphine), the drug may be sequestered in the placenta with decreases in both maternal and fetal concentrations.¹²⁰

The exact MW limit for placental transfer is unknown, although transfer of substances with MW >500 to 600 daltons is limited.¹⁰⁵ Insulin (with an MW of more than 6000) does not cross the placenta because of its size and configuration and because of the effects of placental insulinase enzymes.^36,99 Substances with higher MW tend to cross more slowly and are influenced by maternal concentrations; for example, if maternal concentrations are high, the substance is more likely to cross. These substances may also cross via active transport if a carrier is present. Immunoglobulin G (IgG) with an MW of 150,000 daltons is transported across the placenta via endocytosis and exocytosis (see Chapters 3 and 13).³⁷ Water-soluble substances with an MW of less than 100 daltons diffuse readily; those with an MW greater than 100 diffuse more slowly. Small lipid-soluble substances (MW less than 500 to 600 daltons) cross rapidly and are blood flow–dependent; those with an MW of more than 500 to 600 daltons cross more slowly and may have incomplete transfer.^20,91,120 However, MW is of limited value clinically in that most drugs have MWs less than 600 daltons. Exceptions include thyroid hormones (MW 889), insulin (MW greater than 5000), heparin (MW 20,000 to 40,000), and low-MW heparin (MW 3000 to 5000).^52,68,99,102

Maternal-to-fetal concentration or electrochemical gradients also influence transfer. The maternal-fetal pH gradient influences transfer of drugs and can result in “ion trapping,” with higher concentrations of some drugs in the fetus than in the mother. Nonionized substances cross the placenta more efficiently than ionized substances.³⁶ Normally the fetus and amniotic fluid are slightly more acidotic than the mother by 0.1 to 0.15 pH units.⁹⁹ As a result of this difference, basic drugs may accumulate in the fetus and amniotic fluid with levels higher than in the mother. In the mother, a weak base tends to remain nonionized in her plasma and cross the placenta rapidly. As this weak base comes into contact with the more acidic fetal blood, the drug becomes more ionized, increasing the flow gradient from mother to fetus. The now-ionized drugs cannot return across the placenta to the mother as readily, thus becoming trapped in the fetus.^20,81,99,120 For example, most opioids are weak bases that may accumulate in the fetus, which is one reason that effects of these drugs may persist in the neonatal period. The opposite effect is seen with acidic drugs: that is, these drugs are more likely to be ionized in the mother and thus not cross the placenta as readily.²⁰ For nonionized, lipophilic drugs, the rate-limiting step for placental transfer is blood flow; for polar drugs, the rate-limiting step is diffusion.⁸¹ Hypoxia and acidosis in the fetus can influence transplacental passage of drugs. For example, local anesthetics are weak bases whose degree of ionization depends on pH. If the fetus becomes acidotic, ionization of these drugs increases with accumulation (“ion trapping”) in the fetus and neonate.^47,99,102

Drug metabolites also cross the placenta to the fetus and vice versa. The majority of fetal drug elimination is by transfer back to the mother across the placenta. However, some elimination may occur by fetal metabolism, placental metabolism, or excretion into amniotic fluid.⁹¹ This transfer is also based on physicochemical characteristics, primarily ionization and lipid solubility. Most drug metabolites are polar, because polarity enhances biliary and renal elimination. Once polar substances are transferred to the fetus, elimination back across the placenta is slow and may result in accumulation in the fetus or amniotic fluid.⁹¹ In addition the fetus may metabolize a drug producing polar metabolites. These metabolites can also become trapped and accumulate in the fetus or be excreted into amniotic fluid and reswallowed by the fetus. Examples of drugs that tend to concentrate in amniotic fluid are the β-lactams, such as penicillin G, dicloxacillin, and amiodarone.^36,91

If a drug is transferred slower than the maternal elimination rate, then a significant portion of the drug may be eliminated by the mother before it can be transferred to the fetus. A single dose of a drug given to the mother by intravenous administration tends to cross more quickly to the fetus until concentrations are equalized. As the mother clears the drug from her blood, transfer is reversed as the drug crosses from fetus back to mother. With drugs given repeatedly to reach steady-state concentrations in the mother, protein binding and fetal drug elimination are more critical in determining fetal exposure.

Protein binding.

Drugs that are protein bound, usually to albumin or α1-acid glycoprotein, in the mother or fetus do not cross the placenta. Therefore plasma protein gradients between mother and fetus can also influence transfer. For example, ampicillin has a lower protein binding to albumin, thus increasing the amount of free drug that can cross to the fetus, and resulting in decreased maternal levels. Protein binding of dicloxacillin is 96%. Therefore dicloxacillin would be an appropriate choice to treat maternal infections, but not to treat intrauterine or fetal infection. Another example is propranolol, which is highly protein bound so it crosses much slower than atenolol, which has minimal binding.⁷¹

Maternal albumin levels fall during pregnancy and are about 15% to 20% lower than those in the fetus at term; α1-acid glycoprotein levels in the fetus are only about 37% to 40% of maternal levels.^91,99,120 Thus at term, albumin (or fetal albumin macromolecule) bound drugs may be more highly bound in the fetus, whereas α1-acid glycoprotein drugs are more highly bound in the mother.⁹¹ Binding to proteins in the fetus may increase transfer of the drug by maintaining a concentration gradient across the placenta. Plasma protein binding and thus concentrations of drugs in the mother versus the fetus changes with increasing gestational age for some drugs. The decreased maternal albumin with increasing gestation increases the amount of free drug in the mother available for placental transfer. For example, diazepam binds to albumin. Albumin binding of diazepam is low in the fetus in the first half of gestation. However, in late gestation, as maternal serum albumin levels decrease, more free diazepam is present in maternal serum and, because this is a lipophilic drug, readily crosses the placenta. Thus by term, fetal diazepam levels are greater than maternal levels (Table 7-5).¹⁰⁵ This may increase the risk of neonatal hyperbilirubinemia in that diazepam competes with bilirubin for albumin binding (see “Neonatal Pharmacokinetics”).

