Abstract
Drug therapy during pregnancy can be complex because the physiologic changes of pregnancy may alter drug disposition and effect. Maternal medications may have direct effects on the fetus after placental transfer, or indirect effects through changes in placental and uterine function. Even after delivery, drugs may affect breast-feeding, and drug transfer to breast milk is a concern. Nevertheless, pregnant women still require medications to treat many acute and chronic conditions. The challenge is to find the balance between the benefits and risks associated with therapy. The anesthesia provider should understand the implications of pregnancy on drug disposition and effect. Although not usually responsible for primary maternal drug therapy, the anesthesia provider will encounter women taking many different medications and may need to administer a variety of nonanesthetic drugs during the peripartum period, either for maintenance of chronic therapy or for acute indications, especially when managing critically ill patients. In this chapter, the way maternal physiology affects pharmacology is summarized, placental transfer and maternal and fetal effects of the main classes of drugs encountered during pregnancy are addressed, and drug transfer to breast milk is reviewed, with discussion of the effects of common perioperative drugs. Specific drugs used in the management of individual obstetric conditions are discussed in other chapters.
Keywords
Pregnancy, Lactation, Breast-feeding, Pharmacology, Placental transfer, Breast milk
Chapter Outline
Changes in Drug Disposition and Effect, 314
Drug Use during Pregnancy, 317
General Principles and Teratology, 317
U.S. Food and Drug Administration Categories, 319
Anesthetic Drugs, 320
Analgesics, 320
Sedatives, 320
Anticonvulsants, 320
Psychotropic Drugs, 321
Cardiovascular Drugs, 322
Respiratory Drugs, 322
Anticoagulants, 322
Antiemetics, 323
Antihistamines, 323
Antidiabetic Drugs, 323
Anti-Infective Drugs, 323
Caffeine, 324
Cannabis, 324
Smoking Cessation Therapies, 324
Specific Highly Teratogenic Drugs, 324
Drug Use during Lactation, 324
Transfer of Drugs to Breast Milk, 325
Anesthetic Drugs, 326
Analgesics, 326
Sedatives, 327
Anticonvulsants, 327
Psychotropic Drugs, 327
Cardiovascular Drugs, 327
Respiratory Drugs and Corticosteroids, 328
Anticoagulants, 328
Antihistamines, 328
Antidiabetic Drugs, 328
Anti-Infective Drugs, 329
Alcohol, 329
Caffeine, 329
Cannabis, 329
Drug therapy during pregnancy can be complex because the physiologic changes of pregnancy may alter drug disposition and effect. Maternal medications may have direct effects on the fetus after placental transfer, or indirect effects through changes in placental and uterine function. Even after delivery, drugs may affect breast-feeding, and drug transfer to breast milk is a concern. Nevertheless, pregnant women still require medications to treat many acute and chronic conditions. Worldwide, the use of medications during pregnancy has been increasing, with pregnant women in the United States taking an average of 4.2 medications between 2006 and 2008. Recent data from the United States showed that 97.1% of women took at least one medication during pregnancy, and 30.5% were taking at least five medications. The most common medications were antiemetics, antibiotics, and analgesics. However, at least 10% were taking drugs with long-term effects on the central nervous system such as antidepressants, anticonvulsants, and antipsychotics. The challenge is to find the balance between the benefits and risks associated with therapy.
Maternal variation in drug effect is not usually difficult to manage, and a change in dosing regimen or the choice of drug may be all that is required. The greatest fear and concern is for potential fetal effects that may manifest as teratogenicity with fetal loss or congenital malformations, fetal growth restriction (also known as intrauterine growth restriction), preterm labor, and other complications of pregnancy. After delivery, immediate neonatal adaptation may be affected, and in the longer term there may be impaired neurodevelopment and behavioral problems in childhood.
The anesthesia provider should understand the implications of pregnancy on drug disposition and effect. Although not usually responsible for primary maternal drug therapy, the anesthesia provider will encounter women taking many different medications and may need to administer a variety of nonanesthetic drugs during the peripartum period, either for maintenance of chronic therapy or for acute indications, especially when managing critically ill patients.
In this chapter, the way maternal physiology affects pharmacology is summarized, placental transfer and maternal and fetal effects of the main classes of drugs encountered during pregnancy are addressed, and drug transfer to breast milk is reviewed, with discussion of the effects of common perioperative drugs. Specific drugs used in the management of individual obstetric conditions are discussed in other chapters.