Table 7-5

Fetal and Maternal Protein Binding and Total Concentration Ratios of Selected Drugs During Late Human Gestation

DRUG	PRIMARY BINDING PROTEIN	BOUND IN MOTHER (%)	BOUND IN FETUS (%)	FETUS/MOTHER TOTAL PLASMA CONCENTRATION RATIO
Betamethasone	AGP	60	41	0.33
Bupivacaine	AGP	91	51	0.27
Diazepam	ALB	97	98.5	1.6
Lidocaine	AGP	64	24	0.66
Mepivacaine	AGP	55	36	0.71
N-desmethyl diazepam	ALB	95	97	1.7
Phenobarbital	ALB	41	36	1.0
Phenytoin	ALB	87	82	1.0
Salicylate	ALB	43	54	1.2
Valproic acid	ALB	73	88	1.7

AGP, α1-Acid glycoprotein; ALB, albumin.

From Plonait, S.L. & Nau, H. (2012). Physiochemical and structural properties regulating placental drug transfer. In R.A. Polin, W.W. Fox, & S.H. Abman (Eds.). Fetal and neonatal physiology (4th ed.). Philadelphia: Saunders.

Placental blood flow.

The rate of maternal blood flow to and through the intervillous space and fetal blood flow to and through the villi influence placental transfer, particularly of nonionized, lipophilic substances such as anticonvulsants, alcohol, and opioid derivatives. Contractions decrease transfer so drugs that cross rapidly and are given during a contraction may demonstrate decreased transfer to the fetus. Contractions may also delay clearance of drugs from the fetus.¹²⁰ In addition to uterine contractions, factors that may alter uteroplacental blood flow include maternal position; anesthesia; nicotine, β-lactams, ototoxics and other drugs; emotional or physical stress; and degenerative changes within the placenta that are seen with hypertension, prolonged pregnancy, diabetes, or renal disease.⁷¹

Route of administration.

The route of administration can also affect placental transfer. For example, nalbuphine that is given intramuscularly results in fetal blood levels that are 80% of maternal venous levels; if it is given intravenously, fetal levels are three to six times greater than maternal levels.^81,99 Peak drug concentrations in the fetus (and the infant, if delivered after maternal administration) do not necessarily occur at the same time as in the mother. For example, meperidine peaks at 30 to 50 minutes in the mother, but 90 minutes to 3 hours after maternal administration in the fetus as a result of transfer kinetics across the placenta. Therefore meperidine levels are highest in the infant if given to the mother 90 minutes to 3 hours before delivery; on the other hand, fentanyl is higher in the neonate than mother if given shortly before delivery. Therefore it is reasonable to give meperidine if birth is expected within the hour.

Antibiotics are some of the most commonly prescribed drugs in pregnancy. Because antibiotics cross the placenta primarily by simple diffusion, rate-limiting factors include maternal-fetal concentration gradients, MW, and other physicochemical characteristics of the drug, placental surface area, diffusing distance, and the degree to which the drug is bound to maternal plasma proteins (see Table 7-5). A general pattern of antibiotic distribution to the fetus has been described. After an intravenous dose, peak maternal serum concentrations are seen within 15 minutes then fall exponentially. Peak umbilical cord values are seen in 30 to 60 minutes followed by an exponential fall. Peak amniotic fluid levels are seen in 4 to 5 hours. This lag results from slow excretion in fetal urine due to fetal renal immaturity.¹¹⁴

Placental transporters.

Although many drugs cross the placenta by simple diffusion, some drugs use placental influx or efflux transporters. These transporters are located along the apical membrane of the microvillus brush border facing maternal blood in the intervillous space and on the syncytiotrophoblast basal membrane (facing the fetal connective tissue matrix and blood vessels in the villi) or fetal capillary epithelium to facilitate movement of nutrients and other physiologic substances across the placenta.^{44,58,91,98,102,106,120,126} Some drugs may also be transferred across the placenta by nutrient (influx) transporters, including glucose, carnitine, monoamine, and organic ion carriers.¹⁰² Nonphysiologic substances—some drugs, environmental pollutants, and toxins—if structurally similar to nutrients, may compete for nutrient transporters. The drugs that seem to be particularly able to use this method to cross the placenta include amphetamines, cocaine, cannabinoids, and nicotine and other substances from cigarettes.^44,129 By successfully competing with nutrients for these transporters, nutrient transfer is reduced and fetal growth and development altered. In addition, cephalosporins, ganciclovir, and corticosteroids cross by facilitated diffusion, probably by using carriers that normally transport dipeptides, hormones, and steroids.⁹⁸

The placenta also contains a variety of efflux transporters whose role is to remove steroids and other potentially toxic substances and thus protect the fetus.^{68,71,102,120,129,135} Originally most of the transporters were identified in studies of multidrug resistance in tumors as is reflected in some of their names. Examples of drug efflux transporters in the placenta include members of the APT-binding cassette (ABC) group such as multidrug-resistant gene protein (MRP) 1, commonly called P-glycoprotein (P-gp), MRP-2, MRP-3, and breast cancer resistance protein (BCRP).^{58,68,102,121,126,129,135} P-gp, MRP-2, and BCRP are located on the apical membrane of the syncytiotrophoblast cells facing maternal blood; MRP-1 and MRP-3 are on the basal or fetal side of the trophoblast (see Figure 7-3).^47,68,126 Efflux transporters are also found on the gut, lung, and blood brain barrier and help protect entry of substances into the body and brain. Efflux transporters are under hormonal regulation, for example, BCRP by estradiol, and progesterone and P-gp by glucocorticoids.¹²⁶ Inflammation and infection may alter regulation of these transporters.⁸⁹

Each transporter appears to have specific substrates for which they provide protection. For example, studies of P-gp suggest that it exports cations, steroids, cytotoxic drugs, some antibiotics, opioids, phenobarbital, erythromycin, phenytoin, verapamil, and other substances that enter the placenta back into maternal blood, thus reducing fetal exposure.^{20,58,102,135} BCRP is involved in efflux of flavinoids, zidovudine, cimetidine, glyburide, nitrofurantoin, and the food-borne chemical carcinogen PhiP.^58,68,102 MRP 1 and 3 prevent entry of organic anions and promote excretion and reduce entry of glutathione/glucuronide metabolites into the fetus.⁴⁷ Some transporters may have bidirectional flow which can allow xenobiotics to be transported across the placenta to the fetus.⁶⁸ Thus BCRP and P-gp cannot only decrease the amount of drug reaching the fetus but enhance removal of any drug reaching the fetal circulation.¹²⁹ A drug that is a P-gp or BCRP substrate would be preferred for treating a maternal disorder with minimal fetal drug exposure, whereas a drug that is not a P-gp or BCRP substrate would be preferred for fetal pharmacotherapy.¹²⁰

Deficiency of these transporter proteins increases the risk of teratogenesis from fetal drug and chemical exposure.^58,135 Gene polymorphisms for the ABC efflux transporters may increase or decrease placental transfer of these substances and thus alter fetal susceptibility to effects of maternal drugs.⁵⁸

Fetal drug distribution

Fetal drug distribution is influenced by individual drug characteristics, specificity of individual agents for certain fetal tissues, and receptor function. Some drugs have a greater affinity for a specific fetal tissue that is not necessarily the agent’s expected target tissue. Examples include the high affinity of tetracycline for fetal teeth, warfarin for the fetal bones, and phenytoin for fetal heart tissue. Receptor function of fetal cells increases with increasing gestational age.⁸⁶ Receptors become more specific in their ability to respond to or exclude certain drugs, whereas in the embryo and young fetus, these receptors are less discriminating in excluding drugs, increasing the likelihood of teratogenic effects. Other factors influencing drug distribution in the fetus are gestational age, degree of serum protein binding, and fetal body water compartment and pH.^86,102 Fetal pH is slightly lower than maternal, so weak bases (such as anesthetics, cocaine, meperidine, codeine, hydrocodone, erythromycin, barbiturates, and iodine) become more ionized in the fetus and may accumulate in the relatively more acidotic fetus (“ion trapping”).^47,102 This phenomenon is more likely during the intrapartum period when fetal pH is further decreased.

The fetus has lower levels of serum proteins, increasing the amount of free drug. Fetal proteins may bind some drugs with greater affinity than in the mother (salicylates) and others (ampicillin, benzyl penicillin) with less affinity.⁸¹ Levels of α1-acid glycoprotein are up to three times lower in the fetus than in the mother with a fetal-to-maternal concentration ratio at term of 0.37.^47,91,99,102 The maternal-to-fetal serum concentration ratio of albumin increases to term as fetal albumin concentrations increase and maternal levels decrease (due to hemodilution). Thus this ratio increases from 0.38 at 12 to 15 weeks to 0.66 at 16 to 25 weeks, 0.97 at 26 to 35 weeks and 1.2 after 35 weeks.¹⁰² Even as serum binding proteins increase with advancing gestational age, levels of free drug tend to remain high because of the lowered protein binding affinity. The fetus has an increased Vd due to increased total body water. This results in a reduction in peak volume of drugs, but also wider distribution of drugs in the body and delayed excretion. Factors influencing distribution of drugs and other substances within the fetus are summarized in Table 7-4.

Fetal drug metabolism and elimination

Once a drug reaches the fetal circulation, the drug can (1) be metabolized by the fetal liver, (2) bypass the fetal liver via the ductus venosus to enter specific fetal tissues or body compartments, (3) be eliminated by the fetal kidney into amniotic fluid, or (4) return to the maternal circulation via the umbilical arteries and placenta. Drugs and metabolites in amniotic fluid may diffuse across the fetal membranes and decidua to maternal blood or be swallowed by the fetus. Swallowed drugs or their metabolites are reabsorbed into the fetal blood from the gut and cleared via the placenta.

Drug metabolites are also excreted by the liver into bile and thus into meconium. Polar metabolites may accumulate in amniotic fluid, reaching levels higher than in either the mother or fetus. Examples of drugs that may accumulate in amniotic fluid are ampicillin, amoxicillin, cefuroxime, and cephalothin.⁹⁹ Because most drug metabolites are more polar than the original drug, substances that cross the placenta to the fetus may not return across the placenta to the mother as readily. Therefore, these substances can accumulate in fetal tissues and at levels that may be higher than in the mother.^36,47,81,102 Metabolites of some drugs that the fetus is exposed to in the third trimester, such as opiates and cocaine may also be found in fetal hair.

Fetal drug therapy

Planned fetal drug exposure may occur as a method of treating fetal disorders by administration of drugs to the mother. The most common fetal treatment is administration of glucocorticoids to induce surfactant synthesis and reduce the risk of respiratory distress syndrome in preterm infants (see Chapter 10). Not all glucocorticoids are equally effective, because some are metabolized by the maternal-fetal-placental unit and thus rendered inactive. Inactivation of betamethasone and dexamethasone is limited, so these glucocorticoids are more effective in enhancing surfactant synthesis than drugs such as hydrocortisone, which are rapidly metabolized in the placenta.

Glucocorticoids may prevent development of ambiguous genitalia in female fetuses in families with a history of congenital adrenal hyperplasia. If begun prior to onset of adrenal androgen secretion, these drugs suppress excessive adrenal androgen production and may prevent virilization of the external female genitalia.^71,97 Glucocorticoids act by crossing the placenta and suppressing ACTH production by the fetal pituitary, which reduces adrenal cortex output. Ideally therapy is begun based on family history soon after conception and at least before 6-7 weeks from conception (∼9th week of pregnancy).¹⁶ Maternal adverse effects include Cushing syndrome, hypertension, hyperglycemia, gastric irritation, excess weight gain, and pedal edema.^16,97 Drugs may also be given to the mother to treat several specific inborn errors of metabolism.^16,71,110