Changes in Drug Disposition and Effect
Pharmacogenetics
Genetic differences are responsible for some of the variation in drug response among individuals. Pregnancy does not obviously modify these pharmacogenetic differences, although some obstetric conditions such as preeclampsia are related to complex genetic factors. There are, however, some examples in which underlying genetic differences do affect obstetric management.
The metabolism of codeine to morphine is greatly affected by polymorphisms of the cytochrome P450 (CYP) isoenzyme CYP2D6. It has been recognized only recently that mothers who are ultra-rapid metabolizers of codeine may produce and transfer sufficient morphine through breast milk to cause neonatal central nervous system (CNS) depression and even death. Codeine is now not recommended in women who are breast-feeding.
Two of the possible changes at the β 2 -adrenergic receptor are an arginine-to-glycine substitution at codon 16 (Arg16Gly) and a glutamine-to-glutamic acid substitution at codon 27 (Gln27Glu). Women with Arg16 and/or Gln27 are less likely to have preterm delivery and more likely to have longer labor. Conflicting results are reported for vasopressor requirements in the management of hypotension during spinal anesthesia for cesarean delivery. In North American studies, Gly16 homozygotes and Glu27 homozygotes required less ephedrine, and Arg16 homozygotes required more phenylephrine. However, no differences were detected in an Asian cohort, and a Brazilian group found that Arg16 and Gln27 homozygotes required less ephedrine.
The µ-opioid receptor gene may have an adenine-to-guanine substitution at nucleotide position 118 (A118G). There have been many studies of the effects of this polymorphism on opioid dose requirements and response. Studies in laboring women showed that AA homozygous carriers had an increased intrathecal fentanyl requirement for analgesia. However, most studies of postoperative pain, including after cesarean delivery, have shown that AA polymorphism was associated with less pain. Many other genetic factors influence opioid disposition and response, and even more factors influence pain perception. A meta-analysis found that A118G polymorphism only explained 7% of the variability in opioid requirements. Currently, given the conflicting results and limited clinical effects of genetic polymorphisms, specific single nucleotide polymorphism (SNP) testing does not appear to be indicated in routine obstetric anesthesia practice.
Pharmacokinetic Changes
The major physiologic changes during pregnancy alter drug disposition. However, the magnitude and time course of these changes vary throughout pregnancy and among individuals. The results of many older studies are unreliable because the studies were often of low quality. Making generalizations about the effects of pregnancy on drug disposition can be difficult, and individualized dosing is important. Even though there is increased clearance of many drugs in pregnancy, the standard dosing regimens for many drugs have not been updated for pregnancy, consequently resulting in underdosing.
Maternal Pharmacokinetics
Absorption and uptake.
Oral absorption and bioavailability are not usually affected by pregnancy, although nausea and vomiting may limit oral intake. Intestinal motility is decreased during pregnancy, but gastric emptying is only delayed during labor or after opioid administration. Cardiac output is increased by 30% to 50% during pregnancy, and the increased blood flow to skin and mucous membranes will enhance absorption from these sites. Reduced functional residual capacity and increased minute ventilation lead to increased pulmonary uptake of inhalational anesthetic agents.
Distribution.
The increased cardiac output during pregnancy increases distribution of drug to all tissues. Drugs acting peripherally (e.g., neuromuscular blockers) will be delivered to their site of action more quickly. However, the onset of intravenous and inhalational anesthetics is dependent on the time course of their cerebral drug concentration. A delay in the increase in arterial and brain anesthetic concentration will result from increased peripheral perfusion. However, increased peripheral perfusion will increase the return of drug during the elimination phase. During pregnancy, total body water increases on average by 8 L, and intravascular plasma volume is increased by 40%, whereas extravascular volume increases by a variable amount, depending on weight gain and edema. Thus, hydrophilic drugs, such as neuromuscular blockers, will have a small increase in the volume of distribution. Body fat is increased on average by 4 kg, but this is unimportant given the large volume of distribution of lipophilic drugs.