Anti-infective agents are given to the mother as prophylaxis against group B streptococcal infection, to treat congenital syphilis (penicillin) or toxoplasmosis (pyrimethamine and sulfadiazine), listeria (ampicillin usually in combination with an aminoglycoside), or to prevent infection with human immunodeficiency virus (HIV).^16,47,71,129 In prophylaxis to prevent HIV transmission, zidovudine with protease inhibitors (such as lamivudine) are not substrates for placental drug efflux transporters. Thus these drugs achieve higher fetal blood concentrations and have greater efficacy than other agents whose transfer across the placenta is reduced by these efflux transporters.^47,129 Administration of antibiotics to the mother with the purpose of protecting the fetus is probably reasonably effective for protection of the GI (swallowing of amniotic fluid) and renal (adequate blood flow) systems. The fetal circulation shunts blood away from the lungs, however, which limits delivery of antibiotics to the respiratory tract for protection against congenital pneumonia in the presence of chorioamnionitis. Because amniotic fluid levels of antibiotics are dependent on excretion of the drug in fetal urine, therapeutic levels of antibiotics in amniotic fluid are attained only with a live fetus. This limits the effectiveness of this treatment for chorioamnionitis after intrauterine death.¹¹⁴

Fetal pharmacotherapy has also been used to treat fetal arrhythmias (most often for supraventricular tachycardia, atrial flutter, and fibrillation), hydrops, and congestive heart failure.¹²⁹ Examples of drugs used include digoxin, procainamine, quinidine, propanolol, flecainide, amiodarone, and sotalol.^16,129 Fetal therapy has also been used to treat polyhydramnios (indomethacin), hypothyroidism (intraamniotic thyroxine), hyperthyroidism (propylthiouracil and thiamazole), and severe anemia or thrombocytopenia (blood transfusions).⁷¹ Another example of a preventive fetal drug therapy is the use of folic acid for prevention of neural tube defects (see Chapter 15).

Absorption of oral medications in the neonate is altered by the following: (1) decreased bile salts and pancreatic enzymes; (2) slower gut transit time due to delayed gastric emptying and decreased motility; (3) mucus in the stomach; (4) differences in gastric and duodenal pH; (5) high levels of β-glucuronidase in the duodenum; and (6) intestinal surface area.^{31,32,66,86,93,106} These alterations are more pronounced in preterm and intrauterine growth–restricted (IUGR) infants.^32,93 Oral drug absorption matures by 4 to 5 months of age.³¹ Decreased bile salts and pancreatic enzymes can result in poorer absorption of lipid-soluble substances such as vitamin K, or drugs that must be hydrolyzed for absorption. Slower gut transit time due to delayed gastric emptying and decreased motility initially delays then prolongs absorption. Mucus in the stomach may also delay absorption. Differences in gastric and duodenal pH may partially or totally inactivate some drugs. Absorption of oral drugs by the neonate is also influenced by the drug’s physicochemical characteristics. Drugs such as phenytoin, acetaminophen, and chloramphenicol are absorbed slowly and erratically, whereas penicillin and ampicillin are absorbed more efficiently than in adults because of the higher gastric pH in the neonate.¹⁰⁵ Other drugs such as theophylline, digoxin, and diazepam have oral absorption patterns that are more similar to those in adults.

Gastric and duodenal pH influences drug solubility and ionization. An acid pH increases the absorption of acidic drugs (low pKa) because these drugs tend to stay in a nonionized, lipid-soluble form. A higher pH enhances alkaline drug absorption and slows absorption of acidic drugs. Gastric pH is higher for the first 12 to 24 hours after birth, gradually reaching adult values by 2 years.⁷ Preterm infants who are less than 32 weeks’ gestational age have decreased gastric acid secretion with a more alkaline pH and thus poorer absorption of weak acids and bases.^19,32,93 Gastric emptying is delayed for up to 6 to 8 hours in immature infants and is slower in all infants before 6 to 8 months. This may delay absorption and prolong the time to reach peak drug concentration.^19,66 Oral absorption is also influenced by drug efflux transporter expression on the intestinal lining and type of bacterial flora.^86,95

The neonate’s duodenum has higher levels of β-glucuronidase, an enzyme that unconjugates drugs (e.g., indomethacin, chloramphenicol) that the liver has metabolized via glucuronyl conjugation.^32,66,93 These drugs reenter the blood via the enterohepatic circulation (see Chapter 18) and must be remetabolized by the liver. This increases the half-life and prolongs activity of these drugs.^31,93 Intestinal absorption of drugs, gut transit time, and motility depend on perfusion and food intake. Better gastrointestinal (GI) absorption occurs with drugs of low molecular weight (MW) that are nonionized and lipid-soluble.⁹³ An ill infant who is not being fed may have further impairment of gut function and erratic absorption of oral medications. Intestinal surface area is decreased with genetic disorders such as cystic fibrosis and disorders such as short bowel syndrome and necrotizing enterocolitis, thus reducing absorption.^19,93

Drug distribution

The distribution of drugs is influenced by the infant’s large extracellular fluid space, increased total body water, decreased fat, and decreased plasma protein content and binding. The blood-brain barrier is less well developed, which may result in increased amounts of drugs (especially lipid-soluble substances) reaching and being deposited in the brain.^95,119 The greater total body water and lower fat content in neonates increases the apparent Vd, especially for water-soluble substances.^{14,93,116,122}

The altered Vd in the neonate may reduce peak volumes of drugs and delay excretion. Because of the increased extracellular water, higher doses per kilogram may be needed in the neonate for water-soluble drugs distributed in extracellular fluid. For example, an increased Vd is seen with drugs such as theophylline, caffeine, phenobarbital, phenytoin, digoxin, and aminoglycosides such as gentamicin.^93,116,122 The Vd is further increased with decreasing gestational age, because more immature infants have a greater total body water percentage. VLBW infants may need higher loading doses and a longer dosing interval of some drugs because of their even greater apparent Vd and immature hepatic and renal function. Other factors that alter total body water include those that alter drug distribution by increasing (congestive heart failure, patent ductus arteriosus, syndrome of inappropriate antidiuretic hormone secretion) or decreasing (diuretic use) extracellular water.^31,32

Decreased fat in the newborn, especially preterm and IUGR infants, decreases the apparent Vd for lipophilic drugs.^31,93 Body fat content increases from 1% to 3% at 28 weeks’ gestation to 15% to 28% by term, thus increasing the deposition and distribution of lipid-soluble drugs with increased gestational age.^32,93 In addition, neonatal adipose tissue is more than 50% water (versus approximately 25% in adults), further altering tissue distribution of lipid-soluble drugs.³²