Changes in protein binding are more important clinically. Plasma albumin concentration is reduced to about 70% of normal, whereas α 1 -acid glycoprotein concentration is largely unchanged. Protein binding of drugs may be reduced by increased concentrations of free fatty acids and other endogenous displacing substances. This leads to increased concentrations of free drug, but with chronic drug administration this is offset by increased clearance of that free drug. The total (free + bound) concentration of drug will decrease, and it may be necessary to reset the therapeutic target range lower to compensate. Thus, it is important to know whether monitored concentrations are for free or total drug. Only a few drugs (e.g., theophylline, phenytoin) require monitoring and modification of dose because of changes in protein binding.
Metabolism.
Most drugs are metabolized in the liver, and the rate of metabolism may depend on hepatic blood flow or intrinsic enzyme activity. Although cardiac output is increased in pregnancy, it is not clear whether blood flow to the liver is significantly increased. Most cytochrome P450 isoenzymes (CYP3A4, CYP2D6, and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes (UGT1A4 and UGT2B7) have increased activity during pregnancy, which increases the metabolism of drugs such as phenytoin (CYP2C9), midazolam (CYP3A4), and morphine (UGT2B7). A few isoenzymes (CYP1A2 and CYP2C19) have decreased activity, which reduces the metabolism of drugs such as caffeine and theophylline (CYP1A2).
Elimination.
Renal blood flow is increased by 60% to 80%, and glomerular filtration rate is increased by 50% in pregnancy; thus, the renal excretion of unchanged drugs such as cephalosporin antibiotics is increased. There is also increased activity of many transporter proteins such as renal P-glycoprotein. Increased minute ventilation enhances elimination of inhalational anesthetic agents.
The physiologic changes of pregnancy will affect individual drugs depending on their physicochemical characteristics and metabolic pathways. Bioavailability is not usually changed significantly. Changes in volume of distribution as a result of changes in protein binding may affect drugs such as phenytoin, but monitoring and modification of therapy is usually straightforward. Drugs metabolized by the liver may require increases or decreases in dose, depending on the metabolic pathway involved. Drugs excreted unchanged by the kidneys often require an increased dose.
Placental Transfer and Metabolism
Our understanding of placental transfer and metabolism is rapidly improving (see Chapter 4 ). Early research was often limited to measuring drug concentration in the umbilical vessels and maternal vein at delivery. Results were variable and difficult to interpret, especially for drugs such as anesthetic agents that are administered shortly before delivery. Umbilical blood samples are obtained at variable times after drug exposure, well before steady-state conditions are achieved. The theory of a placental barrier was proposed because maternal and fetal concentrations were often different. However, differences in concentration of binding proteins are mainly responsible for the fetal-maternal distribution of drugs at steady state. The fetal concentration of albumin is slightly greater than that in the mother, but α 1 -acid glycoprotein concentration is only one-third of the maternal value at term. Umbilical-to-maternal blood ratios of total drug may be misleading because it is the free drug that equilibrates across the placenta. Maternal-to-fetal ratios of drugs do not provide information on the rate of drug transfer or the amount of drug that has already been transferred to the fetus.
Drug transfer across the placenta was previously thought to occur mainly by diffusion. This would favor the movement of lipophilic drugs, and placental perfusion would be an important factor affecting transfer. Fetal pH is lower than maternal pH, so that weak bases become more ionized in the fetus, thus limiting their transfer back across the placenta. Normally, the difference in pH is only 0.1 and this “ion trapping” is irrelevant, but fetal acidosis can significantly increase the fetal concentration of drugs such as local anesthetics.
It is now known that the placenta contains many drug transporters that can modify fetal drug exposure. In the treatment of sustained fetal tachyarrhythmia, placental P-glycoprotein, an adenosine triphosphate–dependent drug efflux pump, will reduce net transfer of substrates such as digoxin and verapamil from the mother. Although placental transport of immunoglobulin makes it possible to immunize the mother to protect the newborn, this transport also raises concerns when immunoglobulin tumor necrosis factor antagonists are used to treat maternal diseases.
The placenta contains many active enzymes responsible for Phase I and Phase II biotransformation. Clearance of substrates by UGT in full-term placentas may be sufficient to contribute to overall maternal metabolism.