APT-binding cassette (ABC) drug efflux transporters (that prevent specific toxins from crossing the blood brain barrier or moving into hepatic, renal tubular or intestinal cells) appear to have decreased activity in the newborn.^66,95 This may increase central nervous system permeability to drugs, and alter rates of hepatic and renal clearance.^19,66,95,119 Examples of the transporters are P-glycoprotein (P-gp)/multidrug-resistant gene protein (MRP)-1, MRP-2, MRP-3, and breast cancer resistance protein (BCRP).^86,95 P-gp increases rapidly in the first 3 to 6 months and reaches adult levels by 2 years.⁹⁵

Protein binding is lower in the neonate due to decreased concentrations of binding proteins; altered binding affinity, especially in the presence of fetal albumin, which has a poorer binding capacity; and increased levels of nonesterified fatty acids and bilirubin, which compete for protein binding sites.¹⁹ The major drug-binding proteins are albumin, which generally binds acidic drugs, and α1-acid glycoprotein, which along with lipoproteins generally binds basic drugs.^31,105 Levels of both albumin and α1-acid glycoprotein are low in the neonate, reaching adult levels by about 1 year, resulting in increased free drug levels of substances such as theophylline, digoxin, phenytoin, and many analgesic compounds.^{7,31,32,93,116}

In addition to lower plasma protein levels, the newborn tends to have fewer binding sites and a lower affinity of these sites for drugs such as phenobarbital, phenytoin, penicillin, and theophylline. As a result, the newborn tends to saturate protein binding sites at lower drug concentrations with increased free drug, longer half-lives, and risk of toxicity.^66,93 However, increased levels of free drug can also lead to lower drug levels because the free drug may be more rapidly eliminated by the kidneys.^32,93 Drugs can also bind to albumin outside the vascular space in sites such as cardiac and skeletal muscle. Newborns tend to have more binding to the myocardium than adults, which can result in an increased volume of distribution for drugs such as digoxin.³¹

Protein binding of drugs may also be reduced by acidosis, free fatty acids, maternal drugs from placental transfer before birth, and indirect bilirubin. Drugs and bilirubin compete with each other for binding sites. Bilirubin is displaced from albumin by sulfonamides, ceftriaxone, and chloral hydrate, leading to increased free indirect bilirubin levels. However, bilirubin is more likely to displace drugs than to be displaced. Drugs that may be displaced from albumin by bilirubin include ampicillin, penicillin, phenobarbital, and phenytoin, leading to higher free drug concentrations of these agents.⁹³ Other drugs, such as furosemide and indomethacin, if given together, compete against each other for albumin binding sites.⁹³

Hepatic drug metabolism

Neonates and infants have immature organ systems, especially the lungs (see Chapter 10), kidney (see Chapter 11), and liver (see Chapter 12), which are typical routes for drug excretion. The large surface-to-mass ratio and high metabolic rate of the neonate and infant affect drug metabolism.

Liver enzyme systems necessary for metabolism of many drugs are depressed in the newborn. In the mature liver, oxidation and conjugation result in water-soluble metabolites that are readily excreted into bile. In the fetus, depression of these processes may be an advantage, because lipid-soluble metabolites are more readily transferred across the placenta where they can be handled by the maternal system. The liver smooth endoplasmic reticulum (SER) is the location of many hepatic microsomal enzymes. The neonatal liver has little SER, and activities of many microsomal enzymes are reduced or undetectable at birth, altering drug metabolism.⁸⁵ As a result, drug metabolism may be characterized by slower biotransformation and elimination and increased individual variability.⁹³ The reduced activity of hepatic microsomal enzymes extend the half-life of drugs dependent on them for metabolism and increase the risk of drug intolerance.

Phase I (see Table 7-1) biotransformation reactions are reduced in the fetus and newborn, impairing degradation and increasing half-lives of drugs such as phenytoin, phenobarbital, diazepam, mepivacaine, lidocaine, caffeine, theophylline, phenylbutazone, salicylate, indomethacin, furosemide, and sulfa drugs.^32,86

Both microsomal enzyme (e.g., CYP450 system, NADPH-cytochrome reductase) and extramicrosomal enzyme (e.g., deaminases, esterases) activity are decreased in the newborn, with a rapid increase in activity over the first few weeks after birth.^32,66 CYP3A7 is predominant at birth, peaking shortly after birth, then decreases to low levels within 1 to 2 weeks.^{17,55,56,66,102,108} CYP3A4 activity is low at birth but increases 3-fold in the first 3 months, reaching 20% of adult activity by 1 month and around 70% by 1 year.^7,56,108 CYP2E1 surges within a few hours after birth.¹⁰⁸ Levels of CYP1A1, the isoform responsible for degradation of over half of all drugs in adults, has low activity until 1 to 3 months after birth.^17,31,56 By 2 to 3 weeks of age, liver enzyme systems are maturing at varying rates.¹⁷ Maturation of some enzyme activity may be rapid; other systems mature more slowly. Activity of CYP1A2 and CYP2B6 are minimal at birth and reach 50% of adult activity around a year.^7,56,108 CYPC9 has 20% of adult activity at birth reaching 50% of adult activity by 3 months; CYP2C19 has 30% of adult activity reaching adult activity by 1 year.^7,56,108 Alternative pathways of biotransformation are seen for some drugs in the neonate. For example, methylxanthine metabolism is different in neonates versus adults. In the neonate, theophylline is methylated, some is converted to caffeine, and its clearance is 50% of adults; whereas in adults, theophylline is metabolized to 1,3 dimethyluric acid and other metabolites.^7,31,93,108

There are marked variations in maturation rates of processes for specific drugs and within individual infants. This increases elimination half-lives and the risk of both underdosing and overdosing.^31,32 Maturation is correlated with both postmenstrual age and postbirth age. For example, midazolam and phenytoin are both metabolized by CYP2C9 and CYP2C19. Midazolam clearance increases up to five-fold from 1 to 3 months; low activity of these enzymes in preterm infants increases bioavailability.^7,14,108 Phenytoin biotransformation increases and half-life decreases in early infancy with a half-life of approximately 75 hours in preterm infants, decreasing to about 20s by term and 8 hours by 2 weeks post term.^7,108

Phase II reactions (see Table 7-1), particularly glucuronidation, are also altered in the newborn. Glucuronic acid conjugation (via uridine 5′-diphosphatase glucuronosyltransferase or UGT enzymes), needed for metabolism of drugs such as morphine, acetaminophen, phenytoin, sulfonamides, chloramphenicol, salicylic acid, and indomethacin, is reduced at birth and does not reach adult levels until 24 to 30 months.³¹ An example of maturation of the ability to metabolize drug via glucuronidation is seen with morphine. Morphine glucuronidation is found in preterm infants by 24 weeks’ gestation. Morphine metabolism increases with increasing postmenstrual (PMA), due to maturation of UGT isoforms, so that clearance quadruples from 27 to 40 weeks’ PMA, requiring increased dosages for pain management.^53,95 Zidovudine is also metabolized by glucuronidation and its plasma clearance in infants <2 weeks of age is half that of infants over 2 weeks.¹⁰⁸ Acetaminophen is metabolized by UGT1A6 and UGT1A9. These enzymes are low at birth and reach full activity by 9 to 12 months; bioavailability increases with age due to an increased first pass effect and enzyme maturation.^14,108 UGT1A1 is the major enzyme for bilirubin glucuronidation. Variants of this enzyme lead to reduced activity and prolonged neonatal jaundice. Mutations in the gene for this enzyme occur with Criglar-Najjar syndrome.⁹⁵

Chloramphenicol is eliminated by the kidney after conjugation in the liver. The hepatic glucuronyl transferase system responsible for conjugation of this drug is immature in the neonate (especially in preterm infants), and free (unconjugated) chloramphenicol is eliminated by glomerular filtration, which is reduced in neonates. The result is higher and prolonged peak serum chloramphenicol concentrations. Half-life of chloramphenicol is approximately 20 hours in the neonate and longer in preterm infants, falling to about 10 hours by 21 days (versus 4 to 5 hours in adults).⁷⁵ This results in increased risk of toxicity (“gray baby syndrome”) with aplastic anemia, shock, and cardiovascular collapse.^31,86

Other phase II reactions (sulfate and glycine conjugation) are somewhat decreased but more similar to those in adults.⁹³ Methylation reactions may be more important in infants than in adults for drugs such as theophylline.⁹³ Decreased hydrolysis and increased Vd may prolong the effect of local anesthetic agents. Ligandin (carrier protein Y) needed for hepatocyte uptake of substances including bilirubin and many drugs is low for 5 to 10 days after birth, further altering hepatic clearance of some drugs.

Thus immaturity of liver enzyme systems can delay metabolism and clearance of drugs and increase their serum levels and half-lives. McClary et al. concluded that in terms of drug metabolism and disposition in the neonate:

“1. The rate of drug metabolism is generally low at birth in full-term babies and even lower in premature infants regardless of the specific route of metabolism. Decreased clearance and a prolonged drug half-life require drug administration with longer dosing intervals.

2. Many of the enzymes responsible for metabolism exhibit significant development during the first month of life. Dosing regimens appropriate during the first few days of postnatal life may not be appropriate 3 to 4 weeks after birth because dose requirements may increase and dosing intervals decrease.

3. The development of individual drug-metabolizing enzymes varies widely among neonates and may be delayed in premature infants. Predicting clearance is difficult, and dosing regimens must be individualized for patients based on the careful observation of the patient’s response and tolerance; monitoring of plasma drug concentration may be useful for selected drugs.”^86,p.727

Renal drug excretion

Because of the decreased hepatic metabolism in neonates, the infant is more reliant on renal elimination. However, renal elimination is reduced compared to adults and correlated with both postmenstrual and postbirth ages. Alterations in renal function in neonates can markedly alter the infant’s ability to eliminate drugs and drug metabolites, increasing the half-life and risk of toxic effects and the need for longer dosing intervals. Any pathologic event that alters renal function (e.g., congestive heart failure, respiratory distress syndrome, hypovolemia, ischemia, or hypoxemia) further compromises the ability of the infant to eliminate drugs. In addition, drugs such as indomethacin may decrease glomerular filtration rate (GFR), further impeding excretion.³¹ Renal processes involved in drug handling are GFR, tubular secretion, and, to a lesser extent, tubular reabsorption.

The GFR is significantly lower in the neonate than in adults (see Chapter 11), although partially compensated by an increase in tubular reabsorption. The reduced GFR delays clearance of drugs that are eliminated by the kidneys, leading to prolonged half-lives and longer dosing intervals.^62,127 For example, clearance of indomethacin and many aminoglycosides is 10% to 30% lower than in adults. The GFR is particularly low in the first week after birth, increasing susceptibility to nephrotoxic drugs such as aminoglycosides. Plasma half-lives of many drugs used in the neonate—including penicillin, aminoglycosides, methicillin, furosemide, barbiturates, and digoxin—vary inversely with creatinine clearance (which is a measure of GFR).