Fetal and Neonatal Elimination
The fetus and neonate metabolize drugs, but at a reduced rate compared with adults. The fetal circulation guides drugs transferred across the placenta to undergo first-pass hepatic metabolism, but some drug will bypass the liver. Renal blood flow is minimal until near term, and any excreted products would just pass into the amniotic fluid to be swallowed. Elimination of drugs by the fetus is thus mainly reliant on placental transfer. It would seem prudent to minimize the amount of drug transferred to the neonate and choose drugs that are eliminated rapidly. Relatively large minute ventilation promotes neonatal elimination of inhalational anesthetic agents, and this may be further increased by assisted ventilation.
Pharmacodynamic Changes
Changes in the concentrations of various hormones may alter the response to other substances. In particular, progesterone and endorphins may enhance sedation and antinociception, respectively. A pharmacodynamic difference specifically refers to a change in response to a given effect-site concentration, but it is difficult during pregnancy to carry out the high-fidelity studies necessary for accurate pharmacokinetic-pharmacodynamic modeling. Thus, demonstration of pharmacodynamic changes in pregnancy has been limited to specific experimental designs in which there are large differences in effect.
General Anesthesia
Early animal studies showed that maternal anesthetic requirements were reduced during pregnancy. Minimum alveolar concentration (MAC) values for inhalational agents were reduced by 25% to 40% in pregnant ewes and by 16% to 19% in pregnant rats. Ethical and practical difficulties with research in pregnant women delayed confirmation of this finding in humans. Isoflurane MAC (determined using transcutaneous electrical stimulation instead of the classic skin incision) was decreased by 28% in women undergoing termination of pregnancy at 8 to 12 weeks’ gestation. Similar reductions in MAC were found for enflurane (30%) and halothane (27%). MAC was reduced by 30% in the immediate postpartum period, with a return to nonpregnant values by 12 to 72 hours after delivery ( Fig. 14.1 ).
Increased progesterone is probably the cause of the reduced anesthetic requirement during pregnancy; chronic progesterone administration reduced MAC in rabbits, dogs, and sheep. Although human studies have not found a good correlation between progesterone concentration and the reduction in anesthetic requirement, a poor correlation may be expected if the effect of progesterone is not dose-dependent; it is possible that progesterone concentration only needs to exceed a low threshold to decrease anesthetic requirement. A lower concentration of sevoflurane was required to maintain anesthesia in nonpregnant women during the luteal phase of the menstrual cycle, when progesterone concentration is elevated, compared with during the follicular phase. Progesterone concentration during pregnancy is much greater than that seen during the luteal phase of the menstrual cycle. The reduced MAC during pregnancy may also be a result of the increased endogenous endorphins that mediate the increase in nociceptive threshold during pregnancy; it is well known that opioids reduce MAC.
Pregnancy also alters other measures of anesthetic effect. In early pregnancy, the isoflurane concentration required for hypnosis was reduced by 31% and the bispectral index (BIS) was decreased at isoflurane concentrations over the range 0.1% to 2.0%. During the second trimester, the sevoflurane concentration required to achieve a targeted BIS of 50 was reduced by 31%. Both in early and term pregnancy, the median concentration of nitrous oxide required for loss of consciousness (MAC awake ) was reduced by 25% to 27%. One study did not show any difference in electroencephalographic (EEG) measures between women having cesarean delivery or gynecologic surgery, but there were many confounding factors such as the study being conducted partly during and partly after surgery, the concurrent use of significant doses of fentanyl, large variations in EEG measures, and small sample size.
Data for intravenous anesthetic agents are more variable, partly because of methodologic challenges. It is difficult to produce a stable effect-site concentration of intravenous drugs to allow accurate measurement of drug effect. Increased cardiac output usually results in an increase in intravenous anesthetic dose requirements to produce central effects, and this change would counter any decrease in requirements with pregnancy. The bolus dose of thiopental for hypnosis (failure to open eyes to command) was 17% lower, and that for anesthesia (no purposeful movement to a transcutaneous electrical stimulus) was 18% lower in early pregnancy compared with nonpregnant women ( Fig. 14.2 ). A similar reduction was found in the early postpartum period, less than 60 hours after delivery.
Studies using target-controlled infusions may not be reliable because the pharmacokinetic models may not be accurate in pregnancy, and they are known to predict concentrations poorly at induction of anesthesia. These methodologic problems may be the reason one study found no differences in the concentration of propofol required for loss of consciousness in early pregnancy. Another study used a slow infusion of propofol for induction of anesthesia and found that the dose and calculated effect-site concentrations at loss of consciousness were 8% lower than in nonpregnant women. The reduction in anesthetic requirement for intravenous agents appears to be less (8% to 18%) than that for inhalational agents (approximately 30%). It is not known whether this reflects real differences between the drugs or the methodologic problems just outlined.