Renal maturation progresses at variable rates after birth depending on postmenstrual and post birth ages. The most rapid changes in GFR are seen in the first 7 to 10 days after birth.³¹ The increased half-life of drugs such as digoxin, vancomycin, and indomethacin correlate with both postmenstrual and postbirth age and may be significantly longer in preterm infants.^62,127 Drug levels must be carefully and regularly monitored. Use of drugs such as vancomycin in combination with indomethacin (which decreases GFR) can further decrease vancomycin elimination.⁹³ Renal elimination of drugs is further altered in preterm infants who are younger than 34 weeks’ gestational age. In these infants, GFR increases at birth, but then tends to plateau or increase slowly until about 34 weeks, when nephron maturation is complete (see Chapter 11). As a result, some antibiotics and other drugs are given less frequently to VLBW infants. Serum half-lives of antibiotics change rapidly over the first few weeks after birth as renal function matures. Therefore dosages of these drugs or dosing intervals may need to be increased.⁶⁶ For example, gentamicin dosing intervals range from 24 to 48 hours in more immature infants to every 8 to 12 hours in the term newborn.³¹

Elimination of drugs by tubular secretion is reduced in the neonate for the first 6 months as a result of decreased renal blood flow to the peritubular area, shorter tubular length, decreased energy for carriers, and reduced number of carriers to transport drugs from the blood into the tubule.⁶² This affects drugs such as furosemide and penicillin G, which are therefore more dependent on GFR than tubular secretion for clearance during early infancy. In older children and adults, tubular secretion is the most important mechanism for penicillin excretion (versus GFR in neonates). As a result, penicillin clearance is nearly one fifth that of adults, and penicillin blood levels may persist for three times as long. Urine flow rates can also influence elimination of drugs such as chloramphenicol, phenobarbital, and theophylline by decreasing the concentration gradient due to formation of dilute urine or reducing the time for drug diffusion.⁶²

Principles of teratogenesis

General principles that govern the action of teratogens include the following:

Mechanisms of teratogenesis

Proposed mechanisms of teratogenesis include the following:

Specific proposed teratogenic mechanisms associated with drugs are folate antagonism, oxidative stress, angiotensin-converting enzyme inhibition, angiotensin II receptor antagonism, cyclooygenase-1 and -2 inhibition, 5-hydroxytryptamine-reuptake inhibition, and placental drug transporters.¹³²

Effects of drug exposure in utero

The fetus is a passive recipient of all drugs entering the mother’s system. Drug use in pregnancy is common. From laxatives and antacids to cocaine and heroin, all of these substances are chemicals that may have an effect on the fetus and newborn. Medications are not “approved” for use in pregnancy; rather, medications are “presumed safe” for use in pregnancy. Some classes of drugs are more significant to CNS development and function after birth than are others. Examples of drugs known to produce significant effects are ethanol, tobacco smoke, narcotics, amphetamines, and cocaine.

Drugs and lactation

The majority of breastfeeding women take at least one drug during lactation.^51,118 Many pharmacologic agents and environmental pollutants (as well as alcohol, nicotine, and other abused drugs) can be found in human milk, although usually at levels lower than those in the mother. Drugs cross into breast milk across the milk-blood barrier via the following mechanisms: (1) transcellular diffusion of low molecular weight (<100 to 200 daltons), nonionized, lipid soluble substances such as ethanol, which are pulled across by water flow; (2) intercellular movement of large molecules through spaces between alveolar cells; (3) passive diffusion across a concentration gradient; (4) carrier mediated diffusion of polar substances; and (5) active movement via specific drug transporters.^15,111 A few drugs—nitrofurantoin, acyclovir, ranitidine, and iodine—are actively transported across the blood-milk barrier into human milk by influx transporters.⁵¹

Often, breastfeeding is interrupted or discontinued for maternal therapy even though there are relatively few maternal medications that are not compatible with breastfeeding.^39,41 Even if the mother is on drugs with potential risks, careful monitoring and strategies to minimize infants’ exposure can be often used so that the mother can decide to continue breastfeeding if she chooses. In general, serious side effects in infants are uncommon.

The use of any pharmacologic agent in the breastfeeding woman should be carefully evaluated. Most drugs enter breast milk in some quantity, although few drugs are contraindicated during lactation.²⁴ Often little is known about side effects of less commonly used agents. Some drugs should be used with caution and only as absolutely needed in the lactating woman, with careful monitoring of both infant and mother. The nurse and the mother should be aware of potential hazards of any drug, for both mother and infant. There are many reviews of drugs used during breastfeeding and concerns or potential hazards of specific agents^{3,4,23–25,33,41,51,52,59,87} as well as textbooks and online sites (see Box 7-2 on p. 187).

Drugs taken by a nursing mother reach infants in much smaller amounts through breast milk than drugs from the pregnant woman reach the fetus across the placenta.^82,111 Figure 7-4 illustrates transfer of milk from mother to infant. Drugs from the pregnant woman to the fetus move directly from maternal blood to fetal blood, whereas drugs from the nursing mother to infant pass from mother’s blood into milk and then to the infant’s gut. In the infant’s gut, the drug may be destroyed or absorption reduced due to limitations in GI absorption in infants, especially in the early months. In addition, there are more tissue layers between maternal blood and milk than between maternal and fetal blood across the placenta. This increases the diffusing distance and reduces the efficiency of transfer. Calculated doses of maternal drug received by the infant are generally significantly less than the standard therapeutic doses tolerated by infants without toxicity for most drugs.¹¹¹ Therefore, some drugs that are not recommended during pregnancy may pose little risk during lactation.

Factors influencing the amount and rapidity of drug excretion into milk include drug dosage and duration; route of administration; drug physicochemical characteristics; blood level in maternal circulation; oral bioavailability; protein binding in maternal circulation; maternal physiology and drug handling; blood-milk barrier (Figure 7-4); and infant physiology, drug handling, and maturity (see Table 7-7). Other infant factors to consider include the age of the infant, drug oral bioavailability, amount of milk intake, and the record of the drug’s use as a therapeutic agent in infants.^{15,51,75,86,123} Characteristics of drugs most likely to cross into milk are agents that are lipid-soluble, have low molecular weight (MW), have a long half-life in the mother, have low protein binding, are given to the mother in large doses, or are used for chronic conditions or are used long term so that plasma levels are maintained at steady-state conditions.^5,51,81,86

Infant drug exposure can be calculated by the milk-to-plasma ratio of a drug, percentage of maternal dose, infant dosage (drug concentration in milk times the volume of milk ingested), and estimated infant serum concentration (using oral bioavailability/clearance in the infants).⁸² The milk-to-plasma (M/P) ratio is the most common index and ranges from 0.01 to 6.5 (averaging 0.5 to 1 for most drugs used during lactation).^10,74 This value may be calculated as a single value, but the M/PAUC (where AUC is the area under the curve), which is based on concentration time curves, provides a better estimate of the ratio over a dosing interval. Highly lipid-soluble and water-soluble substances with MW lower than 200 daltons generally have an M/P ratio near 1. High M/P ratios (greater than 1) are seen with weak bases and actively transported substances; a low M/P ratio (less than 1) is generally found with drugs that are weak acids or highly protein bound substances.⁷⁵ Drugs with a low (less than 1) M/P ratio and high maternal and infant clearance rates generally have low risk of infant side effects.³⁹ M/P and M/PAUC ratios are available in several resources.^10,15,52,74

Most drugs cross by passive or facilitated diffusion from higher to lower concentrations between maternal plasma and milk.⁵¹ Some low MW drugs may also cross via membrane pores, while other substances such as immunoglobulins may pass between alveolar cells.¹¹¹ The blood-milk barrier consists of the maternal capillary epithelium, mammary alveolar cell membrane, intracellular structures (including protein micelles and lipid vesicles), and the apical membrane of the mammary alveolar cell (Figure 7-5). The alveolar cell is a lipid barrier that reduces transfer of water-soluble and ionized drugs.¹⁵ Therefore, lipid-soluble drugs cross into milk more readily than water-soluble drugs, although this is somewhat influenced by MW. Concentration of drugs in milk may change with time from birth or during a feeding. For example, drugs such as diazepam and phenobarbital that are highly lipid-soluble may be more concentrated in hindmilk, which has four to five times greater lipid content than foremilk.^10,51 Lipid content is higher in mature milk versus colostrum; thus concentrations of lipid-soluble drugs may be reduced initially after birth.⁸² Efflux transporters such a P-gp may transport some substances out of milk back to maternal plasma.⁵¹

Low MW substances such as ethanol rapidly diffuse across the tissue layers between maternal blood and milk. Water-soluble drugs with an MW of less than 200 daltons can move across the blood-milk barrier via water-filled membrane pores.⁸² Molecules greater than 200 daltons cannot pass through these pores and are transferred more slowly because they must first dissolve in the outer lipid membrane of the alveolar cell, diffuse across the cell, then dissolve in the apical membrane to reach milk. Substances with MWs larger than 800 daltons, such as insulin and heparin, generally do not cross into milk or do so very minimally.^51,75 Larger substances may cross in the first 4 to 10 days after delivery due to larger gaps between alveolar cells during this time.^37,87,98,111

The major milk protein (α-lactalbumin) does not significantly bind drugs. One of the main serum drug-binding proteins (α1 acid-glycoprotein) is not present in milk. Therefore the major milk drug-binding proteins are albumin and lactoferrin, which have markedly decreased binding compared to plasma proteins. Drugs that are highly bound in maternal blood (such as warfarin which is 99% bound) are less likely to cross, because plasma levels of free drug are lower. If a drug is at least 85% bound in maternal blood, measureable concentrations of the drug are unlikely to be found in the infant.⁵ Conversely a drug such as lithium which has no protein binding and a low MW can reach high levels in milk.⁵ Free drug levels may be increased in the mother in the first 5 to 7 weeks postpartum as the lower albumin levels of pregnancy gradually return to nonpregnant values.⁸²

Milk pH (mean of 7.08 with a range of 6.35 to 7.35) is lower than blood pH.¹¹¹ Weak acids are highly ionized in maternal plasma and less likely to cross into milk. However, weak bases (e.g., erythromycin, iodides, antihistamines, barbiturates) tend to be transferred and are at equal or higher concentrations in milk than in maternal plasma.⁸² Colostrum has a mean pH of 7.45, so it is more likely to have higher levels of basic drugs than mature milk.¹¹¹ Ion trapping may occur in milk. Weak bases are generally nonionized and readily cross into milk. As these drugs encounter the low milk pH, they become ionized. This creates a gradient toward movement of more of the drug into milk and reduces the ability of the drug to return across the blood-milk barrier to maternal blood.^15,51,82 Drugs with a pKa greater than 7.2 are most likely to be sequestered in milk.⁵¹

Steady-state concentrations of drugs in the infant are influenced by drug oral bioavailability, dose, and infant clearance. Drugs given to the mother via methods other than oral administration often have a low oral bioavailability. Drugs with high oral bioavailability may be sequestered in milk at high levels. Drugs with low oral bioavailability have only minimal milk transfer.^51,82 This reduces infant exposure since the infant receives these drugs via milk into the gut. The amount of drugs reaching the nursing infant is also influenced by non–steady-state conditions. Milk is supplied on a continuous basis during sucking, so milk drug concentrations at time of feeding tend to reflect maternal plasma levels at that time. Concentrations of drugs in milk (including most narcotics) are independent of volume of milk.

Drugs may also affect lactation via either central or peripheral mechanisms to increase or reduce milk output.^39,51,111 Central mechanisms include increased or decreased oxytocin, prolactin, or CNS dopamine release. Increased dopamine depresses prolactin. Peripheral mechanisms act directly on the breast to alter milk production. Exogenous substances that increase milk production include thyrotropin-releasing hormone, domperidone, metoclopramide, and psychotropic agents such as reserpine, imipramine, and phenothiazine derivatives that interfere with dopamine release.^39,51 Nicotine, estrogens, and possibly pseudoephedrine may also depress lactation.^51,59

Use of combination oral contraceptives by lactating women is controversial, with many differing opinions. Estrogen-containing oral contraceptives should be avoided as they suppress lactation probably through inhibition of prolactin by estrogen.⁵¹ These agents have been associated with decreases in milk production, shorter overall length of time of breastfeeding, and slower infant weight gain, although this is not well documented and the available studies are limited and have significant methodologic limitations.^{15,51,111,124} Truitt and colleagues conducted a systematic review of randomized controlled studies and concluded that existing trials were “insufficient to establish an effect of hormonal contraception, if any, on milk quality and quantity.”¹²⁵ The effects on breast milk production are reportedly most prominent in the first 4 to 6 weeks postpartum.^39,111 Although progestin only or combination agents have been thought to be safer,^39,111 Hale recommends that mothers be advised to avoid progestin agents for 4 to 6 weeks postpartum and that even with use after 6 weeks some mothers report decreased milk synthesis.⁵¹