Regional Anesthesia
The spread of neuraxial block is increased in pregnant women (see Chapter 2 ). This has been shown as early as the first trimester for epidural anesthesia and the second trimester for spinal anesthesia. One small study suggested that although the spread of epidural block was increased, the latency and density of sensory and motor block were not. However, two more recent studies showed that the median effective dose of intrathecal bupivacaine for motor block was decreased by 13% to 35% in pregnant women at term. Magnetic resonance imaging has confirmed that pregnant women have increased epidural blood volume, decreasing the capacity of the epidural space and decreasing the volume of lumbar cerebrospinal fluid. These mechanical factors would explain the increased spread of local anesthetic. However, several studies have also shown that there is increased sensitivity to local anesthetics during pregnancy. The onset of conduction block in the vagus nerve with bupivacaine was faster in pregnant versus nonpregnant rabbits. Sciatic nerve block was of longer duration and the lidocaine content in the nerves was lower at the time of return of deep pain in pregnant versus nonpregnant rats. Sensory nerve action potentials were inhibited to a greater extent during median nerve block at the wrist with lidocaine in pregnant versus nonpregnant women. The increased sensitivity may be caused by progesterone because exogenously administered progesterone increased the susceptibility of rabbit vagus nerves to bupivacaine. One study found no changes in conduction block in pregnant rats and suggested that enhanced block may be caused by pregnancy-induced changes that facilitate diffusion of local anesthetic or an interaction with endogenous analgesic systems.
Analgesia
Pregnancy is associated with increases in nociceptive response thresholds that are mediated by endogenous opioid systems. The changes in threshold can be reproduced using exogenous progesterone and estrogen and appear to involve spinal cord kappa (κ) and delta (δ) opioid receptors and descending spinal α 2 -noradrenergic pathways. Neuropathic pain was also reduced in pregnant rats in a chronic constriction injury model. Human studies continue to produce mixed results. Heat pain threshold was increased in term pregnant women, and this persisted during the first 24 to 48 hours after delivery. However, a longitudinal study found that endogenous pain modulation evaluating both inhibitory and excitatory pain pathways did not change significantly during pregnancy. Given the many different factors that influence pain behavior, especially those unique to pregnancy and delivery, it is difficult to determine how this change in pain threshold influences perioperative analgesic requirements.
Drug Use during Pregnancy
General Principles and Teratology
It would seem prudent to use only drugs considered safe in pregnancy. Unfortunately, the potential adverse effects of many drugs remain unclear. The U.S. Food and Drug Administration (FDA) approved 213 new medications between 2003 and 2012, and only 5% of them had human data in the pregnancy section of the label. Pregnant women are not usually included in early clinical trials, and because of the low incidence of some complications, the first suggestion of adverse effects may be revealed only from postmarketing surveillance and registries of complications. For long-term complications such as impaired neurodevelopment in children of mothers taking drugs acting on the central nervous system, it can be difficult to separate specific drug effects from the influence of the underlying psychological disease and environment. There are often conflicting studies for many adverse events. This uncertainty about safety, and the difficulties in determining what public information is reliable, may convince mothers to refuse appropriate drug treatment. New improved drugs are available in many areas of therapeutics, but many prescribers prefer to use older drugs that have a longer empirical history of safety.
To avoid unnecessary exposure, nonpharmacologic techniques should be used when possible, and drugs should be used only when necessary. The risk-to-benefit ratio should justify the use of a drug given to a pregnant woman, and the minimum effective dose should be employed. Long-term effects of fetal drug exposure may not become apparent for many years. Therefore, physicians and patients should exercise caution in the use of any drug during pregnancy.
Sensitive serum pregnancy tests can diagnose pregnancy as early as 1 week after conception. Before drug therapy is started, a sensitive test should be used if there is any question about drug safety during a potential pregnancy.
Many resources on the safety of drugs in pregnancy are freely available online, in addition to the commercially available databases ( Table 14.1 ). The FDA Office of Women’s Health has created a pregnancy registry website that lists a variety of registries that women who have used specific medications during pregnancy can consult (see Table 14.1 ).
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